Good Laboratory Practice for Nonclinical Laboratory Studies, 58341-58380 [2016-19875]
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Vol. 81
Wednesday,
No. 164
August 24, 2016
Part VI
Department of Health and Human Services
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Food and Drug Administration
21 CFR Parts 16 and 58
Good Laboratory Practice for Nonclinical Laboratory Studies; Proposed
Rule
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Federal Register / Vol. 81, No. 164 / Wednesday, August 24, 2016 / Proposed Rules
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 16 and 58
[Docket No. FDA–2010–N–0548]
Good Laboratory Practice for
Nonclinical Laboratory Studies
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Proposed rule.
The Food and Drug
Administration (FDA) is proposing to
amend the regulations for good
laboratory practice (GLP) for nonclinical
laboratory studies to require a complete
quality system approach, referred to as
a GLP Quality System, when safety and
toxicity studies support or are intended
to support applications or submissions
for products regulated by FDA. We are
proposing additional management
responsibilities and standard operating
procedures (SOPs) consistent with the
proposed requirement for a GLP Quality
System. We also propose to revise the
testing facility definition to reflect
current practices for the conduct of
nonclinical laboratory studies,
particularly multisite studies. These
proposals are intended to build quality
into planning, conducting, and
reporting a nonclinical laboratory study
and to help ensure data quality and
integrity.
SUMMARY:
Submit either electronic or
written comments on the proposed rule
by November 22, 2016. Submit
comments on information collection
issues under the Paperwork Reduction
Act of 1995 by September 23, 2016 see
section IX). See section VII for the
proposed effective date of a final rule
based on this proposed rule.
ADDRESSES: You may submit comments
as follows:
DATES:
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Electronic Submissions
Submit electronic comments in the
following way:
• Federal eRulemaking Portal: https://
www.regulations.gov. Follow the
instructions for submitting comments.
Comments submitted electronically,
including attachments, to https://
www.regulations.gov will be posted to
the docket unchanged. Because your
comment will be made public, you are
solely responsible for ensuring that your
comment does not include any
confidential information that you or a
third party may not wish to be posted,
such as medical information, your or
anyone else’s Social Security number, or
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confidential business information, such
as a manufacturing process. Please note
that if you include your name, contact
information, or other information that
identifies you in the body of your
comments, that information will be
posted on https://www.regulations.gov.
• If you want to submit a comment
with confidential information that you
do not wish to be made available to the
public submit the comment as a written/
paper submission and in the manner
detailed (see ‘‘Written/Paper
Submissions’’ and ‘‘Instructions’’).
Written/Paper Submissions
Submit written/paper submissions as
follows:
• Mail/Hand delivery/Courier (for
written/paper submissions): Division of
Dockets Management (HFA–305), Food
and Drug Administration, 5630 Fishers
Lane, Rm. 1061, Rockville, MD 20852.
• For written/paper comments
submitted to the Division of Dockets
Management, FDA will post your
comment, as well as any attachments,
except for information submitted,
marked and identified, as confidential,
if submitted as detailed in
‘‘Instructions.’’
Instructions: All submissions received
must include the Docket No. FDA–2010
–N–0548 for ‘‘Good Laboratory Practice
for Nonclinical Laboratory Studies.’’
Received comments will be placed in
the docket and, except for those
submitted as ‘‘Confidential
Submissions,’’ publicly viewable at
https://www.regulations.gov or at the
Division of Dockets Management
between 9 a.m. and 4 p.m., Monday
through Friday.
• Confidential Submissions—To
submit a comment with confidential
information that you do not wish to be
made publicly available submit your
comments only as a written/paper
submission. You should submit two
copies total. One copy will include the
information you claim to be confidential
with a heading or cover note that states
‘‘THIS DOCUMENT CONTAINS
CONFIDENTIAL INFORMATION.’’ The
Agency will review this copy, including
the claimed confidential information, in
its consideration of comments. The
second copy, which will have the
claimed confidential information
redacted/blacked out, will be available
for public viewing and posted on https://
www.regulations.gov. Submit both
copies to the Division of Dockets
Management. If you do not wish your
name and contact information to be
made publicly available, you can
provide this information on the cover
sheet and not in the body of your
comments and you must identify this
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information as ‘‘confidential.’’ Any
information marked as ‘‘confidential’’
will not be disclosed except in
accordance with 21 CFR 10.20 and other
applicable disclosure law. For more
information about FDA’s posting of
comments to public dockets, see 80 FR
56469, September 18, 2015, or access
the information at: https://www.fda.gov/
regulatoryinformation/dockets/
default.htm.
Docket: For access to the docket to
read background documents or the
electronic and written/paper comments
received, go to https://
www.regulations.gov and insert the
docket number, found in brackets in the
heading of this document, into the
‘‘Search’’ box and follow the prompts
and/or go to the Division of Dockets
Management, 5630 Fishers Lane, Rm.
1061, Rockville, MD 20852.
Submit comments on information
collection issues to the Office of
Management and Budget (OMB) in the
following ways:
Fax to the Office of Information and
Regulatory Affairs, OMB, Attn: FDA
Desk Officer, FAX: 202–395–7285, or
email to oira_submission@omb.eop.gov.
All comments should be identified with
the title, ‘‘Reporting and Recordkeeping
Requirements for Good Laboratory
Practice for Nonclinical Laboratory
Studies.’’
FOR FURTHER INFORMATION CONTACT:
Vernon Toelle, Office of Surveillance
and Compliance, Center for Veterinary
Medicine, Food and Drug
Administration, 7519 Standish Pl.,
MPN4–142, Rockville, MD 20855, 240–
402–5637; or Kristin Webster Maloney,
Office of Policy and Risk Management,
Office of Regulatory Affairs, Food and
Drug Administration, 10903 New
Hampshire Ave., Bldg. 32, Rm. 4373,
Silver Spring, MD 20993, 240–402–
4993.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Executive Summary
A. Purpose of the Proposed Rule
B. Summary of the Major Provisions of the
Proposed Rule
C. Legal Authority
D. Costs and Benefits
II. Introduction
A. What is the background for this rule?
B. Why is FDA proposing this rule?
III. Description of the Part 58 Proposal
A. What did FDA consider when drafting
this rule?
B. Part 58, Subpart A—General Provisions
C. Part 58, Subpart B—Organization and
Personnel
D. Part 58, Subpart C—Facilities
E. Part 58, Subpart D—Equipment
F. Part 58, Subpart E—Nonclinical
Laboratory Study Operations
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G. Part 58, Subpart F—Test, Control, and
Reference Articles
H. Part 58, Subpart G—Protocol for and
Conduct of a Nonclinical Laboratory
Study
I. Part 58, Subpart J—Records and Reports
J. Part 58, Subpart K—Disqualification of
Any Person Conducting a Phase of a
Nonclinical Laboratory Study
IV. Regulatory Hearing Before FDA
V. Analysis of Environmental Impact
VI. Legal Authority
VII. Proposed Implementation Plan
VIII. Economic Analysis of Impacts
A. Introduction
B. Summary
IX. Paperwork Reduction Act of 1995
X. Federalism
XI. References
I. Executive Summary
A. Purpose of the Proposed Rule
Nonclinical laboratory studies, often
referred to as preclinical studies when
conducted before first-in-human clinical
studies, provide safety or toxicity
information, or both, that is essential for
the development of FDA-regulated
products and help determine the safety
of new food ingredients. For drugs
administered to animals whose products
will be consumed by humans,
nonclinical laboratory studies are
critical for determining safe levels of
residual drug product. For tobacco
products, nonclinical laboratory studies
may provide evidence regarding the
relative toxicities of new or modified
risk tobacco products. FDA’s regulation
of the conduct of nonclinical laboratory
studies is important to help ensure the
quality and integrity of data derived
from those studies, the protection of
human subjects, and that marketing
decisions are based on accurate and
reliable data.
Therefore, FDA proposes to amend
the GLP regulations to require the use of
a complete quality system approach
(proposed GLP Quality System) when a
nonclinical laboratory study supports or
is intended to support an application or
submission to FDA. Part 58 (21 CFR part
58) presently includes many aspects of
a quality system approach. However,
certain fundamentals of a fully
implemented GLP Quality System
considered essential to a quality system,
such as certain SOPs and adequate
management roles, responsibilities, and
accountability, are not presently
required. We therefore propose a fully
implemented GLP Quality System as the
proper framework for building quality
into planning, conducting, and
reporting a nonclinical laboratory study
to help ensure the quality and integrity
of the resulting data used to support
FDA regulatory decisions.
We also propose to amend the GLP
regulations to reflect current practices
for the conduct of nonclinical laboratory
studies, particularly multisite studies,
while allowing industry flexibility to
meet the proposed requirements.
B. Summary of the Major Provisions of
the Proposed Rule
Under the proposed GLP Quality
System, FDA intends to enhance the
current quality system approach for
nonclinical laboratory studies. The GLP
Quality System will provide additional
responsibilities for testing facility
management and new responsibilities
for maintaining SOPs. We propose
modifications to the definition of a
testing facility to be applicable to all
nonclinical laboratory studies, whether
they are conducted at a single facility or
at multiple sites. We propose amending
roles and functions consistent with the
revised testing facility definition. FDA
expects that a GLP Quality System will
provide the appropriate framework for
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building quality into a nonclinical
laboratory study and will result in more
reliable data for FDA to consider when
making regulatory decisions.
C. Legal Authority
FDA proposes to issue this rule under
the authority of the provisions in
sections 351 and 354–360F of the Public
Health Service Act (PHS Act) and the
provisions in the Federal Food, Drug,
and Cosmetic Act (the FD&C Act)
applicable to the conduct of nonclincial
laboratory studies, specifically under
section 701(a) of the FD&C Act (21
U.S.C. 371(a), as essential to
enforcement of the Agency’s
responsibilities under sections 402, 406,
408, 409, 501, 502, 503, 505, 510, 512–
516, 518–520, 571, 721, 801, 905, 910,
and 911 of the FD&C Act (21 U.S.C. 342,
346, 348, 349, 351, 352, 353, 355, 360,
360b–360f, 360h–360j, 360ccc, 379, 381,
387e, 387j, and 387k).
D. Costs and Benefits
Costs estimates of the rule include
annual costs from the additional
reporting and recordkeeping
responsibilities required under the
proposed GLP Quality System. One-time
costs include reading and
understanding the rule, updating
existing SOPs, writing new SOPs, and
training. We estimate annualized costs,
over a 10-year period, at a 7-percent
discount rate would average $51.9
million, or $51.5 million with a 3percent discount rate. We lack sufficient
information to quantify the benefits of
the proposed rule, but we anticipate that
it would result in better quality and
more reliable data to support
applications and submissions to us. The
table summarizes these estimates along
with their ranges.
SUMMARY OF BENEFITS, COSTS AND DISTRIBUTIONAL EFFECTS OF PROPOSED RULE
Units
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Category
Benefits:
Annualized ............
Monetized
$millions/year ....
Annualized ............
Quantified ..............
Qualitative .............
Primary
estimate
Low estimate
........................
........................
........................
2014
7
10
........................
........................
........................
........................
........................
........................
........................
........................
........................
2014
2014
2014
3
7
3
10
10
10
High estimate
Year dollars
Discount rate
(%)
The proposed rule would clarify GLP standards
to facilitate a more consistent approach and
provide greater international consistency. As a
result, we anticipate improvements in the integrity
and quality of data submitted for FDA review
decisions.
Costs:
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Period
covered
(years)
Notes
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SUMMARY OF BENEFITS, COSTS AND DISTRIBUTIONAL EFFECTS OF PROPOSED RULE—Continued
Units
Category
Primary
estimate
Low estimate
High estimate
Year dollars
Discount rate
(%)
Period
covered
(years)
Notes
Annualized ............
Monetized
$millions/year ....
Annualized ............
Quantified ..............
$51.9
$34.4
$69.3
2014
7
10
51.5
........................
........................
34.2
........................
........................
68.9
........................
........................
2014
2014
2014
3
7
3
10
10
10
Qualitative:
Federal ..................
Annualized ............
........................
........................
........................
........................
........................
........................
2014
2014
7
3
10
10
2014
2014
7
3
10
10
Monetized millions/
year ...................
Transfers:
Other .....................
Annualized ............
Monetized millions/
year ...................
Effects:
From:
To:
........................
........................
........................
........................
From:
To:
State, Local or Tribal Government: None estimated.
Small Business: The proposed requirements would likely impose a significant burden on small entities employing fewer
than 10 workers in ‘‘Dental Equipment and Supplies’’ (between 1.87 and 8.94 percent of average annual sales).
However, we do not have data on how many of these dental-equipment small entities perform nonclinical laboratory
studies to support, or intended to support, an application or submission regulated by us; only such entities would be
affected by the rule.
Wages: None estimated.
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II. Introduction
FDA is proposing to amend the GLP
regulations in part 58 to require the use
of a complete quality system approach,
referred to as a GLP Quality System, for
the conduct of nonclinical laboratory
studies when safety or toxicity studies,
or both, support or are intended to
support applications or submissions to
FDA. FDA proposes to define a GLP
Quality System as the organizational
structure, responsibilities, procedures,
processes, and resources for
implementing quality management in
the conduct of nonclinical laboratory
studies.
While many aspects of a quality
system approach are presently included
in part 58, we expect that
implementation of a GLP Quality
System will provide an improved
framework that is more flexible and will
help ensure quality in planning,
conducting, and reporting nonclinical
laboratory studies. Consistent with the
proposed requirement for a GLP Quality
System, we propose additional
management responsibilities, with
accompanying SOPs, to ensure
management’s responsibility for
establishing and maintaining the quality
system. We also propose to revise the
definition of a testing facility to reflect
current practices for the conduct of
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nonclinical laboratory studies,
particularly the conduct of multisite
studies. Conforming modifications are
proposed for consistency with the
proposed GLP Quality System and
today’s prevalence of multisite studies.
FDA is proposing these changes to
help ensure the quality and integrity of
data from nonclinical laboratory studies
conducted in support of applications
and submissions to FDA. We also are
modernizing the regulations to further
the Agency’s efforts to encourage the
implementation of the principles of the
‘‘3Rs,’’ to reduce, refine, and replace
animal use in testing. This approach
seeks to minimize the use of animals in
such testing and promote more humane,
appropriate, and specific test methods
for evaluating product safety. These
proposed changes will clarify and
update the regulations. In particular, we
are proposing changes recognizing the
current prevalence of multisite studies
while adding flexibility consistent with
current practices and the use of everchanging technology.
A. What is the background for this rule?
On December 21, 2010, FDA
published an advanced notice of
proposed rulemaking (ANPRM), ‘‘Good
Laboratory Practice for Nonclinical
Laboratory Studies’’ (December 2010
ANPRM) (75 FR 80011), to solicit
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stakeholder input regarding FDA’s
intention to modify the GLP regulations
in part 58. As stated in the December
2010 ANPRM, FDA is proposing to
require that all facilities conduct
nonclinical laboratory studies under a
GLP Quality System when those studies
support or are intended to support an
application or submission to FDA.
The December 2010 ANPRM
addressed nine specific areas to
consider for amending part 58. Those
nine areas are: (1) The GLP Quality
System, (2) Multisite Studies, (3)
Electronic/Computerized Systems, (4)
Sponsor Responsibilities, (5) Animal
Welfare, (6) Information on Quality
Assurance Inspection Findings, (7)
Process-Based Systems Inspections, (8)
Test and Control Article Information,
and (9) Sample Storage Container
Retention.
FDA received about 90 comments to
the December 2010 ANPRM. Most of the
comments address the nine specific
areas; however, a number of the
comments include additional areas for
FDA’s consideration. All comments
were reviewed and considered by a
working group with representatives
from all FDA Centers, along with
representatives from the U.S.
Environmental Protection Agency
(EPA), the Animal and Plant Health
Inspection Service of the U.S.
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Department of Agriculture (USDA/
APHIS), and the Office of Laboratory
Animal Welfare at the National
Institutes of Health (NIH/OLAW).
In addition to the December 2010
ANPRM comments, we reviewed and
considered the documents of the
working group on GLP of the
Organisation for Economic Co-operation
and Development (OECD), including the
general principles of GLP and consensus
and advisory documents (Ref. 1). The
United States is a signatory to OECD’s
GLP Mutual Acceptance of Data
agreement (Ref. 2) and, as an OECD
member country, FDA participated in
the development of OECD’s GLP
documents. For this proposal, we strive
for consistency with the relevant OECD
documents whenever possible.
B. Why is FDA proposing this rule?
The proposed GLP Quality System
would help to provide a flexible
framework for building quality into
planning, conducting, and reporting a
nonclinical laboratory study, and would
help ensure the integrity of data
submitted to FDA to support FDA
regulatory decisions. The present
regulations do not require certain
fundamentals considered essential to a
complete quality system. For example,
the present regulations do not
specifically require SOPs for developing
and maintaining SOPs, or SOPs for
developing and periodically assessing a
quality system, nor do they provide for
adequate management roles,
responsibilities, and accountability. We
note that a major principle of a complete
quality system is management’s ultimate
responsibility for establishing and
maintaining the quality system.
This proposal also is intended to
update the regulations to reflect today’s
conduct of nonclinical laboratory
studies, particularly the conduct of
multisite studies. For multisite studies
that may have multiple contracts and
subcontracts for various study phases,
effective communication is essential,
especially considering the proposed
requirement for a single final study
report. We agree with the numerous
comments to the December 2010
ANPRM that support a clear delineation
of study responsibilities and effective
communication among all parties
involved in multisite studies.
Some stakeholders suggest that
certain provisions in part 58 are
outdated and hamper efficient use of
present technology (for example,
requiring hard copies of records and
documentation instead of allowing
computerized options). Several industry
organizations approached FDA after the
announcement of the Bioresearch
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Monitoring (BIMO) Modernization
Initiative in 2006 (Ref. 3), requesting
that we modernize the GLP regulations.
One request, among others, was to
remove the requirement that the quality
assurance unit (QAU) must maintain the
master schedule and copies of protocols.
These requests were echoed in several
comments to the December 2010
ANPRM. FDA agrees with those
comments and proposes to update part
58 to help address the use of present
technology.
Because the number of FDA
inspections is limited by competing
priorities and limited resources, we look
to sponsors and nonclinical laboratory
management to help ensure that data
submitted to FDA in support of
applications and submissions are
reliable. For those nonclinical
laboratory studies that are the bases for
allowing a new medical product into
first-in-human clinical studies, the
quality and integrity of the data are
crucial to human subject protection.
This proposal complements the intent
of the original GLP proposed rule to
ensure the quality and integrity of the
resulting data (41 FR 51206 at 51210,
November 19, 1976) (Ref. 4). FDA
expects that requiring a GLP Quality
System will help ensure data quality
and integrity. The proposed GLP
Quality System also will allow the
flexibility to develop site-specific
procedures for related SOPs. Because of
the great diversity in institutions,
research activities, and organizational
structures covered by these regulations,
it is important to have sufficient
flexibility in the regulations to allow the
regulated parties to meet these
requirements in a manner that best suits
their organizational needs.
III. Description of the Part 58 Proposal
A. What did FDA consider when
drafting this rule?
1. Animal Rule
Several comments to the December
2010 ANPRM requested that FDA
modify part 58 to accommodate studies
conducted in animals to support the
effectiveness of human drugs or
biological products when human
efficacy studies are not ethical or
feasible. Those comments refer to the
‘‘Animal Rule’’ (21 CFR parts 314 and
601) (67 FR 37988, May 31, 2002).
The Animal Rule provides a pathway
for FDA to grant marketing approval
based on adequate and well-controlled
animal efficacy studies when the results
of those studies establish that the drugs
or biological products are reasonably
likely to produce clinical benefit in
humans. Products evaluated for efficacy
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under the Animal Rule should be
evaluated for safety under the existing
requirements for establishing the safety
of new drugs and biological products.
The provisions in part 314, subpart I for
drugs and part 601, subpart H for
biological products apply only to
situations when adequate and wellcontrolled human efficacy studies
cannot ethically be conducted because
they would involve deliberate exposure
of healthy human volunteers to a
potentially lethal or permanently
disabling toxic chemical, biological,
radiological, or nuclear substance, and
field trials to study the product’s
effectiveness after an accidental or
hostile exposure have not been feasible.
In the past, FDA has said that ‘‘All
studies subject to this rule must be
conducted in accordance with
preexisting requirements under the good
laboratory practices (21 CFR part 58)
regulations’’ (67 FR 37988 at 37989,
May 31, 2002). FDA made this statement
because part 58 includes requirements
for a quality system structure to ensure
the quality and integrity of animal study
data. These studies are intended to
generate data that are essential for the
approval or licensure of products
intended for human use. Thus, ensuring
the quality and integrity of data from
these studies is critical as they serve as
substantial evidence of effectiveness of
the product.
Part 58 was issued to ensure the
quality and integrity of nonclinical
laboratory studies conducted to assess
the safety of FDA-regulated products. In
response to comments made to the
ANPRM, FDA questions whether any
requirement presently in part 58 or in
this proposal poses a unique or
disproportionate obstacle or burden on
the conduct of certain animal studies
specific to product development under
the Animal Rule.
FDA, however, tentatively concludes
there may be justifiable limitations to
applying GLP regulations when
conducting Animal Rule-specific
studies, especially for studies using
challenge agents that require highcontainment facilities (for example,
biosafety level 4 (BSL–4) 1 laboratory
environments). Therefore, although part
58 embodies critical elements of a
quality system to ensure data quality
1 BSL–4 refers to the practices, safety equipment,
and safeguards required for laboratories that work
with highly infectious and lethal pathogenic
microbes which cause, for example, such lethal
diseases in humans as smallpox, Ebola, or Marburg
virus hemorrhagic fever. BSL–4 is the highest
biosafety level designation possible and means that
the most stringent safeguards are in place to protect
researchers, non-laboratory building occupants, the
general public, and the environment from exposure
to exotic or lethal agents.
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and integrity, FDA also recognizes that
some current part 58 requirements may
not be appropriate, or may require
modification to address adequately data
quality practices for the Animal Rulespecific studies.
Accordingly, although not included in
the regulatory text portion of this
proposal, FDA is considering expanding
part 58 to include the conduct of certain
Animal Rule studies that support
approval or licensure of products for
human use under the established data
quality and integrity standards. We seek
comment on this proposal. In particular,
we invite comment on the possibility of
amending the scope of the regulation in
§ 58.1(a) to encompass not only
nonclinical laboratory studies, but also
to include certain Animal Rule-specific
studies. Correspondingly, we are
considering adding a definition in § 58.3
for ‘‘Animal Rule-specific studies
subject to GLP’’ (for purposes of this
document, ‘‘Animal Rule-specific
studies subject to GLP’’ are referred to
as ‘‘covered Animal Rule studies’’).
Specifically, FDA is considering
including within the definition of
covered Animal Rule studies only the
following types of studies to support
product approval under the Animal
Rule: (1) The adequate and wellcontrolled animal efficacy studies that
serve as substantial evidence of the
effectiveness necessary for approval or
licensure of human drugs or biological
products, respectively; (2)
pharmacokinetic and/or
pharmacodynamic studies in animals
used to select a dose and regimen in
humans; and (3) if seeking qualification
through FDA’s Animal Model
Qualification Program,2 the modeldefining natural history studies.3 4
2 The Animal Model Qualification Program is part
of FDA’s Drug Development Tool (DDT)
Qualification Program. The DDT Program provides
a framework for development and regulatory
acceptance of scientific tools for use in drug
development programs. Qualification of an animal
model is not required for the approval of drugs or
licensure of biologics under the Animal Rule. For
more information about this program, see FDA’s
guidance for industry and FDA staff Qualification
Process for Drug Development Tools (January 2014)
(https://www.fda.gov/downloads/drugs/
guidancecomplianceregulatoryinformation/
guidances/ucm230597.pdf), and the Animal Model
Qualification Program Web site: https://inside.fda.
gov:9003/CDER/OfficeofTranslationalSciences/
BiomarkerQualifications/ucm271856.htm.
3 In the context of animal model qualification, the
model-defining natural history studies are the
animal studies that establish the ranges of values of
key parameters of the disease or condition that will
be specified in the context of use statement for the
qualified model and that will be used as measures
of quality control and quality assurance when the
model is replicated.
4 Natural history studies that will not be used to
support the qualification of an animal model, as
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FDA seeks comment on the impact of
expanding part 58 to include these
covered Animal Rule studies. We also
request comment on what other changes
to the regulations, beyond amending the
scope and definitions, are needed to
address issues unique to covered
Animal Rule studies. FDA specifically
requests comments in response to the
following questions:
1. Would amending part 58 to expand
the scope to include covered Animal
Rule studies establish an appropriate
quality system approach to the conduct
of such studies to ensure data quality
and integrity? If not, what gaps or
shortcomings would remain, and how
should they be addressed?
2. Would such an amendment provide
sufficient clarity and flexibility to
sponsors and investigators? If not, what
alternatives or changes to this approach
are needed?
3. FDA is considering adding a
definition in part 58 for ‘‘Animal Rulespecific studies subject to GLP’’
(referred to as ‘‘covered Animal Rule
studies’’). As discussed in section
III.A.1., the proposed definition
contains three specific types of studies
that would be subject to part 58. Is the
term ‘‘Animal Rule-specific studies
subject to GLP,’’ as defined in § 58.3,
clear and appropriately inclusive?
4. What are the benefits, challenges,
and burdens of amending part 58 to
include covered Animal Rule studies?
a. Would this proposed expansion of
the scope in § 58.1(a) impact entities
conducting covered Animal Rule
studies?
b. Would the proposed expansion of
the scope in § 58.1(a) impact those
entities engaged in conducting
nonclinical laboratory studies to assess
product safety?
c. What could be done to minimize
burdens or costs, including costs or
burdens on small entities, associated
with part 58 compliance for covered
Animal Rule studies?
5. Are there any challenges or
differences involved in the conduct of
covered Animal Rule studies (versus
nonclinical laboratory studies) that
merit different standards or
establishment of a separate regulation?
If so, what are those challenges or
differences, and what alternative(s)
would be preferable?
6. Based on possible differences
identified in question 5, are there any
particular aspects in the current or
proposed part 58 that would be unduly
difficult to meet? What changes to
current part 58, or the proposed
defined in footnote 2, would not be subject to GLP
regulations.
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amendments, could be made to address
or accommodate these issues? For
example:
a. Would it be satisfactory to include
a provision to allow on a case-by-case
basis a covered Animal Rule study
sponsor to seek FDA agreement on
deviations from certain part 58
requirements that may not be
practicable to meet as follows: ‘‘When
the study is an Animal Rule-specific
study subject to GLP, FDA may agree to
deviations from any requirement of this
part that it finds unnecessary to ensure
the quality and integrity of the study by
written agreement with the sponsor
before the conduct of the study. In such
cases, FDA’s acceptance of deviations
from the requirements will be
contingent upon compliance with any
alternative requirements included in
that agreement.’’
b. Would it be workable or
appropriate to entirely exempt covered
Animal Rule studies from certain
requirements of part 58? If so, what
exemption(s) would be necessary or
appropriate?
As discussed in section III.A.1., FDA
considers GLP regulations to be a wellestablished and relevant system for
ensuring data quality and integrity for
covered Animal Rule studies. Therefore,
until a final rule is published, FDA
recommends the use of the current GLP
framework (for example, definitions,
procedures, roles and responsibilities,
and controls) for covered Animal Rule
studies to the extent practicable, and
intends to provide more information
about FDA’s expectations for adapting a
GLP framework to these studies.
Before initiating covered Animal Rule
studies, sponsors should identify
aspects of the studies anticipated to be
challenging with regard to GLP and
propose methods for adapting the
studies to ensure the quality and
integrity of the resulting data. Sponsors
should submit this information to FDA
for concurrence on the data quality and
integrity plan before the studies are
initiated. A guidance document is
available regarding the essential
elements necessary to address efficacy
under the Animal Rule.5
2. ISO 9001 and GLP Quality System
Many comments to the December
2010 ANPRM note that the International
Organization for Standardization (ISO)
9001 is very general and not all aspects
outlined in ISO 9001 are applicable to
GLPs. FDA acknowledges this.
5 See FDA’s guidance for industry Product
Development Under the Animal Rule (October
2015), at https://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/
Guidances/UCM399217.pdf.
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However, ISO 9001 is an internationally
recognized standard for quality systems.
Also, FDA’s Quality System Regulation
(QSR) in part 820 (21 CFR part 820) for
current good manufacturing practice
requirements for medical devices was
harmonized, to the extent possible, with
the ISO 9001: 1994 ‘‘Quality Systems—
Model for Quality Assurance in Design,
Development, Production, Installation
and Servicing.’’
Some comments to the December
2010 ANPRM state that consistency
with the ISO 9001 standard would be
acceptable if we retained what they
perceived as the present flexibility of
the regulations. A number of comments
state that it would be beneficial to
borrow elements of a quality system
from the QSR requirements in part 820
rather than reference ISO 9001:1994.
Many comments also request that we
define the operational areas necessary
for broader adoption of a quality system
approach.
In this proposal, we incorporate
aspects of ISO 9001:1994 that are
consistent with part 820 and our desire
to propose a complete quality system
approach. For example, we propose to
address establishing and maintaining a
GLP quality system by adding to part 58
certain definitions, relevant SOPs, and
management roles and responsibilities
modeled after the part 820
requirements. Our proposed additions
to more fully enable a GLP quality
system will help expand the present
flexibility in part 58. Our proposals also
are consistent with OECD guidance
documents for GLP wherever possible
and, at the very least, do not conflict
with them.
3. Animal Welfare
Many comments to the December
2010 ANPRM note that § 58.90 covers
animal care and thus, FDA investigators
review documentation of animal care
during GLP inspections. This is true. If
animal care is not compliant with
appropriate standards, there is a high
likelihood that such noncompliance
could confound the results of affected
studies. Since the good laboratory
practice regulations were published, the
Animal Welfare Act has been amended
and the public’s perception of animal
welfare has changed. Therefore, we
propose specific responsibilities
regarding animal welfare because the
humane treatment of animals in
research settings is essential to the
quality and integrity of GLP studies.
Many comments to the December
2010 ANPRM state that addressing
animal welfare in part 58 would be a
duplication of USDA/APHIS or the NIH
regulations. That is not our intention.
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FDA has a Memorandum of
Understanding (MOU) (Ref. 5) with
USDA/APHIS and NIH/OLAW
regarding animal welfare oversight. FDA
forwards to the relevant regulatory
agency any concerns regarding animal
welfare observed during FDA
inspections for their followup. Those
animal welfare observations are not
included on a Form FDA 483
(Inspectional Observations) that may be
issued at the close of an FDA
inspection, unless the observations also
show noncompliance with § 58.90.
While this proposal addresses animal
welfare concerns, FDA supports the use
of non-animal testing methods when
scientifically valid alternatives are
available. We encourage sponsors with
questions about non-animal testing
methods to approach FDA early in the
development process for consultation
on the suitability and acceptability of
non-animal tests for their particular
product. This approach reflects FDA’s
position in its May 20, 2010, citizen
petition response to the Mandatory
Alternatives Petition Coalition and
subsequent Agency statements. That
petition requested that FDA require only
non-animal test methods instead of
corresponding animal test methods
whenever such scientifically satisfactory
methods are available. (See Docket No.
FDA–2007–P–0109.)
4. Multisite Studies
As stated in the December 2010
ANPRM, FDA’s intent was simply to
add new definitions relevant to roles
and responsibilities specific to multisite
studies. Many comments to the
December 2010 ANPRM state that the
present regulations are basically
adequate and suggested only minimal
modifications.
Since publication of the December
2010 ANPRM, we have changed our
thinking concerning regulatory changes
needed to address multisite studies. For
example, we have determined that
amending the definition of a testing
facility will help address the current
conduct of multisite studies. We discuss
in section III.B.2. our proposed changes
to that definition.
Many comments to the December
2010 ANPRM suggest that we align our
requirements regarding multisite studies
with the OECD consensus document
entitled, The Application of the OECD
Principles of GLP to the Organisation
and Management of Multi-Site Studies
(Ref. 6). The comments also requested
that we not be as prescriptive as those
OECD directives. We agree with those
comments. We reviewed and considered
this OECD consensus document and
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incorporated into our proposal the same
general concepts, where applicable.
5. GLP Roles and Responsibilities
We propose to maintain the current
GLP roles for management, study
director, and QAU. We propose that the
overarching responsibilities of those
who fulfill these roles remain as
follows: Management is responsible for
establishing and maintaining conditions
and procedures necessary for the
conduct of nonclinical laboratory
studies compliant with GLPs; the study
director, as the sole point of study
control, is responsible for implementing
those procedures in specific studies;
and the QAU is responsible for
inspecting and general oversight of
studies, verifying that they are GLP
compliant or recommending changes
needed for bringing them into
compliance.
These responsibilities complement
each other and sometimes overlap in
multiple areas, providing for a system of
checks and balances. We intend for this
proposal to maintain the authority
necessary for fulfilling each of these
roles while allowing maximum
flexibility for the conduct of a GLPcompliant nonclinical laboratory study.
We are interested in feedback about
whether this proposal will accomplish
our goal of maintaining the necessary
interrelationships among these roles,
and whether our proposal undermines
any one of these roles or fails to provide
adequate flexibility.
B. Part 58, Subpart A—General
Provisions
1. Scope (§ 58.1)
We propose to expand the scope of
FDA-regulated nonclinical laboratory
studies to specifically include toxicity
studies. For purposes of this proposal,
toxicity means the acute or long-term
adverse effects that could result from
use of the FDA-regulated product. While
some nonclinical laboratory studies of
FDA-regulated products evaluate a
product’s safety, including toxicity,
most are conducted solely to determine
a product’s toxicity. For example, when
combined with the results of clinical
trials, determination of toxicity at
various doses can inform an appropriate
risk-to-benefit analysis when relevant to
FDA’s consideration of a product’s
marketing application or submission.
For drugs administered to animals
whose products will be consumed by
humans, toxicity studies are critical for
determining safe levels of residual drug
product. Nonclinical laboratory studies
of food ingredients and food contact
substances provide the basis for
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establishing levels at which a substance
will not, with reasonable certainty, be
harmful under its intended conditions
of use. In the evaluation of tobacco
products, FDA could use the data
derived from nonclinical laboratory
studies to evaluate relative toxicity as
opposed to evaluating safety.
Additional proposed modifications to
the scope in § 58.1 expand the language
to include FDA jurisdictional oversight
of tobacco products as specified in the
FD&C Act, sections 905, 910, and 911.
We also propose to modify and broaden
‘‘medical devices for human use’’ to
‘‘devices’’ to include FDA’s Center for
Veterinary Medicine (CVM), which has
jurisdiction over devices used in
veterinary medicine.
In addition, we propose changing the
provision ‘‘for research and marketing
permits’’ to ‘‘applications or
submissions’’ for FDA-regulated
products. This proposed change will
include the applications and
submissions to FDA listed in the
definitions section of this proposal.
As stated in both the preamble to the
original proposed regulations (original
GLP proposed rule) (41 FR 51206 at
51210) and the preamble to the original
GLP final rule (43 FR 59986 at 59988),
the GLP ‘‘regulations are intended to
ensure, as far as possible, the quality
and integrity of test data that are
submitted to FDA and become the basis
for regulatory decisions made by the
Agency.’’ Therefore, the phrase
‘‘intended to support’’ in present and
proposed § 58.1(a) means that any
nonclinical laboratory study included
within the proposed expanded scope of
Part 58 that is conducted with the intent
that it may support an application or
submission to FDA should be conducted
in compliance with the GLP regulations.
Also, we propose adding § 58.1(c) to
describe what we mean by ‘‘where
appropriate’’ when used in the part 58
regulatory text. This proposal addresses
studies conducted at a single testing
facility as well as at multiple sites. We
propose using ‘‘where appropriate’’ in
many of the revised or added provisions
because not all requirements are
applicable to all studies. For example, a
test site tasked only with interpreting a
study’s histopathology would not
require all of the SOPs required for a
test site responsible for multiple phases.
2. Definitions (§ 58.3)
The current § 58.3 Definitions, is not
alphabetized and includes paragraphs
(a) through (p). We propose to remove
the paragraph designations, add new
definitions, modify certain current
definitions, and alphabetize the
complete listing of definitions.
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We propose modifying current
§ 58.3(e) to change the defined term
from ‘‘Application for research or
marketing permit’’ to ‘‘Applications and
Submissions to FDA’’. We propose this
change because nonclinical laboratory
studies can support applications and
submissions to FDA other than those for
research and marketing. Also, in the
definition for ‘‘Applications and
Submissions to FDA’’ proposed
paragraphs (1) through (35), we add
certain relevant statutory or regulatory
citations for consistency.
We propose including applications
and submissions for tobacco products
described in the FD&C Act. We note that
FDA plans to issue regulations under
section 910(g), providing conditions
under which tobacco products intended
for investigational use may be exempted
from the requirements of chapter IX of
the FD&C Act. It is our intent that
applications for such investigational
tobacco products will be included
within the scope of § 58.3.
We also propose adding those
applications and submissions for FDAregulated products that include
nonclinical laboratory study results but
are not currently specifically included.
For example, Humanitarian Device
Exemption applications are new since
publishing in 1987 the last final rule
modifying part 58. We also propose
expressly adding the medical device
Premarket Notification (also known as a
‘‘510(k)’’ submission).
Attending Veterinarian: We propose
adding a definition for an attending
veterinarian. Our proposed definition is
the same as the definition in USDA’s
Animal Welfare Regulations (9 CFR 1.1)
but without specifics about educational
requirements. We propose defining an
attending veterinarian as a veterinarian
with training, experience, or both in the
care and management of the species
being attended, with direct or delegated
authority for activities involving
animals. We propose this definition
because we propose in part 58 certain
provisions about animal welfare. For
example, we propose that the study
director must defer to the attending
veterinarian when decisions regarding
animal welfare arise, particularly when
animals are in pain or distress.
Batch: We propose changing the
definition of batch currently in § 58.3(n)
to reference the relevant provisions in
§ 58.105 (Test, control, and reference
article characterization) and § 58.107
(Test, control, and reference article
handling). We also add that batch means
a specific quantity or lot of a reference
article (see section III.B.2.), we discuss
the addition of a reference article
definition.
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Contracted Person: We propose
adding a definition for contracted
person to mean a person that assumes,
either directly or indirectly as an
independent contractor, one or more of
the responsibilities for conducting a
nonclinical laboratory study. Several
comments to the December 2010
ANPRM state that the responsibilities of
all persons (any legal entity) involved in
multisite studies need to be addressed
in the regulations. We propose the use
of this term to allow us to address the
comments without specifically
identifying all possible contracted
entities.
The comments also request that FDA
include specifics for multisite studies as
to how responsibilities are to be met and
by whom. In response to these
comments, we intend that a contracted
person includes any person (for
example, testing facility or individual)
that the sponsor contracts with to
conduct a phase (defined activity or set
of activities) of a nonclinical laboratory
study. Also, the term contracted person
includes any person that is under a
subcontract to conduct a phase of a
nonclinical laboratory study.
Contributing Scientist: We propose
adding and defining the term
contributing scientist. A contributing
scientist is an individual responsible for
conducting, interpreting, analyzing, or
performing any service for a phase of a
nonclinical laboratory study. The
current regulation in § 58.185 for
reporting study results refers to
‘‘individual scientists or other
professionals involved in the study’’
(see § 58.185(a)(12)). Our proposal
replaces these scientists or other
professionals with the term contributing
scientist. In addition, when a
contributing scientist is a contracted
independent expert or specialist, we use
the term independent contributing
scientist. See, also, section III.C.6. where
we discuss § 58.37 (Contributing
scientist).
Control Article: We propose
modifying the definition of control
article currently in § 58.3(c) by changing
‘‘medical device for human use’’ to
‘‘device’’ to expand the regulations to
include devices used in veterinary
medicine. Also, the revised definition
proposes to include a ‘‘tobacco
product’’.
Establish: For this part 58 proposal,
the meaning of establish is to define,
document (in writing or electronically),
and implement. We propose adding a
definition for establish to help eliminate
repeating in the applicable regulatory
text the words that define establish. Our
proposed definition is identical to the
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definition of establish in the part 820
quality system regulation in § 820.3(k).
Facility-Based Inspection: We propose
introducing the term facility-based
inspection to mean a QAU inspection
that covers the general facilities and
activities; for example, installations,
support systems, computer systems,
training, environmental monitoring, and
equipment maintenance and calibration.
This addition, along with the definition
of process-based inspection (see section
III.B.2.) would allow for greater
efficiency instead of duplicating, for
each study, inspection of those general
facilities and activities. Our proposed
definition also is consistent with the
definition for facility-based inspection
in the OECD document, Quality
Assurance and GLP (Ref. 7).
GLP Quality System: We propose
adding a definition for GLP Quality
System to mean the organizational
structure, responsibilities, procedures,
processes, and resources for
implementing quality management in
the conduct of nonclinical laboratory
studies. As discussed in section II.B., we
consider a fully implemented GLP
Quality System the proper framework
for building quality into planning,
conducting, and reporting a nonclinical
laboratory study while allowing
flexibility for site-specific procedures.
Lead Quality Assurance Unit: We
propose adding a definition for a lead
quality assurance unit (lead QAU)
meaning the QAU responsible for
quality assurance (QA) in a multisite
nonclinical laboratory study. We
propose that testing facility management
with executive responsibility selects the
lead QAU. The location of the lead QAU
may be at the testing facility, with
another person conducting a phase of
the study, or provided through a
contractual relationship. This definition
is consistent with the definition for lead
QAU in the OECD consensus document,
The Application of the OECD Principles
of GLP to the Organisation and
Management of Multi-Site Studies (Ref.
6).
Management with Executive
Responsibility: We propose adding a
definition for management with
executive responsibility to mean senior
employees of the testing facility or test
site who have the authority to establish
or make changes to the quality policy
and GLP Quality System at their testing
facility or test site. We note that part 820
(see § 820.3(n)) adopted this term
describing senior management to be
consistent with the quality system
specifications in ISO 9001:1994 (61 FR
52602 at 52609, October 7, 1996).
Master Schedule: We propose adding
a definition for master schedule that
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means a compilation of information
used for assessment of workload and the
tracking of nonclinical laboratory
studies. The master schedule will
include information about all
nonclinical laboratory studies
conducted. For multisite studies, the
master schedule also will include the
phases conducted (see proposed
58.31(k)). Our proposed definition of
master schedule is consistent with the
definition in the OECD GLP document,
OECD Principles on Good Laboratory
Practice (Ref. 8). When we discuss
§ 58.31 (Management with executive
responsibility, section III.C.2.), we
elaborate on requirements concerning
the master schedule.
Multisite Study: We propose adding a
definition for multisite study to mean
any study that has phases (defined in
section III.B.2.) conducted at more than
one site. Our proposed definition of
multisite study is consistent with the
definition in the OECD consensus
document, The Application of the OECD
Principles of GLP to the Organisation
and Management of Multi-Site Studies
(Ref. 6).
Nonclinical Laboratory Study: We
propose modifying the current
definition in § 58.3(d) for a nonclinical
laboratory study to add after ‘‘under
laboratory conditions’’ the phrase ‘‘or in
the applicable environment’’. This
addition recognizes that the conduct of
a nonclinical laboratory study is not
limited to a traditional laboratory
environment. We propose to make clear
that the purpose for conducting
nonclinical laboratory studies may be to
determine relative toxicity. For
example, because tobacco products are
not safe, nonclinical laboratory studies
help FDA evaluate the relative toxicities
of those products. We also propose to
update the regulations by changing
‘‘field trials in animals’’ to ‘‘clinical
investigational use in animals’’, which
more accurately describes our intent.
We propose a sentence structure change
in the last sentence in this definition to
clarify our intent, which is often
misinterpreted due to the current
sentence structure.
Phase: We propose adding a
definition for phase to mean a defined
activity or set of activities in the
conduct of a nonclinical laboratory
study. We propose this new definition
to aid in understanding the new
proposed definition of multisite study,
which is any study that has phases
conducted at more than one site. Our
proposed definition is consistent with
the definition of phase in the OECD
consensus document, The Application
of the OECD Principles of GLP to the
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Organisation and Management of MultiSite Studies (Ref. 6).
Principal Investigator: We propose
adding a definition for principal
investigator to mean an individual with
specific responsibilities delegated by the
study director for a phase of a
nonclinical laboratory study. We
propose defining principal investigator
in general terms rather than specifying
the principal investigator’s single role in
a multisite study as defined in the
OECD document, OECD Principles on
Good Laboratory Practice (Ref. 8).
However, we propose that principal
investigator responsibilities are those
delegated by the study director, which
is consistent with OECD principles. See,
also, section III.C.7. where we discuss
§ 58.39 (Principal investigator).
Process-based Inspection: We propose
adding a definition for process-based
inspection to mean inspecting
repetitive, frequently performed
procedures and processes (for example,
certain mutagenicity studies). This
definition recognizes present practice
and allows for greater efficiency, as
noted elsewhere (section III.B.2.). Our
proposed definition is consistent with
the definition for process-based
inspection in the OECD document,
Quality Assurance and GLP (Ref. 7).
Quality: We propose adding a
definition for quality, meaning the
totality of features and characteristics
bearing on the ability of a nonclinical
laboratory study to provide reliable
data.
Quality Assurance Unit (QAU): We
propose modifying the current
definition in § 58.3(l) to remove ‘‘except
the study director’’ and ‘‘designation by
testing facility management’’. Also, we
propose adding a sentence ‘‘The QAU
must be entirely separate from and
independent of the personnel engaged
in the direction and conduct of the
particular study.’’ We propose these
changes for clarity and to be consistent
with our inclusion of multisite studies
and with the statement currently in
§ 58.35.
Quality Policy: We propose adding a
definition for quality policy that is
identical to the definition in § 820.3(u),
meaning ‘‘the overall intentions and
direction of an organization with respect
to quality, as established by
management with executive
responsibility.’’
Raw Data: We propose modifying the
current definition in § 58.3(k) to update
the regulations to address copying
requirements and computerized
systems, and to specifically include the
pathology report. We propose adding to
the definition that raw data means ‘‘all
nonclinical laboratory study records and
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documentation or exact copies that
maintain the original intent and
meaning and are made according to the
person’s certified copy procedures.’’
This additional regulatory text
eliminates the need to provide examples
of what we consider a copy. We also
propose adding ‘‘correspondence’’ and
‘‘other documentation (regardless of
capture medium)’’ to the examples of
raw data. The addition of ‘‘regardless of
capture medium’’ eliminates the need to
provide examples of possible capture
media. Also, we propose including as
raw data ‘‘the signed and dated
pathology report’’ to clarify what we
consider as raw data.
Reference Article: We propose adding
a definition for reference article
consistent with EPA’s GLP regulations
in 40 CFR 160.3 and 792.3 for defining
a ‘‘reference substance’’ to mean an
article used to establish a basis for
comparison of the test article for known
chemical or biological measurements.
We propose this addition to
acknowledge the use of reference
articles in certain studies.
Short-Term Study: We propose adding
a definition for short-term study to
mean when the in-life period (study
period during which data are collected)
is completed within several days or, at
most, a week. Since the pre-specified,
periodic timing of process-based
inspections can result in the lack of an
inspection of a short-term study, this
definition is necessary to address our
proposed addition of process-based
inspections (see also the discussion of
the definition of process-based
inspection in section III.B.2.).
Specimen: We propose adding ‘‘or
retention’’ to the end of the current
definition of specimen in § 58.3(j) to
read, ‘‘Specimen means any material
derived from a test system for
examination, analysis, or retention.’’ We
propose this change because a specimen
may be collected solely for retention
purposes. Also, this proposed change is
consistent with the definition in the
OECD GLP document, OECD Principles
on Good Laboratory Practice (Ref. 8).
Sponsor: We propose modifying the
current definition of sponsor in § 58.3(f)
consistent with our proposal to expand
the scope of part 58, and to address
possible roles of the sponsor in multisite
studies. We propose revising the current
definition in § 58.3(f)(3) to include the
possible roles a sponsor could play in a
multisite study in addition to initiating
and supporting the study. Those roles
and applicable requirements are the
same as those for a testing facility, test
site, or contributing scientist as we
propose to define those terms.
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See, also, section III.B.3. where we
discuss § 58.5 (Sponsor responsibilities).
Standard Operating Procedures
(SOPs): We propose adding a definition
for SOPs to mean documented
procedures describing how to perform
tests or activities normally not specified
in detail in study protocols. We propose
this addition because many proposed
modifications in § 58.31 refer to
required SOPs. This definition is
consistent with the OECD GLP
document, OECD Principles on Good
Laboratory Practice (Ref. 8).
Study-based Inspection: We propose
adding a definition for study-based
inspection to mean the same QAU
inspection specified currently in
§ 58.35(b)(3) for inspecting a critical
operation of the study that is scheduled
according to the study’s chronology or
sequence of events. Our proposed
definition is consistent with the
definition for study-based inspection in
the OECD consensus document, Quality
Assurance and GLP (Ref. 7).
Test Article: We propose modifying
the current definition of test article in
§ 58.3(b) to change ‘‘medical device for
human use’’ to ‘‘device’’ and to add
‘‘tobacco product’’. As discussed in
section III.B.1. concerning the scope of
part 58, we propose these changes to
broaden devices to include FDA’s CVM
and to include FDA’s jurisdiction of
tobacco products.
Test Site: We propose adding a
definition for test site to mean a
‘‘person’’ (currently defined in § 58.3(h))
responsible for a phase of a multisite
nonclinical laboratory study. We
propose that a test site includes
management with executive
responsibility and supporting SOPs for
the conduct of a nonclinical laboratory
study. For a different nonclinical
laboratory study, a test site could
function as a testing facility.
Test System: We propose modifying
the current definition of test system in
§ 58.3(i) to add ‘‘reference’’ article
consistent with our other proposed
changes. See elsewhere in section
III.B.2. for our proposed definition and
explanation for adding a definition of
reference article.
Testing Facility: We propose
removing and replacing most of the
current definition of testing facility in
current § 58.3(g) to update the
regulations consistent with the conduct
of multisite nonclinical laboratory
studies. Our proposed definition is as
follows: ‘‘Testing facility means a
person responsible for conducting,
coordinating, or completing a
nonclinical laboratory study, or any
combination thereof. The testing facility
designates the study director.’’
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We propose this change because, in a
multisite study, the testing facility
might not be the person treating the test
system with the test article as specified
in the current definition. Rather, the
person treating the test system with the
test article might be a contracted or
subcontracted person. Therefore, this
general definition of a testing facility is
necessary to capture all possible
contractual relationships in a multisite
study.
Validation: We propose adding a
definition for validation to mean
confirmation by examination and
provision of objective evidence that the
particular requirements for a specific
intended use of a system or process can
be consistently fulfilled. This proposed
definition is similar to the definition in
§ 820.3(z), and addresses comments to
the December 2010 ANPRM requesting
a definition for validation of a system or
process.
Vehicle: We propose adding a
definition for vehicle to mean any agent
that serves as a carrier and is used to
mix, disperse, or solubilize the test,
control, or reference article for
administration or application to the test
system. This proposal recognizes the
use of vehicles in the conduct of
nonclinical laboratory studies. Our
proposed definition is consistent with
the definition of vehicle in the OECD
GLP document, OECD Principles on
Good Laboratory Practice (Ref. 8), for
describing a carrier for test, control, or
reference articles.
3. Sponsor Responsibilities (§ 58.5)
The present regulations in § 58.10
cover only a sponsor’s responsibilities
to notify a consulting laboratory,
contractor, or grantee that their service
‘‘is part of a nonclinical laboratory study
that must be conducted in compliance
with the provisions of this part [part
58]’’. FDA received many comments to
the December 2010 ANPRM noting that
there are other sponsor responsibilities
implicit throughout the present
regulations, and stating that the study
sponsor must share in the responsibility
for complying with part 58. We agree
with those comments.
Therefore, we propose adding § 58.5
Sponsor responsibilities, that provides
explicit provisions for the presently
implied sponsor responsibilities and
adds new sponsor responsibilities. Our
proposed sponsor responsibilities are
consistent with the preamble to the
original GLP proposed rule stating that
the adequacy and validity of nonclinical
laboratory tests remain the
responsibility of the sponsor of the
product as part of establishing the
marketability of the product (41 FR
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51206 at 51206) (Ref. 4). In addition, we
propose adding provisions consistent
with the OECD advisory document, The
Role and Responsibilities of the Sponsor
in the Application of the Principles of
GLP (Ref. 9).
For each nonclinical laboratory study,
we propose that the sponsor must
ensure the study protocol meets the
requirements specified in § 58.120
(Protocol (see proposed § 58.5(a)
regulatory text, elsewhere in this
document). Also, we propose that the
sponsor must ensure the study protocol
provides for the humane care of
animals 6 (see proposed § 58.5(b)). We
propose these additions because the
sponsor is responsible for developing
the study protocol, either directly or
through a contracted person. To indicate
the sponsor’s approval of the study
protocol, we propose that the sponsor
must sign and date the study protocol
(see proposed § 58.5(c)).
For any phase of a nonclinical
laboratory study that includes the use of
animals, we propose that the sponsor
contract with persons accredited as
following appropriate animal welfare
procedures. If, for any reason, the
sponsor does not use an accredited
person for a phase that includes the use
of animals, we propose that the sponsor
must document the reason for using the
non-accredited person. (See proposed
§ 58.5(d).) If the study supports an
application or submission to FDA, we
propose requiring in the application or
submission the reason for using a nonaccredited person, along with
supporting information to show the
qualifications of that person, such as a
copy of SOPs showing the application of
current animal welfare laws,
regulations, policies, and guidelines.
This information must be included in
the compliance statement. (See
proposed § 58.5(d) and (k).) We are
proposing these requirements to help
ensure animal welfare concerns are
adequately addressed, and to help
safeguard the reliability of study results.
A sponsor may transfer to another
party responsibility for any or all of the
obligations set forth in this part. A party
that assumes any obligation of a sponsor
6 The document, ‘‘International Guiding
Principles for Biomedical Research Involving
Animals,’’ last revised in December 2012, advocates
among other principles, the ‘‘Three Rs’’ of the
ethical use of animals—replacement, refinement,
and reduction (Ref. 10). Additionally, the protocol
must meet the requirements in § 58.90 for animal
care. USDA’s Animal Welfare Act regulations (Code
of Federal Regulations, Title 9, Chapter1,
Subchapter A, Parts 1–4) and the Institute for
Laboratory Animal Research’s Guide for the Care
and Use of Laboratory Animals (Ref. 11), provide
specifics regarding the veterinary care expected
when animals are used for research.
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must comply with the specific
regulations in this chapter applicable to
this obligation and must be subject to
the same regulatory action as a sponsor
for failure to comply with any obligation
assumed under these regulations.
Although a sponsor might transfer
certain responsibilities, the sponsor is
still ultimately responsible for
compliance with all sponsor
responsibilities provided in this
chapter. When referring to the sponsor
throughout this proposal, we also mean
any person that assumes, as an
independent contractor with the
sponsor, one or more of the obligations
of a sponsor.
We propose that the sponsor must
document that the contracted person
conducting a phase of the nonclinical
laboratory study is qualified according
to the provisions in part 58 applicable
for the phase or phases that person is
contracted to perform. (See proposed
§ 58.5(e).) Using qualified contracted
persons is essential for ensuring GLP
compliance and the quality and
integrity of the resulting data.
We propose adding communication
requirements to sponsor
responsibilities. The OECD consensus
document, The Application of the OECD
Principles of GLP to the Organisation
and Management of Multi-Site Studies
(Ref. 6), states that many problems
associated with the conduct of multisite
studies ‘‘can be prevented by clear
allocation of responsibilities and
effective communication among all
parties involved in the conduct of the
study.’’ This includes the sponsor, study
director, management, principal
investigators, QAU, and all other study
personnel. Many comments to the
December 2010 ANPRM repeat this
opinion. We agree and propose that the
sponsor must ensure appropriate lines
of communication are established
(defined, documented in writing or
electronically, and implemented) among
all persons conducting any phase of the
nonclinical laboratory study. We also
propose that communications
established among persons conducting a
phase of the study that involve the
sponsor must be documented by the
sponsor. (See proposed § 58.5(f).)
We propose that the sponsor must
document that test, control, and
reference articles are prepared,
characterized, and labeled according to
part 58, subpart F, and are appropriately
shipped. In addition, the sponsor must
obtain, and provide to the study director
as soon as available, information about
test, control, and reference article
characterization as specified in § 58.105.
(See proposed § 58.5(g).) We propose
this requirement in § 58.5(g), because
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58351
the study director must have
characterization information to help
ensure appropriate dosing of the test
article and to interpret study results in
the final study report.
We propose that the sponsor inform
the study director of any known
potential risks of the test article to
human health or to the environment,
and any measures necessary to protect
study personnel. (See proposed
§ 58.5(h).) Since the sponsor is most
familiar with test article characteristics
because of either direct testing or
receiving results from a contracted
person that characterized the test article,
we propose this requirement as a
sponsor responsibility. If there are
known or suspected risks to human
health or the environment, it is essential
that the study director, as the single
point of study control, is aware of the
risks and the measures necessary to
protect study personnel and the
environment. This is consistent with
OECD’s advisory document, The Role
and Responsibilities of the Sponsor in
the Application of the Principles of GLP
(Ref. 9).
We propose that the sponsor must
review, approve, sign, and date each
protocol amendment before
implementation. (See proposed
§ 58.5(i).) Many comments to the
December 2010 ANPRM recommend
this requirement and we agree. After
initiating the study, the sponsor must be
aware of proposed study protocol
changes and why the changes are
proposed. This requirement is part of
our proposed checks and balances in
part 58 and will help ensure that the
amended protocol complies with GLP.
We propose that the sponsor must
document and update, as necessary, the
archive location of all raw data and
records described in proposed §§ 58.190
and 58.195. When we conduct BIMO
GLP inspections as a result of an
application or submission to FDA, we
rely on the sponsor to provide the
location of the study archives. (See
proposed § 58.5(j).)
We propose that the sponsor must
include, in any application or
submission to FDA that contains the
results of a nonclinical laboratory study,
the final study report of the nonclinical
laboratory study and all amendments to
the final report described in proposed
§ 58.185. Also, we propose that the
sponsor must include either a statement
that the study was conducted in
compliance with the requirements in
part 58 or, if not conducted in
compliance with part 58, a brief
statement of the reason for
noncompliance. (See proposed
§ 58.5(k)). We propose this requirement,
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consistent with the proposed expansion
of the scope, to include all applications
and submissions to FDA supported by
data from nonclinical laboratory studies.
4. Transfer of Responsibilities (§ 58.10)
We propose significant changes to
current § 58.10 to help address the
possibility of multiple contractual
relationships, including subcontracting,
in multisite nonclinical laboratory
studies, and to conform as much as
possible to the regulations in 21 CFR
312.52, Transfer of obligations to a
contract research organization, and 21
CFR 511.1(f), Contract research
organizations. Many comments to the
December 2010 ANPRM suggest that we
specify in part 58 the parties responsible
in a multisite study and how any
transfer of responsibilities is
accomplished. We agree with those
suggestions. We also propose the
changes because the current regulations
address explicitly only testing facilities.
We propose changing the title of
§ 58.10 from ‘‘Applicability to studies
performed under grants and contracts’’
to ‘‘Transfer of responsibilities’’ to
reflect the proposed changes to this
section. We also propose adding
paragraph designations (a), (b), and (c).
In § 58.10(a), we propose to require
written documentation of any transfer of
responsibilities to a ‘‘contracted
person’’, as that term is proposed in
§ 58.3, referring to any person a sponsor
utilizes to provide a service for the
conduct of a nonclinical laboratory
study. Contracted persons may, for
example, serve as the study director,
management with executive
responsibility, the QAU, a testing
facility, a test site, or an independent
contributing scientist. These contracted
persons may further contract with other
individuals or entities. Specifically, we
propose that any responsibility required
by the regulations that is transferred
must be described in writing, and that
any responsibility not covered by the
written description is considered not
transferred.
We propose to add in § 58.10(b) that
any person transferring to a contracted
person any regulatory responsibility for
a phase of a nonclinical laboratory study
must inform that contracted person that
the transferred responsibility is required
to be performed in compliance with the
provisions in part 58. Proposed
paragraph (b) therefore includes what is
currently in § 58.10.
In § 58.10(c), we propose adding that
a contracted person assuming any
regulatory responsibility for a phase of
a nonclinical laboratory study must
comply with the regulations in chapter
I (21 CFR chapter I) applicable to the
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transferred responsibility. That
contracted person will be subject to the
same regulatory requirements as those
regulated persons transferring the
responsibility.
We propose these requirements for
transfer of responsibilities in a
nonclinical laboratory study to help
ensure contracted persons perform any
transferred responsibilities in
compliance with part 58 and to help
ensure the quality and integrity of data
supporting applications and
submissions to FDA. Also, our proposal
is consistent with industry’s desire for
flexible relationships among persons
conducting phases of a nonclinical
laboratory study.
5. Inspection of Any Person Conducting
a Phase of a Nonclinical Laboratory
Study (§ 58.15)
We propose revising § 58.15 to clarify
FDA’s inspection authority to include
inspecting any person that conducts a
phase of a nonclinical laboratory study
of an FDA-regulated product. This
includes all contracted and
subcontracted persons that agree to
assume one or more regulatory
responsibilities. We propose revising
the heading of § 58.15 to be consistent
with these proposed changes.
Also, we propose modifying the
provision about FDA inspection of QAU
records. In the preamble to the original
GLP final rule (43 FR 59986 at 59998,
December 22, 1978) (Ref. 12) and
repeated in FDA’s compliance policy
guide (CPG 7151.02) (Ref. 13), we state
our policy that FDA investigators will
not routinely inspect QAU records.
Exceptions when FDA will inspect QAU
records include ‘‘for cause’’ FDA
inspections, or inspections conducted
under an inspection warrant, or when
necessary for litigation purposes.
Therefore, we propose modifying
§ 58.15(a) to specifically state that the
‘‘records inspection and copying
requirements do not routinely apply to
QAU records of findings and problems,
or to actions recommended and taken’’.
We propose adding for clarity, that
‘‘FDA retains the authority to inspect all
QAU records when necessary to ensure
compliance with this part [part 58]’’.
In § 58.15(b), we propose changing
certain terms for consistency within this
proposal. For example, we propose
changing ‘‘the testing facility’’ to ‘‘any
person conducting a phase of the
nonclinical laboratory study’’.
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C. Part 58, Subpart B—Organization
and Personnel
1. Personnel (§ 58.29)
We propose no changes to the intent
of current § 58.29(a). However, we
propose adding to the end of this
provision clarifying sentences, ‘‘This
must include training and experience
with GLP requirements. Personnel who
work with animals must have both
general and species-specific training
and experience.’’
Several comments to the December
2010 ANPRM state that training on GLP
requirements is essential for all
personnel in a nonclinical laboratory
study. This proposed training
requirement also is consistent with the
personnel requirements in the OECD
Principles on Good Laboratory Practice
(Ref. 8). Therefore, we propose requiring
GLP training to ensure all personnel in
a nonclinical laboratory study
understand how to comply with GLP
and all aspects of a nonclinical
laboratory study are GLP compliant.
As we state elsewhere in section
III.A.3., we propose specific
responsibilities regarding animal
welfare because compliance with
animal care requirements helps ensure
the quality and integrity of study data.
Therefore, we propose that all personnel
involved with animal treatment and
care must have relevant training and
experience, including species-specific
training when applicable.
In § 58.29(b), we propose adding a
requirement that all study personnel
must have access to and comply with
the study protocol and applicable
protocol amendments and SOPs, and
any protocol deviation must be reported
to the study director. In § 58.29(c), we
propose adding a requirement that all
study personnel must record raw data
promptly and accurately as required by
a new regulatory provision in § 58.180
Data quality and integrity. We propose
these new provisions to help ensure
compliance with GLPs and to update
the regulations consistent with current
practices and the prevalence of multisite
studies. This proposal also is consistent
with personnel responsibilities in the
OECD Principles on Good Laboratory
Practice (Ref. 8).
In proposed § 58.29(d) (currently,
§ 58.29(b)), we replace ‘‘Each testing
facility’’ with ‘‘Any person conducting a
phase of a nonclinical laboratory
study’’. We propose this and other
conforming changes in § 58.29 to
address the occurrence of contracting
and subcontracting in multisite studies,
to update the regulations, and for
consistency with our proposals in part
58.
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2. Testing Facility Management With
Executive Responsibility (§ 58.31)
We propose significant changes in
§ 58.31 consistent with our proposal
requiring a GLP Quality System. To
clarify who is responsible for the
proposed requirements in § 58.31, we
propose adding ‘‘with executive
responsibility’’ to the current heading of
‘‘Testing facility management.’’ We
propose this change to specify that
upper management at a testing facility
or test site is ultimately responsible for
GLP compliance. We also propose
summarizing in the introductory
paragraph the expanded responsibilities
of management consistent with the
regulatory text in part 820 (see § 820.20).
The current provisions in § 58.31(c)
through (g) require only assurances that
certain activities are available,
performed, understood, or
communicated. For those
responsibilities currently in § 58.31, we
propose clarifying and expanding them,
requiring actions and referencing
specific SOPs (where applicable). We
also propose adding new
responsibilities consistent with a GLP
Quality System and the conduct of
multisite studies.
We propose a new § 58.31(a) requiring
testing facility management with
executive responsibility to establish and
update written GLP Quality System
SOPs. For continuing oversight of the
GLP Quality System, in new § 58.31(b),
we propose requiring testing facility
management with executive
responsibility to review at specified and
sufficient intervals and document that
the GLP Quality System meets the
requirements in proposed part 58. We
propose that testing facility management
with executive responsibility is
responsible for overseeing the
implementation of the requirements in
proposed § 58.31(b), according to
established procedures to be included in
proposed § 58.81(b)(2) (establishment
and periodic review of a GLP Quality
System).
In § 58.31(e), we propose that testing
facility management with executive
responsibility appoint and document
the appointment of a management
representative who is a member of the
testing facility management with
authority over and responsibility for
documenting that GLP Quality System
requirements are effectively established
and maintained. We also propose that
this appointed member reports to
management with executive
responsibility about the performance of
the GLP Quality System, which includes
reports from the QAU. Appointment of
this individual is an organizational
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responsibility of the testing facility
management with executive
responsibility such as in part 820,
Quality System Regulation, the model
for the GLP Quality System.
In § 58.31(f), we propose that testing
facility management with executive
responsibility is responsible for
documenting that all persons in a
multisite study follow adequate
equipment-related SOPs. In § 58.31(h),
we propose this same management is
responsible for documenting that all
study personnel are trained to perform
their assigned functions. In § 58.31(k),
we propose this same management is
responsible for appointing a person to
maintain the master schedule along
with other requirements concerning the
master schedule, such as requiring in a
master schedule the core information
presently specified under QAU
responsibilities in § 58.35(b)(1). This
core information is essential on each
master schedule to ensure consistent
identification across all persons
(individuals or entities) in a multisite
study. We propose adding § 58.31(m),
requiring testing facility management
with executive responsibility to review
all protocols to ensure that
environmental, animal welfare, or work
resource issues or issues with scientific
methodology do not affect or bias any
phase of the study’s conduct.
We propose adding § 58.31(r) to
require testing facility management with
executive responsibility to review the
suitability and effectiveness of the QAU
or lead QAU, as applicable, at defined
intervals and with sufficient frequency,
according to established SOPs as
required in proposed § 58.81(b)(17).
Periodic review of the QAU’s capability
to fulfill their responsibilities helps to
ensure the quality and integrity of study
data and is also consistent with a
quality system.
We propose adding § 58.31(u),
requiring testing facility management
with executive responsibility to
establish SOPs for archiving records and
materials generated during the course of
a nonclinical laboratory study,
including the designation and
replacement of the archivist and any
supporting staff. This archiving process
is an essential aspect of compliance
with GLPs because maintenance of raw
data and specimens from a specific
study enables reconstruction of that
study for verification of the information
in the final study report and
confirmation of the study’s compliance
with part 58.
These and other proposals in § 58.31
are consistent with the preamble to the
original GLP final rule that states, ‘‘A
determination of the adequacy of each
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58353
standard operating procedure is the
responsibility of the management’’ (43
FR 59986 at 60002) (Ref. 12). Also, our
proposals are responsive to many
comments to the December 2010
ANPRM asking that we define
operational areas necessary for broader
adoption of a quality system approach
to the conduct of nonclinical laboratory
studies.
Rather than specifying how essential
activities of a GLP Quality System must
be conducted, we propose requiring
management with executive
responsibility at testing facilities and
test sites to establish essential SOPs.
This flexible approach would allow
testing facilities and test sites to
establish SOPs best suited to their
specific organizational structure.
3. Test Site Management With Executive
Responsibility (§ 58.32)
We propose updating the regulations
by adding § 58.32. This new provision
would address the current prevalence of
multisite studies and require test site
management with executive
responsibility to comply with relevant
requirements in proposed § 58.31 and
develop and maintain SOPs described
in § 58.81, ‘‘where appropriate’’, as that
term is proposed in § 58.1(c).
We expect that a test site, like a
testing facility, has management with
executive responsibility and appropriate
SOPs. Therefore, while a test site might
be conducting a phase of a particular
multisite study, for a different study the
same test site could function as a testing
facility by coordinating, conducting, or
completing the entire study.
4. Study Director (§ 58.33)
In § 58.33, we propose modifying and
adding study director requirements to
update the regulations and to address
the prevalence of multisite studies. We
propose certain study director
requirements for consistency with our
other proposals in part 58 (for example,
our proposals for a GLP Quality System
and for checks and balances to help
ensure data quality and integrity).
In § 58.33(a), we propose keeping the
current requirement that the study
director is the single point of study
control. We propose adding that the
study director cannot delegate overall
responsibility for a nonclinical
laboratory study. This proposed
addition clarifies and emphasizes that a
study director cannot delegate oversight
of an entire nonclinical laboratory
study, even though a study director may
delegate to a principal investigator
certain responsibilities.
This proposed change is consistent
with FDA’s longstanding interpretation
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of a study director’s responsibilities and
consistent with present FDA and EPA
GLP regulations. This proposed addition
also is consistent with the OECD
consensus document, The Role and
Responsibilities of the Study Director in
GLP Studies (Ref. 14). Many comments
to the December 2010 ANPRM stress the
importance of the study director
remaining the single point of study
control.
We propose in § 58.33(a)(2) the study
director’s responsibility for
implementing procedures that ensure
adequate communication among all
study personnel and with the sponsor,
as applicable, because communication
is essential in a nonclinical laboratory
study.
In § 58.33(b), we propose new
requirements for the study director for
documenting, consulting, signing, and
archiving (see proposed §§ 58.33(b)(2)
through (7) and (12) through (14)). In
§ 58.33(b)(13), we propose that the study
director must sign and date the final
study report. FDA agrees with OECD’s
discussion in this regard in both the
OECD Principles on Good Laboratory
Practice (Ref. 8) and the consensus
document, The Role and
Responsibilities of the Study Director in
GLP Studies (Ref. 14). The study
director’s signature on the final study
report indicates acceptance of
responsibility for the validity of the data
and the extent to which the study
complies with GLP principles. We also
recognize that we use the terms retain
and archive interchangeably throughout
this proposal (see, for example,
proposed § 58.33(b)(14)), and we seek
comment on which term is preferred by
industry.
We propose adding in § 58.33(b)(5)
and (6) new study director
responsibilities affecting the welfare of
test animals. When a protocol and its
amendments impact test animal use, we
propose the study director must
document that a committee whose
function is ensuring the appropriate and
humane care of animals must first
review and approve the protocol and
applicable amendments before initiating
the study or implementing the
amendments. The study director also
must document that such a committee
has reviewed and approved general
procedures for commonly conducted
animal tests. Any protocol requiring
only those tests, with their approved
parameters, would not require
additional review before study
initiation. However, if a protocol
increases the numbers of animals to be
used or alters any of the approved
testing parameters, specific review and
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approval of that protocol would be
required before study initiation.
We propose in 58.35(b)(6), that the
study director must consult with the
attending veterinarian during review of
proposed study protocols to determine
potential animal welfare concerns and
appropriate responses to likely
contingencies. Early identification of
potential animal welfare concerns
benefits the test animals because they
will receive prompt care, which
improves the quality of the data
collected.
In 58.33(b)(11), we propose adding
that the study director must document
that all applicable GLP regulations are
followed and include a study
compliance statement in the final study
report. FDA agrees with the statement in
the OECD consensus document, The
Role and Responsibilities of the Study
Director in GLP Studies (Ref. 14) that the
study director should ascertain that GLP
requirements are fully complied with in
every phase of a study, that the study
protocol is faithfully followed, and that
all observations, including any
deviations from the protocol, are fully
documented.
In § 58.33(b)(14), we propose adding a
timeframe for archiving of no later than
2 weeks after the study completion date.
We think that timely archiving of raw
data, documents, protocols, specimens,
and final reports will help prevent their
loss or destruction. Stakeholders
requesting modernizing part 58 asked
specifically for a reasonable time period
after the study completion date to
complete study archiving. Numerous
comments to the December 2010
ANPRM agree, particularly with regard
to archiving computerized systems. We
propose the 2-week timeframe to allow
flexibility for archiving material without
jeopardizing study material integrity.
5. Quality Assurance Unit (QAU)
(§ 58.35)
In § 58.35, we propose keeping the
QAU functions currently in the
regulations. We propose modifying
§ 58.35(a) by separating it into
paragraph (1) QAU function and
paragraph (2) QAU location. We
propose this change for consistency
with our other proposals in part 58 (for
example, to address the location of the
lead QAU for multisite studies), and in
response to comments to the December
2010 ANPRM requesting a clear
description of the relationship between
the QAU and testing facility
management.
We propose in § 58.35(a)(2)(ii) that,
for multisite studies, testing facility
management with executive
responsibility must designate a lead
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QAU. The concept of a lead QAU is
consistent with the discussion in the
preamble of the original GLP final rule
stating that when portions of a study
must be contracted to a site that lacks
a QAU ‘‘the person letting the contract,
and not the contract facility, is
responsible for the performance of the
quality assurance functions’’ (43 FR
59986 at 59997) (Ref. 12). This change
also is consistent with the OECD
consensus document, Quality
Assurance and GLP (Ref. 7). Several
comments to the December 2010
ANPRM specifically note the need for a
lead QAU in multisite studies.
We propose several modifications to
current § 58.35(b). We propose changing
the present QAU requirement to
maintain a copy of the master schedule
and all protocols to require that the
QAU maintain ‘‘access’’ to them. For
example, if the QAU is a contracted
person, then the QAU might not have
overall knowledge about the person (i.e.,
testing facility) to which they are
providing QA services. However, the
QAU requires ‘‘access’’ to the master
schedule and protocols to ensure GLP
compliance.
We recognize that many sites have a
central computerized system for
maintenance of essential documents.
Our proposed change about QAU access
to the master schedule responds to
stakeholder requests to modernize part
58 and also to comments to the
December 2010 ANPRM. This change
also is consistent with our proposal in
§ 58.195(d) that management with
executive responsibility must ensure
‘‘maintenance’’ of the master schedule
and copies of study protocols.
Because the lead QAU is responsible
for ensuring GLP compliance of all
phases of a multisite study, we propose
that the lead QAU must maintain access
to the master schedule of any person
that lacks a QAU. We consider the
master schedule an important tool for
determining whether a person is capable
of conducting a GLP compliant study.
For example, a person with numerous
scheduled studies still in progress may
lack sufficient resources to begin the
conduct of a GLP compliant study.
Also, as many comments to the
December 2010 ANPRM suggest, we
propose removing the word ‘‘sheet’’
from the term ‘‘master schedule sheet’’.
We propose removing ‘‘sheet’’ because
we do not want to imply that a paper
copy is required for electronic systems.
In new § 58.35(b)(3), we propose
requiring the QAU to review the study
protocol before initiating the study and
all protocol amendments before
implementing them, along with
documenting this review. In new
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§ 58.35(b)(4), we propose requiring the
QAU to review all SOPs applicable to a
given nonclinical laboratory study along
with documenting this review. Current
regulations state the QAU is
‘‘responsible for monitoring each study
to assure management that the facilities,
equipment, personnel, methods,
practices, records, and controls are in
conformance’’ with GLPs (current
§ 58.35(a)).
Our proposed initial review by the
QAU of the study protocol and
applicable facility SOPs will help
ensure compliance with part 58 from
the start of the study. Otherwise, when
the study is underway, amendments to
the study protocol and SOPs might be
needed if QAU inspections reveal
compliance deficiencies.
We propose in § 58.35(b)(5)
expanding the types of QAU inspections
recognized by FDA by adding processbased and facility-based inspections.7
Many comments to the December 2010
ANPRM request this change consistent
with QAU inspections described in the
OECD consensus document, Quality
Assurance and GLP (Ref. 7), specifically
supporting an appropriate mix of studyspecific and process-based inspections.
However, many comments to the
December 2010 ANPRM express
concern about how process-based
inspection results will be appropriately
considered for all relevant studies,
particularly when an inspection reveals
problems. This concern is especially
relevant to any phase involving a shortterm study, as we propose to define this
term. Process-based inspections are
conducted on a prearranged schedule,
which is not connected to the timing of
any particular nonclinical laboratory
study. Therefore, a facility utilizing
process-based inspections might
conduct a short-term study that is not
inspected during its in-life period (that
is, during the time data are collected).
This concern also is addressed in the
OECD consensus document, The
Application of the GLP Principles to
Short Term Studies (Ref. 15).
To ensure that any problem revealed
during a process-based inspection is
properly captured in the reports of all
relevant studies, we propose adding
§ 58.35(e). This provision requires
preparation of a written certification, by
the person conducting a phase of the
study, whenever a process-based
inspection reveals problems. As
proposed, this certification requires
documenting actions taken to properly
7 The term ‘‘study-based inspection’’ is not used
in current FDA regulations; however, this type of
inspection is equivalent to the QAU inspection
currently required in part 58.
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inform, and modify (when applicable),
reports for all studies impacted by the
results of that process or procedure.
While a management responsibility, we
propose adding this requirement in
§ 58.35 because of its similarity to the
existing requirement in current
§ 58.35(d) for management to provide an
FDA representative, upon request, a
certification regarding the
implementation of required QAU
inspections.
In § 58.35(b)(7) (a redesignation and
revision of current § 58.35(b)(4)), we
propose expanding the requirement that
the QAU must submit to management
with executive responsibility and the
study director a periodic written status
report on each study. We propose that
these periodic reports ‘‘discuss the
overall progress and compliance status
of the study and include any problems
observed and the corrective actions
taken.’’ In conjunction with this
requirement, we propose that the
content and frequency of these reports
be specified in SOPs as required in
proposed § 58.81(b)(21).
We propose this revision in
§ 58.35(b)(7) because feedback to
management with executive
responsibility and the study director
about the overall progress and
compliance status of the study is
essential to ensure study compliance.
We intend these periodic reports to give
a general overview of the study. We
expect these periodic reports to
complement any inspection reports for
the study, which only provide a
snapshot in time.
We are interested in receiving
feedback about the use and relevance of
periodic status reports. Specifically, we
are seeking comment about whether
QAUs regularly provide such reports
and whether they are useful to the study
director and management when
provided.
Consistent with our proposals
addressing multisite studies, we
propose adding in new § 58.35(b)(8)
(revision of current § 58.35(b)(5)) that
the lead QAU must identify all
deviations occurring in the entire study,
including deviations identified by any
other existing QAUs participating in the
study. We expect this requirement may
be facilitated by principal investigator
reports to the study director,
documentation by other existing QAUs,
and direct oversight by the lead QAU of
independent contributing scientists and
any persons conducting a phase of the
study lacking either a principal
investigator or a QAU or both. We
propose this requirement to ensure the
lead QAU is made aware of protocol
deviations in a timely manner. This
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awareness will help alert the lead QAU
to the need to correct or modify relevant
SOPs and the study protocol when
necessary to maintain data integrity.
The remaining additions we propose
in § 58.35 relate to QAU oversight of the
integrity of data in the final study
report. Current responsibilities in
§ 58.35(b)(6) (revised and redesignated
as § 58.35(b)(10)) are to ensure the
quality and integrity of the final study
report. Therefore, we propose in
§ 58.35(b)(9)that the QAU must audit
the reports of all contributing scientists
and all existing principal investigators.
Currently § 58.35(b)(6) requires the
QAU to assure that the ‘‘reported results
accurately reflect the raw data of the
nonclinical laboratory study.’’ However,
QAU members might not have the
scientific judgment needed for
evaluating the scientific merits of the
final report and determining whether
the results accurately reflect the data. In
the preamble to the original GLP final
rule (43 FR 59986 at 59998, comment
90) (Ref. 12), we agreed that ‘‘the QAU
should not attempt to evaluate the
scientific merits of the final report.’’
Therefore, in § 58.35(b)(9) and (10), we
propose clarifying our intent.
Specifically, we propose that the QAU
must audit all contributing scientists’
reports and any report amendments to
ensure they include a report of all data
and reflect the protocol, and
amendments, and applicable SOPs. This
requires that all data generated during
the study are included and discussed,
which is essential for the full
transparency necessary for
reconstruction of the study.
For multisite studies, we propose that
other QAUs participating in the study
must audit the reports and report
amendments of any principal
investigators and all contributing
scientists for whom they are
responsible. We also propose in
§ 58.35(b)(9), for any person that lacks a
QAU, that the lead QAU audits the
reports and amendments of all
contributing scientists and any principal
investigators. This includes audits of
any independent contributing scientist.
This proposed requirement will ensure
all data from a nonclinical laboratory
study will receive QAU review, thus
improving the quality and integrity of
the final study report.
In § 58.35(b)(10), we propose that the
QAU must verify that all original and
amended signed and dated reports from
contributing scientists are appended to
the final study report. For multisite
studies, we propose that the lead QAU
is responsible for this requirement.
Under existing regulations that require
providing the final study report and any
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amendments, we expect that both
original and amended versions of
reports from all contributing scientists
be appended to the final study report.
The proposed changes make this
expectation a specific requirement. This
requirement will allow the study
sponsor and FDA reviewers to have
access to the original conclusions for
each phase and any modifications made
as a result of interactions among those
involved with the study. We propose
this requirement to address the potential
inadvertent or intentional introduction
of bias that may result when only the
final amended version of contributing
scientists’ reports are included.
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6. Contributing Scientist (§ 58.37)
As discussed in section III.B.2., we
propose adding a definition for a
contributing scientist. In that definition,
we include an independent contributing
scientist as an individual expert or
specialist who is an independently
employed contracted person. We
propose adding responsibilities for
contributing and independent
contributing scientists to help facilitate
the development of a GLP Quality
System. To describe the responsibilities
of these positions, we propose adding
§ 58.37(a) and (b), respectively.
When a contributing scientist is
responsible for a phase, we propose in
§ 58.37(a) that the contributing scientist
must comply with part 58; provide a
signed and dated report for inclusion in
the final study report; and permit
oversight by the designated QAU. (See
proposed § 58.37(a)(1) through (3)).
In § 58.37(b), we propose
requirements for an independent
contributing scientist in addition to
those requirements in § 58.37(a). The
proposed requirements in § 58.37(b)
include, among others, that independent
contributing scientists must document,
maintain, and update information about
their education, training, and
experience related to their
responsibilities for a particular phase.
Also, we propose they must archive all
materials as required by the protocol
and by proposed § 58.195.
Our proposal for adding § 58.37 is
consistent with the expectations in the
present regulations for individual
scientists and professionals. We propose
these requirements in part to help
clarify the regulations.
7. Principal Investigator (§ 58.39)
We propose adding § 58.39 to include
principal investigator requirements
related to a principal investigator’s
responsibilities for a phase of a
nonclinical laboratory study. We
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propose that designating a principal
investigator is optional.
The OECD Principles on Good
Laboratory Practice (Ref. 8) includes the
term principal investigator solely in
reference to multisite studies. We
recognize, however, the possibility of a
testing facility employing a principal
investigator for a single-site study. For
example, a single-site study conducted
in a facility situated on a large campus
with multiple buildings might have one
or more principal investigators.
We also recognize that a testing
facility may conduct a multisite study
where, at all sites, only the study
director oversees the study. Several
comments to the December 2010
ANPRM note these various practices.
We therefore propose in § 58.39
principal investigator requirements for
specific responsibilities in one or more
phases as delegated to the principal
investigator by the study director.
We propose principal investigator
responsibilities consistent with a
principal investigator’s role of ensuring
compliance with part 58 for a specific
phase. For example, we propose the
principal investigator must document
and report to the study director all
deviations the principal investigator
observes during the conduct of the
study. These requirements also are
consistent with the responsibilities of a
principal investigator in The
Application of the OECD Principles of
GLP to the Organisation and
Management of Multi-Site Studies (Ref.
6), and with a GLP Quality System.
articles’’ for consistency with our other
proposals.
D. Part 58, Subpart C—Facilities
1. Standard Operating Procedures
(SOPs) (§ 58.81)
1. General (§ 58.41)
In § 58.41, we propose changing
‘‘Each testing facility shall be’’ to ‘‘Any
person conducting a phase of a
nonclinical laboratory study must have
facilities’’ of suitable size and
construction to facilitate the proper
conduct of nonclinical laboratory
studies. We propose this change to
include multisite studies.
2. Animal Care Facilities (§ 58.43)
In § 58.43, we propose changes to
include multisite studies and to cover
any phase involving the use of animals.
We propose these changes consistent
with our proposal revising the testing
facility definition and our goal of
applying the GLP regulations to all
nonclinical laboratory studies,
including multisite studies.
3. Facilities for Handling Test, Control,
and Reference Articles (§ 58.47)
In § 58.47 we propose adding
‘‘reference’’ to refer to ‘‘reference
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E. Part 58, Subpart D—Equipment
1. Equipment Design (§ 58.61)
In § 58.61, we propose adding that
equipment includes computerized
systems. We also propose adding in
§ 58.61, equipment used for
maintenance, archiving, and retrieval of
data. We propose these additions to
update and clarify the regulations.
2. Maintenance and Calibration of
Equipment (§ 58.63)
In § 58.63, we propose adding to
paragraph (a) maintenance, archiving,
and retrieval of data. In paragraph (b),
we propose changing the citation
reference from § 58.81(b)(11) to (14) and
adding a reference to the written SOP
requirement in § 58.81(b)(15). Also, in
paragraph (b), we propose adding ‘‘as
applicable’’ to address the possibility of
a multisite study. We propose these
changes for consistency with our other
proposed changes in part 58 and to
update the regulations to address
multisite studies.
F. Part 58, Subpart E—Nonclinical
Laboratory Study Operations
Consistent with our proposals in part
58 to address multisite studies, we
propose revising the heading of subpart
E from ‘‘Testing Facilities Operation’’ to
‘‘Nonclinical Laboratory Study
Operations’’. Also, accordingly, we
propose modifying the sections in
subpart E.
We propose modifying § 58.81
Standard operating procedures (SOPs),
consistent with our proposals for a GLP
Quality System and to address multisite
studies. In § 58.81(a), we propose
adding to the current requirement that
a testing facility must have written
SOPs, that all test sites, too, must have
written SOPs. Also, in § 58.81(a), we
propose changing ‘‘management’’ to
‘‘management with executive
responsibility’’.
In § 58.81(b), consistent with our
proposal in § 58.81(a), we propose
adding that the testing facility and all
test sites must establish SOPs for an
applicable phase of a nonclinical
laboratory study. As discussed in
section III.B.1., we use the terms
‘‘applicable phases’’ and ‘‘where
appropriate’’ because in a multisite
study no one person will conduct all
phases of the study. Therefore, each
person requires SOPs only for those
phases which that person conducts.
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We propose adding to the current list
of SOPs in § 58.81(b) numerous topics
that require SOPs. For example, we
propose adding that SOPs must include
an SOP for preparing, modifying, and
administering all SOPs. We propose
these additional SOP requirements
because they are essential components
of a complete quality system approach
(i.e., the proposed GLP Quality System)
and also address the current prevalence
of multisite studies.
Our proposal in § 58.81 will require
initial efforts by testing facilities and
test sites to modify or add SOPs as
needed for a GLP Quality System.
However, once established, the GLP
Quality System will facilitate greater
flexibility and efficiency for the conduct
of nonclinical laboratory studies and,
over time, will help reduce costs.
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2. Animal Care (§ 58.90)
In § 58.90, we propose modifying
paragraph (b) to require, throughout the
study, evaluation of the health status of
test animals according to acceptable
veterinary medical practices for the care
of test animals. We propose this change
because proper animal care is essential
during the entire study to ensure the
welfare of test animals and the integrity
of test results. However, test animal
evaluations can be performed by the
attending veterinarian or appropriatelytrained personnel who are delegated
this responsibility by the attending
veterinarian.
In § 58.90(c), we propose removing
from the third sentence the phrase
‘‘provided that such treatment does not
interfere with the study’’, and replacing
this phrase with ‘‘as deemed necessary
by the study’s attending veterinarian.’’
We propose few changes in § 58.90(d)
and (e). In the first sentence of current
§ 58.90(d), we propose replacing
‘‘excluding suckling rodents’’ with
‘‘except nursing neonates’’ to update the
regulation to be more inclusive and
appropriate. In § 58.90(e), we propose
adding the word ‘‘reference’’ to conform
to changes proposed elsewhere in this
document.
We propose these changes in § 58.90
to update and clarify the regulations,
and because test animal welfare
concerns are an essential part of a GLP
Quality System.
G. Part 58, Subpart F—Test, Control,
and Reference Articles
We propose adding the term
‘‘Reference’’ to the heading in subpart F,
and in certain applicable provisions in
subpart F. We also propose adding in
subpart F specifics concerning tobacco
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products, and a reference to method
validation.8
1. Test, Control, and Reference Article
Characterization (§ 58.105)
We propose modifying § 58.105 to
require that all information about test,
control, and reference article
characterization be provided to the
study director as soon as available. This
information is necessary for determining
appropriate dosing and drafting
conclusions in the final study report.
The lack of this information limits the
important test result discussion in the
final study report.
Reports submitted to FDA must
provide study information based on the
characteristics of the product (test
article) studied. We expect a test article
to be characterized to the extent
required to interpret the study properly.
For nonclinical laboratory studies
conducted in support of initiating
clinical ‘‘first-in-human’’ studies, this
characterization information is
particularly important for human
subject protection.
We propose modification of
§ 58.105(a) to exclude the use of a
marketed tobacco product’s labeling to
characterize such a product if it is used
as a control or reference article in a
nonclinical laboratory study. The
labeling of currently marketed tobacco
products does not provide the
information required for full product
characterization. That is, the chemical
composition (including mainstream
smoke composition), microbiological
composition, and design parameters of
the product are not fully described in
tobacco product labels. Thus, the
composition and toxicant deliveries of
currently marketed tobacco products are
less well defined in tobacco product
labeling than the safety and efficacy
information described in the labels of
marketed drug products. Therefore, FDA
notes that when using a marketed
tobacco product as a control or reference
article, the marketed tobacco product’s
characteristics must be determined and
documented as required in this part.
We propose revising and
redesignating the current provisions in
§ 58.105(b), (c), and (d). These proposed
changes are necessary for consistency
with our other proposals in part 58,
such as the addition of reference
articles.
8 There is a draft guidance document regarding
bioanalytical method validation, ‘‘Bioanalytical
Method Validation Draft Guidance’’ (Ref. 16). When
final, this guidance will provide FDA’s current
thinking. We consider many of the general
principles in this draft guidance document
applicable to method validation in nonclinical
laboratory studies.
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The current regulations imply that
empty containers from test articles must
be retained. Comments to the December
2010 ANPRM did not see the need to
retain the empty containers provided
appropriate product information is
maintained and test article
accountability is fully documented. We
agree with those comments and propose
to remove this implied requirement. To
provide for adequate test article
accountability, in lieu of retaining
empty test article containers, we
propose requiring in § 58.105(d) that the
study director verify and document by
dated signature the distribution and
final disposition of the test article.
2. Test, Control, and Reference Article
Handling (§ 58.107)
We propose minimal conforming
changes in § 58.107, such as adding
‘‘reference’’ to the section heading and
first sentence.
3. Mixtures of Articles with Carriers
(§ 58.113)
We propose modifying § 58.113 by
adding ‘‘reference’’ to the provisions
proposed in § 58.113(a), (a)(1), (a)(2),
(b)(2), and (d). Also, we propose
requiring that the results from the
determination of the uniformity,
concentration, and stability of mixtures
of test articles with carriers are provided
to the study director as soon as
available. We propose these changes in
§ 58.113 for the same reasons we
propose changes in § 58.105.
H. Part 58, Subpart G—Protocol for and
Conduct of a Nonclinical Laboratory
Study
1. Protocol (§ 58.120)
We propose modifying § 58.120 to
address multisite studies more
specifically, and to provide consistency
with our other proposed changes
discussed elsewhere.
Many comments to the December
2010 ANPRM suggest that the study
protocol identify all sites participating
in a multisite study. We agree, and
propose adding in § 58.120(a)(3) that the
protocol contain contact information for
all persons conducting a phase of the
nonclinical laboratory study.
Current § 58.120(a)(6) includes in the
protocol the methods for controlling
bias. We propose adding to this
provision the analysis and reporting of
study test results and procedures to be
followed if a study includes a peer
review of any phase. Also, for multisite
studies, we propose adding a
requirement that the protocol identify
the person(s) conducting the phases of
the nonclinical laboratory study.
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We propose expanding current
§ 58.120(a)(10) to clarify that the
protocol must include a listing of the
study-specific records that are required
to be maintained. We think this
clarification will help assure that studyspecific records are maintained.
Current § 58.120(a)(11) requires the
date of protocol approval by the
sponsor, and the dated signature of the
study director. We propose expanding
this provision to indicate study protocol
approval by the dated signature of the
study sponsor, the study director,
independent contributing scientists,
principal investigators, and any other
person conducting a phase of the
nonclinical laboratory study, as
applicable.
We propose redesignating and
modifying § 58.120(b) as § 58.120(d). In
§ 58.120(d), we propose requiring,
before implementing any change or
revision to an approved protocol, that
the study sponsor and the study director
document their approval of the change
or revision. For a multisite study, any
person affected by the proposed changes
(for example, the principal investigator
or independent contributing scientist)
also must document approval. We
consider a person’s dated signature on
the protocol revision to be acceptable
documentation indicating approval. We
propose that these signed and dated
protocol amendments must be
maintained with the protocol.
Before initiating any study using
animals, we propose requiring in new
§ 58.120(b) protocol review and
approval by ‘‘a committee whose
function is to ensure that the care and
use of animals in studies is appropriate
and humane’’. In new § 58.120(e), we
propose the same review and approval
by this committee before implementing
any protocol changes that affect animal
welfare. These additions are consistent
with the proposal in § 58.33(b)(5) that
the study director must ensure that all
studies that include the use of animals
are approved by such a committee.
In new § 58.120(c), we propose
requiring that the study sponsor and
testing facility management with
executive responsibility sign and date a
statement that the study will be
conducted in compliance with part 58.
We propose appending this statement to
the protocol. This proposal is consistent
with the requirement in § 58.10(b) that
a sponsor must inform a contracted
person that the study must be
conducted in compliance with chapter I.
This proposal also is consistent with the
requirements discussed elsewhere in
this document that the study director
documents applicable GLP regulations
are followed (section III.C.4.), and that
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the QAU ensures studies conform to the
regulations in part 58 (section III.C.5.).
I. Part 58, Subpart J—Records and
Reports
2. Conduct of a Nonclinical Laboratory
Study (§ 58.130)
1. Data Quality and Integrity (§ 58.180)
We propose adding a new § 58.180 for
data quality and integrity. Ensuring data
quality and integrity in a nonclinical
laboratory study is one of our critical
goals in this part 58 proposal. Therefore,
we propose adding this separate
§ 58.180 to clearly identify requirements
for data quality and integrity. We
propose this new section in subpart J
because data are part of study records
and reports.
We propose moving to this new
section, and revising, the requirements
in current § 58.130(e). In § 58.180(a), we
propose creating the acronym
‘‘ALCOA’’. This is a mnemonic that
signifies quality data to stakeholders
that conduct clinical and nonclinical
studies. We propose therefore that all
nonclinical laboratory study data are
‘‘accurate, legible, contemporaneous,
original, and attributable’’.
In § 58.180(b), we propose modifying
and updating the provisions currently in
§ 58.130(e) to address electronic data
capture and maintenance. Numerous
comments to the December 2010
ANPRM note that part 11 (21 CFR part
11, ‘‘Electronic Records; Electronic
Signatures’’) is applicable to part 58 and
therefore parts 11 and 58 should be
consistent. We agree, and do not intend
to duplicate in part 58 the requirements
in part 11. As a result, we propose that
electronic records systems need to be
compliant with applicable regulations.
In § 58.180(c), we propose adding that
the final study report must contain all
data accrued during the study. This
proposed requirement is consistent with
our proposal in § 58.120(b)(6) requiring
that the protocol describe methods for
controlling bias. We propose this
requirement because selective data
inclusion in the study analysis could
introduce bias into the final study
report.
We propose redesignating current
§ 58.130(a) through (c), as (d), (f), and (g)
respectively. In new proposed
§ 58.130(a), we require demonstration
that all analytical methods are accurate,
sufficiently precise, and sensitive
enough to result in accurate and
reproducible data. We expect this
requirement will help ensure data
quality and integrity as its intent is to
produce accurate and reproducible data.
This requirement also is consistent with
requirements in part 320 (21 CFR part
320), ‘‘Bioavailability and
Bioequivalence Requirements’’ (see
§ 320.29(a)).
In new § 58.130(b), we propose
conducting test, control, and reference
article characterization as specified in
part 58, subpart F. We propose this
requirement to clarify our current and
future expectations regarding test,
control, and reference article
characterization.
In new § 58.130(c), we propose that
‘‘humane care and ethical treatment of
test animals must be considered in
advance and upheld in conjunction
with achieving study objectives.’’ We
propose this provision is consistent
with our other proposals addressing
animal welfare discussed elsewhere in
section III.A.3.
In new § 58.130(e), we propose that
any change to the protocol must be
approved as an amendment. We propose
this requirement consistent with the
proposed requirement in § 58.120(d) for
approval of protocol amendments.
However, we understand the
importance of test animal welfare along
with maintaining the integrity of the
study. Therefore, FDA intends to
evaluate on a case-by-case basis certain
circumstances when a protocol
deviation is necessary to prevent a
potential hazard to animal welfare or
study integrity.
In proposed § 58.130(h) (revised and
redesignated current § 58.130(d)),
postmortem observations must be
available to the pathologist unless
specified otherwise in the study
protocol. We understand that some
study protocols might blind the
pathologist to postmortem observations.
We expect, however, in most cases the
pathologist will not need to be blinded
to postmortem observations.
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2. Reporting of Nonclinical Laboratory
Study Results (§ 58.185)
Study data must be maintained in a
manner that allows for ‘‘reconstruction
of the study for the purpose of assessing
the quality and integrity of the results or
the reinterpretation of the data in the
light of later findings’’ (41 FR 51206 at
51215) (Ref. 4). Study records and
reports required in part 58, subpart J, are
acceptable in electronic or paper
medium, or a combination of both. In
§ 58.185, we propose eliminating any
current requirements that might impede
a fully computerized facility.
Many comments to the December
2010 ANPRM suggest we allow testing
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facilities to develop an integrated final
study report. This integrated final study
report would be in lieu of individual
scientists’ reports, which the study
director must then compile and discuss
in an integrated final study report. The
preamble to the original GLP final rule
states that individual reports are
required as part of the final report to
ensure the findings of the individual
scientists are accurately reflected (43 FR
59986 at 60009) (Ref. 12). Also, in the
preamble to the 1987 final rule
amending part 58, FDA thought that
reports combining data, information,
and views from scientists of different
disciplines would obscure the
individual scientist’s accountability for
accurate reporting (see 52 FR 33768 at
33778).
We continue to affirm these
statements. However, we support
processes used for the efficient review
of the draft study report to facilitate
completion of the final study report.
In § 58.185, we propose adding
general statements for consistency with
our other part 58 proposals. We propose
adding two provisions specific to
animal welfare. In § 58.185(a)(2), we
propose requiring that final study
reports contain the names of all study
attending veterinarians. We propose
redesignating and modifying
§ 58.185(a)(9) as (a)(10) to add the
example of ‘‘all health-related issues
reported by an attending veterinarian or
appropriately designated personnel
during the course of the study’’. This
provision recognizes that circumstances
affecting the quality and integrity of the
data could include health-related issues
noted and reported by the attending
veterinarian or appropriately designated
personnel. We propose this addition to
help ensure that all untoward healthrelated observations of test animals are
captured and reported so that FDA
reviewers can consider their possible
effect on study results.
We propose redesignating and
modifying § 58.185(a)(12) as (a)(13) to be
consistent with the EPA’s GLP
regulations (see 40 CFR 160.185(a)(12)
and 792.185(a)(12)). That is, we propose
requiring a signed and dated report from
each person conducting an analysis or
evaluation of study data or specimens
after data generation was completed. We
propose this addition to provide
transparency regarding the review of
study findings and the development of
conclusions submitted in the final study
report.
In new § 58.185(a)(16), we propose
that the study director provide with the
final study report a statement about the
study’s extent of compliance with part
58, including any study deviations. This
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requirement is consistent with OECD’s
consensus document The Role and
Responsibilities of the Study Director in
GLP Studies (Ref. 14) and addresses a
recommendation from stakeholders who
requested that FDA modernize part 58.
Many testing facilities provide
services internationally and therefore,
this statement is commonly seen in final
study reports submitted to FDA. Such a
statement also is included in EPA’s
study profile templates, which outline
the necessary documents for submission
of supporting data.9 FDA presently
requires such a compliance statement
from the applicant for applications and
submissions for research and marketing
and frequently receives the study
director’s statement in fulfillment of, or
at least as the primary basis for, the
required statement.
Several comments to the December
2010 ANPRM suggest modifying part 58
to include requirements for studies
discontinued before completion. In
response to this suggestion, we propose
new § 58.185(d) requiring the study
director to write, sign, and date a short
written summary report closing the
study and discussing why the study was
discontinued. This report and study
material must be archived as required in
§ 58.190 in case of future study review
or study completion.
3. Storage and Retrieval of Records and
Data (§ 58.190)
We propose modifying § 58.190(a) to
add reserve samples to those items
generated as a result of a nonclinical
laboratory study that must be retained.
We also propose adding a requirement
for retention of ‘‘Correspondence and
other documents relating to
interpretation and evaluation of data,
other than those documents contained
in the final study report.’’ We propose
this addition to harmonize with the EPA
GLP regulations (see 40 CFR 160.190(a)
and 792.190(a)) and to clarify our
requirement for retaining these
documents.
Our other proposed modifications in
§ 58.190 provide timeframes for
archiving required study material and
requirements for the SOPs about
archiving to include procedures specific
to removing study material from the
archives. Stakeholders who asked that
we modernize part 58 requested a
reasonable timeframe after the study
completion date to complete study
archiving. Comments to the December
9 A link to those templates is provided in the
Pesticide Registration Notice 2011–3 ‘‘Standard
Format for Data Submitted Under the Federal
Insecticide, Fungicide, and Rodenticide Act and
Certain Provisions of the Federal Food, Drug, and
Cosmetic Act’’ (Ref.17).
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58359
2010 ANPRM also made this request.
The SOP requirement for procedures
specific to removing study material from
the archives is to address concerns that
material in the archives could be lost or
destroyed if removed without having in
place adequate and specific procedures.
We propose that archiving occur no
later than 2 weeks after the study
completion date (see study completion
date defined in § 58.3). We propose this
2-week timeframe to prevent required
material from being inadvertently
misplaced, lost, or destroyed over the
long term. We understand that certain
situations may prevent archiving study
material during, or at the completion of,
a nonclinical laboratory study as
currently required of the study director
in § 58.33(f).
We also propose, when the study
sponsor delays finalizing the final study
report, that the study director must
complete, sign, and date the final study
report and archive all study material no
later than 6 months after completion of
the last draft of the final study report.
Additionally, if the study sponsor stops
a nonclinical laboratory study before all
protocol requirements are complete, a
decision about discontinuing the study
must be made no later than 6 months
after stopping the study. For
discontinued studies, a summary report
and study material must be archived
within 2 weeks of the study director
signing the summary report. We propose
these timeframes to provide the
requested flexibility without
compromising the integrity of study
material.
4. Retention of Records (§ 58.195)
We propose modifying § 58.195(b) to
conform with§ 58.190(a) for the listing
arrangement. We also propose
modifying § 58.195(b)(1) to address
those applications and submissions to
FDA that might not result in an
approval, clearance, or a premarket
authorization. We therefore propose
adding an additional required retention
period from the date an application or
submission is administratively closed
by FDA. ‘‘Administratively closed’’
includes those applications and
submissions closed administratively
with or without a decision.
In § 58.195(h), we propose adding a
statement recognizing that a change of
archive location may be due to reasons
other than closure of a testing facility.
For example, changes in ownership as
well as changes in physical location
would change the archive location. We
also propose including a timeframe of
‘‘no later than 10 working days after the
transfer occurs’’ for reporting to FDA
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and the study sponsor a change in
archive location.
We propose this timeframe to ensure
that FDA is informed of the location of
study materials if a GLP BIMO
inspection of the study is warranted.
This requirement is necessary to prevent
waste of inspectional resources and
delay in receiving FDA inspectional
findings, which provide FDA reviewers
information about data quality and
integrity.
Other proposed changes to § 58.195
are for consistency with our proposals
throughout this document and to update
the regulations consistent with current
practices.
J. Part 58, Subpart K—Disqualification
of Any Person Conducting a Phase of a
Nonclinical Laboratory Study
We propose modifying subpart K to
extend the authority of the
Commissioner of Food and Drugs to
disqualify any person conducting a
phase of a nonclinical laboratory study
upon finding either or both of the
conditions for disqualification in the
proposed revisions in § 58.202. We
propose adding any person conducting
a phase of a nonclinical laboratory study
for consistency with other modifications
throughout this proposal.
We propose modifying § 58.202 to
clarify the conditions for
disqualification. To help provide
uniformity in FDA regulations, we
propose adding as a basis for initiating
disqualification proceedings the
repeated or deliberate submission of
false information in any required report.
FDA intends to reserve disqualification
for the rare case when the rejection of
a particular study is an inadequate
regulatory response (see 43 FR 59986 at
60011) (Ref. 12).
In addition, we propose to amend the
current provision in § 58.206(a) so that
a person disqualified under part 58
would no longer be eligible to receive a
test article under part 511, New Animal
Drugs For Investigational Use. A clinical
investigator who is ineligible to receive
a test article under part 511 also would
be ineligible to conduct any nonclinical
laboratory study that is intended to
support an application for a research or
marketing permit.
For certain FDA-regulated products,
such as new animal drugs, the study
subjects are animals in both
‘‘nonclinical laboratory studies’’ and
‘‘clinical investigations.’’ In the new
animal drug approval process,
nonclinical laboratory studies, such as
those that target animal safety and
human food safety, may be essential in
determining whether to approve an
application for a research or marketing
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permit for a new animal drug. For new
animal drugs, the same clinical
investigator could conduct both
nonclinical laboratory studies and
clinical investigations. Therefore, we
propose this action to help protect the
safety and welfare of animal research
subjects involved in FDA-regulated
nonclinical laboratory studies and
clinical investigations, and to help
ensure the reliability and integrity of the
data submitted to FDA to support FDA
decisions concerning new animal drugs.
Concurrent with this proposal, FDA is
publishing elsewhere in this issue of the
Federal Register a proposal to amend
§ 511.1(c), to expand the scope of
clinical investigator disqualification
under part 511. Under the current
regulations, a clinical investigator
disqualified by the Commissioner is
ineligible to receive the particular type
of test article regulated under that part
(e.g. new animal drugs in § 511.1(c)) and
is ineligible to conduct any clinical
investigation that supports an
application for a research or marketing
permit for products regulated by FDA.
Under the proposed amendment to part
511, a clinical investigator disqualified
under part 511 also would be ineligible
to conduct any nonclinical laboratory
study intended to support an
application for a research or marketing
permit for a new animal drug.
When a clinical investigator is
disqualified pursuant to part 511, the
basis for that disqualification typically
is the repeated or deliberate submission
of false information to FDA or a sponsor
in any required report. For new animal
drugs, the same investigator could
conduct both nonclinical laboratory
studies and clinical investigations. The
proposed amendment to part 511 would
make a clinical investigator disqualified
under part 511 ineligible to conduct any
nonclinical laboratory study intended to
support an application for a research or
marketing permit for a new animal drug.
In addition, the proposed amendment to
part 511 would help to provide
consistency for disqualification
proceedings in parts 58 and 511.8.
Other proposed provisions in
§§ 58.200, 58.202, 58.204, 58.206,
58.210, 58.213, 58.215, and 58.217 are
for clarity and consistency with our
proposals throughout this document. In
§ 58.210, when a study is determined to
be unacceptable, we propose to
eliminate from consideration data in
support of the application or submission
to FDA, as defined in proposed § 58.3.
We also propose to add that such
elimination may serve as new
information justifying appropriate
regulatory action not limited to
termination or withdrawal of approval.
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We propose modifying § 58.219 to
reference § 58.210(b) and to require an
FDA inspection of a disqualified person
before reinstatement can be considered.
Presently, § 58.219 states that the
Commissioner ‘‘may’’ require such an
inspection. Before a request for
reinstatement can be appropriately
considered by FDA, we propose
requiring an inspection. This inspection
would help provide additional
information about the disqualified
person that may be relevant to the
consideration for reinstatement.
IV. Regulatory Hearing Before FDA
We propose to add to 21 CFR
16.1(b)(2) a new provision for 21 CFR
part 58, subpart K relating to
disqualifying any person that conducts
a phase of nonclinical laboratory studies
of FDA-regulated products.
V. Analysis of Environmental Impact
The Agency has determined under 21
CFR 25.30(h) that this action is of a type
that does not individually or
cumulatively have a significant effect on
the human environment. Therefore,
neither an environmental assessment
nor an environmental impact statement
is required.
VI. Legal Authority
Legal authority to issue good
laboratory practice regulations exists
under section 701(a) of the FD&C Act,
as essential to enforcement of the
Agency’s responsibilities under sections
402, 406, 408, 409, 501, 502, 503, 505,
510, 512–516, 518–520, 571, 721, 801,
905, 910, and 911 of the FD&C Act; and,
sections 351 and 354–360F of the PHS
Act.
VII. Proposed Implementation Plan
FDA proposes that any final rule that
may issue based on this proposal
become effective 1 year after the date of
publication of the final rule in the
Federal Register.
VIII. Economic Analysis of Impacts
A. Introduction
We have examined the impacts of the
proposed rule under Executive Order
12866, Executive Order 13563, the
Regulatory Flexibility Act (5 U.S.C.
601–612), and the Unfunded Mandates
Reform Act of 1995 (Pub. L. 104–4).
Executive Orders 12866 and 13563
direct Agencies to assess all costs and
benefits of available regulatory
alternatives and, when regulation is
necessary, to select regulatory
approaches that maximize net benefits
(including potential economic,
environmental, public health and safety,
and other advantages; distributive
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impacts; and equity). We have
developed a comprehensive Economic
Analysis of Impacts that assesses the
impacts of the proposed rule. We
believe that this proposed rule is not a
significant regulatory action as defined
by Executive Order 12866.
The Regulatory Flexibility Act
requires Agencies to analyze regulatory
options that would minimize any
significant impact of a rule on small
entities. Because the proposed
requirements are likely to impose a
significant burden on small entities
employing fewer than 10 workers in
‘‘Dental Equipment and Supplies’’
(between 1.87 and 8.94 percent of
average annual sales), we find that the
proposed rule would have a significant
economic impact on a substantial
number of small entities, but the
impacts are uncertain.
Section 202(a) of the Unfunded
Mandates Reform Act of 1995 requires
that Agencies prepare a written
statement, which includes an
assessment of anticipated costs and
benefits, before proposing ‘‘any rule that
includes any Federal mandate that may
result in the expenditure by State, local,
and tribal governments, in the aggregate,
or by the private sector, of $100,000,000
or more (adjusted annually for inflation)
in any one year.’’ The current threshold
after adjustment for inflation is $146
million, using the most current (2015)
Implicit Price Deflator for the Gross
Domestic Product. This proposed rule
would not result in an expenditure in
any year that meets or exceeds this
amount.
B. Summary
This proposed rule would amend the
regulations regarding GLPs and would
require that nonclinical laboratory
studies (sometimes referred to as
preclinical studies) follow a complete
quality system approach, referred to as
a GLP Quality System, when safety and
toxicity studies support or are intended
to support applications and submissions
to FDA. The proposed rule would
expand the scope to include all
products for which nonclinical
laboratory studies are currently
conducted that are not explicitly
discussed in the current regulations,
specifically tobacco products. The
proposed expanded scope also includes
all applications and submissions under
the FD&C Act that can be supported by
the results of nonclinical laboratory
studies. In addition, the proposed rule
would introduce and modify
definitions, terms, and organizational
and personnel roles and responsibilities
consistent with the implementation of
the proposed GLP Quality System and
the prevalence of multisite studies.
Finally, the proposed rule would
incorporate wording consistent with
some of the existing domestic and
international guidelines, rules or
regulations covering good laboratory
practices such as those established by
the OECD.
Costs of the rule, when final, would
include annual and one-time costs.
Annual costs would include the
additional reporting and recordkeeping
responsibilities required under the
proposed GLP Quality System. One-time
costs include reading and
understanding the rule, updating
58361
existing SOPs, writing new SOPs, and
training. Combined, all costs annualized
over a ten-year period at a 7-percent
discount rate are estimated to range
between $34.4 million and $69.3
million, with an average annualized cost
of $51.9 million. By contrast, with a 3
percent discount rate, annualized cost
would range from $34.2 million to $68.9
million, with an average annualized cost
of $51.5 million.
Conducting nonclinical laboratory
studies under the proposed GLP Quality
System is expected to improve the
reliability and quality of the data that
support applications and submissions to
us, including those applications and
submissions that lead to the use of new
medical products in first-in-human
clinical studies. In addition, the
proposed system is conducive to
improving compliance and
accountability by all involved in the
conduct of nonclinical laboratory
studies.
As described, we understand the
potential effects on small entities. We
therefore seek comment, particularly
from small entities, about the proposed
effective date of 1 year after the date of
publication of any final rule that may
issue (see section VII. Proposed
Implementation Plan).
The full discussion of economic
impacts is available in docket FDA–
2010–N–0548 at https://www.regulations.
gov and at https://www.fda.gov/
AboutFDA/ReportsManualsForms/
Reports/EconomicAnalyses/default.htm
(Ref. 18).
Table 1 summarizes the costs and
benefits.
TABLE 1—SUMMARY OF BENEFITS, COSTS AND DISTRIBUTIONAL EFFECTS OF PROPOSED RULE 1
Units
Category
Benefits:
Annualized ............
Monetized
$millions/year ....
Annualized ............
Quantified ..............
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Qualitative .............
Costs:
Annualized ............
Monetized
$millions/year ....
Annualized ............
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Primary
estimate
Low estimate
........................
........................
........................
2014
7
10
........................
........................
........................
........................
........................
........................
........................
........................
........................
2014
2014
2014
3
7
3
10
10
10
High estimate
Year dollars
Discount rate
(%)
Period
covered
(years)
Notes
The proposed rule would clarify GLP standards
to facilitate a more consistent approach and
provide greater international consistency. As a
result, we anticipate improvements in the integrity
and quality of data submitted for FDA review
decisions.
$51.9
$34.4
$69.3
2014
7
10
51.5
........................
34.2
........................
68.9
........................
2014
2014
3
7
10
10
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TABLE 1—SUMMARY OF BENEFITS, COSTS AND DISTRIBUTIONAL EFFECTS OF PROPOSED RULE 1—Continued
Units
Category
Quantified ..............
Qualitative
Transfers:
Federal ..................
Annualized ............
Primary
estimate
Low estimate
........................
........................
........................
2014
3
10
........................
........................
........................
........................
........................
........................
2014
2014
7
3
10
10
2014
2014
7
3
10
10
Monetized
$millions/year ....
........................
........................
Monetized
$millions/year ....
Year dollars
From:
Other .....................
Annualized ............
High estimate
From:
Effects: .........................
Discount rate
(%)
Period
covered
(years)
Notes
To:
........................
........................
........................
........................
To:
State, Local or Tribal Government: None estimated.
Small Business: The proposed requirements would likely impose a significant burden on small entities employing fewer
than 10 workers in ‘‘Dental Equipment and Supplies’’ (between 1.87 and 8.94 percent of average annual sales).
However, we do not have data on how many of these dental-equipment small entities perform nonclinical laboratory
studies to support, or intended to support, an application or submission regulated by us; only such entities would be
affected by the rule.
Wages: None estimated.
1 Full Disclosure Preliminary Impact Analysis of the proposed rule ‘‘Good Laboratory Practice for Nonclinical Laboratory Studies,’’ Docket No.
FDA–2010–N–0548. (Available at: https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.)
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IX. Paperwork Reduction Act of 1995
This proposed rule contains
information collection provisions that
are subject to review by the Office of
Management and Budget (OMB) under
the Paperwork Reduction Act of 1995
(44 U.S.C. 3501–3520). A description of
these provisions is given in the
Description section of this document
with an estimate of the annual reporting
and recordkeeping burden. Included in
the estimate is the time for reviewing
instructions, searching existing data
sources, gathering and maintaining the
data needed, and completing and
reviewing each collection of
information.
FDA invites comments on: (1)
Whether the proposed collection of
information is necessary for the proper
performance of FDA’s functions,
including whether the information will
have practical utility; (2) the accuracy of
FDA’s estimate of the burden of the
proposed collection of information,
including the validity of the
methodology and assumptions used; (3)
ways to enhance the quality, utility, and
clarity of the information to be
collected; and (4) ways to minimize the
burden of the collection of information
on respondents, including through the
use of automated collection techniques,
when appropriate, and other forms of
information technology.
Title: Reporting and Recordkeeping
Requirements for Good Laboratory
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Practice for Nonclinical Laboratory
Studies—OMB Control Number 0910–
0119—Revision
Description: This proposed rule
would revise the existing information
collection requirements in the GLP
regulations to provide for the
development and implementation of a
GLP Quality System and to reflect
current procedures for the conduct of
nonclinical laboratory studies,
particularly multisite studies.
Description of respondents:
Respondents to the information
collection are persons conducting a
phase of a nonclinical laboratory study
that is within the proposed expanded
scope of part 58, including their
personnel, independent contributing
scientists, and study sponsors as the
latter two terms are defined in this
proposed rule; universities; or
government agencies.
Reporting: Currently, the GLP
regulations include requirements to: (1)
Report the results of QAU inspections;
(2) submit periodic QAU study reports;
(3) provide a QAU statement as part of
the final study report; (4) provide the
results of test and control article
characterization and the testing of
mixtures of test and control articles with
carriers; (5) report a change in archive
location; and (6) prepare in writing a
final study report containing an overall
interpretation of nonclinical laboratory
studies.
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The proposed rule will revise these
requirements to include: (1) A final
study report incorporating additional
information about all persons
conducting one or more nonclinical
laboratory study phases and a study
director’s compliance statement; (2)
QAU reports on facility-based
inspections and process-based
inspections, where conducted; (3)
written certification whenever a
process-based QAU inspection reveals
problems, with documentation that
records the actions taken; (4) summaries
of the closeout of discontinued studies;
(5) notification of the change of archival
site within a specified timeframe; (6)
reports by the study sponsor to the
study director of known risks of the test
article and necessary measures to
protect study personnel; and (7) reports
by the study sponsor to the study
director of the results of characterization
of any reference articles that may be
employed in a study as well of mixtures
of such reference articles with carriers.
Finally, for sponsors who submit the
results of nonclinical laboratory studies
in support of applications or
submissions to FDA that are proposed
additions to the scope of part 58 and
that lack enacting regulations, (8)
submission of the final study report and
a GLP compliance statement.
QAU inspection reports provide the
study director and management with
executive responsibility information
about the progress of a study and its
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compliance with GLP regulations so
they can take any corrective actions
required to ensure the quality and
integrity of the data. Test, control, and
reference article information helps
ensure proper dosing of the test
system(s) and allows interpretation of
study results in the final study report.
The study sponsor receives the final
study report and commonly submits the
report in support of an application or
submission to FDA. The information in
the final study report gives FDA’s
scientific review experts the information
needed to help determine the safety or
toxicity of the test article or both. FDA
needs such safety and toxicity
information to make regulatory
decisions regarding the test article,
including permitting the conduct of
clinical studies on human subjects,
determining safe levels of residual drug
for drugs administered to animals
whose products will be consumed by
humans, and marketing new products
for both human and non-human animal
use. Since a number of the additional
applications and submissions proposed
for the scope expansion do not have
enacting regulations, inclusion in part
58 is necessary.
We estimate the reporting burden of
this collection of information as follows:
TABLE 2—ESTIMATED ONE-TIME REPORTING BURDEN 1
Number of
respondents
Activity
Read and Understand the Proposed Rule: Sponsors of
Nonclinical Laboratory Studies .........................................
Read and Understand the Proposed Rule: Testing Facilities of Nonclinical Laboratory Studies ..............................
Total ..............................................................................
1 There
Number of
responses per
respondent
Total annual
responses
Average
burden per
response
Total hours
2,193
1
2,193
7.2
15,790
300
1
300
18
5,400
........................
........................
2,493
........................
21,190
are no capital costs or operating and maintenance costs associated with this collection of information.
Table 2 shows the estimated one-time
burden associated with the new
reporting provisions of the proposed
rule. We expect that persons conducting
a phase of a nonclinical laboratory study
that is within the proposed expanded
scope of part 58 will need to read and
understand the proposed rule. We
expect that some entities would face
lower complexity from reading the
proposed rule and some entities would
face higher complexity. In the
Preliminary Regulatory Impact Analysis
(PRIA), we calculated lower and upper
estimates of time to read and
understand the proposed rule under a
low-complexity scenario for sponsors of
nonclinical laboratory studies who
would face fewer provisions. Our
estimates under a high-complexity
scenario apply to testing facilities of
nonclinical laboratory studies that
would have to read and understand
more provisions in the rule. As stated in
the PRIA, we estimate that there are
2193 sponsors of nonclinical laboratory
studies and 300 testing facilities of
nonclinical laboratory studies. We
estimate that the 2193 sponsors of
nonclinical laboratory studies will take
from 4.8 to 9.6 hours, for an average of
7.2 hours, to read and understand the
proposed rule. We expect that the 300
testing facilities of nonclinical
laboratory studies will take from 12 to
24 hours, for an average of 18 hours, to
read and understand the proposed rule.
TABLE 3—ESTIMATED RECURRING REPORTING BURDEN 1
Number of
respondents
21 CFR Section
Sponsor provides test, control, and reference article characterization and risk information (§ 58.5(g) & (h)) ...........
Sponsor provides nonclinical laboratory study report in
support of applications and submissions (§ 58.5(k)) ........
Expanded content of QAU statement in final study report
(§ 58.35(b)(11)) .................................................................
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Total hours
6,580
1
6,580
10
1
10
15
150
18,075
.25
(15 minutes)
4,518.75
300
60.25
10
300
2
60.25
20
18,075
5
2
100
36,150
300
60.25
18,075
.5
(30 minutes)
9,037.5
300
2
600
2
1,200
30
200
200
1
10
5
30
2,000
1,000
5
1
8
150
2,000
8,000
300
10
3,000
.5
(30 minutes)
1,500
67,465
........................
69,386.25
........................
........................
are no capital costs or operating and maintenance costs associated with this collection of information.
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Average
burden per
response
5
Summary report of close-out for discontinued studies
(§ 58.185(d)) .....................................................................
Reports
by
independent
contributing
scientists
(§ 58.37(a)(2)) ...................................................................
Principal Investigator (PI) reports of deviations (§ 58.39(c))
PI study report & compliance statement (§ 58.39 (d)) .........
Management report of personnel deviations from protocol
(§ 58.29(b)) .......................................................................
1 There
Total annual
responses
1,316
Management report of actions taken when a processbased inspection reveals problems (§ 58.35(e)) ..............
Expanded contents of final study report (§ 58.185(a)) ........
Compliance statement by study director appended to final
study report (§ 58.185(a)(16)) ..........................................
Total ..............................................................................
Number of
responses per
respondent
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Table 3 shows the estimated recurring
reporting burden associated with the
proposed rule. Together, this results in
a total of 90,576.25 hours and 69,958
responses.
Recordkeeping: Currently, the GLP
regulations include requirements that
respondents must record: (1) Personnel
job descriptions and summaries of
training and experience; (2) master
schedules, protocols, and protocol
amendments; (3) equipment inspection,
maintenance, calibration, and testing
records; (4) SOPs; (5) documentation of
feed and water analyses and animal
treatments; (6) test article accountability
records; and (7) study documentation,
including raw data.
This proposed rule will add to the
existing requirements with regard to
initial changes and additions to SOPs
for both testing facilities and test sites
to develop, implement, and maintain a
GLP Quality System and to expand
many SOPs to specifically include
multisite studies.
This proposed rule would also
expand personnel record maintenance
to require records of training and
experience on GLP requirements and
species-specific animal care. In
addition, this proposed rule includes
revisions to the required content of
study protocols as part of a GLP Quality
System and for multisite study specifics.
The additional documentation by
management with executive
responsibility and study directors is for
the implementation of a GLP Quality
System and the resulting additional
burden is nominal. Documentation by
independent contributing scientists, as
defined in this proposed rule, includes
records these individuals would usually
retain, so a nominal added burden is
predicted.
To implement the proposed checks
and balances discussed previously in
the preamble, proposed revisions will
require that added documentation be
made by the study director and the QAU
to ensure the viability of the proposed
GLP Quality System (see Table 5).
This proposed rule also adds
requirements for the study sponsor to
maintain records of: (1) Protocol and
protocol amendment approval; (2) the
accreditation status of a contracted
person (as defined in this proposed rule)
that conducts a phase of the study that
involves the use of animals; (3) test,
control, and reference article
characterization; and (4) the
qualifications of all contracted persons.
In addition, the proposed rule
includes recordkeeping requirements for
nonclinical laboratory studies that
choose to utilize the option of having a
principal investigator, particularly for
multisite studies. These individuals will
have recordkeeping responsibilities
comparable to those of the study
director for the nonclinical laboratory
study phases for which they are
responsible.
The persons potentially retaining
nonclinical laboratory study documents
are persons conducting a phase of a
nonclinical laboratory study that is
within the proposed expanded scope of
part 58, including independent
contributing scientists, and study
sponsors as defined in this proposed
rule. Results of nonclinical laboratory
studies may be used by firms in support
of applications and submissions to FDA,
including applications and submissions
for research and marketing of new
products. The additional documentation
of the conduct and data collection of
nonclinical laboratory studies of FDAregulated products will help ensure the
quality and integrity of final study
reports. FDA conducts on-site reviews
of records and study reports during
inspections of persons conducting one
or more nonclinical laboratory study
phases to verify the reliability of results
submitted in support of applications
and submissions to FDA.
We estimate the recordkeeping
burden of this collection of information
as follows:
TABLE 4—ESTIMATED ONE-TIME RECORDKEEPING BURDEN 1
Number of
recordkeepers
Activity
Number of
records per
recordkeeper
Average
burden per
recordkeeping
Total annual
records
Total hours
Update Existing SOPs .........................................................
Write New SOPs ..................................................................
Training ................................................................................
300
300
300
12
10
2
3,600
3,000
600
7.5
24
14
27,000
72,000
8,400
Total ..............................................................................
........................
........................
7,200
........................
107,400
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1 There
are no capital costs or operating and maintenance costs associated with this collection of information.
Table 4 shows the estimated one-time
burden associated with the revised
recordkeeping provisions of the
proposed rule. We expect that the 300
testing facilities of nonclinical
laboratory studies will need to update
existing SOPs and to write new SOPs.
In the PRIA, we estimated that each
facility would need to update 12
existing SOPs and write 10 new SOPs.
We calculated lower and upper
estimates of time to update existing
SOPs and to write new SOPs. We
estimate that it will take from 4 to 11
hours, for an average of 7.5 hours, to
update 12 existing SOPs. We estimate
that it will take from 15 to 33 hours, for
an average of 24 hours, to write 10 new
SOPs. We also expect that the 300
testing facilities of nonclinical
laboratory studies will need to conduct
training. In the PRIA, we estimated that
for the low estimate one person would
be doing the training and one person
would be trained. By contrast, for the
high estimate, we estimated that also
one person would be doing the training
and potentially three people would
receive such training, for an average of
two employees for each facility. We
calculated lower and upper estimates of
time to train, estimating that it will take
from 5 to 23 hours, for an average of 14
hours, to train.
TABLE 5—ESTIMATED RECURRING RECORDKEEPING BURDEN 1
Number of
recordkeepers
Number of
records per
recordkeeper
Total annual
records
Average
burden per
recordkeeping
Sponsor documentation (§ 58.5):
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Federal Register / Vol. 81, No. 164 / Wednesday, August 24, 2016 / Proposed Rules
58365
TABLE 5—ESTIMATED RECURRING RECORDKEEPING BURDEN 1—Continued
Number of
records per
recordkeeper
Number of
recordkeepers
Average
burden per
recordkeeping
Total annual
records
Total hours
—(c) protocol approval and (i) all amendments .....................................................
—(b) animal welfare .................................
—(d) accreditation status of testing facility
2,193
1,316
1,316
100
5
5
219,300
6,580
6,580
1
2
.5
(30 minutes)
219,300
13,160
3,290
—(g) test, control, and reference article
parameters ............................................
1,316
5
6,580
3,290
—(j) archival locations ..............................
2,193
62.25
136,514
—(e) qualifications of contracted persons
Documentation by management with executive responsibility:
—GLP
training
and
experience
(§ 58.29(a) & (d)) ...................................
1,316
5
6,580
.5
(30 minutes)
.25
(15 minutes)
2
300
500
150,000
.25
(15 minutes)
37,500
—Animal care training and experience
(§ 58.29(a) & (d)) ...................................
300
5
1,500
.25
(15 minutes)
375
—all persons are qualified for multisite
studies (§ 58.31(i)) .................................
300
500
150,000
.25
(15 minutes)
37,500
—Periodic review of GLP Quality System
(§ 58.31(b)) ............................................
300
.25
75
37.5
—Periodic review of QAU (§ 58.31(r)) ......
300
1
300
.5
(30 minutes)
.5
(30 minutes)
—Appointment of management representative (§ 58.31(e)) .........................
300
.1
30
.25
(15 minutes)
7.5
—all test sites have master schedule
(§ 58.31(j)) .............................................
300
15
4,500
.25
(15 minutes)
1,125
—appointment of person to manage master schedule (§ 58.31(k)) .......................
300
0.1
30
.25
(15 minutes)
7.5
—selection of lead QAU for multisite studies
(§ 58.31(p)) ...................................................
300
5
1,500
.25
(15 minutes)
375
—QAU review of protocols, SOPs, & their
amendments (§ 58.31(q)) .............................
300
5
1,500
.25
(15 minutes)
375
300
17
5,100
1.5
7,650
300
17
5,100
1.5
7,650
150
5
750
.25
(15 minutes)
187.5
—audits of final reports of contributing
scientists (§ 58.35(b)(9)) ........................
300
600
180,000
.5
(30 minutes)
90,000
—audits of principal investigator (reports
(§ 58.35(b)(9)) ........................................
300
120
36,000
.5
(30 minutes)
18,000
—audits of final study reports for multisite
studies (§ 58.35(b)(10)) .........................
300
60
18,000
.5
(30 minutes)
9,000
Study Director
—Multisite
study
need
for
PIs
(§ 58.33(b)(7)(ii)) ....................................
—communications (§ 58.33(b)(12)) ..........
300
300
180
180
54,000
54,000
54,000
13,500
300
60
18,000
1
.25
(15 minutes)
1
300
17
5,100
.25
(15 minutes)
1,275
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QAU:
—review of study protocols + amendments (§ 58.35(b)3)) ..............................
—SOPs
review
+
amendments
(§ 58.35(b)(4)) ........................................
—facility and process-based inspections
(§ 58.35(b)(5)) ........................................
—protocol followed (§ 58.33(b)(1)) ...........
—QAU review of protocol & SOPs
(§ 58.33(b)(2)) ........................................
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13,160
150
18,000
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TABLE 5—ESTIMATED RECURRING RECORDKEEPING BURDEN 1—Continued
Number of
records per
recordkeeper
Number of
recordkeepers
Average
burden per
recordkeeping
Total annual
records
Total hours
—management provided adequate resources (§ 58.33(b)(3)) ..........................
300
5
1,500
.5
(30 minutes)
750
—computerized
systems
validated
(§ 58.33(b)(4)) ........................................
300
5
1,500
375
—Committee review 58.33(b)(5) ..............
300
17
5,100
.25
(15 minutes)
.25
(15 minutes)
—multisite study personnel qualified
(§ 58.33(b)(7)(i)) ....................................
—test system as required (§ 58.33(b)(10))
300
300
15
5
4,500
1,500
1
.25
(15 minutes)
1
1,275
4,500
375
—GLP compliance (§ 58.33(b)(11)) ..........
—test article accountability when containers disposed of (§ 58.105(d)) ..........
300
60
18,000
18,000
300
6
1,800
.25
(15 minutes)
450
Independent contributing scientists:
—Education, training, and experience
(§ 58.37(b)(2)) ........................................
30
1
30
7.5
—Archive location (§ 58.37(b)(4)) .............
30
1
30
—Appropriate animal care (§ 58.37(b)(3))
2
1
2
.25
(15 minutes)
.25
(15 minutes)
.5
(30 minutes)
—Protocol + amendment acceptance
(§ 58.39(a)) ............................................
200
5
1,000
—Study deviations (§ 58.39(c)) ................
200
10
2,000
—Archive location (§ 58.39((e)) ................
200
40
8,000
Recordkeeping (§ 58.195) .........................
300
251.5
Total ...................................................
............................
............................
7.5
1
PIs:
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75,450
.25
(15 minutes)
.5
(30 minutes)
.25
(15 minutes)
3.9
250
294,255
1,188,031
............................
906,289.5
1,000
2,000
are no capital costs or operating and maintenance costs associated with this collection of information.
Table 5 shows the estimated recurring
recordkeeping burden associated with
the proposed rule. Together, this results
in a total of 1,013,689.5 hours and
1,195,231 records.
To ensure that comments on
information collection are received,
OMB recommends that written
comments be faxed to the Office of
Information and Regulatory Affairs,
OMB (see ADDRESSES). All comments
should be identified with the title of the
information collection.
In compliance with the Paperwork
Reduction Act of 1995 (44 U.S.C.
3407(d)), the Agency has submitted the
information collection provisions of this
proposed rule to OMB for review. These
requirements will not be effective until
FDA obtains OMB approval. FDA will
publish a notice concerning OMB
approval of these requirements in the
Federal Register.
X. Federalism
FDA has analyzed this proposed rule
according to the principles set forth in
Executive Order 13132. FDA has
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determined that the proposed rule, if
finalized, would not contain policies
that would have substantial direct
effects on the States, on the relationship
between the National Government and
the States, or on the distribution of
power and responsibilities among the
various levels of government.
Accordingly, the Agency tentatively
concludes that the proposed rule does
not contain policies that have
federalism implications as defined in
the Executive order and, consequently,
a federalism summary impact statement
is not required.
XI. References
The following references are on
display in the Division of Dockets
Management (see ADDRESSES and are
available for viewing by interested
persons between 9 a.m. and 4 p.m.,
Monday through Friday; they are also
available electronically at https://
www.regulations.gov. FDA has verified
the Web site addresses, as of the date
this document publishes in the Federal
PO 00000
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Register, but Web sites are subject to
change over time.
1. ‘‘OECD Series on Principles of Good
Laboratory Practice (GLP) and Compliance
Monitoring,’’ (the link provided is to an
index of all OECD documents related to
GLPs, with links to each of the individual
documents) (https://www.oecd.org/chemical
safety/testingofchemicals/oecdserieson
principlesofgoodlaboratorypracticeglpand
compliancemonitoring.htm).
2. ‘‘Mutual Acceptance of Data (MAD),’’
(https://www.oecd.org/env/ehs/mutual
acceptanceofdatamad.htm).
3. FDA, ‘‘FDA Announces New Initiative to
Modernize the Regulation of Clinical Trials
and Bioresearch Monitoring,’’ FDA News
Release, June 26, 2006 (https://www.fda.gov/
NewsEvents/Newsroom/Press
Announcements/2006/ucm108677.htm).
4. FDA, ‘‘Nonclinical Laboratory Studies;
Proposed Regulations for Good Laboratory
Practice Regulations’’ 41 FR 51206
(November 19, 1976).
5. MOU 225–06–4000. ‘‘Memorandum of
Understanding Among the Animal and Plant
Health Inspection Service, U.S. Department
of Agriculture, and the Food and Drug
Administration, U.S. Department of Health
and Human Services, and the National
Institutes of Health, U.S. Department of
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Federal Register / Vol. 81, No. 164 / Wednesday, August 24, 2016 / Proposed Rules
Health and Human Services, Concerning
Laboratory Animal Welfare,’’ (https://
www.fda.gov/AboutFDA/Partnerships
Collaborations/MemorandaofUnderstanding
MOUs/DomesticMOUs/ucm247294.htm).
6. ‘‘OECD Series on Principles of Good
Laboratory Practice and Compliance
Monitoring Number 13,’’ The Application of
the OECD Principles of GLP to the
Organisation and Management of Multi-Site
Studies; Consensus Document of the Working
Group on Good Laboratory Practice (https://
search.oecd.org/officialdocuments/display
documentpdf/?doclanguage=en&cote=env/
jm/mono(2002)9).
7. ‘‘OECD Series on Principles of Good
Laboratory Practice and Compliance
Monitoring Number 4 (Revised),’’ Consensus
Document; Quality Assurance and GLP
(https://search.oecd.org/officialdocuments/
displaydocumentpdf/?doclanguage=
en&cote=env/jm/mono(99)20).
8. ‘‘OECD Series on Principles of Good
Laboratory Practice and Compliance
Monitoring Number 1,’’ The OECD Principles
on Good Laboratory Practice (https://
search.oecd.org/officialdocuments/display
documentpdf/?doclanguage=en&cote=env/
mc/chem(98)17).
9. ‘‘OECD Series on Principles of Good
Laboratory Practice and Compliance
Monitoring Number 11,’’ Advisory Document
of the Panel on Good Laboratory Practices,
The Role and Responsibilities of the Sponsor
in the Application of the Principles of GLP
(https://search.oecd.org/officialdocuments/
displaydocumentpdf/?doclanguage=
en&cote=env/mc/chem(98)16).
10. Council for International Organization
of Medical Sciences and The International
Council for Laboratory Animal Science,
International Guiding Principles for
Biomedical Research Involving Animals,
December 2012 (revised) (https://www.cioms
.ch/images/stories/CIOMS/IGP2012.pdf).
11. Institute for Laboratory Animal
Research, Guide for the Care and Use of
Laboratory Animals, Eighth Edition, 2011
(https://grants.nih.gov/grants/olaw/Guide-forthe-Care-and-Use-of-Laboratory-Animals.
pdf).
12. FDA, ‘‘Nonclinical Laboratory Studies,
Good Laboratory Practice Regulations,’’ Final
Rule, 43 FR 59986 (December 22, 1978).
13. Compliance Policy Guide (CPG
7151.02), Sec. 130.300—FDA Access to
Results of Quality Assurance Program Audits
and Inspections (https://www.fda.gov/ICECI/
ComplianceManuals/CompliancePolicy
GuidanceManual/ucm073841.htm).
14. ‘‘OECD Series on Principles of Good
Laboratory Practice and Compliance
Monitoring Number 8 (Revised),’’ Consensus
Document, The Role and Responsibilities of
the Study Director in GLP Studies (https://
search.oecd.org/officialdocuments/display
documentpdf/?doclanguage=en&cote=env/
jm/mono(99)24).
15. ‘‘OECD Series on Principles of Good
Laboratory Practice and Compliance
Monitoring Number 7 (Revised),’’ Consensus
Document, The Application of the GLP
Principles to Short Term Studies (https://
search.oecd.org/officialdocuments/display
documentpdf/?doclanguage=en&cote=env/
jm/mono(99)23).
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22:10 Aug 23, 2016
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16. Bioanalytical Method Validation Draft
Guidance for Industry (https://www.fda.gov/
downloads/Drugs/GuidanceCompliance
RegulatoryInformation/Guidances/UCM
368107.pdf).
17. Pesticide Registration Notice 2011–3
‘‘Standard Format for Data Submitted Under
the Federal Insecticide, Fungicide, and
Rodenticide Act and Certain Provisions of
the Federal Food, Drug, and Cosmetic Act’’
(https://www.epa.gov/sites/production/files/
2014-04/documents/pr2011-3.pdf) (Study
profile templates available at https://
www.epa.gov/pesticide-registration/studyprofile-templates).
18. Full Analysis of Economic Impacts
(Docket Number FDA–2010–N–0548).
Preliminary Regulatory Impact Analysis,
Initial Regulatory Flexibility Analysis, and
Unfunded Mandates Reform Act Analysis for
Good Laboratory Practice for Nonclinical
Laboratory Studies; Proposed Rule, available
at https://www.fda.gov/AboutFDA/Reports
ManualsForms/Reports/EconomicAnalyses/
default.htm.
List of Subjects
21 CFR Part 16
Administrative practice and
procedure.
21 CFR Part 58
Laboratories, Reporting and
recordkeeping requirements.
Therefore, under the Federal Food,
Drug, and Cosmetic Act and under
authority delegated to the Commissioner
of Food and Drugs, it is proposed that
21 CFR parts 16 and 58 be amended as
follows:
PART 16—REGULATORY HEARING
BEFORE THE FOOD AND DRUG
ADMINISTRATION
1. The authority citation for part 16
continues to read as follows:
■
Authority: 15 U.S.C. 1451–1461; 21 U.S.C.
141–149, 321–394, 467f, 679, 821, 1034; 28
U.S.C. 2112; 42 U.S.C. 201–262, 263b, 364.
2. In § 16.1, amend paragraph (b)(2) by
removing the entry for § 58.204(b) and
adding an entry for §§ 58.200 through
58.219 to read as follows:
■
§ 16.1
Scope.
*
*
*
*
*
(b) * * *
(2) * * *
§§ 58.200 through 58.219 (see part 58,
subpart K of this chapter), relating to
disqualifying any person conducting a
phase of a nonclinical laboratory study
of FDA-regulated products.
*
*
*
*
*
PART 58—GOOD LABORATORY
PRACTICE FOR NONCLINICAL
LABORATORY STUDIES
3. The authority citation for part 58 is
revised to read as follows:
■
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Authority: 21 U.S.C. 342, 346, 346a, 348,
351, 352, 353, 355, 360, 360b–360f, 360h–
360j, 360ccc, 371, 379e, 381, 387e, 387j,
387k; 42 U.S.C. 216, 262, 263b–263n.
4. In § 58.1, revise paragraph (a) and
add paragraph (c) to read as follows:
■
§ 58.1
Scope.
(a) This part prescribes good
laboratory practices (GLPs) for
conducting nonclinical laboratory
studies of safety or toxicity or both that
support or are intended to support an
application or submission for products
regulated by the Food and Drug
Administration (FDA), including food
and color additives, animal food
additives, human and animal drugs,
devices, biological products, electronic
products, and tobacco products.
Applications and submissions to FDA
affected by these regulations include
those listed in § 58.3. Compliance with
this part is intended to assure the
quality and integrity of data from
nonclinical laboratory studies filed or
submitted pursuant to sections 402, 406,
408, 409, 501, 502, 503, 505, 510, 512–
516, 518–520, 571, 701, 721, 801, 905,
910, and 911 of the Federal Food, Drug,
and Cosmetic Act and sections 351 and
354–360F of the Public Health Service
Act.
*
*
*
*
*
(c) In this part the term ‘‘where
appropriate’’ is used several times.
When a requirement is qualified by
‘‘where appropriate,’’ it is deemed to be
‘‘appropriate’’ unless justification can be
otherwise documented. A requirement
is ‘‘appropriate’’ if non-implementation
could reasonably be expected to result
in a nonclinical laboratory study whose
results lack the required reliability.
■ 5. Revise § 58.3 to read as follows:
§ 58.3
Definitions.
As used in this part, the following
terms have the meanings specified:
Applications and Submissions to FDA
include:
(1) A color additive petition,
described in section 721 of the Federal
Food, Drug, and Cosmetic Act, and as
described in part 71 of this chapter.
(2) A food additive petition, described
in section 409 of the Federal Food, Drug
and Cosmetic Act, and as described in
parts 171 and 571 of this chapter.
(3) Data and information regarding a
substance submitted as part of the
procedures for establishing that a
substance is generally recognized as safe
for use, which use results or may
reasonably be expected to result,
directly or indirectly, in its becoming a
component or otherwise affecting the
characteristics of any food, described in
§§ 170.35 and 570.25 of this chapter.
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(4) Data and information regarding a
food additive submitted as part of the
procedures regarding food additives
permitted to be used on an interim basis
pending additional study, described in
§ 180.1 of this chapter.
(5) A petition for a nutrient content
claim, described in section 403 of the
Federal Food, Drug, and Cosmetic Act,
and as described in subpart D of part
101 of this chapter.
(6) A petition for a health claim,
described in section 403 of the Federal
Food, Drug, and Cosmetic Act, and as
described in subpart E of part 101 of this
chapter.
(7) An investigational new drug
application, described in section 505(i)
of the Federal Food, Drug, and Cosmetic
Act, and as described in part 312 of this
chapter.
(8) Applications for FDA approval to
market a new drug, described in section
505 of the Federal Food, Drug, and
Cosmetic Act, and as described in part
314 of this chapter.
(9) Data and information regarding an
over-the-counter drug for human use,
submitted as part of the procedures for
classifying such drugs as generally
recognized as safe and effective and not
misbranded, described in part 330 of
this chapter.
(10) Data and information about a
substance submitted as part of the
procedures for establishing a tolerance
for unavoidable contaminants in food
and food-packaging materials, described
in sections 406, 408, and 409 of the
Federal Food, Drug, and Cosmetic Act,
and as described in parts 109 and 509
of this chapter.
(11) A notice of claimed
investigational exemption for a new
animal drug, section 512(j) of the
Federal Food, Drug, and Cosmetic Act,
and as described in described in part
511 of this chapter.
(12) New animal drug applications,
described in section 512 of the Federal
Food, Drug, and Cosmetic Act, and as
described in part 514 of this chapter.
(13) An abbreviated application for a
new animal drug, described in section
512(b) of the Federal Food, Drug, and
Cosmetic Act.
(14) An application for conditional
approval of new animal drugs for minor
use and minor species, described in
section 571(a)(2) of the Federal Food,
Drug, and Cosmetic Act, and as
described in part 516 of this chapter.
(15) Authorization to market edible
products from experimental animals as
described in parts 170 and 570 of this
chapter.
(16) A request to establish or amend
an import tolerance described in section
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512 of the Federal Food, Drug, and
Cosmetic Act.
(17) [Reserved]
(18) An application for a biologics
license, described in section 351 of the
Public Health Service Act, and as
described in part 601 of this chapter.
(19) An application for an
investigational device exemption,
described in section 520(g) of the
Federal Food, Drug, and Cosmetic Act,
and as described in part 812 of this
chapter.
(20) An application for premarket
approval of a medical device, described
in section 515 of the Federal Food,
Drug, and Cosmetic Act, and as
described in part 814 of this chapter.
(21) An application for humanitarian
device exemption, authorized under
section 520(m) of the Federal Food,
Drug, and Cosmetic Act, and as
described in part 814, subpart H of this
chapter.
(22) A product development protocol
for a medical device, described in
section 515 of the Federal Food, Drug,
and Cosmetic Act, and as described in
part 814 of this chapter.
(23) A premarket notification
submission for a medical device as
authorized under section 510(k) of the
Federal Food, Drug, and Cosmetic Act,
and as described in part 807, subpart E
of this chapter.
(24) Data and information regarding a
medical device submitted as part of the
procedures for classifying such devices
described in part 860, subpart B of this
chapter, reclassification petitions
described in part 860, subpart C of this
chapter, and requests associated with
the evaluation of automatic class III
designations, authorized under section
513(f)(2) of the Federal Food, Drug, and
Cosmetic Act.
(25) Data and information regarding a
medical device submitted as part of the
procedures for establishing, amending,
or revoking a performance standard for
such devices, described in section 514
of the Federal Food, Drug, and Cosmetic
Act, and as described in part 861 of this
chapter.
(26) Data and information regarding
an electronic product submitted as part
of the procedures for obtaining an
exemption from notification of a
radiation safety defect or failure of
compliance with a radiation safety
performance standard, described in
subpart D of part 1003 of this chapter.
(27) Data and information regarding
an electronic product submitted as part
of the procedures for establishing,
amending, or repealing a standard for
such product, described in section 358
of the Public Health Service Act.
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(28) Data and information regarding
an electronic product submitted as part
of the procedures for obtaining a
variance from any electronic product
performance standard as described in
§ 1010.4 of this chapter.
(29) Data and information regarding
an electronic product submitted as part
of the procedures for granting,
amending, or extending an exemption
from any electronic product
performance standard, as described in
§ 1010.5 of this chapter.
(30) A premarket notification for a
food contact substance, described in
section 409 of the Federal Food, Drug,
and Cosmetic Act, and as described in
part 170, subpart D of this chapter.
(31) [Reserved]
(32) A premarket application for a
new tobacco product, as described in
section 910(b)(1) of the Federal Food,
Drug, and Cosmetic Act.
(33) A substantial equivalence report
as described in section 905(j) of the
Federal Food, Drug, and Cosmetic Act.
(34) A request for exemption under
section 905(j)(3) of the Federal Food,
Drug, and Cosmetic Act, and as
described in part 1107 of this chapter.
(35) An application or submission
related to a modified risk tobacco
product, as described in section 911of
the Federal Food, Drug, and Cosmetic
Act.
Attending veterinarian means a
veterinarian who has training or
experience or both in the care and
management of the species being
attended and who has direct or
delegated authority for activities
involving animals.
Batch means a specific quantity or lot
of a test, control, or reference article that
has been characterized according to
§ 58.105 and handled according to
§ 58.107.
Contracted person means a person
who assumes, either directly or
indirectly as an independent contractor,
one or more responsibilities for the
conduct of a nonclinical laboratory
study.
Contributing scientist means an
individual responsible for the conduct,
interpretation, analysis, or any other
service for a phase of a nonclinical
laboratory study. An individual expert
or specialist who is an independently
employed contracted person, as defined
in this section, is an independent
contributing scientist.
Control article means any food
additive, color additive, drug, biological
product, electronic product, device,
tobacco product, or any article other
than a test article, reference article, feed,
or water that is administered to the test
system in the course of a nonclinical
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laboratory study for the purpose of
establishing a basis for comparison with
the test article.
Establish means define, document (in
writing or electronically), and
implement.
Facility-based inspection means an
inspection which is not based on
specific studies but covers general
facilities and activities, for example,
installations, support systems, computer
systems, training, environmental
monitoring, and equipment
maintenance and calibration.
GLP Quality System means the
organizational structure,
responsibilities, procedures, processes,
and resources for implementing quality
management in the conduct of a
nonclinical laboratory study.
Lead quality assurance unit (lead
QAU) means the QAU responsible for
quality assurance (QA) in a multisite
nonclinical laboratory study. Testing
facility management with executive
responsibility selects the lead QAU.
Management with executive
responsibility means those senior
employees of a testing facility or test site
who have the authority to establish or
make changes to the quality policy and
GLP Quality System at the testing
facility and test site, respectively.
Master schedule means a compilation
of information used for assessment of
workload and the tracking of
nonclinical laboratory studies.
Multisite study means any study that
has phases conducted at more than one
site.
Nonclinical laboratory study means in
vivo or in vitro experiments in which
test articles are studied prospectively in
test systems under laboratory conditions
or in the applicable environment to
determine their safety or toxicity or
both. The term does not include studies
involving human subjects, clinical
studies, or clinical investigational use in
animals. The term does not include
basic exploratory studies carried out to
determine whether a test article has any
potential utility or basic exploratory
studies to determine the physical or
chemical characteristics of a test article.
Person includes an individual,
partnership, corporation, association,
scientific or academic establishment,
government agency, or organizational
unit thereof, and any other legal entity.
Phase means a defined activity or set
of activities in the conduct of a
nonclinical laboratory study.
Principal investigator means an
individual who has specific
responsibilities for one or more phases
of a nonclinical laboratory study as
delegated by the study director.
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Process-based inspection means an
inspection conducted to monitor
procedures or processes of a repetitive
nature that are very frequently
performed. Process-based inspections
are conducted on a prearranged
schedule, which is not connected to the
timing of any particular nonclinical
laboratory study. Performance of
process-based inspections covering
processes or procedures that occur with
a very high frequency (for example,
certain mutagenicity studies) may cause
some studies to be uninspected during
the in-life period of the study, as
defined in this section within the
definition of Short-term study.
Quality means the totality of features
and characteristics that bear on the
ability of a nonclinical laboratory study
to provide data that can be relied upon.
Quality assurance unit (QAU) means
any person or organizational element
designated to perform the duties relating
to quality assurance (QA) of nonclinical
laboratory studies. For any given study,
the QAU must be entirely separate from
and independent of the personnel
engaged in the direction and conduct of
the study.
Quality policy means the overall
intentions and direction of an
organization with respect to quality, as
established by management with
executive responsibility.
Raw data means all original
nonclinical laboratory study records and
documentation or exact copies that
maintain the original intent and
meaning and are made according to the
person’s certified copy procedures. Raw
data includes any laboratory
worksheets, correspondence, notes, and
other documentation (regardless of
capture medium) that are the result of
original observations and activities of a
nonclinical laboratory study and are
necessary for the reconstruction and
evaluation of the report of that study.
Raw data also includes the signed and
dated pathology report.
Reference article means any chemical
substance or mixture, or analytical
standard, or material other than a test
article, control article, feed, or water
that is administered to or used in
analyzing the test system in the course
of a study for the purposes of
establishing the basis for comparison
with the test article for known chemical
or biological measurements.
Short-term study means a study for
which the in-life period is completed
within several days or a week at most.
The in-life period of a study is that
period during which data are collected.
Specimen means any material derived
from a test system for examination,
analysis, or retention.
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Sponsor means: (1) A person that
initiates and supports, by provision of
financial or other resources, a
nonclinical laboratory study; or
(2) A person that submits a
nonclinical laboratory study in support
of an application or submission to FDA;
or
(3) A person that initiates a
nonclinical laboratory study and
functions as, and has the same
responsibilities as, a testing facility, test
site, or contributing scientist, as those
terms are defined in this section.
Standard operating procedures
(SOPs) means documented procedures
which describe how to perform tests or
activities normally not specified in
detail in study protocols.
Study-based inspection means an
inspection of a critical operation of the
study which is scheduled according to
the chronology of the given study.
Management with executive
responsibility at the testing facility and/
or test site identifies which operations
are critical before initiation of the study.
Study completion date means the date
the final report is signed by the study
director.
Study director means the individual
responsible for the overall conduct of a
nonclinical laboratory study.
Study initiation date means the date
the protocol is signed by the study
director.
Test article means any food additive,
color additive, drug, biological product,
electronic product, device, tobacco
product, or any other article subject to
regulation under the Federal Food,
Drug, and Cosmetic Act or under
sections 351 and 354–360F of the Public
Health Service Act.
Test site means a person who is
responsible for one or more phases of a
multisite nonclinical laboratory study.
A test site includes management with
executive responsibility and supporting
SOPs relevant to the conduct of
nonclinical laboratory studies.
Test system means any animal, plant,
microorganism, or subparts thereof to
which the test, control, or reference
article is administered or added for
study. Test system also includes
appropriate groups or components of
the system not treated with the test,
control, or reference articles.
Testing facility means the person
responsible for coordinating,
conducting, or completing a nonclinical
laboratory study, or any combination
thereof. The testing facility designates
the study director.
Validation means confirmation by
examination and provision of objective
evidence that the particular
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requirements for a specific intended use
can be consistently fulfilled.
Vehicle means any agent which serves
as a carrier and is used to mix, disperse,
or solubilize the test, control, or
reference article for administration or
application to the test system.
■ 6. Add § 58.5 to subpart A to read as
follows:
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§ 58.5
Sponsor responsibilities.
For each nonclinical laboratory study,
the sponsor must:
(a) Ensure the nonclinical laboratory
study protocol (the study protocol)
meets the requirements in § 58.120.
(b) Ensure that the study protocol
provides for humane care and ethical
treatment of animals.
(c) Sign and date the study protocol
to indicate approval.
(d) Contract with persons accredited
as following appropriate animal welfare
procedures for phases of a nonclinical
laboratory study that include the use of
animals. If these contracted persons are
not accredited, document this fact, the
reason for using a non-accredited
person, and the qualifications of the
non-accredited person. This information
must be included in the compliance
statement required in paragraph (k) in
this section.
(e) Document that any contracted
person conducting a phase of a
nonclinical laboratory study is qualified
according to the provisions in this part.
(f) Ensure that appropriate lines of
communication are established among
all persons conducting a phase of the
nonclinical laboratory study and
document all study-related
communications that involve the
sponsor.
(g) Document that test, control, and
reference articles are prepared,
characterized, and labeled according to
subpart F of this part, and are
appropriately shipped. Obtain, and
provide to the study director as soon as
available, information regarding test,
control, and reference article
characterization as specified in § 58.105.
(h) Inform the study director of any
known potential risks of the test article
to human health or the environment and
any measures necessary to protect study
personnel and the environment.
(i) Review, approve, sign, and date
each protocol amendment before
implementation.
(j) Document and update as necessary
the archive location of all raw data and
records as described in §§ 58.190 and
58.195.
(k) Include, in any application or
submission to FDA that includes the
results of a nonclinical laboratory study,
the final study report and all
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amendments. If a summary report of the
nonclinical laboratory study is included
in such applications or submissions, a
copy of the final study report, as
described in § 58.185, must be
appended or provided elsewhere within
the application or submission. Also,
include either a statement that the study
was conducted in compliance with the
requirements set forth in this part, or, if
the study was not conducted in
compliance with these regulations, a
brief statement of the reason for the
noncompliance.
■ 7. Revise § 58.10 to read as follows:
§ 58.10
Transfer of responsibilities.
(a) Any person utilizing the services
of a contracted person (as defined in
§ 58.3) to perform a phase (as defined in
§ 58.3) of a nonclinical laboratory study
may transfer to the contracted person
any regulatory responsibility in this
chapter, unless delegation of such
responsibility is expressly prohibited.
Any such transfer must be described in
writing. Any responsibility not covered
by the written description is deemed not
transferred.
(b) Any person transferring to a
contracted person any responsibility for
a phase of a nonclinical laboratory study
must inform that contracted person that
the transferred responsibility must be
performed in compliance with the
provisions in this part.
(c) A contracted person assuming any
responsibility for a phase of a
nonclinical laboratory study must
comply with the regulations in this
chapter applicable to the transferred
responsibility and is subject to the same
regulatory actions as those transferring
the responsibility.
■ 8. Revise § 58.15 to read as follows:
§ 58.15 Inspection of any person
conducting a phase of a nonclinical
laboratory study.
(a) Any person conducting a phase of
a nonclinical laboratory study must
permit, at reasonable times and in a
reasonable manner, an authorized
employee of FDA to inspect and copy
all records and inspect all specimens
required to be maintained for
nonclinical laboratory studies within
the scope of this part and, where
applicable, to collect reserve samples for
such studies. The records inspection
and copying requirements do not
routinely apply to QAU records of
findings and problems or to actions
recommended and taken. However, FDA
retains the authority to inspect all QAU
records when necessary to ensure
compliance with this part.
(b) FDA will not consider a
nonclinical laboratory study submitted
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in support of an application or
submission to FDA if any person
conducting a phase of the nonclinical
laboratory study refuses to permit
inspection. The determination that a
nonclinical laboratory study will not be
considered in support of an application
or submission to FDA does not,
however, relieve the applicant of any
obligation under any other applicable
statute or regulation to submit the
results of the study to FDA.
■ 9. Revise § 58.29 to read as follows:
§ 58.29
Personnel.
(a) Each individual engaged in the
conduct of, or responsible for the
supervision of, a nonclinical laboratory
study must have education, training,
and experience, or a combination
thereof, to enable that individual to
perform the assigned functions. This
must include training and experience
with GLP requirements. Personnel who
work with animals must have both
general and species-specific training
and experience.
(b) All study personnel must have
access to and comply with the protocol
and all applicable protocol amendments
and SOPs. Any deviation must be
reported to the study director.
(c) All study personnel must record
raw data, as defined in § 58.3, promptly
and accurately as required by § 58.180.
(d) Any person conducting a phase of
a nonclinical laboratory study must
maintain a current summary of training
and experience and a job description for
each individual in the person’s
employment engaged in or supervising
the phase of the study for which the
person is responsible.
(e) There must be a sufficient number
of personnel for the timely and proper
conduct of the study according to the
protocol.
(f) Personnel must take necessary
personal sanitation and health
precautions designed to avoid
contamination of test, control, and
reference articles and test systems.
(g) Personnel engaged in a nonclinical
laboratory study must wear clothing
appropriate for the duties they perform.
Such clothing must be changed as often
as necessary to prevent microbiological,
radiological, or chemical contamination
of test systems and test, control, and
reference articles.
(h) Any individual found at any time
to have an illness that may adversely
affect the quality and integrity of the
nonclinical laboratory study must be
excluded from direct contact with test
systems; test, control, and reference
articles; and any other operation or
function that may adversely affect the
study until the condition is corrected.
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All personnel must be instructed to
report to their immediate supervisors
any health or medical conditions that
may reasonably be considered to have
an adverse effect on a nonclinical
laboratory study.
■ 10. Revise § 58.31 to read as follows:
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§ 58.31 Testing facility management with
executive responsibility.
Management with executive
responsibility is ultimately responsible
for the GLP Quality System and must
establish policy and objectives for a GLP
Quality System and a commitment to
quality, as defined in § 58.3.
Management with executive
responsibility must ensure that the
quality policy, as defined in § 58.3, is
implemented and maintained at all
levels of the organization. Management
with executive responsibility must:
(a) Establish and update written SOPs,
as required in § 58.81(b)(2) for a GLP
Quality System.
(b) Review the suitability and
effectiveness of the GLP Quality System
at defined intervals and with sufficient
frequency according to established
procedures, to be included in SOPs for
the GLP Quality System (§ 58.81(b)(2)),
to ensure that the GLP Quality System
satisfies the established quality policy
and objectives and the requirements of
this part. The dates and results of these
reviews must be documented.
(c) Establish and maintain an
adequate organizational structure
(personnel, resources, facilities,
equipment, materials, and
methodologies) to ensure that all testing
complies with the established GLP
Quality System, according to the
requirements of this part.
(d) Establish procedures, to be
included in SOPs for the GLP Quality
System (§ 58.81(b)(2)), for the
appropriate responsibility, authority,
and interrelationship among all
personnel who manage, perform, and
assess work affecting quality, and
provide the independence and authority
necessary to perform these tasks.
(e) Appoint and document the
appointment of, according to procedures
to be included in SOPs for the GLP
Quality System (§ 58.81(b)(2)), a
management representative who is a
member of the testing facility
management with authority over and
responsibility for:
(1) Documenting that GLP Quality
System requirements are effectively
established and effectively maintained;
and
(2) Reporting on the performance of
the GLP Quality System to management
with executive responsibility for review,
including all reports from the QAU.
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(f) Establish SOPs for equipment, as
required in § 58.81(b)(14), including
standards for appropriate
documentation of equipment validation,
as defined in § 58.3. For multisite
studies, document that any person
conducting a phase of the nonclinical
laboratory study follows adequate
equipment-related SOPs.
(g) Establish SOPs to ensure that
computerized systems are suitable for
their intended purposes and are
appropriately validated, operated, and
maintained as required in § 58.81(b)(15).
(h) Document that all study personnel
are trained to perform their assigned
functions.
(i) Establish SOPs, as required in
§ 58.81(b)(18), for ensuring and
documenting the qualifications of any
person conducting a phase of a
nonclinical laboratory study.
(j) Establish SOPs for the development
and maintenance of the master schedule
as required in § 58.81(b)(13).
(k) Appoint and document the
appointment of a person to maintain the
master schedule. The master schedule
must be indexed by test article and
contain the identification of the test
system, the nature of the study, the date
the study was initiated, the current
status of each study, the identity of the
sponsor, and the name of the study
director. For multisite studies, the
master schedule of each person
conducting a phase of a nonclinical
laboratory study must also include the
specific phases that person conducts.
(l) Establish procedures, to be
included in SOPs for multisite studies
required in § 58.81(b)(18), for the
transfer of data, specimens, and samples
among all persons conducting phases of
the nonclinical laboratory study;
verification of the accuracy and
completeness of any translations of
SOPs and protocols, when applicable;
and storage, return, or disposal of test,
control, and reference articles, as
applicable.
(m) Review all protocols to determine
that there are no environmental, animal
welfare, or work resource issues or
issues with scientific methodology that
might affect or bias any phase of the
conduct of the proposed study.
Document the review and acceptance of
each protocol.
(n) Establish SOPs, as required in
§ 58.81(b)(3), for designation of a study
director, as described in § 58.33, before
the study is initiated and prompt
replacement of the study director if it
becomes necessary to do so during the
conduct of a study.
(o) Establish procedures, to be
included in SOPs for the GLP Quality
System (§ 58.81(b)(2)), to ensure a clear
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line of communication among the study
director, principal investigator(s),
QAU(s), the sponsor, and all study
personnel, as applicable.
(p) Provide for a QAU as described in
§ 58.35. Before initiating a multisite
study, as defined in § 58.3, designate
and document the designation of the
lead QAU with overall responsibility for
the entire study. Provide the
information described in § 58.35(a) of
the lead QAU to all persons involved in
the conduct of the study and all QAUs
serving those persons.
(q) Establish procedures, to be
included in SOPs for the GLP Quality
System (§ 58.81(b)(2)), to ensure QAU
review of SOPs and study protocols to
verify that they meet GLP requirements.
This review must be documented.
(r) Review the suitability and
effectiveness of the QAU or lead QAU,
as applicable, at defined intervals and
with sufficient frequency, according to
established SOPs as required in
§ 58.81(b)(17), to ensure that the QAU
satisfies established quality policy and
objectives and the requirements of this
part. For multisite studies, testing
facility management with executive
responsibility must periodically review
the suitability and effectiveness of the
lead QAU. The dates and results of
reviews of the QAU must be
documented.
(s) Establish SOPs, as required in
§ 58.81(b)(6), for the receipt of
information regarding the
characterization of all test, control, and
reference articles or mixtures, including
data on their identity, strength, purity,
stability, and uniformity, as applicable.
(t) Establish SOPs, with appropriate
timeframes, for the conduct of QAU
inspections and for the receipt, review,
and followup of all concerns, problems,
and regulatory deviations reported by
the QAU. These SOPs must include
procedures for correcting reported
problems and, as necessary, for
modification of relevant SOPs to
prevent a recurrence of any problems, as
required in § 58.81(b)(20) and (21).
(u) Establish SOPs, as required in
§ 58.81(b)(13), for the development and
maintenance of an archive system,
including the designation and
replacement of the archivist and any
supporting staff.
(v) Establish procedures to ensure
maintenance of a historical file of all
SOPs as required in § 58.81(b)(1).
■ 11. Add § 58.32 to subpart B to read
as follows:
§ 58.32 Test site management with
executive responsibility.
For multisite studies, each test site
participating in the study must have
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management with executive
responsibility for the test site who must:
(a) Comply with responsibilities
delineated for testing facility
management with executive
responsibility, as described in section
§ 58.31, where appropriate.
(b) Develop and maintain SOPs as
specified in § 58.81, where appropriate.
■ 12. Revise § 58.33 to read as follows:
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§ 58.33
Study director.
(a) For each nonclinical laboratory
study, a scientist or other professional of
appropriate education, training, and
experience, or combination thereof,
must be identified as the study director.
The study director represents the single
point of study control and has overall
responsibility, which cannot be
delegated, for:
(1) The technical conduct of the entire
study;
(2) The implementation of procedures
to ensure adequate communication
among all study personnel and with the
study sponsor, as applicable; and
(3) The interpretation, analysis,
documentation, and reporting of results
and study compliance.
(b) The study director must:
(1) Approve the protocol, including
any changes, as provided by § 58.120,
and document that it is followed.
(2) Document that the QAU has
reviewed the protocol and all applicable
SOPs, and any amendments, before
study initiation and implementation of
applicable amendments to ensure that
they are compliant with GLP
requirements.
(3) Document that testing facility
management with executive
responsibility has committed adequate
resources for the conduct of the specific
study.
(4) Document that computerized
systems are validated and fit for use in
the specific study.
(5) For studies requiring the use of
animals, document that the initial
protocol and any amendments that
impact the use of animals are reviewed
and approved, as required in § 58.120(b)
and (e), by a committee whose function
is to ensure that the care and use of
animals in studies is appropriate and
humane, before study initiation and the
implementation of applicable
amendments.
(6) Consult with the attending
veterinarian, as defined in § 58.3, during
review of proposed study protocols to
determine potential animal welfare
concerns and appropriate responses to
likely contingencies. Defer to the
attending veterinarian when decisions
regarding animal welfare arise,
particularly when animals are in pain or
distress.
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(7) For multisite studies:
(i) Document the qualifications of any
person conducting a phase of the
nonclinical laboratory study.
(ii) Determine and document the need
for principal investigators.
(8) Document that all experimental
data, including observations of
unanticipated responses of the test
system, are accurately recorded and
verified.
(9) Document unforeseen
circumstances that may affect the
quality and integrity of the nonclinical
laboratory study when they occur and
the corrective action taken.
(10) Document that test systems are as
specified in the approved study
protocol.
(11) Document that all applicable GLP
regulations are followed and include a
study compliance statement in the final
study report.
(12) Document all communications
with all persons conducting a phase of
the nonclinical laboratory study and
with the sponsor, as applicable.
(13) Sign and date the final study
report.
(14) Archive all raw data,
documentation, protocols, specimens,
reserve samples, and final reports no
later than 2 weeks after the study
completion date.
■
13. Revise § 58.35 to read as follows:
§ 58.35
Quality assurance unit (QAU).
(a)(1) Function. A QAU must monitor
each study to assure management that
the facilities, equipment, personnel,
methods, practices, records, and
controls are in conformance with the
regulations in this part. For any given
study, the QAU must be entirely
separate from and independent of the
personnel engaged in the direction and
conduct of the study.
(2) Location and identity. (i) For
studies conducted entirely at the testing
facility, the QAU can consist of
personnel at the facility itself or be a
separately contracted unit.
(ii) For multisite studies, a lead QAU
must be designated by testing facility
management with executive
responsibility and must have
responsibility for the QA of the entire
study. The lead QAU can consist of
personnel at the testing facility, be a
QAU for another person conducting a
phase of the study, or be a separately
contracted unit. QAUs for persons
conducting a phase of the study must
coordinate with the lead QAU as
specified in SOPs as described in
§ 58.81(b)(17) and (20). The lead QAU
has direct QA responsibility for any
person lacking a QAU.
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(b) QAUs must: (1) Maintain access to
the master schedule (defined in § 58.3)
of all nonclinical laboratory studies
conducted by the person employing the
QAU or contracting for QA services. For
multisite studies, the lead QAU must
maintain access to the master schedule
of any person lacking a QAU.
(2) Maintain access to copies of all
protocols pertaining to all nonclinical
laboratory studies for which the QAU is
responsible.
(3) Review all protocols before study
initiation, and all protocol amendments
before implementation, to ensure that
they can be conducted in compliance
with this part. This review must be
documented.
(4) Review all SOPs to be used for the
conduct of all phases of a nonclinical
laboratory study to assess their clarity
and compliance with this part. This
review must be documented.
(5) Inspect each nonclinical laboratory
study for which the QAU is responsible
at intervals adequate to ensure the
integrity of the specific study.
Inspections must determine compliance
with the protocol, applicable SOPs, and
the requirements of this part. These can
include study-based, process-based, and
facility-based inspections as defined in
§ 58.3 and as specified in SOPs as
required in § 58.81(b)(20). For multisite
studies, the lead QAU must coordinate
the conduct of study inspections with
any other existing QAUs, as specified in
SOPs as required in § 58.81(b)(20). Upon
discovery, any problems found during
an inspection which are likely to affect
study integrity must be reported to the
study director and management with
executive responsibility for the study or
studies affected.
(6) Maintain written and properly
signed records of all inspections that
include the date of the inspection, the
individual performing the inspection,
findings and problems, action
recommended and taken to resolve
existing problems, and any scheduled
date for reinspection. For study-specific
inspections, reports must also include
the identity of the study and the phase
of the study inspected.
(7) Periodically submit to
management with executive
responsibility and the study director
written status reports on each study that
discuss the overall progress and
compliance status of the study and that
include any problems observed and the
corrective actions taken. The content
and frequency of these reports must be
specified in SOPs, as described in
§ 58.81(b)(21).
(8) Determine that no deviations from
approved protocols or SOPs were made
without proper authorization and
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documentation. For multisite studies,
the lead QAU is responsible for
identifying all deviations that occur
across the entire study, including
deviations identified by all other QAUs
participating in the study, as described
in SOPs in § 58.81(b)(17).
(9) Audit the reports of all
contributing scientists, and any
amendments to such reports, to ensure
such reports reflect the protocol and all
amendments, accurately describe the
methods and SOPs, and report all of the
raw data of the specific phases covered
by each report. For multisite studies,
QAUs for persons conducting a phase of
the study must audit the reports of any
principal investigators and all
contributing scientists for whom they
are responsible, and any amendments to
such reports, as specified in SOPs as
described in § 58.81(b)(17). The lead
QAU must audit the reports, and any
amendments to such reports, of any
principal investigators and all
contributing scientists for any person
lacking a QAU and of any independent
contributing scientists.
(10) Audit the final study report, and
any amendments to this report, to
ensure that such report accurately
describes the methods and SOPs, all raw
data of the nonclinical laboratory study
are reported, and that all original and
amended signed and dated reports from
all contributing scientists are appended.
For multisite studies, this is the
responsibility of the lead QAU.
(11) Prepare, sign, and date a
statement to be included with the final
study report that specifies:
(i) The dates of study-specific
inspections, process-based inspections
if applicable, and facility-based
inspections;
(ii) Findings reported to management
with executive responsibility and to the
study director; and
(iii) The dates of QAU audits of the
reports of all contributing scientists
(including any independent
contributing scientists), any principal
investigators, and of the final study
report and all amendments to such. For
multisite studies, this is the
responsibility of the lead QAU. When
other persons conducting a phase of the
study have QAUs, those QAUs must
provide to the lead QAU such
statements regarding the audits they
conducted, for appending to the final
study report.
(c) The responsibilities and
procedures applicable to the QAU, the
records maintained by the QAU, and the
method of indexing such records must
be in writing and must be maintained as
specified in SOPs as required in
§ 58.81(b)(17). For multisite studies, the
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lead QAU and all other QAUs
participating in the study must maintain
those documents relevant to their
oversight. These SOPs as well as
documentation of the dates of all QAU
inspections, the study or process or
procedure, or facility inspected as
applicable, the phase or segment of the
study inspected for study-specific
inspections, and the name of the
individual performing the inspection
must be made available for inspection to
authorized employees of FDA.
(d) A designated representative of
FDA must, upon request, be given
access to the written SOPs established
for QAU inspections. If requested by
FDA, the person inspected must certify
that inspections are being implemented,
performed, documented, and followed
up according to this part.
(e) If a person conducting a phase of
a nonclinical laboratory study chooses
to conduct process-based inspections,
that person must prepare a written
certification, as specified in SOPs as
required in § 58.81(b)(21), whenever a
process-based inspection reveals
problems. This certification must
document actions taken to properly
inform and, when applicable, modify
reports for all studies impacted by the
results of the process or procedure in
question.
■ 14. Add § 58.37 to subpart B to read
as follows:
independent contributing scientist will
conduct and the applicable
requirements of this part. Date and sign
any protocol amendments applicable to
the phases of the nonclinical laboratory
study conducted by the independent
contributing scientist to indicate
agreement.
(2) Maintain and update
documentation of education, training,
and experience pertinent to those
phases of the nonclinical laboratory
studies for which the independent
contributing scientist is responsible.
(3) If conducting phases of a
nonclinical laboratory study that
include the use of animals:
(i) Document that housing, feeding,
handling, and care of the animals as
specified in § 58.90 are available.
(ii) Document that an attending
veterinarian is available for consult and
deferred to as necessary, particularly
when animals are in pain or distress.
(iii) Document corrective actions
required to assure the humane care and
ethical treatment of animals.
(4) Archive all materials pertinent to
all phases of the nonclinical laboratory
the independent contributing scientist
conducted, as required by the protocol
and § 58.195; document when and
where archiving was completed.
■ 15. Add § 58.39 to subpart B to read
as follows:
§ 58.37
The study director can delegate to
principal investigators responsibility for
phases of a nonclinical laboratory study
but not responsibility for an entire
study. For all phases of the nonclinical
laboratory study for which the principal
investigator is responsible, a principal
investigator must:
(a) Sign and date the study protocol,
and any applicable amendments, to
document agreement to comply with the
protocol requirements and the
applicable requirements of this part.
(b) Verify that the study is conducted
according to the requirements of this
part.
(c) Document all deviations noted
during the conduct of the study, report
those deviations to the study director as
soon as possible after discovery, and
document that the information was
forwarded to the study director.
(d) Submit to the study director
either:
(1) The signed and dated reports from
all contributing scientists for whom the
principal investigator is responsible and
any amendments to such reports, any
raw data not covered by such reports,
and a signed compliance statement
indicating any areas of noncompliance;
or
Contributing scientist.
(a) Each contributing scientist must:
(1) Conduct, oversee, analyze, and
provide any other service for the
conduct of all phases of the nonclinical
laboratory study for which the
contributing scientist is responsible
according to the requirements of this
part.
(2) Provide a signed and dated report
of all phases for which the contributing
scientist is responsible, to be included
in the final study report. When there are
amendments to the original report,
provide a signed and dated copy of the
amended report, to be included in the
final study report along with the
original report. Provide the report, and
all amendments, to the study director
or, when a multisite study employs
principal investigators, through the
principal investigator.
(3) Permit oversight by the designated
QAU.
(b) In addition to the requirements in
paragraphs (a)(1) through (3) of this
section, an independent contributing
scientist must:
(1) Date and sign the study protocol
to indicate agreement to comply with
protocol requirements for all phases of
the nonclinical laboratory study the
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(2) Signed and dated report of all
phases for inclusion in the final study
report. The signed report must include
the original principal investigator’s
report and any amendments, reports of
all contributing scientists for whom the
principal investigator is responsible and
any amendments to such reports, and a
signed compliance statement indicating
any areas of noncompliance.
(e) Document that all materials and
records are appropriately archived, as
required by the protocol and § 58.195.
■ 16. Revise § 58.41 to read as follows:
§ 58.41
General.
Any person conducting a phase of a
nonclinical laboratory study must have
facilities of suitable size and
construction to facilitate the proper
conduct of nonclinical laboratory
studies. Facilities must be designed so
that there is a degree of separation that
will prevent any function or activity
from having an adverse effect on the
study.
■ 17. In § 58.43, revise paragraphs (a),
(b), and (d) to read as follows:
asabaliauskas on DSK3SPTVN1PROD with PROPOSALS
§ 58.43
Animal care facilities.
(a) Any person conducting a phase of
a nonclinical laboratory study that
utilizes animals must have a sufficient
number of animal rooms or areas, as
needed, to assure proper:
(1) Separation of species or test
systems,
(2) Isolation of individual projects,
(3) Quarantine of animals, and
(4) Routine or specialized housing of
animals.
(b) Any person conducting a phase of
a nonclinical laboratory study that
utilizes animals must have a number of
animal rooms or areas separate from
those described in paragraph (a) of this
section to ensure isolation of studies
being done with test systems or test,
control, or reference articles known to
be biohazardous, including volatile
substances, aerosols, radioactive
materials, and infectious agents.
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(d) When animals are housed,
facilities must exist for the collection
and disposal of all animal waste and
refuse or for safe sanitary storage of
waste before removal from any facility
at which a phase of a nonclinical
laboratory study that utilizes animals is
conducted. Disposal facilities must be
so provided and operated as to
minimize vermin infestation, odors,
disease hazards, and environmental
contamination.
■ 18. Revise § 58.47 to read as follows:
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§ 58.47 Facilities for handling test, control,
and reference articles.
§ 58.81 Standard operating procedures
(SOPs).
(a) As necessary to prevent
contamination or mixups, there must be
separate areas for:
(1) Receipt and storage of the test,
control, and reference articles.
(2) Mixing of the test, control, and
reference articles with a carrier, e.g.,
feed.
(3) Storage of the test, control, and
reference article mixtures.
(b) Storage areas for the test, control,
and reference articles and test, control,
and reference article mixtures must be
separate from areas housing the test
systems and must be adequate to
preserve the characteristics of the
articles and mixtures, including their
identity, strength, purity, and stability,
as applicable.
■ 19. Revise § 58.61 to read as follows:
(a) The testing facility and all test
sites must have SOPs in writing setting
forth nonclinical laboratory study
procedures that management with
executive responsibility is satisfied are
adequate to ensure the quality and
integrity of the data generated in the
course of a study. All deviations from
SOPs in a study must be authorized by
the study director and must be
documented in the raw data. Significant
changes in established SOPs must be
properly authorized in writing by
management with executive
responsibility.
(b) The testing facility and all test
sites must establish SOPs for all
applicable phases of a nonclinical
laboratory study. Where appropriate,
SOPs must include the following:
(1) Preparation, modification, and
administration of all SOPs. These must
include procedures for developing and
maintaining a historical file of SOPs and
all revisions, including the dates of such
revisions.
(2) Establishment and periodic review
of a GLP Quality System.
(3) Designation and replacement of
the study director.
(4) Animal room preparation.
(5) Animal care.
(6) Receipt, identification, storage,
handling, mixing, and method of
sampling of the test, control, and
reference articles.
(7) Test system observations for in
vivo and in vitro testing, as applicable.
(8) Laboratory tests.
(9) Handling of animals found
moribund or dead during study.
(10) Necropsy of animals or post
mortem examination of animals.
(11) Collection and identification of
specimens.
(12) Histopathology.
(13) Data handling, storage, and
retrieval, including maintenance of the
master schedule and all study protocols,
and the establishment and maintenance
of an archive system.
(14) Validation, maintenance, and
calibration of equipment.
(15) Ensuring computerized systems
are suitable for their intended purpose
and are appropriately validated,
operated, and maintained and that
electronic records from computerized
systems are readily available for review
and assessment.
(16) Transfer, proper placement, and
identification of animals.
(17) QAU functions, including QA
oversight for multisite studies.
(18) Multisite studies.
(19) Designation and replacement of a
principal investigator.
§ 58.61
Equipment design.
Equipment, including computerized
systems, used in the generation,
measurement, maintenance, archiving,
retrieval, or assessment of data (or any
combination thereof) and equipment
used for facility environmental control
must be of appropriate design and
adequate capacity to function according
to the protocol and must be suitably
located for operation, inspection,
cleaning, and maintenance.
■ 20. In § 58.63, revise paragraphs (a)
and (b) to read as follows:
§ 58.63 Maintenance and calibration of
equipment.
(a) Equipment must be adequately
inspected, cleaned, and maintained.
Equipment used for the generation,
measurement, maintenance, archiving,
retrieval, or assessment of data (or any
combination thereof) must be
adequately tested, calibrated, and
standardized, as applicable.
(b) The written SOPs required under
§ 58.81(b)(14) and (15) must set forth in
sufficient detail the methods, materials,
and schedules to be used in the routine
inspection, cleaning, maintenance,
testing, calibration, and standardization
of equipment, as applicable, and must
specify, when appropriate, remedial
action to be taken in the event of failure
or malfunction of equipment. The
written SOPs must designate the person
responsible for the performance of each
operation.
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■ 21. Revise the heading of subpart E to
read as follows:
Subpart E—Nonclinical Laboratory
Study Operations
■
22. Revise § 58.81 to read as follows:
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(20) Planning, performing,
documenting, and reporting inspections
conducted by the QAU.
(21) Receipt, review, and followup of
all concerns, problems, and regulatory
deviations reported by the QAU,
including the frequency and content of
periodic study reports required by
§ 58.35(b)(7), and for modifying relevant
SOPs when necessary to prevent
recurrence.
(22) Certifying copies of study records
as true copies of the original that
maintain the original intent and
meaning.
(c) Each laboratory area must have
immediately available laboratory
manuals and SOPs relative to the
laboratory procedures being performed.
Published literature may be used as a
supplement to SOPs.
■ 23. In § 58.90, revise paragraphs (b)
through (e) to read as follows:
§ 58.90
Animal care.
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(b) All newly received animals from
outside sources must be isolated and
their health status must be evaluated
according to acceptable veterinary
medical practices. Also, throughout the
study, all test animals must be evaluated
for their health status according to
acceptable veterinary medical practices.
(c) At the initiation of a nonclinical
laboratory study, animals must be free
of any disease or condition that might
interfere with the purpose or conduct of
the study. If, during the course of the
study, the animals contract such a
disease or condition, the diseased
animals must be isolated, if necessary.
These animals may be treated for
disease or signs of disease as deemed
necessary by the study’s attending
veterinarian. The diagnosis, treatment
authorizations, treatment description,
and each treatment date must be
documented and must be retained as
part of the study raw data.
(d) Warm-blooded animals, except
nursing neonates, used in laboratory
procedures that require manipulations
and observations over an extended
period of time or in studies that require
the animals to be removed from and
returned to their home cages for any
reason (e.g., cage cleaning, treatment,
etc.), must receive appropriate
identification. All information needed
to specifically identify each animal
within an animal-housing unit must
appear on the outside of that unit.
(e) Animals of different species must
be housed in separate rooms when
necessary. Animals of the same species,
but used in different studies, should not
ordinarily be housed in the same room
when inadvertent exposure to control,
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reference, or test articles or animal
mixup could affect the outcome of
either study. If such mixed housing is
necessary, adequate differentiation by
space and identification must be made.
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■ 24. Revise the heading of subpart F to
read as follows:
Subpart F—Test, Control, and
Reference Articles
■
25. Revise § 58.105 to read as follows:
§ 58.105 Test, control, and reference
article characterization.
(a) For all test, control, and reference
articles other than tobacco products, the
identity, strength, purity, and
composition or other characteristics
which will appropriately define the test,
control, or reference article must be
determined for each batch and must be
documented. For test, control, and
reference articles for tobacco products,
the chemical composition (including
mainstream or aerosol smoke
composition, when applicable),
microbiological characterization
(fermented tobacco products), and
design parameters which will
appropriately define the test, control, or
reference article must be determined for
each batch and must be documented.
These analyses must be performed by
the sponsor or by a contracted person
either:
(1) Before study initiation, or
(2) Concomitantly according to
written SOPs as required in
§ 58.81(b)(6). The results of such
analyses must be provided to the study
director as soon as available. In those
cases where marketed products are used
as control or reference articles, with the
exception of tobacco products, such
products can be characterized by their
labeling.
(b) Methods of synthesis, fabrication,
or derivation of the test, control, and
reference articles must be documented
by the person who conducts the
analyses.
(c) The stability of each test, control,
and reference article must be
determined as required by the
conditions of the study either:
(1) Before study initiation, or
(2) Concomitantly according to
written SOPs, as required in
§ 58.81(b)(6), which provide for periodic
analysis of each batch. The results of
such testing must be provided to the
study director as soon as available.
(d) Each storage container for a test,
control, or reference article must be
labeled by name; Chemical Abstract
Service (CAS) number or code number,
where such identification exists; batch
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number; expiration date, if any; and,
where applicable, storage conditions
necessary to maintain the identity,
strength, purity, and composition of the
test, control, or reference article, other
than tobacco products. For tobacco
product test, control, and reference
articles, labeling must include storage
conditions necessary to maintain the
chemical composition (including
mainstream smoke composition),
microbiological composition, and
design parameters, where applicable.
Storage containers must be assigned to
a particular test article for the duration
of the study. Empty test article
containers may be disposed of once the
study director verifies and documents
the distribution and final disposition of
the test article. Approval for the
disposal of empty containers must be in
writing and signed and dated by the
study director.
(e) For studies of more than 4 weeks
duration, reserve samples from each
batch of test, control, and reference
article must be retained for the period
of time provided by § 58.195.
■ 26. In § 58.107, revise the heading and
introductory text to read as follows:
§ 58.107 Test, control, and reference
article handling.
Procedures must be established, as
required in § 58.81(b)(6), for a system for
the handling of the test, control, and
reference articles to ensure that:
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*
*
■ 27. Revise § 58.113 to read as follows:
§ 58.113
Mixtures of articles with carriers.
(a) For each test, control, and
reference article that is mixed with a
carrier, tests by appropriate analytical
methods must be conducted:
(1) To determine the uniformity of the
mixture and to determine, periodically,
the concentration of the test, control, or
reference article in the mixture; and
(2) To determine the stability of the
test, control, and reference articles in
the mixture as required by the
conditions of the study.
(b) Determination of uniformity,
concentration, and stability must be
conducted either:
(1) Before study initiation; or
(2) Concomitantly according to
written SOPs, as required by
§ 58.81(b)(6), which provide for periodic
analysis of the test, control, or reference
articles in the mixture.
(c) The results of such testing,
performed by the sponsor or by a
contracted person, must be provided to
the study director as soon as available.
(d) Where any of the components of
the test, control, or reference article
carrier mixture has an expiration date,
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that date must be clearly shown on the
container. If more than one component
has an expiration date, the earliest
expiration date must be shown.
■ 28. Revise § 58.120 to read as follows:
asabaliauskas on DSK3SPTVN1PROD with PROPOSALS
§ 58.120
Protocol.
(a) Each study must have an approved
written protocol that clearly indicates
the specific objectives and all methods
for the conduct of the study. The
protocol must contain, where
appropriate, the following information:
(1) A descriptive title and statement of
the purpose of the study.
(2) Identification of test, control, and
reference articles by:
(i) Name;
(ii) Chemical Abstract Service (CAS)
number or code number, where such
identification exists;
(iii) The name and address of the
manufacturer(s); and
(iv) The person(s) determining their
characteristics, as applicable.
(3) The name and contact information
(including address, phone number,
email address, and facsimile number)
for the sponsor and the testing facility
and the name and affiliation of the
study director. Also, for multisite
studies, the contact information for all
persons conducting a phase of the
nonclinical laboratory study, including
all principal investigators and
independent contributing scientists.
(4) The number, body weight range,
sex, source of supply, species, strain,
substrain, and age of the test system.
(5) The procedure for identification of
the test system.
(6) A description of the experimental
design, including the methods for the
control of bias in the conduct of the
study and the analysis and reporting of
study test results and procedures to be
followed when a study includes a peer
review of any phase. For multisite
studies, identification of which phases
of the nonclinical laboratory study will
be conducted by which person or
persons.
(7) A description or identification, as
applicable, of the diet used in the study
as well as solvents, emulsifiers, and/or
other materials used to solubilize or
suspend the test, control, or reference
articles, as applicable, before mixing
with the carrier. The description must
include specifications for acceptable
levels of contaminants that are
reasonably expected to be present in the
dietary materials and are known to be
capable of interfering with the purpose
or conduct of the study if present at
levels greater than established by the
specifications.
(8) Each dosage level, expressed in
milligrams per kilogram of body weight
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or other appropriate units, of the test,
control, or reference article to be
administered and the method and
frequency of administration. For each
test, control, or reference article that is
mixed with a carrier for administration,
limits for the results of concentration,
uniformity, and stability testing and the
name and address of the person
conducting the testing.
(9) The type and frequency of tests,
analyses, and measurements to be made.
(10) A list or description of the
records to be maintained for the specific
study. For multisite studies, the archive
location(s) of study materials and
records from all phases of the
nonclinical laboratory study.
(11) The dated signature of the study
sponsor, the study director,
independent contributing scientists,
principal investigators, and any other
person conducting a phase of the
nonclinical laboratory study, as
applicable.
(12) A statement of the proposed
statistical methods to be used.
(b) For studies that include the use of
animals, a committee whose function is
to ensure that the care and use of
animals is appropriate and humane
must review and approve the study
before initiation of the study and
approval must be documented.
(c) A statement that the study must be
conducted in compliance with the
provisions of this part, to be signed and
dated by the study sponsor and testing
facility management with executive
responsibility, must be appended to the
protocol.
(d) All changes in or revisions of an
approved protocol and the reasons for
the changes must be documented. These
amendments to the protocol must be
signed and dated by the study sponsor
and the study director. For multisite
studies, these amendments must also be
signed and dated by all independent
contributing scientists, principal
investigators, and any other person
conducting a phase of the nonclinical
laboratory study affected by the
amendment. Signed and dated
amendments must be maintained with
the protocol.
(e) A committee whose function is to
ensure that the care and use of animals
in studies is appropriate and humane
must review and approve any protocol
changes that would impact animal
welfare before implementation and
approval must be documented.
■ 29. Revise § 58.130 to read as follows:
§ 58.130 Conduct of a nonclinical
laboratory study.
(a) The analytical methods used for all
phases of a nonclinical laboratory study
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must be demonstrated to be accurate
and of sufficient sensitivity to measure,
with appropriate precision, the analytes
in question.
(b) Test, control, and reference article
characterization testing must be
conducted as described in subpart F of
this part.
(c) Humane care and ethical treatment
of test animals must be considered in
advance and upheld in conjunction
with achieving study objectives. The
attending veterinarian must be included
in consultations regarding the impact of
a given protocol on the welfare of test
animals, in particular the recognition
and alleviation of species-specific pain
or distress and methods of euthanasia.
The attending veterinarian must be
deferred to when decisions regarding
animal welfare arise, particularly when
animals are in pain or distress.
(d) The nonclinical laboratory study
must be conducted according to the
protocol. The person responsible for a
given phase of a nonclinical laboratory
study must sign and date the protocol,
as required in § 58.120(a)(11), before
initiation of that phase of the study.
(e) Any change to the protocol must
be approved as an amendment, as
required in § 58.120(d), before
implementation.
(f) The test systems must be
monitored in conformity with the
protocol.
(g) Specimens must be identified by
test system, study, nature, and date of
collection. This information must be
located on the specimen container or
must accompany the specimen in a
manner that precludes error in the
recording and storage of data.
(h) Records of gross findings for a
specimen from post mortem
observations must be available to a
pathologist when examining that
specimen histopathologically, unless
specified otherwise in the study
protocol.
■ 30. Add § 58.180 to subpart J to read
as follows:
§ 58.180
Data quality and integrity.
(a) All data generated during the
conduct of a nonclinical laboratory
study must be accurate, legible,
contemporaneous, original, and
attributable (ALCOA). Also, data must
be credible, internally consistent, and
corroborated.
(b) All data must be recorded
indelibly, directly, and promptly to a
permanent medium at the time of
observation and must identify
unambiguously the person entering the
data. Any change to any entry must be
made so as not to obscure the original
entry, must indicate the reason for such
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change, must indicate when the change
was made, and must identify who made
the change. When data are either
captured or maintained, or both
captured and maintained electronically,
these requirements are fulfilled by the
use of an electronic records system fully
compliant with applicable regulations.
(c) All data accrued as required in
paragraphs (a) and (b) of this section
must be included in the final study
report.
■ 31. Revise § 58.185 to read as follows:
asabaliauskas on DSK3SPTVN1PROD with PROPOSALS
§ 58.185 Reporting of nonclinical
laboratory study results.
(a) A final study report must be
prepared for each nonclinical laboratory
study and must include the following:
(1) Name and address of the testing
facility and the dates on which the
study was initiated and completed. For
multisite studies, additionally the name
and address of any person conducting a
phase of the nonclinical laboratory
study, including the location of all
independent contributing scientists.
(2) Names of the attending
veterinarians for all phases of the
nonclinical laboratory study that
included the use of animals.
(3) Objectives and procedures stated
in the approved protocol, including any
changes in the original protocol.
(4) Statistical methods employed for
analyzing the data.
(5) Test, control, and reference articles
identified by:
(i) Name;
(ii) Chemical Abstract Service (CAS)
number or code number, where such
identification exists;
(iii) Strength, purity, and composition
or other appropriate characteristics, and
for tobacco products as described in
§ 58.105(a);
(iv) The name and address of the
manufacturer(s); and
(v) The name and address of the
person(s) conducting the testing to
define their characteristics, as
applicable.
(6) Stability of test, control, and
reference articles under the conditions
of administration, including the name
and address of the person(s) conducting
the testing.
(7) A description of the methods used,
including methods for the control of
bias in the conduct of the study and the
analysis and reporting of test results.
(8) A description of the test system
used. Where applicable, the final study
report must include the number of
animals used, sex, body weight range,
source of supply, species, strain and
substrain, age, and procedure used for
identification.
(9) A description of the dosage,
dosage regimen, route of administration,
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and duration, including the results of
testing conducted to determine the
concentration, uniformity, and stability
of mixtures of articles with carriers, as
applicable, and the name and address of
the person conducting the testing.
(10) A description of all
circumstances that may have affected
the quality or integrity of the data,
including those documented by the
study director as described in
§ 58.33(b)(9) and all health-related
issues reported by an attending
veterinarian or appropriately designated
personnel during the course of the study
as described in § 58.90(b) and (c).
(11) The name and affiliation of the
study director, the names of all
contributing scientists, principal
investigators, and other professionals,
the sponsor, and all supervisory
personnel who were involved in the
study or in the preparation or review of
the final study report.
(12) A description of the
transformations, calculations, or
operations performed on the data, a
summary and analysis of the data, and
a statement of the conclusions drawn
from the analysis.
(13) The original, and any amended,
signed and dated reports of each of the
contributing scientists, principal
investigators, or any other person
involved in the study, including each
person who conducted an analysis or
evaluation of data or specimens from
the study after data generation was
completed. These reports must contain
all data generated.
(14) The locations where all
specimens, reserve samples, raw data,
and the final study report are to be
stored.
(15) The statement prepared and
signed by the responsible QAU as
described in § 58.35(b)(11).
(16) A statement by the study director
of the study’s extent of compliance with
this part, including a discussion of any
study deviations found to impact the
integrity of the study as described in
§ 58.185(a)(10).
(b) The final report must be signed
and dated by the study director.
(c) Corrections or additions to a final
report must be in the form of an
amendment by the study director. The
amendment must clearly identify that
part of the final report that is being
added to or corrected and the reasons
for the correction or addition, and must
be signed and dated by the person
responsible.
(d) If for any reason a study is
discontinued before completion, the
study director must write, sign, and date
a short summary report closing the
study. This report must discuss the
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reasons for closure and must be
archived, along with all study material,
as described in § 58.190.
■ 32. Revise § 58.190 to read as follows:
§ 58.190 Storage and retrieval of records
and data.
(a) All raw data, documentation,
protocols, final reports, reserve samples,
and specimens (except those specimens
obtained from mutagenicity tests and
wet specimens of blood, urine, feces,
and biological fluids) generated as a
result of a nonclinical laboratory study
must be retained. Correspondence and
other documents relating to
interpretation and evaluation of data,
other than those documents contained
in the final study report, must also be
retained.
(b) There must be archives for orderly
storage and expedient retrieval of all
raw data, documentation, protocols,
specimens, and interim and final
reports. Conditions of storage must
minimize deterioration of the
documents or specimens in accordance
with the requirements for the time
period of their retention and the nature
of the documents or specimens. A
testing facility may contract with
commercial archives to provide a
repository for all material to be retained.
Raw data and specimens may be
retained elsewhere provided that the
archives have specific reference to those
other locations.
(c) Material retained or referred to in
the archives must be indexed to permit
expedient retrieval.
(d) All study material described in
paragraph (a) of this section must be
archived no later than 2 weeks after the
study completion date (as defined in
§ 58.3).
(e) If a sponsor delays completion of
the final study report, the study director
must complete, sign, and date the final
study report and archive all study
material no later than 6 months after
completion of the last draft of the final
study report.
(f) If a study sponsor halts a
nonclinical laboratory study before all
protocol-required testing is completed, a
decision that the study is discontinued
must be made no later than 6 months
after the study was stopped. Once the
study has been determined to be
discontinued, the study director must
prepare a summary report, as required
by § 58.185(d). The summary report and
all study material must be archived no
later than 2 weeks after the study
director signs the summary report.
(g) An individual must be identified
as responsible for the archives.
Archiving specifications for multisite
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studies must also be included in the
approved study protocol.
(h) Only authorized personnel can
have access to the archives.
(i) SOPs regarding archiving, required
in § 58.81(b)(13), must include specific
procedures for removal of study
materials from the archives, including
maximum timeframes material can
remain outside of the archives.
■ 33. Revise § 58.195 to read as follows:
asabaliauskas on DSK3SPTVN1PROD with PROPOSALS
§ 58.195
Retention of records.
(a) Record retention requirements set
forth in this section do not supersede
the record retention requirements of any
other regulations in this chapter nor do
they supersede any other legal
requirements elsewhere in applicable
statutes or regulations.
(b) Except as provided in paragraph
(c) of this section, all raw data,
documentation, protocols, final study
reports, reserve samples, and specimens
pertaining to a nonclinical laboratory
study and required to be made by this
part must be retained in the archive(s)
for whichever of the following periods
is shortest:
(1) A period of at least 2 years
following the date on which an
application or submission to FDA, in
support of which the results of the
nonclinical laboratory study were
submitted, is approved or cleared by
FDA, a premarket authorization is
issued, or the application or submission
is administratively closed. This
requirement does not apply to studies
supporting investigational new drug
applications (INDs) or applications for
investigational device exemptions
(IDEs), records of which are governed by
the provisions of paragraph (b)(2) of this
section.
(2) A period of at least 5 years
following the date on which the results
of the nonclinical laboratory study are
submitted to FDA in support of an
application or submission.
(3) In other situations (e.g., where the
nonclinical laboratory study does not
result in the submission of the study in
support of an application or submission
to FDA), a period of at least 2 years
following the study completion date or
the date on which the study is
terminated or discontinued.
(c) Wet specimens (except those
specimens obtained from mutagenicity
tests and wet specimens of blood, urine,
feces, and biological fluids), samples of
test, control, and reference articles, and
specially prepared material, which are
relatively fragile and differ markedly in
stability and quality during storage,
must be retained only as long as the
quality of the preparation affords
evaluation. In no case is retention
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required for longer periods than those
set forth in paragraphs (a) and (b) of this
section.
(d) Management with executive
responsibility must ensure maintenance
of the master schedule and copies of
study protocols, as specified in SOPs as
described in § 58.81(b)(13) and as
specified in paragraphs (a) and (b) of
this section. QAUs must maintain
records of QAU inspections, as required
by § 58.35(c) for the period of time
specified in paragraphs (a) and (b) of
this section.
(e) Summaries of training and
experience and job descriptions
required to be maintained by § 58.29(d)
may be retained along with all other
employment records for the length of
time specified in paragraphs (a) and (b)
of this section.
(f) Records and reports of the
maintenance and calibration and
inspection of equipment, as required by
§ 58.63(b) and (c), must be retained for
the length of time specified in paragraph
(b) of this section.
(g) Records required by this part may
be retained either as original records or
as true copies that maintain the original
intent and meaning and are made
according to the person’s SOPs as
described in § 58.81(b)(22).
(h) If a facility conducting nonclinical
laboratory testing goes out of business or
for any reason can no longer serve as the
archive site for a particular study, all
raw data, documentation, and other
material specified in this section must
be transferred to the archives of the
sponsor of the study or to another
appropriate archive facility. The facility
must notify FDA in writing (and the
study sponsor if not the recipient of the
study material) of the transfer no later
than 10 working days after the transfer
occurs.
(i) A copy of the notification of
change of archive site, as required by
paragraph (h) of this section, can serve
as the amendment to the final study
report required in § 58.185(c) when
appended to that report.
■ 34. Revise the heading of subpart K to
read as follows:
Subpart K—Disqualification of Any
Person Conducting a Phase of a
Nonclinical Laboratory Study
■
35. Revise § 58.200 to read as follows:
§ 58.200
Purpose.
(a) The purposes of disqualification
are:
(1) To permit the exclusion from
consideration of completed studies for
which a phase was conducted by any
person failing to comply with the
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requirements of the GLP regulations
until it can be adequately demonstrated
that such noncompliance did not occur
during, or did not affect the validity or
acceptability of data generated by, a
particular study; and
(2) To exclude from consideration all
studies completed after the date of
disqualification until the disqualified
person can satisfy the Commissioner
that it will conduct studies in
compliance with such regulations.
(b) The determination that a
nonclinical laboratory study may not be
considered in support of an application
or submission to FDA does not,
however, relieve the applicant of any
obligation under any other applicable
regulation to submit the results of the
study to FDA.
■ 36. Revise § 58.202 to read as follows:
§ 58.202
Grounds for disqualification.
FDA may disqualify any person
conducting a phase of a nonclinical
laboratory study upon finding that
person repeatedly or deliberately failed
to comply with one or more of the
regulations set forth in this part (or any
other regulations regarding such
facilities in this chapter) or repeatedly
or deliberately submitted false
information in any required report.
■ 37. In § 58.204, revise paragraph (a) to
read as follows:
§ 58.204 Notice of and opportunity for
hearing on proposed disqualification.
(a) Whenever FDA has information
indicating that grounds exist under
§ 58.202, which justifies disqualification
of any person conducting a phase of a
nonclinical laboratory study, FDA may
issue to that person a written notice
proposing that person be disqualified.
*
*
*
*
*
■ 38. Revise § 58.206 to read as follows:
§ 58.206
Final order on disqualification.
(a) If the Commissioner, after the
regulatory hearing, or after the time for
requesting a hearing expires without a
request being made, upon an evaluation
of the administrative record of the
disqualification proceeding, makes the
findings required in § 58.202, the
Commissioner issues a final order
disqualifying that person. Such order
must include a statement of the basis for
that determination. Upon issuing a final
order, the Commissioner notifies (with a
copy of the order) the disqualified
person of the action. The notification
also will explain that a person who is
disqualified under this part will be
ineligible to receive a test article under
part 511 of this chapter. A clinical
investigator ineligible to receive a test
article under part 511 of this chapter
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will be ineligible to conduct any
nonclinical laboratory study intended to
support an application for a research or
marketing permit for a new animal drug.
(b) If the Commissioner, after a
regulatory hearing or after the time for
requesting a hearing expires without a
request being made, upon an evaluation
of the administrative record of the
disqualification proceeding, does not
make the findings required in § 58.202,
the Commissioner issues a final order
terminating the disqualification
proceeding. Such order must include a
statement of the basis for that
determination. Upon issuing a final
order the Commissioner notifies that
person and provides a copy of the order.
■ 39. Revise § 58.210 to read as follows:
asabaliauskas on DSK3SPTVN1PROD with PROPOSALS
§ 58.210
Actions upon disqualification.
(a) Once a person has been
disqualified, each application and
submission to FDA containing or relying
upon any nonclinical laboratory study
for which a phase was conducted by the
disqualified person may be examined to
determine whether such study was or
would be essential to a decision. If it is
determined that a study was or would
be essential, FDA must also determine
whether the study is acceptable,
notwithstanding the disqualification of
that person. Any study for which a
phase was conducted by the
disqualified person before
disqualification may be presumed to be
unacceptable, and the person relying on
the study may be required to establish
that the study was not affected by the
circumstances that led to the
disqualification, e.g., by submitting
validating information. If the study is
then determined to be unacceptable,
such data will be eliminated from
consideration in support of the
application or submission to FDA and
such elimination may serve as new
information justifying appropriate
regulatory action.
(b) No nonclinical laboratory study for
which any phase was begun by a
disqualified person after the date of that
person’s disqualification can be
considered in support of any
application or submission to FDA,
unless the disqualified person has been
reinstated under § 58.219. The
determination that a study may not be
considered in support of an application
or submission to FDA does not,
however, relieve the applicant of any
obligation under any other applicable
regulation to submit the results of the
study to FDA.
■ 40. Revise § 58.213 to read as follows:
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§ 58.213 Public disclosure of information
regarding disqualification.
(a) Upon issuance of a final order
disqualifying a person under
§ 58.206(a), the Commissioner may
notify all or any interested persons.
Such notice may be given at the
discretion of the Commissioner
whenever the Commissioner believes
that such disclosure would further the
public interest or would promote
compliance with the GLP regulations set
forth in this part. Such notice, if given,
must include a copy of the final order
issued under § 58.206(a) and must state
that the disqualification constitutes a
determination by FDA that nonclinical
laboratory studies for which a phase
was performed by the disqualified
person will not be considered by FDA
in support of any application or
submission to FDA. If such notice is
sent to another Federal Government
agency, FDA will recommend that the
agency also consider whether or not it
should accept nonclinical laboratory
studies for which a phase was
performed by the disqualified person. If
such notice is sent to any other person,
it states that it is given because of the
relationship between the disqualified
person and the person being notified
and that FDA is not advising or
recommending that any action be taken
by the person notified.
(b) A determination that a person has
been disqualified and the administrative
record regarding such determination are
disclosable to the public under part 20
of this chapter.
■ 41. Revise § 58.215 to read as follows:
§ 58.215 Alternative or additional actions
to disqualification.
(a) Disqualification of any person
under this subpart is independent of,
and neither in lieu of nor a precondition
to, other proceedings or actions
authorized by the Federal Food, Drug,
and Cosmetic Act. FDA may, at any
time, institute against a disqualified
person or against the sponsor of a
nonclinical laboratory study that has
been submitted to FDA, or both, any
appropriate judicial proceedings (civil
or criminal) and any other appropriate
regulatory action, including civil money
penalties, in addition to or in lieu of,
and before, simultaneously with, or
subsequent to, disqualification. FDA
may also refer the matter to another
Federal, State, or local government law
enforcement or regulatory agency for
such action as that agency deems
appropriate.
(b) FDA may refuse to consider any
particular nonclinical laboratory study
in support of an application or
submission to FDA, if it finds that the
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study was not conducted according to
the GLP regulations set forth in this
part, without disqualifying any person
that conducted one or more phases of
the study or undertaking other
regulatory action.
■ 42. Revise § 58.217 to read as follows:
§ 58.217 Suspension or termination of any
person conducting a phase of a nonclinical
laboratory study by a sponsor.
Termination of any person conducting
a phase of a nonclinical laboratory study
by a sponsor is independent of, and
neither in lieu of nor a precondition to,
proceedings or actions authorized by
this subpart. If a sponsor terminates or
suspends any person conducting a
phase of a nonclinical laboratory study
from further participation in a study
that is being conducted as part of any
application or submission to FDA that
has been submitted to any Center of
FDA (whether approved or cleared,
premarket authorization issued, or
administratively closed), the sponsor
must notify that Center in writing
within 15 working days of the action;
the notice must include a statement of
the reasons for such action. Suspension
or termination of any person conducting
a phase of a nonclinical laboratory study
by a sponsor does not relieve the
sponsor of any obligation under any
other applicable regulation to submit
the results of the study to FDA.
■ 43. Revise § 58.219 to read as follows:
§ 58.219
person.
Reinstatement of a disqualified
Any person that has been disqualified
may be reinstated as an acceptable
source of data for a phase of a
nonclinical laboratory study to be
submitted to FDA if the Commissioner
determines, upon an evaluation of
materials submitted by that person, as
well as the results from an FDA
inspection of that person, that
procedures are in place that would
allow that person to conduct a phase of
future nonclinical laboratory studies in
compliance with the GLP regulations set
forth in this part. As noted in
§ 58.210(b), no nonclinical laboratory
study for which a phase was begun by
a disqualified person after the date of
that person’s disqualification is
considered in support of any
application or submission to FDA,
unless that person has been reinstated.
A disqualified person that wishes to be
so reinstated must present in writing to
the Commissioner reasons why it
believes it should be reinstated and a
detailed description of the corrective
actions it has taken or intends to take to
assure that the acts or omissions which
led to its disqualification will not recur.
E:\FR\FM\24AUP5.SGM
24AUP5
58380
Federal Register / Vol. 81, No. 164 / Wednesday, August 24, 2016 / Proposed Rules
asabaliauskas on DSK3SPTVN1PROD with PROPOSALS
The disqualified person must also state
its availability for inspection. If a
disqualified person is reinstated, the
Commissioner must so notify that
person and all organizations and
persons who were notified, under
VerDate Sep<11>2014
22:10 Aug 23, 2016
Jkt 238001
§ 58.213 of the disqualification of that
person. A determination that a
disqualified person has been reinstated
is disclosable to the public under part
20 of this chapter.
PO 00000
Dated: August 16, 2016.
Peter Lurie,
Associate Commissioner for Public Health
Strategy and Analysis.
[FR Doc. 2016–19875 Filed 8–23–16; 8:45 am]
BILLING CODE 4164–01–P
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Agencies
[Federal Register Volume 81, Number 164 (Wednesday, August 24, 2016)]
[Proposed Rules]
[Pages 58341-58380]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-19875]
[[Page 58341]]
Vol. 81
Wednesday,
No. 164
August 24, 2016
Part VI
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Parts 16 and 58
Good Laboratory Practice for Nonclinical Laboratory Studies; Proposed
Rule
Federal Register / Vol. 81 , No. 164 / Wednesday, August 24, 2016 /
Proposed Rules
[[Page 58342]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 16 and 58
[Docket No. FDA-2010-N-0548]
Good Laboratory Practice for Nonclinical Laboratory Studies
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
the regulations for good laboratory practice (GLP) for nonclinical
laboratory studies to require a complete quality system approach,
referred to as a GLP Quality System, when safety and toxicity studies
support or are intended to support applications or submissions for
products regulated by FDA. We are proposing additional management
responsibilities and standard operating procedures (SOPs) consistent
with the proposed requirement for a GLP Quality System. We also propose
to revise the testing facility definition to reflect current practices
for the conduct of nonclinical laboratory studies, particularly
multisite studies. These proposals are intended to build quality into
planning, conducting, and reporting a nonclinical laboratory study and
to help ensure data quality and integrity.
DATES: Submit either electronic or written comments on the proposed
rule by November 22, 2016. Submit comments on information collection
issues under the Paperwork Reduction Act of 1995 by September 23, 2016
see section IX). See section VII for the proposed effective date of a
final rule based on this proposed rule.
ADDRESSES: You may submit comments as follows:
Electronic Submissions
Submit electronic comments in the following way:
Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
If you want to submit a comment with confidential
information that you do not wish to be made available to the public
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').
Written/Paper Submissions
Submit written/paper submissions as follows:
Mail/Hand delivery/Courier (for written/paper
submissions): Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
For written/paper comments submitted to the Division of
Dockets Management, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-2010-N-0548 for ``Good Laboratory Practice for Nonclinical
Laboratory Studies.'' Received comments will be placed in the docket
and, except for those submitted as ``Confidential Submissions,''
publicly viewable at https://www.regulations.gov or at the Division of
Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.
Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Division of Dockets Management. If you do not
wish your name and contact information to be made publicly available,
you can provide this information on the cover sheet and not in the body
of your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: https://www.fda.gov/regulatoryinformation/dockets/default.htm.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Division of Dockets Management, 5630 Fishers
Lane, Rm. 1061, Rockville, MD 20852.
Submit comments on information collection issues to the Office of
Management and Budget (OMB) in the following ways:
Fax to the Office of Information and Regulatory Affairs, OMB, Attn:
FDA Desk Officer, FAX: 202-395-7285, or email to
oira_submission@omb.eop.gov. All comments should be identified with the
title, ``Reporting and Recordkeeping Requirements for Good Laboratory
Practice for Nonclinical Laboratory Studies.''
FOR FURTHER INFORMATION CONTACT: Vernon Toelle, Office of Surveillance
and Compliance, Center for Veterinary Medicine, Food and Drug
Administration, 7519 Standish Pl., MPN4-142, Rockville, MD 20855, 240-
402-5637; or Kristin Webster Maloney, Office of Policy and Risk
Management, Office of Regulatory Affairs, Food and Drug Administration,
10903 New Hampshire Ave., Bldg. 32, Rm. 4373, Silver Spring, MD 20993,
240-402-4993.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Executive Summary
A. Purpose of the Proposed Rule
B. Summary of the Major Provisions of the Proposed Rule
C. Legal Authority
D. Costs and Benefits
II. Introduction
A. What is the background for this rule?
B. Why is FDA proposing this rule?
III. Description of the Part 58 Proposal
A. What did FDA consider when drafting this rule?
B. Part 58, Subpart A--General Provisions
C. Part 58, Subpart B--Organization and Personnel
D. Part 58, Subpart C--Facilities
E. Part 58, Subpart D--Equipment
F. Part 58, Subpart E--Nonclinical Laboratory Study Operations
[[Page 58343]]
G. Part 58, Subpart F--Test, Control, and Reference Articles
H. Part 58, Subpart G--Protocol for and Conduct of a Nonclinical
Laboratory Study
I. Part 58, Subpart J--Records and Reports
J. Part 58, Subpart K--Disqualification of Any Person Conducting
a Phase of a Nonclinical Laboratory Study
IV. Regulatory Hearing Before FDA
V. Analysis of Environmental Impact
VI. Legal Authority
VII. Proposed Implementation Plan
VIII. Economic Analysis of Impacts
A. Introduction
B. Summary
IX. Paperwork Reduction Act of 1995
X. Federalism
XI. References
I. Executive Summary
A. Purpose of the Proposed Rule
Nonclinical laboratory studies, often referred to as preclinical
studies when conducted before first-in-human clinical studies, provide
safety or toxicity information, or both, that is essential for the
development of FDA-regulated products and help determine the safety of
new food ingredients. For drugs administered to animals whose products
will be consumed by humans, nonclinical laboratory studies are critical
for determining safe levels of residual drug product. For tobacco
products, nonclinical laboratory studies may provide evidence regarding
the relative toxicities of new or modified risk tobacco products. FDA's
regulation of the conduct of nonclinical laboratory studies is
important to help ensure the quality and integrity of data derived from
those studies, the protection of human subjects, and that marketing
decisions are based on accurate and reliable data.
Therefore, FDA proposes to amend the GLP regulations to require the
use of a complete quality system approach (proposed GLP Quality System)
when a nonclinical laboratory study supports or is intended to support
an application or submission to FDA. Part 58 (21 CFR part 58) presently
includes many aspects of a quality system approach. However, certain
fundamentals of a fully implemented GLP Quality System considered
essential to a quality system, such as certain SOPs and adequate
management roles, responsibilities, and accountability, are not
presently required. We therefore propose a fully implemented GLP
Quality System as the proper framework for building quality into
planning, conducting, and reporting a nonclinical laboratory study to
help ensure the quality and integrity of the resulting data used to
support FDA regulatory decisions.
We also propose to amend the GLP regulations to reflect current
practices for the conduct of nonclinical laboratory studies,
particularly multisite studies, while allowing industry flexibility to
meet the proposed requirements.
B. Summary of the Major Provisions of the Proposed Rule
Under the proposed GLP Quality System, FDA intends to enhance the
current quality system approach for nonclinical laboratory studies. The
GLP Quality System will provide additional responsibilities for testing
facility management and new responsibilities for maintaining SOPs. We
propose modifications to the definition of a testing facility to be
applicable to all nonclinical laboratory studies, whether they are
conducted at a single facility or at multiple sites. We propose
amending roles and functions consistent with the revised testing
facility definition. FDA expects that a GLP Quality System will provide
the appropriate framework for building quality into a nonclinical
laboratory study and will result in more reliable data for FDA to
consider when making regulatory decisions.
C. Legal Authority
FDA proposes to issue this rule under the authority of the
provisions in sections 351 and 354-360F of the Public Health Service
Act (PHS Act) and the provisions in the Federal Food, Drug, and
Cosmetic Act (the FD&C Act) applicable to the conduct of nonclincial
laboratory studies, specifically under section 701(a) of the FD&C Act
(21 U.S.C. 371(a), as essential to enforcement of the Agency's
responsibilities under sections 402, 406, 408, 409, 501, 502, 503, 505,
510, 512-516, 518-520, 571, 721, 801, 905, 910, and 911 of the FD&C Act
(21 U.S.C. 342, 346, 348, 349, 351, 352, 353, 355, 360, 360b-360f,
360h-360j, 360ccc, 379, 381, 387e, 387j, and 387k).
D. Costs and Benefits
Costs estimates of the rule include annual costs from the
additional reporting and recordkeeping responsibilities required under
the proposed GLP Quality System. One-time costs include reading and
understanding the rule, updating existing SOPs, writing new SOPs, and
training. We estimate annualized costs, over a 10-year period, at a 7-
percent discount rate would average $51.9 million, or $51.5 million
with a 3-percent discount rate. We lack sufficient information to
quantify the benefits of the proposed rule, but we anticipate that it
would result in better quality and more reliable data to support
applications and submissions to us. The table summarizes these
estimates along with their ranges.
Summary of Benefits, Costs and Distributional Effects of Proposed Rule
--------------------------------------------------------------------------------------------------------------------------------------------------------
Units
------------------------------------------------
Category Primary Low estimate High estimate Period Notes
estimate Year dollars Discount rate covered
(%) (years)
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Benefits:
Annualized.......................... .............. .............. .............. 2014 7 10
Monetized $millions/year............ .............. .............. .............. 2014 3 10
Annualized.......................... .............. .............. .............. 2014 7 10
Quantified.......................... .............. .............. .............. 2014 3 10
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Qualitative......................... The proposed rule would clarify GLP standards
to facilitate a more consistent approach and
provide greater international consistency. As
a result, we anticipate improvements in the
integrity and quality of data submitted for
FDA review decisions.
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Costs:
[[Page 58344]]
Annualized.......................... $51.9 $34.4 $69.3 2014 7 10
Monetized $millions/year............ 51.5 34.2 68.9 2014 3 10
Annualized.......................... .............. .............. .............. 2014 7 10
Quantified.......................... .............. .............. .............. 2014 3 10
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Qualitative:
Federal............................. .............. .............. .............. 2014 7 10
Annualized.......................... .............. .............. .............. 2014 3 10
---------------------------------------------------------------------------------------------------------------
Monetized millions/year............. From:
To:
---------------------------------------------------------------------------------------------------------------
Transfers:
Other............................... .............. .............. .............. 2014 7 10
Annualized.......................... .............. .............. .............. 2014 3 10
---------------------------------------------------------------------------------------------------------------
Monetized millions/year............. From:
To:
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Effects: State, Local or Tribal Government: None estimated.
Small Business: The proposed requirements would likely impose a significant burden on small entities employing
fewer than 10 workers in ``Dental Equipment and Supplies'' (between 1.87 and 8.94 percent of average annual
sales). However, we do not have data on how many of these dental-equipment small entities perform nonclinical
laboratory studies to support, or intended to support, an application or submission regulated by us; only such
entities would be affected by the rule.
Wages: None estimated.
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II. Introduction
FDA is proposing to amend the GLP regulations in part 58 to require
the use of a complete quality system approach, referred to as a GLP
Quality System, for the conduct of nonclinical laboratory studies when
safety or toxicity studies, or both, support or are intended to support
applications or submissions to FDA. FDA proposes to define a GLP
Quality System as the organizational structure, responsibilities,
procedures, processes, and resources for implementing quality
management in the conduct of nonclinical laboratory studies.
While many aspects of a quality system approach are presently
included in part 58, we expect that implementation of a GLP Quality
System will provide an improved framework that is more flexible and
will help ensure quality in planning, conducting, and reporting
nonclinical laboratory studies. Consistent with the proposed
requirement for a GLP Quality System, we propose additional management
responsibilities, with accompanying SOPs, to ensure management's
responsibility for establishing and maintaining the quality system. We
also propose to revise the definition of a testing facility to reflect
current practices for the conduct of nonclinical laboratory studies,
particularly the conduct of multisite studies. Conforming modifications
are proposed for consistency with the proposed GLP Quality System and
today's prevalence of multisite studies.
FDA is proposing these changes to help ensure the quality and
integrity of data from nonclinical laboratory studies conducted in
support of applications and submissions to FDA. We also are modernizing
the regulations to further the Agency's efforts to encourage the
implementation of the principles of the ``3Rs,'' to reduce, refine, and
replace animal use in testing. This approach seeks to minimize the use
of animals in such testing and promote more humane, appropriate, and
specific test methods for evaluating product safety. These proposed
changes will clarify and update the regulations. In particular, we are
proposing changes recognizing the current prevalence of multisite
studies while adding flexibility consistent with current practices and
the use of ever-changing technology.
A. What is the background for this rule?
On December 21, 2010, FDA published an advanced notice of proposed
rulemaking (ANPRM), ``Good Laboratory Practice for Nonclinical
Laboratory Studies'' (December 2010 ANPRM) (75 FR 80011), to solicit
stakeholder input regarding FDA's intention to modify the GLP
regulations in part 58. As stated in the December 2010 ANPRM, FDA is
proposing to require that all facilities conduct nonclinical laboratory
studies under a GLP Quality System when those studies support or are
intended to support an application or submission to FDA.
The December 2010 ANPRM addressed nine specific areas to consider
for amending part 58. Those nine areas are: (1) The GLP Quality System,
(2) Multisite Studies, (3) Electronic/Computerized Systems, (4) Sponsor
Responsibilities, (5) Animal Welfare, (6) Information on Quality
Assurance Inspection Findings, (7) Process-Based Systems Inspections,
(8) Test and Control Article Information, and (9) Sample Storage
Container Retention.
FDA received about 90 comments to the December 2010 ANPRM. Most of
the comments address the nine specific areas; however, a number of the
comments include additional areas for FDA's consideration. All comments
were reviewed and considered by a working group with representatives
from all FDA Centers, along with representatives from the U.S.
Environmental Protection Agency (EPA), the Animal and Plant Health
Inspection Service of the U.S.
[[Page 58345]]
Department of Agriculture (USDA/APHIS), and the Office of Laboratory
Animal Welfare at the National Institutes of Health (NIH/OLAW).
In addition to the December 2010 ANPRM comments, we reviewed and
considered the documents of the working group on GLP of the
Organisation for Economic Co-operation and Development (OECD),
including the general principles of GLP and consensus and advisory
documents (Ref. 1). The United States is a signatory to OECD's GLP
Mutual Acceptance of Data agreement (Ref. 2) and, as an OECD member
country, FDA participated in the development of OECD's GLP documents.
For this proposal, we strive for consistency with the relevant OECD
documents whenever possible.
B. Why is FDA proposing this rule?
The proposed GLP Quality System would help to provide a flexible
framework for building quality into planning, conducting, and reporting
a nonclinical laboratory study, and would help ensure the integrity of
data submitted to FDA to support FDA regulatory decisions. The present
regulations do not require certain fundamentals considered essential to
a complete quality system. For example, the present regulations do not
specifically require SOPs for developing and maintaining SOPs, or SOPs
for developing and periodically assessing a quality system, nor do they
provide for adequate management roles, responsibilities, and
accountability. We note that a major principle of a complete quality
system is management's ultimate responsibility for establishing and
maintaining the quality system.
This proposal also is intended to update the regulations to reflect
today's conduct of nonclinical laboratory studies, particularly the
conduct of multisite studies. For multisite studies that may have
multiple contracts and subcontracts for various study phases, effective
communication is essential, especially considering the proposed
requirement for a single final study report. We agree with the numerous
comments to the December 2010 ANPRM that support a clear delineation of
study responsibilities and effective communication among all parties
involved in multisite studies.
Some stakeholders suggest that certain provisions in part 58 are
outdated and hamper efficient use of present technology (for example,
requiring hard copies of records and documentation instead of allowing
computerized options). Several industry organizations approached FDA
after the announcement of the Bioresearch Monitoring (BIMO)
Modernization Initiative in 2006 (Ref. 3), requesting that we modernize
the GLP regulations. One request, among others, was to remove the
requirement that the quality assurance unit (QAU) must maintain the
master schedule and copies of protocols. These requests were echoed in
several comments to the December 2010 ANPRM. FDA agrees with those
comments and proposes to update part 58 to help address the use of
present technology.
Because the number of FDA inspections is limited by competing
priorities and limited resources, we look to sponsors and nonclinical
laboratory management to help ensure that data submitted to FDA in
support of applications and submissions are reliable. For those
nonclinical laboratory studies that are the bases for allowing a new
medical product into first-in-human clinical studies, the quality and
integrity of the data are crucial to human subject protection.
This proposal complements the intent of the original GLP proposed
rule to ensure the quality and integrity of the resulting data (41 FR
51206 at 51210, November 19, 1976) (Ref. 4). FDA expects that requiring
a GLP Quality System will help ensure data quality and integrity. The
proposed GLP Quality System also will allow the flexibility to develop
site-specific procedures for related SOPs. Because of the great
diversity in institutions, research activities, and organizational
structures covered by these regulations, it is important to have
sufficient flexibility in the regulations to allow the regulated
parties to meet these requirements in a manner that best suits their
organizational needs.
III. Description of the Part 58 Proposal
A. What did FDA consider when drafting this rule?
1. Animal Rule
Several comments to the December 2010 ANPRM requested that FDA
modify part 58 to accommodate studies conducted in animals to support
the effectiveness of human drugs or biological products when human
efficacy studies are not ethical or feasible. Those comments refer to
the ``Animal Rule'' (21 CFR parts 314 and 601) (67 FR 37988, May 31,
2002).
The Animal Rule provides a pathway for FDA to grant marketing
approval based on adequate and well-controlled animal efficacy studies
when the results of those studies establish that the drugs or
biological products are reasonably likely to produce clinical benefit
in humans. Products evaluated for efficacy under the Animal Rule should
be evaluated for safety under the existing requirements for
establishing the safety of new drugs and biological products. The
provisions in part 314, subpart I for drugs and part 601, subpart H for
biological products apply only to situations when adequate and well-
controlled human efficacy studies cannot ethically be conducted because
they would involve deliberate exposure of healthy human volunteers to a
potentially lethal or permanently disabling toxic chemical, biological,
radiological, or nuclear substance, and field trials to study the
product's effectiveness after an accidental or hostile exposure have
not been feasible.
In the past, FDA has said that ``All studies subject to this rule
must be conducted in accordance with preexisting requirements under the
good laboratory practices (21 CFR part 58) regulations'' (67 FR 37988
at 37989, May 31, 2002). FDA made this statement because part 58
includes requirements for a quality system structure to ensure the
quality and integrity of animal study data. These studies are intended
to generate data that are essential for the approval or licensure of
products intended for human use. Thus, ensuring the quality and
integrity of data from these studies is critical as they serve as
substantial evidence of effectiveness of the product.
Part 58 was issued to ensure the quality and integrity of
nonclinical laboratory studies conducted to assess the safety of FDA-
regulated products. In response to comments made to the ANPRM, FDA
questions whether any requirement presently in part 58 or in this
proposal poses a unique or disproportionate obstacle or burden on the
conduct of certain animal studies specific to product development under
the Animal Rule.
FDA, however, tentatively concludes there may be justifiable
limitations to applying GLP regulations when conducting Animal Rule-
specific studies, especially for studies using challenge agents that
require high-containment facilities (for example, biosafety level 4
(BSL-4) \1\ laboratory environments). Therefore, although part 58
embodies critical elements of a quality system to ensure data quality
[[Page 58346]]
and integrity, FDA also recognizes that some current part 58
requirements may not be appropriate, or may require modification to
address adequately data quality practices for the Animal Rule-specific
studies.
---------------------------------------------------------------------------
\1\ BSL-4 refers to the practices, safety equipment, and
safeguards required for laboratories that work with highly
infectious and lethal pathogenic microbes which cause, for example,
such lethal diseases in humans as smallpox, Ebola, or Marburg virus
hemorrhagic fever. BSL-4 is the highest biosafety level designation
possible and means that the most stringent safeguards are in place
to protect researchers, non-laboratory building occupants, the
general public, and the environment from exposure to exotic or
lethal agents.
---------------------------------------------------------------------------
Accordingly, although not included in the regulatory text portion
of this proposal, FDA is considering expanding part 58 to include the
conduct of certain Animal Rule studies that support approval or
licensure of products for human use under the established data quality
and integrity standards. We seek comment on this proposal. In
particular, we invite comment on the possibility of amending the scope
of the regulation in Sec. 58.1(a) to encompass not only nonclinical
laboratory studies, but also to include certain Animal Rule-specific
studies. Correspondingly, we are considering adding a definition in
Sec. 58.3 for ``Animal Rule-specific studies subject to GLP'' (for
purposes of this document, ``Animal Rule-specific studies subject to
GLP'' are referred to as ``covered Animal Rule studies'').
Specifically, FDA is considering including within the definition of
covered Animal Rule studies only the following types of studies to
support product approval under the Animal Rule: (1) The adequate and
well-controlled animal efficacy studies that serve as substantial
evidence of the effectiveness necessary for approval or licensure of
human drugs or biological products, respectively; (2) pharmacokinetic
and/or pharmacodynamic studies in animals used to select a dose and
regimen in humans; and (3) if seeking qualification through FDA's
Animal Model Qualification Program,\2\ the model-defining natural
history studies.3 4
---------------------------------------------------------------------------
\2\ The Animal Model Qualification Program is part of FDA's Drug
Development Tool (DDT) Qualification Program. The DDT Program
provides a framework for development and regulatory acceptance of
scientific tools for use in drug development programs. Qualification
of an animal model is not required for the approval of drugs or
licensure of biologics under the Animal Rule. For more information
about this program, see FDA's guidance for industry and FDA staff
Qualification Process for Drug Development Tools (January 2014)
(https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm230597.pdf),
and the Animal Model Qualification Program Web site: https://inside.fda.gov:9003/CDER/OfficeofTranslationalSciences/BiomarkerQualifications/ucm271856.htm.
\3\ In the context of animal model qualification, the model-
defining natural history studies are the animal studies that
establish the ranges of values of key parameters of the disease or
condition that will be specified in the context of use statement for
the qualified model and that will be used as measures of quality
control and quality assurance when the model is replicated.
\4\ Natural history studies that will not be used to support the
qualification of an animal model, as defined in footnote 2, would
not be subject to GLP regulations.
---------------------------------------------------------------------------
FDA seeks comment on the impact of expanding part 58 to include
these covered Animal Rule studies. We also request comment on what
other changes to the regulations, beyond amending the scope and
definitions, are needed to address issues unique to covered Animal Rule
studies. FDA specifically requests comments in response to the
following questions:
1. Would amending part 58 to expand the scope to include covered
Animal Rule studies establish an appropriate quality system approach to
the conduct of such studies to ensure data quality and integrity? If
not, what gaps or shortcomings would remain, and how should they be
addressed?
2. Would such an amendment provide sufficient clarity and
flexibility to sponsors and investigators? If not, what alternatives or
changes to this approach are needed?
3. FDA is considering adding a definition in part 58 for ``Animal
Rule-specific studies subject to GLP'' (referred to as ``covered Animal
Rule studies''). As discussed in section III.A.1., the proposed
definition contains three specific types of studies that would be
subject to part 58. Is the term ``Animal Rule-specific studies subject
to GLP,'' as defined in Sec. 58.3, clear and appropriately inclusive?
4. What are the benefits, challenges, and burdens of amending part
58 to include covered Animal Rule studies?
a. Would this proposed expansion of the scope in Sec. 58.1(a)
impact entities conducting covered Animal Rule studies?
b. Would the proposed expansion of the scope in Sec. 58.1(a)
impact those entities engaged in conducting nonclinical laboratory
studies to assess product safety?
c. What could be done to minimize burdens or costs, including costs
or burdens on small entities, associated with part 58 compliance for
covered Animal Rule studies?
5. Are there any challenges or differences involved in the conduct
of covered Animal Rule studies (versus nonclinical laboratory studies)
that merit different standards or establishment of a separate
regulation? If so, what are those challenges or differences, and what
alternative(s) would be preferable?
6. Based on possible differences identified in question 5, are
there any particular aspects in the current or proposed part 58 that
would be unduly difficult to meet? What changes to current part 58, or
the proposed amendments, could be made to address or accommodate these
issues? For example:
a. Would it be satisfactory to include a provision to allow on a
case-by-case basis a covered Animal Rule study sponsor to seek FDA
agreement on deviations from certain part 58 requirements that may not
be practicable to meet as follows: ``When the study is an Animal Rule-
specific study subject to GLP, FDA may agree to deviations from any
requirement of this part that it finds unnecessary to ensure the
quality and integrity of the study by written agreement with the
sponsor before the conduct of the study. In such cases, FDA's
acceptance of deviations from the requirements will be contingent upon
compliance with any alternative requirements included in that
agreement.''
b. Would it be workable or appropriate to entirely exempt covered
Animal Rule studies from certain requirements of part 58? If so, what
exemption(s) would be necessary or appropriate?
As discussed in section III.A.1., FDA considers GLP regulations to
be a well-established and relevant system for ensuring data quality and
integrity for covered Animal Rule studies. Therefore, until a final
rule is published, FDA recommends the use of the current GLP framework
(for example, definitions, procedures, roles and responsibilities, and
controls) for covered Animal Rule studies to the extent practicable,
and intends to provide more information about FDA's expectations for
adapting a GLP framework to these studies.
Before initiating covered Animal Rule studies, sponsors should
identify aspects of the studies anticipated to be challenging with
regard to GLP and propose methods for adapting the studies to ensure
the quality and integrity of the resulting data. Sponsors should submit
this information to FDA for concurrence on the data quality and
integrity plan before the studies are initiated. A guidance document is
available regarding the essential elements necessary to address
efficacy under the Animal Rule.\5\
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\5\ See FDA's guidance for industry Product Development Under
the Animal Rule (October 2015), at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM399217.pdf.
---------------------------------------------------------------------------
2. ISO 9001 and GLP Quality System
Many comments to the December 2010 ANPRM note that the
International Organization for Standardization (ISO) 9001 is very
general and not all aspects outlined in ISO 9001 are applicable to
GLPs. FDA acknowledges this.
[[Page 58347]]
However, ISO 9001 is an internationally recognized standard for quality
systems. Also, FDA's Quality System Regulation (QSR) in part 820 (21
CFR part 820) for current good manufacturing practice requirements for
medical devices was harmonized, to the extent possible, with the ISO
9001: 1994 ``Quality Systems--Model for Quality Assurance in Design,
Development, Production, Installation and Servicing.''
Some comments to the December 2010 ANPRM state that consistency
with the ISO 9001 standard would be acceptable if we retained what they
perceived as the present flexibility of the regulations. A number of
comments state that it would be beneficial to borrow elements of a
quality system from the QSR requirements in part 820 rather than
reference ISO 9001:1994. Many comments also request that we define the
operational areas necessary for broader adoption of a quality system
approach.
In this proposal, we incorporate aspects of ISO 9001:1994 that are
consistent with part 820 and our desire to propose a complete quality
system approach. For example, we propose to address establishing and
maintaining a GLP quality system by adding to part 58 certain
definitions, relevant SOPs, and management roles and responsibilities
modeled after the part 820 requirements. Our proposed additions to more
fully enable a GLP quality system will help expand the present
flexibility in part 58. Our proposals also are consistent with OECD
guidance documents for GLP wherever possible and, at the very least, do
not conflict with them.
3. Animal Welfare
Many comments to the December 2010 ANPRM note that Sec. 58.90
covers animal care and thus, FDA investigators review documentation of
animal care during GLP inspections. This is true. If animal care is not
compliant with appropriate standards, there is a high likelihood that
such noncompliance could confound the results of affected studies.
Since the good laboratory practice regulations were published, the
Animal Welfare Act has been amended and the public's perception of
animal welfare has changed. Therefore, we propose specific
responsibilities regarding animal welfare because the humane treatment
of animals in research settings is essential to the quality and
integrity of GLP studies.
Many comments to the December 2010 ANPRM state that addressing
animal welfare in part 58 would be a duplication of USDA/APHIS or the
NIH regulations. That is not our intention. FDA has a Memorandum of
Understanding (MOU) (Ref. 5) with USDA/APHIS and NIH/OLAW regarding
animal welfare oversight. FDA forwards to the relevant regulatory
agency any concerns regarding animal welfare observed during FDA
inspections for their followup. Those animal welfare observations are
not included on a Form FDA 483 (Inspectional Observations) that may be
issued at the close of an FDA inspection, unless the observations also
show noncompliance with Sec. 58.90.
While this proposal addresses animal welfare concerns, FDA supports
the use of non-animal testing methods when scientifically valid
alternatives are available. We encourage sponsors with questions about
non-animal testing methods to approach FDA early in the development
process for consultation on the suitability and acceptability of non-
animal tests for their particular product. This approach reflects FDA's
position in its May 20, 2010, citizen petition response to the
Mandatory Alternatives Petition Coalition and subsequent Agency
statements. That petition requested that FDA require only non-animal
test methods instead of corresponding animal test methods whenever such
scientifically satisfactory methods are available. (See Docket No. FDA-
2007-P-0109.)
4. Multisite Studies
As stated in the December 2010 ANPRM, FDA's intent was simply to
add new definitions relevant to roles and responsibilities specific to
multisite studies. Many comments to the December 2010 ANPRM state that
the present regulations are basically adequate and suggested only
minimal modifications.
Since publication of the December 2010 ANPRM, we have changed our
thinking concerning regulatory changes needed to address multisite
studies. For example, we have determined that amending the definition
of a testing facility will help address the current conduct of
multisite studies. We discuss in section III.B.2. our proposed changes
to that definition.
Many comments to the December 2010 ANPRM suggest that we align our
requirements regarding multisite studies with the OECD consensus
document entitled, The Application of the OECD Principles of GLP to the
Organisation and Management of Multi-Site Studies (Ref. 6). The
comments also requested that we not be as prescriptive as those OECD
directives. We agree with those comments. We reviewed and considered
this OECD consensus document and incorporated into our proposal the
same general concepts, where applicable.
5. GLP Roles and Responsibilities
We propose to maintain the current GLP roles for management, study
director, and QAU. We propose that the overarching responsibilities of
those who fulfill these roles remain as follows: Management is
responsible for establishing and maintaining conditions and procedures
necessary for the conduct of nonclinical laboratory studies compliant
with GLPs; the study director, as the sole point of study control, is
responsible for implementing those procedures in specific studies; and
the QAU is responsible for inspecting and general oversight of studies,
verifying that they are GLP compliant or recommending changes needed
for bringing them into compliance.
These responsibilities complement each other and sometimes overlap
in multiple areas, providing for a system of checks and balances. We
intend for this proposal to maintain the authority necessary for
fulfilling each of these roles while allowing maximum flexibility for
the conduct of a GLP-compliant nonclinical laboratory study.
We are interested in feedback about whether this proposal will
accomplish our goal of maintaining the necessary interrelationships
among these roles, and whether our proposal undermines any one of these
roles or fails to provide adequate flexibility.
B. Part 58, Subpart A--General Provisions
1. Scope (Sec. 58.1)
We propose to expand the scope of FDA-regulated nonclinical
laboratory studies to specifically include toxicity studies. For
purposes of this proposal, toxicity means the acute or long-term
adverse effects that could result from use of the FDA-regulated
product. While some nonclinical laboratory studies of FDA-regulated
products evaluate a product's safety, including toxicity, most are
conducted solely to determine a product's toxicity. For example, when
combined with the results of clinical trials, determination of toxicity
at various doses can inform an appropriate risk-to-benefit analysis
when relevant to FDA's consideration of a product's marketing
application or submission.
For drugs administered to animals whose products will be consumed
by humans, toxicity studies are critical for determining safe levels of
residual drug product. Nonclinical laboratory studies of food
ingredients and food contact substances provide the basis for
[[Page 58348]]
establishing levels at which a substance will not, with reasonable
certainty, be harmful under its intended conditions of use. In the
evaluation of tobacco products, FDA could use the data derived from
nonclinical laboratory studies to evaluate relative toxicity as opposed
to evaluating safety.
Additional proposed modifications to the scope in Sec. 58.1 expand
the language to include FDA jurisdictional oversight of tobacco
products as specified in the FD&C Act, sections 905, 910, and 911. We
also propose to modify and broaden ``medical devices for human use'' to
``devices'' to include FDA's Center for Veterinary Medicine (CVM),
which has jurisdiction over devices used in veterinary medicine.
In addition, we propose changing the provision ``for research and
marketing permits'' to ``applications or submissions'' for FDA-
regulated products. This proposed change will include the applications
and submissions to FDA listed in the definitions section of this
proposal.
As stated in both the preamble to the original proposed regulations
(original GLP proposed rule) (41 FR 51206 at 51210) and the preamble to
the original GLP final rule (43 FR 59986 at 59988), the GLP
``regulations are intended to ensure, as far as possible, the quality
and integrity of test data that are submitted to FDA and become the
basis for regulatory decisions made by the Agency.'' Therefore, the
phrase ``intended to support'' in present and proposed Sec. 58.1(a)
means that any nonclinical laboratory study included within the
proposed expanded scope of Part 58 that is conducted with the intent
that it may support an application or submission to FDA should be
conducted in compliance with the GLP regulations.
Also, we propose adding Sec. 58.1(c) to describe what we mean by
``where appropriate'' when used in the part 58 regulatory text. This
proposal addresses studies conducted at a single testing facility as
well as at multiple sites. We propose using ``where appropriate'' in
many of the revised or added provisions because not all requirements
are applicable to all studies. For example, a test site tasked only
with interpreting a study's histopathology would not require all of the
SOPs required for a test site responsible for multiple phases.
2. Definitions (Sec. 58.3)
The current Sec. 58.3 Definitions, is not alphabetized and
includes paragraphs (a) through (p). We propose to remove the paragraph
designations, add new definitions, modify certain current definitions,
and alphabetize the complete listing of definitions.
We propose modifying current Sec. 58.3(e) to change the defined
term from ``Application for research or marketing permit'' to
``Applications and Submissions to FDA''. We propose this change because
nonclinical laboratory studies can support applications and submissions
to FDA other than those for research and marketing. Also, in the
definition for ``Applications and Submissions to FDA'' proposed
paragraphs (1) through (35), we add certain relevant statutory or
regulatory citations for consistency.
We propose including applications and submissions for tobacco
products described in the FD&C Act. We note that FDA plans to issue
regulations under section 910(g), providing conditions under which
tobacco products intended for investigational use may be exempted from
the requirements of chapter IX of the FD&C Act. It is our intent that
applications for such investigational tobacco products will be included
within the scope of Sec. 58.3.
We also propose adding those applications and submissions for FDA-
regulated products that include nonclinical laboratory study results
but are not currently specifically included. For example, Humanitarian
Device Exemption applications are new since publishing in 1987 the last
final rule modifying part 58. We also propose expressly adding the
medical device Premarket Notification (also known as a ``510(k)''
submission).
Attending Veterinarian: We propose adding a definition for an
attending veterinarian. Our proposed definition is the same as the
definition in USDA's Animal Welfare Regulations (9 CFR 1.1) but without
specifics about educational requirements. We propose defining an
attending veterinarian as a veterinarian with training, experience, or
both in the care and management of the species being attended, with
direct or delegated authority for activities involving animals. We
propose this definition because we propose in part 58 certain
provisions about animal welfare. For example, we propose that the study
director must defer to the attending veterinarian when decisions
regarding animal welfare arise, particularly when animals are in pain
or distress.
Batch: We propose changing the definition of batch currently in
Sec. 58.3(n) to reference the relevant provisions in Sec. 58.105
(Test, control, and reference article characterization) and Sec.
58.107 (Test, control, and reference article handling). We also add
that batch means a specific quantity or lot of a reference article (see
section III.B.2.), we discuss the addition of a reference article
definition.
Contracted Person: We propose adding a definition for contracted
person to mean a person that assumes, either directly or indirectly as
an independent contractor, one or more of the responsibilities for
conducting a nonclinical laboratory study. Several comments to the
December 2010 ANPRM state that the responsibilities of all persons (any
legal entity) involved in multisite studies need to be addressed in the
regulations. We propose the use of this term to allow us to address the
comments without specifically identifying all possible contracted
entities.
The comments also request that FDA include specifics for multisite
studies as to how responsibilities are to be met and by whom. In
response to these comments, we intend that a contracted person includes
any person (for example, testing facility or individual) that the
sponsor contracts with to conduct a phase (defined activity or set of
activities) of a nonclinical laboratory study. Also, the term
contracted person includes any person that is under a subcontract to
conduct a phase of a nonclinical laboratory study.
Contributing Scientist: We propose adding and defining the term
contributing scientist. A contributing scientist is an individual
responsible for conducting, interpreting, analyzing, or performing any
service for a phase of a nonclinical laboratory study. The current
regulation in Sec. 58.185 for reporting study results refers to
``individual scientists or other professionals involved in the study''
(see Sec. 58.185(a)(12)). Our proposal replaces these scientists or
other professionals with the term contributing scientist. In addition,
when a contributing scientist is a contracted independent expert or
specialist, we use the term independent contributing scientist. See,
also, section III.C.6. where we discuss Sec. 58.37 (Contributing
scientist).
Control Article: We propose modifying the definition of control
article currently in Sec. 58.3(c) by changing ``medical device for
human use'' to ``device'' to expand the regulations to include devices
used in veterinary medicine. Also, the revised definition proposes to
include a ``tobacco product''.
Establish: For this part 58 proposal, the meaning of establish is
to define, document (in writing or electronically), and implement. We
propose adding a definition for establish to help eliminate repeating
in the applicable regulatory text the words that define establish. Our
proposed definition is identical to the
[[Page 58349]]
definition of establish in the part 820 quality system regulation in
Sec. 820.3(k).
Facility-Based Inspection: We propose introducing the term
facility-based inspection to mean a QAU inspection that covers the
general facilities and activities; for example, installations, support
systems, computer systems, training, environmental monitoring, and
equipment maintenance and calibration. This addition, along with the
definition of process-based inspection (see section III.B.2.) would
allow for greater efficiency instead of duplicating, for each study,
inspection of those general facilities and activities. Our proposed
definition also is consistent with the definition for facility-based
inspection in the OECD document, Quality Assurance and GLP (Ref. 7).
GLP Quality System: We propose adding a definition for GLP Quality
System to mean the organizational structure, responsibilities,
procedures, processes, and resources for implementing quality
management in the conduct of nonclinical laboratory studies. As
discussed in section II.B., we consider a fully implemented GLP Quality
System the proper framework for building quality into planning,
conducting, and reporting a nonclinical laboratory study while allowing
flexibility for site-specific procedures.
Lead Quality Assurance Unit: We propose adding a definition for a
lead quality assurance unit (lead QAU) meaning the QAU responsible for
quality assurance (QA) in a multisite nonclinical laboratory study. We
propose that testing facility management with executive responsibility
selects the lead QAU. The location of the lead QAU may be at the
testing facility, with another person conducting a phase of the study,
or provided through a contractual relationship. This definition is
consistent with the definition for lead QAU in the OECD consensus
document, The Application of the OECD Principles of GLP to the
Organisation and Management of Multi-Site Studies (Ref. 6).
Management with Executive Responsibility: We propose adding a
definition for management with executive responsibility to mean senior
employees of the testing facility or test site who have the authority
to establish or make changes to the quality policy and GLP Quality
System at their testing facility or test site. We note that part 820
(see Sec. 820.3(n)) adopted this term describing senior management to
be consistent with the quality system specifications in ISO 9001:1994
(61 FR 52602 at 52609, October 7, 1996).
Master Schedule: We propose adding a definition for master schedule
that means a compilation of information used for assessment of workload
and the tracking of nonclinical laboratory studies. The master schedule
will include information about all nonclinical laboratory studies
conducted. For multisite studies, the master schedule also will include
the phases conducted (see proposed 58.31(k)). Our proposed definition
of master schedule is consistent with the definition in the OECD GLP
document, OECD Principles on Good Laboratory Practice (Ref. 8). When we
discuss Sec. 58.31 (Management with executive responsibility, section
III.C.2.), we elaborate on requirements concerning the master schedule.
Multisite Study: We propose adding a definition for multisite study
to mean any study that has phases (defined in section III.B.2.)
conducted at more than one site. Our proposed definition of multisite
study is consistent with the definition in the OECD consensus document,
The Application of the OECD Principles of GLP to the Organisation and
Management of Multi-Site Studies (Ref. 6).
Nonclinical Laboratory Study: We propose modifying the current
definition in Sec. 58.3(d) for a nonclinical laboratory study to add
after ``under laboratory conditions'' the phrase ``or in the applicable
environment''. This addition recognizes that the conduct of a
nonclinical laboratory study is not limited to a traditional laboratory
environment. We propose to make clear that the purpose for conducting
nonclinical laboratory studies may be to determine relative toxicity.
For example, because tobacco products are not safe, nonclinical
laboratory studies help FDA evaluate the relative toxicities of those
products. We also propose to update the regulations by changing ``field
trials in animals'' to ``clinical investigational use in animals'',
which more accurately describes our intent. We propose a sentence
structure change in the last sentence in this definition to clarify our
intent, which is often misinterpreted due to the current sentence
structure.
Phase: We propose adding a definition for phase to mean a defined
activity or set of activities in the conduct of a nonclinical
laboratory study. We propose this new definition to aid in
understanding the new proposed definition of multisite study, which is
any study that has phases conducted at more than one site. Our proposed
definition is consistent with the definition of phase in the OECD
consensus document, The Application of the OECD Principles of GLP to
the Organisation and Management of Multi-Site Studies (Ref. 6).
Principal Investigator: We propose adding a definition for
principal investigator to mean an individual with specific
responsibilities delegated by the study director for a phase of a
nonclinical laboratory study. We propose defining principal
investigator in general terms rather than specifying the principal
investigator's single role in a multisite study as defined in the OECD
document, OECD Principles on Good Laboratory Practice (Ref. 8).
However, we propose that principal investigator responsibilities are
those delegated by the study director, which is consistent with OECD
principles. See, also, section III.C.7. where we discuss Sec. 58.39
(Principal investigator).
Process-based Inspection: We propose adding a definition for
process-based inspection to mean inspecting repetitive, frequently
performed procedures and processes (for example, certain mutagenicity
studies). This definition recognizes present practice and allows for
greater efficiency, as noted elsewhere (section III.B.2.). Our proposed
definition is consistent with the definition for process-based
inspection in the OECD document, Quality Assurance and GLP (Ref. 7).
Quality: We propose adding a definition for quality, meaning the
totality of features and characteristics bearing on the ability of a
nonclinical laboratory study to provide reliable data.
Quality Assurance Unit (QAU): We propose modifying the current
definition in Sec. 58.3(l) to remove ``except the study director'' and
``designation by testing facility management''. Also, we propose adding
a sentence ``The QAU must be entirely separate from and independent of
the personnel engaged in the direction and conduct of the particular
study.'' We propose these changes for clarity and to be consistent with
our inclusion of multisite studies and with the statement currently in
Sec. 58.35.
Quality Policy: We propose adding a definition for quality policy
that is identical to the definition in Sec. 820.3(u), meaning ``the
overall intentions and direction of an organization with respect to
quality, as established by management with executive responsibility.''
Raw Data: We propose modifying the current definition in Sec.
58.3(k) to update the regulations to address copying requirements and
computerized systems, and to specifically include the pathology report.
We propose adding to the definition that raw data means ``all
nonclinical laboratory study records and
[[Page 58350]]
documentation or exact copies that maintain the original intent and
meaning and are made according to the person's certified copy
procedures.'' This additional regulatory text eliminates the need to
provide examples of what we consider a copy. We also propose adding
``correspondence'' and ``other documentation (regardless of capture
medium)'' to the examples of raw data. The addition of ``regardless of
capture medium'' eliminates the need to provide examples of possible
capture media. Also, we propose including as raw data ``the signed and
dated pathology report'' to clarify what we consider as raw data.
Reference Article: We propose adding a definition for reference
article consistent with EPA's GLP regulations in 40 CFR 160.3 and 792.3
for defining a ``reference substance'' to mean an article used to
establish a basis for comparison of the test article for known chemical
or biological measurements. We propose this addition to acknowledge the
use of reference articles in certain studies.
Short-Term Study: We propose adding a definition for short-term
study to mean when the in-life period (study period during which data
are collected) is completed within several days or, at most, a week.
Since the pre-specified, periodic timing of process-based inspections
can result in the lack of an inspection of a short-term study, this
definition is necessary to address our proposed addition of process-
based inspections (see also the discussion of the definition of
process-based inspection in section III.B.2.).
Specimen: We propose adding ``or retention'' to the end of the
current definition of specimen in Sec. 58.3(j) to read, ``Specimen
means any material derived from a test system for examination,
analysis, or retention.'' We propose this change because a specimen may
be collected solely for retention purposes. Also, this proposed change
is consistent with the definition in the OECD GLP document, OECD
Principles on Good Laboratory Practice (Ref. 8).
Sponsor: We propose modifying the current definition of sponsor in
Sec. 58.3(f) consistent with our proposal to expand the scope of part
58, and to address possible roles of the sponsor in multisite studies.
We propose revising the current definition in Sec. 58.3(f)(3) to
include the possible roles a sponsor could play in a multisite study in
addition to initiating and supporting the study. Those roles and
applicable requirements are the same as those for a testing facility,
test site, or contributing scientist as we propose to define those
terms.
See, also, section III.B.3. where we discuss Sec. 58.5 (Sponsor
responsibilities).
Standard Operating Procedures (SOPs): We propose adding a
definition for SOPs to mean documented procedures describing how to
perform tests or activities normally not specified in detail in study
protocols. We propose this addition because many proposed modifications
in Sec. 58.31 refer to required SOPs. This definition is consistent
with the OECD GLP document, OECD Principles on Good Laboratory Practice
(Ref. 8).
Study-based Inspection: We propose adding a definition for study-
based inspection to mean the same QAU inspection specified currently in
Sec. 58.35(b)(3) for inspecting a critical operation of the study that
is scheduled according to the study's chronology or sequence of events.
Our proposed definition is consistent with the definition for study-
based inspection in the OECD consensus document, Quality Assurance and
GLP (Ref. 7).
Test Article: We propose modifying the current definition of test
article in Sec. 58.3(b) to change ``medical device for human use'' to
``device'' and to add ``tobacco product''. As discussed in section
III.B.1. concerning the scope of part 58, we propose these changes to
broaden devices to include FDA's CVM and to include FDA's jurisdiction
of tobacco products.
Test Site: We propose adding a definition for test site to mean a
``person'' (currently defined in Sec. 58.3(h)) responsible for a phase
of a multisite nonclinical laboratory study. We propose that a test
site includes management with executive responsibility and supporting
SOPs for the conduct of a nonclinical laboratory study. For a different
nonclinical laboratory study, a test site could function as a testing
facility.
Test System: We propose modifying the current definition of test
system in Sec. 58.3(i) to add ``reference'' article consistent with
our other proposed changes. See elsewhere in section III.B.2. for our
proposed definition and explanation for adding a definition of
reference article.
Testing Facility: We propose removing and replacing most of the
current definition of testing facility in current Sec. 58.3(g) to
update the regulations consistent with the conduct of multisite
nonclinical laboratory studies. Our proposed definition is as follows:
``Testing facility means a person responsible for conducting,
coordinating, or completing a nonclinical laboratory study, or any
combination thereof. The testing facility designates the study
director.''
We propose this change because, in a multisite study, the testing
facility might not be the person treating the test system with the test
article as specified in the current definition. Rather, the person
treating the test system with the test article might be a contracted or
subcontracted person. Therefore, this general definition of a testing
facility is necessary to capture all possible contractual relationships
in a multisite study.
Validation: We propose adding a definition for validation to mean
confirmation by examination and provision of objective evidence that
the particular requirements for a specific intended use of a system or
process can be consistently fulfilled. This proposed definition is
similar to the definition in Sec. 820.3(z), and addresses comments to
the December 2010 ANPRM requesting a definition for validation of a
system or process.
Vehicle: We propose adding a definition for vehicle to mean any
agent that serves as a carrier and is used to mix, disperse, or
solubilize the test, control, or reference article for administration
or application to the test system. This proposal recognizes the use of
vehicles in the conduct of nonclinical laboratory studies. Our proposed
definition is consistent with the definition of vehicle in the OECD GLP
document, OECD Principles on Good Laboratory Practice (Ref. 8), for
describing a carrier for test, control, or reference articles.
3. Sponsor Responsibilities (Sec. 58.5)
The present regulations in Sec. 58.10 cover only a sponsor's
responsibilities to notify a consulting laboratory, contractor, or
grantee that their service ``is part of a nonclinical laboratory study
that must be conducted in compliance with the provisions of this part
[part 58]''. FDA received many comments to the December 2010 ANPRM
noting that there are other sponsor responsibilities implicit
throughout the present regulations, and stating that the study sponsor
must share in the responsibility for complying with part 58. We agree
with those comments.
Therefore, we propose adding Sec. 58.5 Sponsor responsibilities,
that provides explicit provisions for the presently implied sponsor
responsibilities and adds new sponsor responsibilities. Our proposed
sponsor responsibilities are consistent with the preamble to the
original GLP proposed rule stating that the adequacy and validity of
nonclinical laboratory tests remain the responsibility of the sponsor
of the product as part of establishing the marketability of the product
(41 FR
[[Page 58351]]
51206 at 51206) (Ref. 4). In addition, we propose adding provisions
consistent with the OECD advisory document, The Role and
Responsibilities of the Sponsor in the Application of the Principles of
GLP (Ref. 9).
For each nonclinical laboratory study, we propose that the sponsor
must ensure the study protocol meets the requirements specified in
Sec. 58.120 (Protocol (see proposed Sec. 58.5(a) regulatory text,
elsewhere in this document). Also, we propose that the sponsor must
ensure the study protocol provides for the humane care of animals \6\
(see proposed Sec. 58.5(b)). We propose these additions because the
sponsor is responsible for developing the study protocol, either
directly or through a contracted person. To indicate the sponsor's
approval of the study protocol, we propose that the sponsor must sign
and date the study protocol (see proposed Sec. 58.5(c)).
---------------------------------------------------------------------------
\6\ The document, ``International Guiding Principles for
Biomedical Research Involving Animals,'' last revised in December
2012, advocates among other principles, the ``Three Rs'' of the
ethical use of animals--replacement, refinement, and reduction (Ref.
10). Additionally, the protocol must meet the requirements in Sec.
58.90 for animal care. USDA's Animal Welfare Act regulations (Code
of Federal Regulations, Title 9, Chapter1, Subchapter A, Parts 1-4)
and the Institute for Laboratory Animal Research's Guide for the
Care and Use of Laboratory Animals (Ref. 11), provide specifics
regarding the veterinary care expected when animals are used for
research.
---------------------------------------------------------------------------
For any phase of a nonclinical laboratory study that includes the
use of animals, we propose that the sponsor contract with persons
accredited as following appropriate animal welfare procedures. If, for
any reason, the sponsor does not use an accredited person for a phase
that includes the use of animals, we propose that the sponsor must
document the reason for using the non-accredited person. (See proposed
Sec. 58.5(d).) If the study supports an application or submission to
FDA, we propose requiring in the application or submission the reason
for using a non-accredited person, along with supporting information to
show the qualifications of that person, such as a copy of SOPs showing
the application of current animal welfare laws, regulations, policies,
and guidelines. This information must be included in the compliance
statement. (See proposed Sec. 58.5(d) and (k).) We are proposing these
requirements to help ensure animal welfare concerns are adequately
addressed, and to help safeguard the reliability of study results.
A sponsor may transfer to another party responsibility for any or
all of the obligations set forth in this part. A party that assumes any
obligation of a sponsor must comply with the specific regulations in
this chapter applicable to this obligation and must be subject to the
same regulatory action as a sponsor for failure to comply with any
obligation assumed under these regulations. Although a sponsor might
transfer certain responsibilities, the sponsor is still ultimately
responsible for compliance with all sponsor responsibilities provided
in this chapter. When referring to the sponsor throughout this
proposal, we also mean any person that assumes, as an independent
contractor with the sponsor, one or more of the obligations of a
sponsor.
We propose that the sponsor must document that the contracted
person conducting a phase of the nonclinical laboratory study is
qualified according to the provisions in part 58 applicable for the
phase or phases that person is contracted to perform. (See proposed
Sec. 58.5(e).) Using qualified contracted persons is essential for
ensuring GLP compliance and the quality and integrity of the resulting
data.
We propose adding communication requirements to sponsor
responsibilities. The OECD consensus document, The Application of the
OECD Principles of GLP to the Organisation and Management of Multi-Site
Studies (Ref. 6), states that many problems associated with the conduct
of multisite studies ``can be prevented by clear allocation of
responsibilities and effective communication among all parties involved
in the conduct of the study.'' This includes the sponsor, study
director, management, principal investigators, QAU, and all other study
personnel. Many comments to the December 2010 ANPRM repeat this
opinion. We agree and propose that the sponsor must ensure appropriate
lines of communication are established (defined, documented in writing
or electronically, and implemented) among all persons conducting any
phase of the nonclinical laboratory study. We also propose that
communications established among persons conducting a phase of the
study that involve the sponsor must be documented by the sponsor. (See
proposed Sec. 58.5(f).)
We propose that the sponsor must document that test, control, and
reference articles are prepared, characterized, and labeled according
to part 58, subpart F, and are appropriately shipped. In addition, the
sponsor must obtain, and provide to the study director as soon as
available, information about test, control, and reference article
characterization as specified in Sec. 58.105. (See proposed Sec.
58.5(g).) We propose this requirement in Sec. 58.5(g), because the
study director must have characterization information to help ensure
appropriate dosing of the test article and to interpret study results
in the final study report.
We propose that the sponsor inform the study director of any known
potential risks of the test article to human health or to the
environment, and any measures necessary to protect study personnel.
(See proposed Sec. 58.5(h).) Since the sponsor is most familiar with
test article characteristics because of either direct testing or
receiving results from a contracted person that characterized the test
article, we propose this requirement as a sponsor responsibility. If
there are known or suspected risks to human health or the environment,
it is essential that the study director, as the single point of study
control, is aware of the risks and the measures necessary to protect
study personnel and the environment. This is consistent with OECD's
advisory document, The Role and Responsibilities of the Sponsor in the
Application of the Principles of GLP (Ref. 9).
We propose that the sponsor must review, approve, sign, and date
each protocol amendment before implementation. (See proposed Sec.
58.5(i).) Many comments to the December 2010 ANPRM recommend this
requirement and we agree. After initiating the study, the sponsor must
be aware of proposed study protocol changes and why the changes are
proposed. This requirement is part of our proposed checks and balances
in part 58 and will help ensure that the amended protocol complies with
GLP.
We propose that the sponsor must document and update, as necessary,
the archive location of all raw data and records described in proposed
Sec. Sec. 58.190 and 58.195. When we conduct BIMO GLP inspections as a
result of an application or submission to FDA, we rely on the sponsor
to provide the location of the study archives. (See proposed Sec.
58.5(j).)
We propose that the sponsor must include, in any application or
submission to FDA that contains the results of a nonclinical laboratory
study, the final study report of the nonclinical laboratory study and
all amendments to the final report described in proposed Sec. 58.185.
Also, we propose that the sponsor must include either a statement that
the study was conducted in compliance with the requirements in part 58
or, if not conducted in compliance with part 58, a brief statement of
the reason for noncompliance. (See proposed Sec. 58.5(k)). We propose
this requirement,
[[Page 58352]]
consistent with the proposed expansion of the scope, to include all
applications and submissions to FDA supported by data from nonclinical
laboratory studies.
4. Transfer of Responsibilities (Sec. 58.10)
We propose significant changes to current Sec. 58.10 to help
address the possibility of multiple contractual relationships,
including subcontracting, in multisite nonclinical laboratory studies,
and to conform as much as possible to the regulations in 21 CFR 312.52,
Transfer of obligations to a contract research organization, and 21 CFR
511.1(f), Contract research organizations. Many comments to the
December 2010 ANPRM suggest that we specify in part 58 the parties
responsible in a multisite study and how any transfer of
responsibilities is accomplished. We agree with those suggestions. We
also propose the changes because the current regulations address
explicitly only testing facilities.
We propose changing the title of Sec. 58.10 from ``Applicability
to studies performed under grants and contracts'' to ``Transfer of
responsibilities'' to reflect the proposed changes to this section. We
also propose adding paragraph designations (a), (b), and (c).
In Sec. 58.10(a), we propose to require written documentation of
any transfer of responsibilities to a ``contracted person'', as that
term is proposed in Sec. 58.3, referring to any person a sponsor
utilizes to provide a service for the conduct of a nonclinical
laboratory study. Contracted persons may, for example, serve as the
study director, management with executive responsibility, the QAU, a
testing facility, a test site, or an independent contributing
scientist. These contracted persons may further contract with other
individuals or entities. Specifically, we propose that any
responsibility required by the regulations that is transferred must be
described in writing, and that any responsibility not covered by the
written description is considered not transferred.
We propose to add in Sec. 58.10(b) that any person transferring to
a contracted person any regulatory responsibility for a phase of a
nonclinical laboratory study must inform that contracted person that
the transferred responsibility is required to be performed in
compliance with the provisions in part 58. Proposed paragraph (b)
therefore includes what is currently in Sec. 58.10.
In Sec. 58.10(c), we propose adding that a contracted person
assuming any regulatory responsibility for a phase of a nonclinical
laboratory study must comply with the regulations in chapter I (21 CFR
chapter I) applicable to the transferred responsibility. That
contracted person will be subject to the same regulatory requirements
as those regulated persons transferring the responsibility.
We propose these requirements for transfer of responsibilities in a
nonclinical laboratory study to help ensure contracted persons perform
any transferred responsibilities in compliance with part 58 and to help
ensure the quality and integrity of data supporting applications and
submissions to FDA. Also, our proposal is consistent with industry's
desire for flexible relationships among persons conducting phases of a
nonclinical laboratory study.
5. Inspection of Any Person Conducting a Phase of a Nonclinical
Laboratory Study (Sec. 58.15)
We propose revising Sec. 58.15 to clarify FDA's inspection
authority to include inspecting any person that conducts a phase of a
nonclinical laboratory study of an FDA-regulated product. This includes
all contracted and subcontracted persons that agree to assume one or
more regulatory responsibilities. We propose revising the heading of
Sec. 58.15 to be consistent with these proposed changes.
Also, we propose modifying the provision about FDA inspection of
QAU records. In the preamble to the original GLP final rule (43 FR
59986 at 59998, December 22, 1978) (Ref. 12) and repeated in FDA's
compliance policy guide (CPG 7151.02) (Ref. 13), we state our policy
that FDA investigators will not routinely inspect QAU records.
Exceptions when FDA will inspect QAU records include ``for cause'' FDA
inspections, or inspections conducted under an inspection warrant, or
when necessary for litigation purposes. Therefore, we propose modifying
Sec. 58.15(a) to specifically state that the ``records inspection and
copying requirements do not routinely apply to QAU records of findings
and problems, or to actions recommended and taken''. We propose adding
for clarity, that ``FDA retains the authority to inspect all QAU
records when necessary to ensure compliance with this part [part 58]''.
In Sec. 58.15(b), we propose changing certain terms for
consistency within this proposal. For example, we propose changing
``the testing facility'' to ``any person conducting a phase of the
nonclinical laboratory study''.
C. Part 58, Subpart B--Organization and Personnel
1. Personnel (Sec. 58.29)
We propose no changes to the intent of current Sec. 58.29(a).
However, we propose adding to the end of this provision clarifying
sentences, ``This must include training and experience with GLP
requirements. Personnel who work with animals must have both general
and species-specific training and experience.''
Several comments to the December 2010 ANPRM state that training on
GLP requirements is essential for all personnel in a nonclinical
laboratory study. This proposed training requirement also is consistent
with the personnel requirements in the OECD Principles on Good
Laboratory Practice (Ref. 8). Therefore, we propose requiring GLP
training to ensure all personnel in a nonclinical laboratory study
understand how to comply with GLP and all aspects of a nonclinical
laboratory study are GLP compliant.
As we state elsewhere in section III.A.3., we propose specific
responsibilities regarding animal welfare because compliance with
animal care requirements helps ensure the quality and integrity of
study data. Therefore, we propose that all personnel involved with
animal treatment and care must have relevant training and experience,
including species-specific training when applicable.
In Sec. 58.29(b), we propose adding a requirement that all study
personnel must have access to and comply with the study protocol and
applicable protocol amendments and SOPs, and any protocol deviation
must be reported to the study director. In Sec. 58.29(c), we propose
adding a requirement that all study personnel must record raw data
promptly and accurately as required by a new regulatory provision in
Sec. 58.180 Data quality and integrity. We propose these new
provisions to help ensure compliance with GLPs and to update the
regulations consistent with current practices and the prevalence of
multisite studies. This proposal also is consistent with personnel
responsibilities in the OECD Principles on Good Laboratory Practice
(Ref. 8).
In proposed Sec. 58.29(d) (currently, Sec. 58.29(b)), we replace
``Each testing facility'' with ``Any person conducting a phase of a
nonclinical laboratory study''. We propose this and other conforming
changes in Sec. 58.29 to address the occurrence of contracting and
subcontracting in multisite studies, to update the regulations, and for
consistency with our proposals in part 58.
[[Page 58353]]
2. Testing Facility Management With Executive Responsibility (Sec.
58.31)
We propose significant changes in Sec. 58.31 consistent with our
proposal requiring a GLP Quality System. To clarify who is responsible
for the proposed requirements in Sec. 58.31, we propose adding ``with
executive responsibility'' to the current heading of ``Testing facility
management.'' We propose this change to specify that upper management
at a testing facility or test site is ultimately responsible for GLP
compliance. We also propose summarizing in the introductory paragraph
the expanded responsibilities of management consistent with the
regulatory text in part 820 (see Sec. 820.20).
The current provisions in Sec. 58.31(c) through (g) require only
assurances that certain activities are available, performed,
understood, or communicated. For those responsibilities currently in
Sec. 58.31, we propose clarifying and expanding them, requiring
actions and referencing specific SOPs (where applicable). We also
propose adding new responsibilities consistent with a GLP Quality
System and the conduct of multisite studies.
We propose a new Sec. 58.31(a) requiring testing facility
management with executive responsibility to establish and update
written GLP Quality System SOPs. For continuing oversight of the GLP
Quality System, in new Sec. 58.31(b), we propose requiring testing
facility management with executive responsibility to review at
specified and sufficient intervals and document that the GLP Quality
System meets the requirements in proposed part 58. We propose that
testing facility management with executive responsibility is
responsible for overseeing the implementation of the requirements in
proposed Sec. 58.31(b), according to established procedures to be
included in proposed Sec. 58.81(b)(2) (establishment and periodic
review of a GLP Quality System).
In Sec. 58.31(e), we propose that testing facility management with
executive responsibility appoint and document the appointment of a
management representative who is a member of the testing facility
management with authority over and responsibility for documenting that
GLP Quality System requirements are effectively established and
maintained. We also propose that this appointed member reports to
management with executive responsibility about the performance of the
GLP Quality System, which includes reports from the QAU. Appointment of
this individual is an organizational responsibility of the testing
facility management with executive responsibility such as in part 820,
Quality System Regulation, the model for the GLP Quality System.
In Sec. 58.31(f), we propose that testing facility management with
executive responsibility is responsible for documenting that all
persons in a multisite study follow adequate equipment-related SOPs. In
Sec. 58.31(h), we propose this same management is responsible for
documenting that all study personnel are trained to perform their
assigned functions. In Sec. 58.31(k), we propose this same management
is responsible for appointing a person to maintain the master schedule
along with other requirements concerning the master schedule, such as
requiring in a master schedule the core information presently specified
under QAU responsibilities in Sec. 58.35(b)(1). This core information
is essential on each master schedule to ensure consistent
identification across all persons (individuals or entities) in a
multisite study. We propose adding Sec. 58.31(m), requiring testing
facility management with executive responsibility to review all
protocols to ensure that environmental, animal welfare, or work
resource issues or issues with scientific methodology do not affect or
bias any phase of the study's conduct.
We propose adding Sec. 58.31(r) to require testing facility
management with executive responsibility to review the suitability and
effectiveness of the QAU or lead QAU, as applicable, at defined
intervals and with sufficient frequency, according to established SOPs
as required in proposed Sec. 58.81(b)(17). Periodic review of the
QAU's capability to fulfill their responsibilities helps to ensure the
quality and integrity of study data and is also consistent with a
quality system.
We propose adding Sec. 58.31(u), requiring testing facility
management with executive responsibility to establish SOPs for
archiving records and materials generated during the course of a
nonclinical laboratory study, including the designation and replacement
of the archivist and any supporting staff. This archiving process is an
essential aspect of compliance with GLPs because maintenance of raw
data and specimens from a specific study enables reconstruction of that
study for verification of the information in the final study report and
confirmation of the study's compliance with part 58.
These and other proposals in Sec. 58.31 are consistent with the
preamble to the original GLP final rule that states, ``A determination
of the adequacy of each standard operating procedure is the
responsibility of the management'' (43 FR 59986 at 60002) (Ref. 12).
Also, our proposals are responsive to many comments to the December
2010 ANPRM asking that we define operational areas necessary for
broader adoption of a quality system approach to the conduct of
nonclinical laboratory studies.
Rather than specifying how essential activities of a GLP Quality
System must be conducted, we propose requiring management with
executive responsibility at testing facilities and test sites to
establish essential SOPs. This flexible approach would allow testing
facilities and test sites to establish SOPs best suited to their
specific organizational structure.
3. Test Site Management With Executive Responsibility (Sec. 58.32)
We propose updating the regulations by adding Sec. 58.32. This new
provision would address the current prevalence of multisite studies and
require test site management with executive responsibility to comply
with relevant requirements in proposed Sec. 58.31 and develop and
maintain SOPs described in Sec. 58.81, ``where appropriate'', as that
term is proposed in Sec. 58.1(c).
We expect that a test site, like a testing facility, has management
with executive responsibility and appropriate SOPs. Therefore, while a
test site might be conducting a phase of a particular multisite study,
for a different study the same test site could function as a testing
facility by coordinating, conducting, or completing the entire study.
4. Study Director (Sec. 58.33)
In Sec. 58.33, we propose modifying and adding study director
requirements to update the regulations and to address the prevalence of
multisite studies. We propose certain study director requirements for
consistency with our other proposals in part 58 (for example, our
proposals for a GLP Quality System and for checks and balances to help
ensure data quality and integrity).
In Sec. 58.33(a), we propose keeping the current requirement that
the study director is the single point of study control. We propose
adding that the study director cannot delegate overall responsibility
for a nonclinical laboratory study. This proposed addition clarifies
and emphasizes that a study director cannot delegate oversight of an
entire nonclinical laboratory study, even though a study director may
delegate to a principal investigator certain responsibilities.
This proposed change is consistent with FDA's longstanding
interpretation
[[Page 58354]]
of a study director's responsibilities and consistent with present FDA
and EPA GLP regulations. This proposed addition also is consistent with
the OECD consensus document, The Role and Responsibilities of the Study
Director in GLP Studies (Ref. 14). Many comments to the December 2010
ANPRM stress the importance of the study director remaining the single
point of study control.
We propose in Sec. 58.33(a)(2) the study director's responsibility
for implementing procedures that ensure adequate communication among
all study personnel and with the sponsor, as applicable, because
communication is essential in a nonclinical laboratory study.
In Sec. 58.33(b), we propose new requirements for the study
director for documenting, consulting, signing, and archiving (see
proposed Sec. Sec. 58.33(b)(2) through (7) and (12) through (14)). In
Sec. 58.33(b)(13), we propose that the study director must sign and
date the final study report. FDA agrees with OECD's discussion in this
regard in both the OECD Principles on Good Laboratory Practice (Ref. 8)
and the consensus document, The Role and Responsibilities of the Study
Director in GLP Studies (Ref. 14). The study director's signature on
the final study report indicates acceptance of responsibility for the
validity of the data and the extent to which the study complies with
GLP principles. We also recognize that we use the terms retain and
archive interchangeably throughout this proposal (see, for example,
proposed Sec. 58.33(b)(14)), and we seek comment on which term is
preferred by industry.
We propose adding in Sec. 58.33(b)(5) and (6) new study director
responsibilities affecting the welfare of test animals. When a protocol
and its amendments impact test animal use, we propose the study
director must document that a committee whose function is ensuring the
appropriate and humane care of animals must first review and approve
the protocol and applicable amendments before initiating the study or
implementing the amendments. The study director also must document that
such a committee has reviewed and approved general procedures for
commonly conducted animal tests. Any protocol requiring only those
tests, with their approved parameters, would not require additional
review before study initiation. However, if a protocol increases the
numbers of animals to be used or alters any of the approved testing
parameters, specific review and approval of that protocol would be
required before study initiation.
We propose in 58.35(b)(6), that the study director must consult
with the attending veterinarian during review of proposed study
protocols to determine potential animal welfare concerns and
appropriate responses to likely contingencies. Early identification of
potential animal welfare concerns benefits the test animals because
they will receive prompt care, which improves the quality of the data
collected.
In 58.33(b)(11), we propose adding that the study director must
document that all applicable GLP regulations are followed and include a
study compliance statement in the final study report. FDA agrees with
the statement in the OECD consensus document, The Role and
Responsibilities of the Study Director in GLP Studies (Ref. 14) that
the study director should ascertain that GLP requirements are fully
complied with in every phase of a study, that the study protocol is
faithfully followed, and that all observations, including any
deviations from the protocol, are fully documented.
In Sec. 58.33(b)(14), we propose adding a timeframe for archiving
of no later than 2 weeks after the study completion date. We think that
timely archiving of raw data, documents, protocols, specimens, and
final reports will help prevent their loss or destruction. Stakeholders
requesting modernizing part 58 asked specifically for a reasonable time
period after the study completion date to complete study archiving.
Numerous comments to the December 2010 ANPRM agree, particularly with
regard to archiving computerized systems. We propose the 2-week
timeframe to allow flexibility for archiving material without
jeopardizing study material integrity.
5. Quality Assurance Unit (QAU) (Sec. 58.35)
In Sec. 58.35, we propose keeping the QAU functions currently in
the regulations. We propose modifying Sec. 58.35(a) by separating it
into paragraph (1) QAU function and paragraph (2) QAU location. We
propose this change for consistency with our other proposals in part 58
(for example, to address the location of the lead QAU for multisite
studies), and in response to comments to the December 2010 ANPRM
requesting a clear description of the relationship between the QAU and
testing facility management.
We propose in Sec. 58.35(a)(2)(ii) that, for multisite studies,
testing facility management with executive responsibility must
designate a lead QAU. The concept of a lead QAU is consistent with the
discussion in the preamble of the original GLP final rule stating that
when portions of a study must be contracted to a site that lacks a QAU
``the person letting the contract, and not the contract facility, is
responsible for the performance of the quality assurance functions''
(43 FR 59986 at 59997) (Ref. 12). This change also is consistent with
the OECD consensus document, Quality Assurance and GLP (Ref. 7).
Several comments to the December 2010 ANPRM specifically note the need
for a lead QAU in multisite studies.
We propose several modifications to current Sec. 58.35(b). We
propose changing the present QAU requirement to maintain a copy of the
master schedule and all protocols to require that the QAU maintain
``access'' to them. For example, if the QAU is a contracted person,
then the QAU might not have overall knowledge about the person (i.e.,
testing facility) to which they are providing QA services. However, the
QAU requires ``access'' to the master schedule and protocols to ensure
GLP compliance.
We recognize that many sites have a central computerized system for
maintenance of essential documents. Our proposed change about QAU
access to the master schedule responds to stakeholder requests to
modernize part 58 and also to comments to the December 2010 ANPRM. This
change also is consistent with our proposal in Sec. 58.195(d) that
management with executive responsibility must ensure ``maintenance'' of
the master schedule and copies of study protocols.
Because the lead QAU is responsible for ensuring GLP compliance of
all phases of a multisite study, we propose that the lead QAU must
maintain access to the master schedule of any person that lacks a QAU.
We consider the master schedule an important tool for determining
whether a person is capable of conducting a GLP compliant study. For
example, a person with numerous scheduled studies still in progress may
lack sufficient resources to begin the conduct of a GLP compliant
study.
Also, as many comments to the December 2010 ANPRM suggest, we
propose removing the word ``sheet'' from the term ``master schedule
sheet''. We propose removing ``sheet'' because we do not want to imply
that a paper copy is required for electronic systems.
In new Sec. 58.35(b)(3), we propose requiring the QAU to review
the study protocol before initiating the study and all protocol
amendments before implementing them, along with documenting this
review. In new
[[Page 58355]]
Sec. 58.35(b)(4), we propose requiring the QAU to review all SOPs
applicable to a given nonclinical laboratory study along with
documenting this review. Current regulations state the QAU is
``responsible for monitoring each study to assure management that the
facilities, equipment, personnel, methods, practices, records, and
controls are in conformance'' with GLPs (current Sec. 58.35(a)).
Our proposed initial review by the QAU of the study protocol and
applicable facility SOPs will help ensure compliance with part 58 from
the start of the study. Otherwise, when the study is underway,
amendments to the study protocol and SOPs might be needed if QAU
inspections reveal compliance deficiencies.
We propose in Sec. 58.35(b)(5) expanding the types of QAU
inspections recognized by FDA by adding process-based and facility-
based inspections.\7\ Many comments to the December 2010 ANPRM request
this change consistent with QAU inspections described in the OECD
consensus document, Quality Assurance and GLP (Ref. 7), specifically
supporting an appropriate mix of study-specific and process-based
inspections.
---------------------------------------------------------------------------
\7\ The term ``study-based inspection'' is not used in current
FDA regulations; however, this type of inspection is equivalent to
the QAU inspection currently required in part 58.
---------------------------------------------------------------------------
However, many comments to the December 2010 ANPRM express concern
about how process-based inspection results will be appropriately
considered for all relevant studies, particularly when an inspection
reveals problems. This concern is especially relevant to any phase
involving a short-term study, as we propose to define this term.
Process-based inspections are conducted on a prearranged schedule,
which is not connected to the timing of any particular nonclinical
laboratory study. Therefore, a facility utilizing process-based
inspections might conduct a short-term study that is not inspected
during its in-life period (that is, during the time data are
collected). This concern also is addressed in the OECD consensus
document, The Application of the GLP Principles to Short Term Studies
(Ref. 15).
To ensure that any problem revealed during a process-based
inspection is properly captured in the reports of all relevant studies,
we propose adding Sec. 58.35(e). This provision requires preparation
of a written certification, by the person conducting a phase of the
study, whenever a process-based inspection reveals problems. As
proposed, this certification requires documenting actions taken to
properly inform, and modify (when applicable), reports for all studies
impacted by the results of that process or procedure. While a
management responsibility, we propose adding this requirement in Sec.
58.35 because of its similarity to the existing requirement in current
Sec. 58.35(d) for management to provide an FDA representative, upon
request, a certification regarding the implementation of required QAU
inspections.
In Sec. 58.35(b)(7) (a redesignation and revision of current Sec.
58.35(b)(4)), we propose expanding the requirement that the QAU must
submit to management with executive responsibility and the study
director a periodic written status report on each study. We propose
that these periodic reports ``discuss the overall progress and
compliance status of the study and include any problems observed and
the corrective actions taken.'' In conjunction with this requirement,
we propose that the content and frequency of these reports be specified
in SOPs as required in proposed Sec. 58.81(b)(21).
We propose this revision in Sec. 58.35(b)(7) because feedback to
management with executive responsibility and the study director about
the overall progress and compliance status of the study is essential to
ensure study compliance. We intend these periodic reports to give a
general overview of the study. We expect these periodic reports to
complement any inspection reports for the study, which only provide a
snapshot in time.
We are interested in receiving feedback about the use and relevance
of periodic status reports. Specifically, we are seeking comment about
whether QAUs regularly provide such reports and whether they are useful
to the study director and management when provided.
Consistent with our proposals addressing multisite studies, we
propose adding in new Sec. 58.35(b)(8) (revision of current Sec.
58.35(b)(5)) that the lead QAU must identify all deviations occurring
in the entire study, including deviations identified by any other
existing QAUs participating in the study. We expect this requirement
may be facilitated by principal investigator reports to the study
director, documentation by other existing QAUs, and direct oversight by
the lead QAU of independent contributing scientists and any persons
conducting a phase of the study lacking either a principal investigator
or a QAU or both. We propose this requirement to ensure the lead QAU is
made aware of protocol deviations in a timely manner. This awareness
will help alert the lead QAU to the need to correct or modify relevant
SOPs and the study protocol when necessary to maintain data integrity.
The remaining additions we propose in Sec. 58.35 relate to QAU
oversight of the integrity of data in the final study report. Current
responsibilities in Sec. 58.35(b)(6) (revised and redesignated as
Sec. 58.35(b)(10)) are to ensure the quality and integrity of the
final study report. Therefore, we propose in Sec. 58.35(b)(9)that the
QAU must audit the reports of all contributing scientists and all
existing principal investigators.
Currently Sec. 58.35(b)(6) requires the QAU to assure that the
``reported results accurately reflect the raw data of the nonclinical
laboratory study.'' However, QAU members might not have the scientific
judgment needed for evaluating the scientific merits of the final
report and determining whether the results accurately reflect the data.
In the preamble to the original GLP final rule (43 FR 59986 at 59998,
comment 90) (Ref. 12), we agreed that ``the QAU should not attempt to
evaluate the scientific merits of the final report.'' Therefore, in
Sec. 58.35(b)(9) and (10), we propose clarifying our intent.
Specifically, we propose that the QAU must audit all contributing
scientists' reports and any report amendments to ensure they include a
report of all data and reflect the protocol, and amendments, and
applicable SOPs. This requires that all data generated during the study
are included and discussed, which is essential for the full
transparency necessary for reconstruction of the study.
For multisite studies, we propose that other QAUs participating in
the study must audit the reports and report amendments of any principal
investigators and all contributing scientists for whom they are
responsible. We also propose in Sec. 58.35(b)(9), for any person that
lacks a QAU, that the lead QAU audits the reports and amendments of all
contributing scientists and any principal investigators. This includes
audits of any independent contributing scientist. This proposed
requirement will ensure all data from a nonclinical laboratory study
will receive QAU review, thus improving the quality and integrity of
the final study report.
In Sec. 58.35(b)(10), we propose that the QAU must verify that all
original and amended signed and dated reports from contributing
scientists are appended to the final study report. For multisite
studies, we propose that the lead QAU is responsible for this
requirement. Under existing regulations that require providing the
final study report and any
[[Page 58356]]
amendments, we expect that both original and amended versions of
reports from all contributing scientists be appended to the final study
report. The proposed changes make this expectation a specific
requirement. This requirement will allow the study sponsor and FDA
reviewers to have access to the original conclusions for each phase and
any modifications made as a result of interactions among those involved
with the study. We propose this requirement to address the potential
inadvertent or intentional introduction of bias that may result when
only the final amended version of contributing scientists' reports are
included.
6. Contributing Scientist (Sec. 58.37)
As discussed in section III.B.2., we propose adding a definition
for a contributing scientist. In that definition, we include an
independent contributing scientist as an individual expert or
specialist who is an independently employed contracted person. We
propose adding responsibilities for contributing and independent
contributing scientists to help facilitate the development of a GLP
Quality System. To describe the responsibilities of these positions, we
propose adding Sec. 58.37(a) and (b), respectively.
When a contributing scientist is responsible for a phase, we
propose in Sec. 58.37(a) that the contributing scientist must comply
with part 58; provide a signed and dated report for inclusion in the
final study report; and permit oversight by the designated QAU. (See
proposed Sec. 58.37(a)(1) through (3)).
In Sec. 58.37(b), we propose requirements for an independent
contributing scientist in addition to those requirements in Sec.
58.37(a). The proposed requirements in Sec. 58.37(b) include, among
others, that independent contributing scientists must document,
maintain, and update information about their education, training, and
experience related to their responsibilities for a particular phase.
Also, we propose they must archive all materials as required by the
protocol and by proposed Sec. 58.195.
Our proposal for adding Sec. 58.37 is consistent with the
expectations in the present regulations for individual scientists and
professionals. We propose these requirements in part to help clarify
the regulations.
7. Principal Investigator (Sec. 58.39)
We propose adding Sec. 58.39 to include principal investigator
requirements related to a principal investigator's responsibilities for
a phase of a nonclinical laboratory study. We propose that designating
a principal investigator is optional.
The OECD Principles on Good Laboratory Practice (Ref. 8) includes
the term principal investigator solely in reference to multisite
studies. We recognize, however, the possibility of a testing facility
employing a principal investigator for a single-site study. For
example, a single-site study conducted in a facility situated on a
large campus with multiple buildings might have one or more principal
investigators.
We also recognize that a testing facility may conduct a multisite
study where, at all sites, only the study director oversees the study.
Several comments to the December 2010 ANPRM note these various
practices. We therefore propose in Sec. 58.39 principal investigator
requirements for specific responsibilities in one or more phases as
delegated to the principal investigator by the study director.
We propose principal investigator responsibilities consistent with
a principal investigator's role of ensuring compliance with part 58 for
a specific phase. For example, we propose the principal investigator
must document and report to the study director all deviations the
principal investigator observes during the conduct of the study. These
requirements also are consistent with the responsibilities of a
principal investigator in The Application of the OECD Principles of GLP
to the Organisation and Management of Multi-Site Studies (Ref. 6), and
with a GLP Quality System.
D. Part 58, Subpart C--Facilities
1. General (Sec. 58.41)
In Sec. 58.41, we propose changing ``Each testing facility shall
be'' to ``Any person conducting a phase of a nonclinical laboratory
study must have facilities'' of suitable size and construction to
facilitate the proper conduct of nonclinical laboratory studies. We
propose this change to include multisite studies.
2. Animal Care Facilities (Sec. 58.43)
In Sec. 58.43, we propose changes to include multisite studies and
to cover any phase involving the use of animals. We propose these
changes consistent with our proposal revising the testing facility
definition and our goal of applying the GLP regulations to all
nonclinical laboratory studies, including multisite studies.
3. Facilities for Handling Test, Control, and Reference Articles (Sec.
58.47)
In Sec. 58.47 we propose adding ``reference'' to refer to
``reference articles'' for consistency with our other proposals.
E. Part 58, Subpart D--Equipment
1. Equipment Design (Sec. 58.61)
In Sec. 58.61, we propose adding that equipment includes
computerized systems. We also propose adding in Sec. 58.61, equipment
used for maintenance, archiving, and retrieval of data. We propose
these additions to update and clarify the regulations.
2. Maintenance and Calibration of Equipment (Sec. 58.63)
In Sec. 58.63, we propose adding to paragraph (a) maintenance,
archiving, and retrieval of data. In paragraph (b), we propose changing
the citation reference from Sec. 58.81(b)(11) to (14) and adding a
reference to the written SOP requirement in Sec. 58.81(b)(15). Also,
in paragraph (b), we propose adding ``as applicable'' to address the
possibility of a multisite study. We propose these changes for
consistency with our other proposed changes in part 58 and to update
the regulations to address multisite studies.
F. Part 58, Subpart E--Nonclinical Laboratory Study Operations
Consistent with our proposals in part 58 to address multisite
studies, we propose revising the heading of subpart E from ``Testing
Facilities Operation'' to ``Nonclinical Laboratory Study Operations''.
Also, accordingly, we propose modifying the sections in subpart E.
1. Standard Operating Procedures (SOPs) (Sec. 58.81)
We propose modifying Sec. 58.81 Standard operating procedures
(SOPs), consistent with our proposals for a GLP Quality System and to
address multisite studies. In Sec. 58.81(a), we propose adding to the
current requirement that a testing facility must have written SOPs,
that all test sites, too, must have written SOPs. Also, in Sec.
58.81(a), we propose changing ``management'' to ``management with
executive responsibility''.
In Sec. 58.81(b), consistent with our proposal in Sec. 58.81(a),
we propose adding that the testing facility and all test sites must
establish SOPs for an applicable phase of a nonclinical laboratory
study. As discussed in section III.B.1., we use the terms ``applicable
phases'' and ``where appropriate'' because in a multisite study no one
person will conduct all phases of the study. Therefore, each person
requires SOPs only for those phases which that person conducts.
[[Page 58357]]
We propose adding to the current list of SOPs in Sec. 58.81(b)
numerous topics that require SOPs. For example, we propose adding that
SOPs must include an SOP for preparing, modifying, and administering
all SOPs. We propose these additional SOP requirements because they are
essential components of a complete quality system approach (i.e., the
proposed GLP Quality System) and also address the current prevalence of
multisite studies.
Our proposal in Sec. 58.81 will require initial efforts by testing
facilities and test sites to modify or add SOPs as needed for a GLP
Quality System. However, once established, the GLP Quality System will
facilitate greater flexibility and efficiency for the conduct of
nonclinical laboratory studies and, over time, will help reduce costs.
2. Animal Care (Sec. 58.90)
In Sec. 58.90, we propose modifying paragraph (b) to require,
throughout the study, evaluation of the health status of test animals
according to acceptable veterinary medical practices for the care of
test animals. We propose this change because proper animal care is
essential during the entire study to ensure the welfare of test animals
and the integrity of test results. However, test animal evaluations can
be performed by the attending veterinarian or appropriately-trained
personnel who are delegated this responsibility by the attending
veterinarian.
In Sec. 58.90(c), we propose removing from the third sentence the
phrase ``provided that such treatment does not interfere with the
study'', and replacing this phrase with ``as deemed necessary by the
study's attending veterinarian.'' We propose few changes in Sec.
58.90(d) and (e). In the first sentence of current Sec. 58.90(d), we
propose replacing ``excluding suckling rodents'' with ``except nursing
neonates'' to update the regulation to be more inclusive and
appropriate. In Sec. 58.90(e), we propose adding the word
``reference'' to conform to changes proposed elsewhere in this
document.
We propose these changes in Sec. 58.90 to update and clarify the
regulations, and because test animal welfare concerns are an essential
part of a GLP Quality System.
G. Part 58, Subpart F--Test, Control, and Reference Articles
We propose adding the term ``Reference'' to the heading in subpart
F, and in certain applicable provisions in subpart F. We also propose
adding in subpart F specifics concerning tobacco products, and a
reference to method validation.\8\
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\8\ There is a draft guidance document regarding bioanalytical
method validation, ``Bioanalytical Method Validation Draft
Guidance'' (Ref. 16). When final, this guidance will provide FDA's
current thinking. We consider many of the general principles in this
draft guidance document applicable to method validation in
nonclinical laboratory studies.
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1. Test, Control, and Reference Article Characterization (Sec. 58.105)
We propose modifying Sec. 58.105 to require that all information
about test, control, and reference article characterization be provided
to the study director as soon as available. This information is
necessary for determining appropriate dosing and drafting conclusions
in the final study report. The lack of this information limits the
important test result discussion in the final study report.
Reports submitted to FDA must provide study information based on
the characteristics of the product (test article) studied. We expect a
test article to be characterized to the extent required to interpret
the study properly. For nonclinical laboratory studies conducted in
support of initiating clinical ``first-in-human'' studies, this
characterization information is particularly important for human
subject protection.
We propose modification of Sec. 58.105(a) to exclude the use of a
marketed tobacco product's labeling to characterize such a product if
it is used as a control or reference article in a nonclinical
laboratory study. The labeling of currently marketed tobacco products
does not provide the information required for full product
characterization. That is, the chemical composition (including
mainstream smoke composition), microbiological composition, and design
parameters of the product are not fully described in tobacco product
labels. Thus, the composition and toxicant deliveries of currently
marketed tobacco products are less well defined in tobacco product
labeling than the safety and efficacy information described in the
labels of marketed drug products. Therefore, FDA notes that when using
a marketed tobacco product as a control or reference article, the
marketed tobacco product's characteristics must be determined and
documented as required in this part.
We propose revising and redesignating the current provisions in
Sec. 58.105(b), (c), and (d). These proposed changes are necessary for
consistency with our other proposals in part 58, such as the addition
of reference articles.
The current regulations imply that empty containers from test
articles must be retained. Comments to the December 2010 ANPRM did not
see the need to retain the empty containers provided appropriate
product information is maintained and test article accountability is
fully documented. We agree with those comments and propose to remove
this implied requirement. To provide for adequate test article
accountability, in lieu of retaining empty test article containers, we
propose requiring in Sec. 58.105(d) that the study director verify and
document by dated signature the distribution and final disposition of
the test article.
2. Test, Control, and Reference Article Handling (Sec. 58.107)
We propose minimal conforming changes in Sec. 58.107, such as
adding ``reference'' to the section heading and first sentence.
3. Mixtures of Articles with Carriers (Sec. 58.113)
We propose modifying Sec. 58.113 by adding ``reference'' to the
provisions proposed in Sec. 58.113(a), (a)(1), (a)(2), (b)(2), and
(d). Also, we propose requiring that the results from the determination
of the uniformity, concentration, and stability of mixtures of test
articles with carriers are provided to the study director as soon as
available. We propose these changes in Sec. 58.113 for the same
reasons we propose changes in Sec. 58.105.
H. Part 58, Subpart G--Protocol for and Conduct of a Nonclinical
Laboratory Study
1. Protocol (Sec. 58.120)
We propose modifying Sec. 58.120 to address multisite studies more
specifically, and to provide consistency with our other proposed
changes discussed elsewhere.
Many comments to the December 2010 ANPRM suggest that the study
protocol identify all sites participating in a multisite study. We
agree, and propose adding in Sec. 58.120(a)(3) that the protocol
contain contact information for all persons conducting a phase of the
nonclinical laboratory study.
Current Sec. 58.120(a)(6) includes in the protocol the methods for
controlling bias. We propose adding to this provision the analysis and
reporting of study test results and procedures to be followed if a
study includes a peer review of any phase. Also, for multisite studies,
we propose adding a requirement that the protocol identify the
person(s) conducting the phases of the nonclinical laboratory study.
[[Page 58358]]
We propose expanding current Sec. 58.120(a)(10) to clarify that
the protocol must include a listing of the study-specific records that
are required to be maintained. We think this clarification will help
assure that study-specific records are maintained.
Current Sec. 58.120(a)(11) requires the date of protocol approval
by the sponsor, and the dated signature of the study director. We
propose expanding this provision to indicate study protocol approval by
the dated signature of the study sponsor, the study director,
independent contributing scientists, principal investigators, and any
other person conducting a phase of the nonclinical laboratory study, as
applicable.
We propose redesignating and modifying Sec. 58.120(b) as Sec.
58.120(d). In Sec. 58.120(d), we propose requiring, before
implementing any change or revision to an approved protocol, that the
study sponsor and the study director document their approval of the
change or revision. For a multisite study, any person affected by the
proposed changes (for example, the principal investigator or
independent contributing scientist) also must document approval. We
consider a person's dated signature on the protocol revision to be
acceptable documentation indicating approval. We propose that these
signed and dated protocol amendments must be maintained with the
protocol.
Before initiating any study using animals, we propose requiring in
new Sec. 58.120(b) protocol review and approval by ``a committee whose
function is to ensure that the care and use of animals in studies is
appropriate and humane''. In new Sec. 58.120(e), we propose the same
review and approval by this committee before implementing any protocol
changes that affect animal welfare. These additions are consistent with
the proposal in Sec. 58.33(b)(5) that the study director must ensure
that all studies that include the use of animals are approved by such a
committee.
In new Sec. 58.120(c), we propose requiring that the study sponsor
and testing facility management with executive responsibility sign and
date a statement that the study will be conducted in compliance with
part 58. We propose appending this statement to the protocol. This
proposal is consistent with the requirement in Sec. 58.10(b) that a
sponsor must inform a contracted person that the study must be
conducted in compliance with chapter I. This proposal also is
consistent with the requirements discussed elsewhere in this document
that the study director documents applicable GLP regulations are
followed (section III.C.4.), and that the QAU ensures studies conform
to the regulations in part 58 (section III.C.5.).
2. Conduct of a Nonclinical Laboratory Study (Sec. 58.130)
We propose redesignating current Sec. 58.130(a) through (c), as
(d), (f), and (g) respectively. In new proposed Sec. 58.130(a), we
require demonstration that all analytical methods are accurate,
sufficiently precise, and sensitive enough to result in accurate and
reproducible data. We expect this requirement will help ensure data
quality and integrity as its intent is to produce accurate and
reproducible data. This requirement also is consistent with
requirements in part 320 (21 CFR part 320), ``Bioavailability and
Bioequivalence Requirements'' (see Sec. 320.29(a)).
In new Sec. 58.130(b), we propose conducting test, control, and
reference article characterization as specified in part 58, subpart F.
We propose this requirement to clarify our current and future
expectations regarding test, control, and reference article
characterization.
In new Sec. 58.130(c), we propose that ``humane care and ethical
treatment of test animals must be considered in advance and upheld in
conjunction with achieving study objectives.'' We propose this
provision is consistent with our other proposals addressing animal
welfare discussed elsewhere in section III.A.3.
In new Sec. 58.130(e), we propose that any change to the protocol
must be approved as an amendment. We propose this requirement
consistent with the proposed requirement in Sec. 58.120(d) for
approval of protocol amendments. However, we understand the importance
of test animal welfare along with maintaining the integrity of the
study. Therefore, FDA intends to evaluate on a case-by-case basis
certain circumstances when a protocol deviation is necessary to prevent
a potential hazard to animal welfare or study integrity.
In proposed Sec. 58.130(h) (revised and redesignated current Sec.
58.130(d)), postmortem observations must be available to the
pathologist unless specified otherwise in the study protocol. We
understand that some study protocols might blind the pathologist to
postmortem observations. We expect, however, in most cases the
pathologist will not need to be blinded to postmortem observations.
I. Part 58, Subpart J--Records and Reports
1. Data Quality and Integrity (Sec. 58.180)
We propose adding a new Sec. 58.180 for data quality and
integrity. Ensuring data quality and integrity in a nonclinical
laboratory study is one of our critical goals in this part 58 proposal.
Therefore, we propose adding this separate Sec. 58.180 to clearly
identify requirements for data quality and integrity. We propose this
new section in subpart J because data are part of study records and
reports.
We propose moving to this new section, and revising, the
requirements in current Sec. 58.130(e). In Sec. 58.180(a), we propose
creating the acronym ``ALCOA''. This is a mnemonic that signifies
quality data to stakeholders that conduct clinical and nonclinical
studies. We propose therefore that all nonclinical laboratory study
data are ``accurate, legible, contemporaneous, original, and
attributable''.
In Sec. 58.180(b), we propose modifying and updating the
provisions currently in Sec. 58.130(e) to address electronic data
capture and maintenance. Numerous comments to the December 2010 ANPRM
note that part 11 (21 CFR part 11, ``Electronic Records; Electronic
Signatures'') is applicable to part 58 and therefore parts 11 and 58
should be consistent. We agree, and do not intend to duplicate in part
58 the requirements in part 11. As a result, we propose that electronic
records systems need to be compliant with applicable regulations.
In Sec. 58.180(c), we propose adding that the final study report
must contain all data accrued during the study. This proposed
requirement is consistent with our proposal in Sec. 58.120(b)(6)
requiring that the protocol describe methods for controlling bias. We
propose this requirement because selective data inclusion in the study
analysis could introduce bias into the final study report.
2. Reporting of Nonclinical Laboratory Study Results (Sec. 58.185)
Study data must be maintained in a manner that allows for
``reconstruction of the study for the purpose of assessing the quality
and integrity of the results or the reinterpretation of the data in the
light of later findings'' (41 FR 51206 at 51215) (Ref. 4). Study
records and reports required in part 58, subpart J, are acceptable in
electronic or paper medium, or a combination of both. In Sec. 58.185,
we propose eliminating any current requirements that might impede a
fully computerized facility.
Many comments to the December 2010 ANPRM suggest we allow testing
[[Page 58359]]
facilities to develop an integrated final study report. This integrated
final study report would be in lieu of individual scientists' reports,
which the study director must then compile and discuss in an integrated
final study report. The preamble to the original GLP final rule states
that individual reports are required as part of the final report to
ensure the findings of the individual scientists are accurately
reflected (43 FR 59986 at 60009) (Ref. 12). Also, in the preamble to
the 1987 final rule amending part 58, FDA thought that reports
combining data, information, and views from scientists of different
disciplines would obscure the individual scientist's accountability for
accurate reporting (see 52 FR 33768 at 33778).
We continue to affirm these statements. However, we support
processes used for the efficient review of the draft study report to
facilitate completion of the final study report.
In Sec. 58.185, we propose adding general statements for
consistency with our other part 58 proposals. We propose adding two
provisions specific to animal welfare. In Sec. 58.185(a)(2), we
propose requiring that final study reports contain the names of all
study attending veterinarians. We propose redesignating and modifying
Sec. 58.185(a)(9) as (a)(10) to add the example of ``all health-
related issues reported by an attending veterinarian or appropriately
designated personnel during the course of the study''. This provision
recognizes that circumstances affecting the quality and integrity of
the data could include health-related issues noted and reported by the
attending veterinarian or appropriately designated personnel. We
propose this addition to help ensure that all untoward health-related
observations of test animals are captured and reported so that FDA
reviewers can consider their possible effect on study results.
We propose redesignating and modifying Sec. 58.185(a)(12) as
(a)(13) to be consistent with the EPA's GLP regulations (see 40 CFR
160.185(a)(12) and 792.185(a)(12)). That is, we propose requiring a
signed and dated report from each person conducting an analysis or
evaluation of study data or specimens after data generation was
completed. We propose this addition to provide transparency regarding
the review of study findings and the development of conclusions
submitted in the final study report.
In new Sec. 58.185(a)(16), we propose that the study director
provide with the final study report a statement about the study's
extent of compliance with part 58, including any study deviations. This
requirement is consistent with OECD's consensus document The Role and
Responsibilities of the Study Director in GLP Studies (Ref. 14) and
addresses a recommendation from stakeholders who requested that FDA
modernize part 58.
Many testing facilities provide services internationally and
therefore, this statement is commonly seen in final study reports
submitted to FDA. Such a statement also is included in EPA's study
profile templates, which outline the necessary documents for submission
of supporting data.\9\ FDA presently requires such a compliance
statement from the applicant for applications and submissions for
research and marketing and frequently receives the study director's
statement in fulfillment of, or at least as the primary basis for, the
required statement.
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\9\ A link to those templates is provided in the Pesticide
Registration Notice 2011-3 ``Standard Format for Data Submitted
Under the Federal Insecticide, Fungicide, and Rodenticide Act and
Certain Provisions of the Federal Food, Drug, and Cosmetic Act''
(Ref.17).
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Several comments to the December 2010 ANPRM suggest modifying part
58 to include requirements for studies discontinued before completion.
In response to this suggestion, we propose new Sec. 58.185(d)
requiring the study director to write, sign, and date a short written
summary report closing the study and discussing why the study was
discontinued. This report and study material must be archived as
required in Sec. 58.190 in case of future study review or study
completion.
3. Storage and Retrieval of Records and Data (Sec. 58.190)
We propose modifying Sec. 58.190(a) to add reserve samples to
those items generated as a result of a nonclinical laboratory study
that must be retained. We also propose adding a requirement for
retention of ``Correspondence and other documents relating to
interpretation and evaluation of data, other than those documents
contained in the final study report.'' We propose this addition to
harmonize with the EPA GLP regulations (see 40 CFR 160.190(a) and
792.190(a)) and to clarify our requirement for retaining these
documents.
Our other proposed modifications in Sec. 58.190 provide timeframes
for archiving required study material and requirements for the SOPs
about archiving to include procedures specific to removing study
material from the archives. Stakeholders who asked that we modernize
part 58 requested a reasonable timeframe after the study completion
date to complete study archiving. Comments to the December 2010 ANPRM
also made this request. The SOP requirement for procedures specific to
removing study material from the archives is to address concerns that
material in the archives could be lost or destroyed if removed without
having in place adequate and specific procedures.
We propose that archiving occur no later than 2 weeks after the
study completion date (see study completion date defined in Sec.
58.3). We propose this 2-week timeframe to prevent required material
from being inadvertently misplaced, lost, or destroyed over the long
term. We understand that certain situations may prevent archiving study
material during, or at the completion of, a nonclinical laboratory
study as currently required of the study director in Sec. 58.33(f).
We also propose, when the study sponsor delays finalizing the final
study report, that the study director must complete, sign, and date the
final study report and archive all study material no later than 6
months after completion of the last draft of the final study report.
Additionally, if the study sponsor stops a nonclinical laboratory study
before all protocol requirements are complete, a decision about
discontinuing the study must be made no later than 6 months after
stopping the study. For discontinued studies, a summary report and
study material must be archived within 2 weeks of the study director
signing the summary report. We propose these timeframes to provide the
requested flexibility without compromising the integrity of study
material.
4. Retention of Records (Sec. 58.195)
We propose modifying Sec. 58.195(b) to conform withSec. 58.190(a)
for the listing arrangement. We also propose modifying Sec.
58.195(b)(1) to address those applications and submissions to FDA that
might not result in an approval, clearance, or a premarket
authorization. We therefore propose adding an additional required
retention period from the date an application or submission is
administratively closed by FDA. ``Administratively closed'' includes
those applications and submissions closed administratively with or
without a decision.
In Sec. 58.195(h), we propose adding a statement recognizing that
a change of archive location may be due to reasons other than closure
of a testing facility. For example, changes in ownership as well as
changes in physical location would change the archive location. We also
propose including a timeframe of ``no later than 10 working days after
the transfer occurs'' for reporting to FDA
[[Page 58360]]
and the study sponsor a change in archive location.
We propose this timeframe to ensure that FDA is informed of the
location of study materials if a GLP BIMO inspection of the study is
warranted. This requirement is necessary to prevent waste of
inspectional resources and delay in receiving FDA inspectional
findings, which provide FDA reviewers information about data quality
and integrity.
Other proposed changes to Sec. 58.195 are for consistency with our
proposals throughout this document and to update the regulations
consistent with current practices.
J. Part 58, Subpart K--Disqualification of Any Person Conducting a
Phase of a Nonclinical Laboratory Study
We propose modifying subpart K to extend the authority of the
Commissioner of Food and Drugs to disqualify any person conducting a
phase of a nonclinical laboratory study upon finding either or both of
the conditions for disqualification in the proposed revisions in Sec.
58.202. We propose adding any person conducting a phase of a
nonclinical laboratory study for consistency with other modifications
throughout this proposal.
We propose modifying Sec. 58.202 to clarify the conditions for
disqualification. To help provide uniformity in FDA regulations, we
propose adding as a basis for initiating disqualification proceedings
the repeated or deliberate submission of false information in any
required report. FDA intends to reserve disqualification for the rare
case when the rejection of a particular study is an inadequate
regulatory response (see 43 FR 59986 at 60011) (Ref. 12).
In addition, we propose to amend the current provision in Sec.
58.206(a) so that a person disqualified under part 58 would no longer
be eligible to receive a test article under part 511, New Animal Drugs
For Investigational Use. A clinical investigator who is ineligible to
receive a test article under part 511 also would be ineligible to
conduct any nonclinical laboratory study that is intended to support an
application for a research or marketing permit.
For certain FDA-regulated products, such as new animal drugs, the
study subjects are animals in both ``nonclinical laboratory studies''
and ``clinical investigations.'' In the new animal drug approval
process, nonclinical laboratory studies, such as those that target
animal safety and human food safety, may be essential in determining
whether to approve an application for a research or marketing permit
for a new animal drug. For new animal drugs, the same clinical
investigator could conduct both nonclinical laboratory studies and
clinical investigations. Therefore, we propose this action to help
protect the safety and welfare of animal research subjects involved in
FDA-regulated nonclinical laboratory studies and clinical
investigations, and to help ensure the reliability and integrity of the
data submitted to FDA to support FDA decisions concerning new animal
drugs.
Concurrent with this proposal, FDA is publishing elsewhere in this
issue of the Federal Register a proposal to amend Sec. 511.1(c), to
expand the scope of clinical investigator disqualification under part
511. Under the current regulations, a clinical investigator
disqualified by the Commissioner is ineligible to receive the
particular type of test article regulated under that part (e.g. new
animal drugs in Sec. 511.1(c)) and is ineligible to conduct any
clinical investigation that supports an application for a research or
marketing permit for products regulated by FDA. Under the proposed
amendment to part 511, a clinical investigator disqualified under part
511 also would be ineligible to conduct any nonclinical laboratory
study intended to support an application for a research or marketing
permit for a new animal drug.
When a clinical investigator is disqualified pursuant to part 511,
the basis for that disqualification typically is the repeated or
deliberate submission of false information to FDA or a sponsor in any
required report. For new animal drugs, the same investigator could
conduct both nonclinical laboratory studies and clinical
investigations. The proposed amendment to part 511 would make a
clinical investigator disqualified under part 511 ineligible to conduct
any nonclinical laboratory study intended to support an application for
a research or marketing permit for a new animal drug. In addition, the
proposed amendment to part 511 would help to provide consistency for
disqualification proceedings in parts 58 and 511.8.
Other proposed provisions in Sec. Sec. 58.200, 58.202, 58.204,
58.206, 58.210, 58.213, 58.215, and 58.217 are for clarity and
consistency with our proposals throughout this document. In Sec.
58.210, when a study is determined to be unacceptable, we propose to
eliminate from consideration data in support of the application or
submission to FDA, as defined in proposed Sec. 58.3. We also propose
to add that such elimination may serve as new information justifying
appropriate regulatory action not limited to termination or withdrawal
of approval.
We propose modifying Sec. 58.219 to reference Sec. 58.210(b) and
to require an FDA inspection of a disqualified person before
reinstatement can be considered. Presently, Sec. 58.219 states that
the Commissioner ``may'' require such an inspection. Before a request
for reinstatement can be appropriately considered by FDA, we propose
requiring an inspection. This inspection would help provide additional
information about the disqualified person that may be relevant to the
consideration for reinstatement.
IV. Regulatory Hearing Before FDA
We propose to add to 21 CFR 16.1(b)(2) a new provision for 21 CFR
part 58, subpart K relating to disqualifying any person that conducts a
phase of nonclinical laboratory studies of FDA-regulated products.
V. Analysis of Environmental Impact
The Agency has determined under 21 CFR 25.30(h) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
VI. Legal Authority
Legal authority to issue good laboratory practice regulations
exists under section 701(a) of the FD&C Act, as essential to
enforcement of the Agency's responsibilities under sections 402, 406,
408, 409, 501, 502, 503, 505, 510, 512-516, 518-520, 571, 721, 801,
905, 910, and 911 of the FD&C Act; and, sections 351 and 354-360F of
the PHS Act.
VII. Proposed Implementation Plan
FDA proposes that any final rule that may issue based on this
proposal become effective 1 year after the date of publication of the
final rule in the Federal Register.
VIII. Economic Analysis of Impacts
A. Introduction
We have examined the impacts of the proposed rule under Executive
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L.
104-4). Executive Orders 12866 and 13563 direct Agencies to assess all
costs and benefits of available regulatory alternatives and, when
regulation is necessary, to select regulatory approaches that maximize
net benefits (including potential economic, environmental, public
health and safety, and other advantages; distributive
[[Page 58361]]
impacts; and equity). We have developed a comprehensive Economic
Analysis of Impacts that assesses the impacts of the proposed rule. We
believe that this proposed rule is not a significant regulatory action
as defined by Executive Order 12866.
The Regulatory Flexibility Act requires Agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because the proposed requirements are likely to
impose a significant burden on small entities employing fewer than 10
workers in ``Dental Equipment and Supplies'' (between 1.87 and 8.94
percent of average annual sales), we find that the proposed rule would
have a significant economic impact on a substantial number of small
entities, but the impacts are uncertain.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that Agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $146 million, using the most current (2015) Implicit
Price Deflator for the Gross Domestic Product. This proposed rule would
not result in an expenditure in any year that meets or exceeds this
amount.
B. Summary
This proposed rule would amend the regulations regarding GLPs and
would require that nonclinical laboratory studies (sometimes referred
to as preclinical studies) follow a complete quality system approach,
referred to as a GLP Quality System, when safety and toxicity studies
support or are intended to support applications and submissions to FDA.
The proposed rule would expand the scope to include all products for
which nonclinical laboratory studies are currently conducted that are
not explicitly discussed in the current regulations, specifically
tobacco products. The proposed expanded scope also includes all
applications and submissions under the FD&C Act that can be supported
by the results of nonclinical laboratory studies. In addition, the
proposed rule would introduce and modify definitions, terms, and
organizational and personnel roles and responsibilities consistent with
the implementation of the proposed GLP Quality System and the
prevalence of multisite studies. Finally, the proposed rule would
incorporate wording consistent with some of the existing domestic and
international guidelines, rules or regulations covering good laboratory
practices such as those established by the OECD.
Costs of the rule, when final, would include annual and one-time
costs. Annual costs would include the additional reporting and
recordkeeping responsibilities required under the proposed GLP Quality
System. One-time costs include reading and understanding the rule,
updating existing SOPs, writing new SOPs, and training. Combined, all
costs annualized over a ten-year period at a 7-percent discount rate
are estimated to range between $34.4 million and $69.3 million, with an
average annualized cost of $51.9 million. By contrast, with a 3 percent
discount rate, annualized cost would range from $34.2 million to $68.9
million, with an average annualized cost of $51.5 million.
Conducting nonclinical laboratory studies under the proposed GLP
Quality System is expected to improve the reliability and quality of
the data that support applications and submissions to us, including
those applications and submissions that lead to the use of new medical
products in first-in-human clinical studies. In addition, the proposed
system is conducive to improving compliance and accountability by all
involved in the conduct of nonclinical laboratory studies.
As described, we understand the potential effects on small
entities. We therefore seek comment, particularly from small entities,
about the proposed effective date of 1 year after the date of
publication of any final rule that may issue (see section VII. Proposed
Implementation Plan).
The full discussion of economic impacts is available in docket FDA-
2010-N-0548 at https://www.regulations.gov and at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm (Ref.
18).
Table 1 summarizes the costs and benefits.
Table 1--Summary of Benefits, Costs and Distributional Effects of Proposed Rule \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Units
------------------------------------------------
Category Primary Low estimate High estimate Period Notes
estimate Year dollars Discount rate covered
(%) (years)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
Annualized.......................... .............. .............. .............. 2014 7 10
Monetized $millions/year............ .............. .............. .............. 2014 3 10
Annualized.......................... .............. .............. .............. 2014 7 10
Quantified......................... .............. .............. .............. 2014 3 10
---------------------------------------------------------------------------------------------------------------
Qualitative......................... The proposed rule would clarify GLP standards
to facilitate a more consistent approach and
provide greater international consistency. As
a result, we anticipate improvements in the
integrity and quality of data submitted for
FDA review decisions.
---------------------------------------------------------------------------------------------------------------
Costs:
Annualized.......................... $51.9 $34.4 $69.3 2014 7 10
Monetized $millions/year............ 51.5 34.2 68.9 2014 3 10
Annualized.......................... .............. .............. .............. 2014 7 10
[[Page 58362]]
Quantified.......................... .............. .............. .............. 2014 3 10
Qualitative
Transfers:
Federal............................. .............. .............. .............. 2014 7 10
Annualized.......................... .............. .............. .............. 2014 3 10
---------------------------------------------------------------------------------------------------------------
Monetized $millions/year............ From:
To:
---------------------------------------------------------------------------------------------------------------
Other............................... .............. .............. .............. 2014 7 10
Annualized.......................... .............. .............. .............. 2014 3 10
---------------------------------------------------------------------------------------------------------------
Monetized $millions/year............ From:
To:
---------------------------------------------------------------------------------------------------------------
Effects:................................ State, Local or Tribal Government: None estimated.
Small Business: The proposed requirements would likely impose a significant burden on small entities employing
fewer than 10 workers in ``Dental Equipment and Supplies'' (between 1.87 and 8.94 percent of average annual
sales). However, we do not have data on how many of these dental-equipment small entities perform nonclinical
laboratory studies to support, or intended to support, an application or submission regulated by us; only such
entities would be affected by the rule.
Wages: None estimated.
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Full Disclosure Preliminary Impact Analysis of the proposed rule ``Good Laboratory Practice for Nonclinical Laboratory Studies,'' Docket No. FDA-
2010-N-0548. (Available at: https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.)
IX. Paperwork Reduction Act of 1995
This proposed rule contains information collection provisions that
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). A
description of these provisions is given in the Description section of
this document with an estimate of the annual reporting and
recordkeeping burden. Included in the estimate is the time for
reviewing instructions, searching existing data sources, gathering and
maintaining the data needed, and completing and reviewing each
collection of information.
FDA invites comments on: (1) Whether the proposed collection of
information is necessary for the proper performance of FDA's functions,
including whether the information will have practical utility; (2) the
accuracy of FDA's estimate of the burden of the proposed collection of
information, including the validity of the methodology and assumptions
used; (3) ways to enhance the quality, utility, and clarity of the
information to be collected; and (4) ways to minimize the burden of the
collection of information on respondents, including through the use of
automated collection techniques, when appropriate, and other forms of
information technology.
Title: Reporting and Recordkeeping Requirements for Good Laboratory
Practice for Nonclinical Laboratory Studies--OMB Control Number 0910-
0119--Revision
Description: This proposed rule would revise the existing
information collection requirements in the GLP regulations to provide
for the development and implementation of a GLP Quality System and to
reflect current procedures for the conduct of nonclinical laboratory
studies, particularly multisite studies.
Description of respondents: Respondents to the information
collection are persons conducting a phase of a nonclinical laboratory
study that is within the proposed expanded scope of part 58, including
their personnel, independent contributing scientists, and study
sponsors as the latter two terms are defined in this proposed rule;
universities; or government agencies.
Reporting: Currently, the GLP regulations include requirements to:
(1) Report the results of QAU inspections; (2) submit periodic QAU
study reports; (3) provide a QAU statement as part of the final study
report; (4) provide the results of test and control article
characterization and the testing of mixtures of test and control
articles with carriers; (5) report a change in archive location; and
(6) prepare in writing a final study report containing an overall
interpretation of nonclinical laboratory studies.
The proposed rule will revise these requirements to include: (1) A
final study report incorporating additional information about all
persons conducting one or more nonclinical laboratory study phases and
a study director's compliance statement; (2) QAU reports on facility-
based inspections and process-based inspections, where conducted; (3)
written certification whenever a process-based QAU inspection reveals
problems, with documentation that records the actions taken; (4)
summaries of the closeout of discontinued studies; (5) notification of
the change of archival site within a specified timeframe; (6) reports
by the study sponsor to the study director of known risks of the test
article and necessary measures to protect study personnel; and (7)
reports by the study sponsor to the study director of the results of
characterization of any reference articles that may be employed in a
study as well of mixtures of such reference articles with carriers.
Finally, for sponsors who submit the results of nonclinical laboratory
studies in support of applications or submissions to FDA that are
proposed additions to the scope of part 58 and that lack enacting
regulations, (8) submission of the final study report and a GLP
compliance statement.
QAU inspection reports provide the study director and management
with executive responsibility information about the progress of a study
and its
[[Page 58363]]
compliance with GLP regulations so they can take any corrective actions
required to ensure the quality and integrity of the data. Test,
control, and reference article information helps ensure proper dosing
of the test system(s) and allows interpretation of study results in the
final study report. The study sponsor receives the final study report
and commonly submits the report in support of an application or
submission to FDA. The information in the final study report gives
FDA's scientific review experts the information needed to help
determine the safety or toxicity of the test article or both. FDA needs
such safety and toxicity information to make regulatory decisions
regarding the test article, including permitting the conduct of
clinical studies on human subjects, determining safe levels of residual
drug for drugs administered to animals whose products will be consumed
by humans, and marketing new products for both human and non-human
animal use. Since a number of the additional applications and
submissions proposed for the scope expansion do not have enacting
regulations, inclusion in part 58 is necessary.
We estimate the reporting burden of this collection of information
as follows:
Table 2--Estimated One-Time Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
Number of Average
Activity Number of responses per Total annual burden per Total hours
respondents respondent responses response
----------------------------------------------------------------------------------------------------------------
Read and Understand the Proposed 2,193 1 2,193 7.2 15,790
Rule: Sponsors of Nonclinical
Laboratory Studies.............
Read and Understand the Proposed 300 1 300 18 5,400
Rule: Testing Facilities of
Nonclinical Laboratory Studies.
-------------------------------------------------------------------------------
Total....................... .............. .............. 2,493 .............. 21,190
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
Table 2 shows the estimated one-time burden associated with the new
reporting provisions of the proposed rule. We expect that persons
conducting a phase of a nonclinical laboratory study that is within the
proposed expanded scope of part 58 will need to read and understand the
proposed rule. We expect that some entities would face lower complexity
from reading the proposed rule and some entities would face higher
complexity. In the Preliminary Regulatory Impact Analysis (PRIA), we
calculated lower and upper estimates of time to read and understand the
proposed rule under a low-complexity scenario for sponsors of
nonclinical laboratory studies who would face fewer provisions. Our
estimates under a high-complexity scenario apply to testing facilities
of nonclinical laboratory studies that would have to read and
understand more provisions in the rule. As stated in the PRIA, we
estimate that there are 2193 sponsors of nonclinical laboratory studies
and 300 testing facilities of nonclinical laboratory studies. We
estimate that the 2193 sponsors of nonclinical laboratory studies will
take from 4.8 to 9.6 hours, for an average of 7.2 hours, to read and
understand the proposed rule. We expect that the 300 testing facilities
of nonclinical laboratory studies will take from 12 to 24 hours, for an
average of 18 hours, to read and understand the proposed rule.
Table 3--Estimated Recurring Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
Number of Average
21 CFR Section Number of responses per Total annual burden per Total hours
respondents respondent responses response
----------------------------------------------------------------------------------------------------------------
Sponsor provides test, control, 1,316 5 6,580 1 6,580
and reference article
characterization and risk
information (Sec. 58.5(g) &
(h))............................
Sponsor provides nonclinical 10 1 10 15 150
laboratory study report in
support of applications and
submissions (Sec. 58.5(k))....
Expanded content of QAU statement 300 60.25 18,075 .25 4,518.75
in final study report (Sec. (15 minutes)
58.35(b)(11))...................
Management report of actions 10 2 20 5 100
taken when a process-based
inspection reveals problems
(Sec. 58.35(e))...............
Expanded contents of final study 300 60.25 18,075 2 36,150
report (Sec. 58.185(a)).......
Compliance statement by study 300 60.25 18,075 .5 9,037.5
director appended to final study (30 minutes)
report (Sec. 58.185(a)(16))...
Summary report of close-out for 300 2 600 2 1,200
discontinued studies (Sec.
58.185(d))......................
Reports by independent 30 1 30 5 150
contributing scientists (Sec.
58.37(a)(2))....................
Principal Investigator (PI) 200 10 2,000 1 2,000
reports of deviations (Sec.
58.39(c)).......................
PI study report & compliance 200 5 1,000 8 8,000
statement (Sec. 58.39 (d))....
Management report of personnel 300 10 3,000 .5 1,500
deviations from protocol (Sec. (30 minutes)
58.29(b)).......................
------------------------------------------------------------------------------
Total........................ .............. ............. 67,465 .............. 69,386.25
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
[[Page 58364]]
Table 3 shows the estimated recurring reporting burden associated
with the proposed rule. Together, this results in a total of 90,576.25
hours and 69,958 responses.
Recordkeeping: Currently, the GLP regulations include requirements
that respondents must record: (1) Personnel job descriptions and
summaries of training and experience; (2) master schedules, protocols,
and protocol amendments; (3) equipment inspection, maintenance,
calibration, and testing records; (4) SOPs; (5) documentation of feed
and water analyses and animal treatments; (6) test article
accountability records; and (7) study documentation, including raw
data.
This proposed rule will add to the existing requirements with
regard to initial changes and additions to SOPs for both testing
facilities and test sites to develop, implement, and maintain a GLP
Quality System and to expand many SOPs to specifically include
multisite studies.
This proposed rule would also expand personnel record maintenance
to require records of training and experience on GLP requirements and
species-specific animal care. In addition, this proposed rule includes
revisions to the required content of study protocols as part of a GLP
Quality System and for multisite study specifics.
The additional documentation by management with executive
responsibility and study directors is for the implementation of a GLP
Quality System and the resulting additional burden is nominal.
Documentation by independent contributing scientists, as defined in
this proposed rule, includes records these individuals would usually
retain, so a nominal added burden is predicted.
To implement the proposed checks and balances discussed previously
in the preamble, proposed revisions will require that added
documentation be made by the study director and the QAU to ensure the
viability of the proposed GLP Quality System (see Table 5).
This proposed rule also adds requirements for the study sponsor to
maintain records of: (1) Protocol and protocol amendment approval; (2)
the accreditation status of a contracted person (as defined in this
proposed rule) that conducts a phase of the study that involves the use
of animals; (3) test, control, and reference article characterization;
and (4) the qualifications of all contracted persons.
In addition, the proposed rule includes recordkeeping requirements
for nonclinical laboratory studies that choose to utilize the option of
having a principal investigator, particularly for multisite studies.
These individuals will have recordkeeping responsibilities comparable
to those of the study director for the nonclinical laboratory study
phases for which they are responsible.
The persons potentially retaining nonclinical laboratory study
documents are persons conducting a phase of a nonclinical laboratory
study that is within the proposed expanded scope of part 58, including
independent contributing scientists, and study sponsors as defined in
this proposed rule. Results of nonclinical laboratory studies may be
used by firms in support of applications and submissions to FDA,
including applications and submissions for research and marketing of
new products. The additional documentation of the conduct and data
collection of nonclinical laboratory studies of FDA-regulated products
will help ensure the quality and integrity of final study reports. FDA
conducts on-site reviews of records and study reports during
inspections of persons conducting one or more nonclinical laboratory
study phases to verify the reliability of results submitted in support
of applications and submissions to FDA.
We estimate the recordkeeping burden of this collection of
information as follows:
Table 4--Estimated One-Time Recordkeeping Burden \1\
----------------------------------------------------------------------------------------------------------------
Number of Average
Activity Number of records per Total annual burden per Total hours
recordkeepers recordkeeper records recordkeeping
----------------------------------------------------------------------------------------------------------------
Update Existing SOPs............ 300 12 3,600 7.5 27,000
Write New SOPs.................. 300 10 3,000 24 72,000
Training........................ 300 2 600 14 8,400
-------------------------------------------------------------------------------
Total....................... .............. .............. 7,200 .............. 107,400
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
Table 4 shows the estimated one-time burden associated with the
revised recordkeeping provisions of the proposed rule. We expect that
the 300 testing facilities of nonclinical laboratory studies will need
to update existing SOPs and to write new SOPs. In the PRIA, we
estimated that each facility would need to update 12 existing SOPs and
write 10 new SOPs. We calculated lower and upper estimates of time to
update existing SOPs and to write new SOPs. We estimate that it will
take from 4 to 11 hours, for an average of 7.5 hours, to update 12
existing SOPs. We estimate that it will take from 15 to 33 hours, for
an average of 24 hours, to write 10 new SOPs. We also expect that the
300 testing facilities of nonclinical laboratory studies will need to
conduct training. In the PRIA, we estimated that for the low estimate
one person would be doing the training and one person would be trained.
By contrast, for the high estimate, we estimated that also one person
would be doing the training and potentially three people would receive
such training, for an average of two employees for each facility. We
calculated lower and upper estimates of time to train, estimating that
it will take from 5 to 23 hours, for an average of 14 hours, to train.
Table 5--Estimated Recurring Recordkeeping Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number of Average burden
Number of records per Total annual per Total hours
recordkeepers recordkeeper records recordkeeping
--------------------------------------------------------------------------------------------------------------------------------------------------------
Sponsor documentation (Sec. 58.5):
[[Page 58365]]
--(c) protocol approval and (i) all amendments............ 2,193 100 219,300 1 219,300
--(b) animal welfare...................................... 1,316 5 6,580 2 13,160
--(d) accreditation status of testing facility............ 1,316 5 6,580 .5 3,290
(30 minutes)
--(g) test, control, and reference article parameters..... 1,316 5 6,580 .5 3,290
(30 minutes)
--(j) archival locations.................................. 2,193 62.25 136,514 .25 34,128.5
(15 minutes)
--(e) qualifications of contracted persons................ 1,316 5 6,580 2 13,160
Documentation by management with executive responsibility:
--GLP training and experience (Sec. 58.29(a) & (d))..... 300 500 150,000 .25 37,500
(15 minutes)
--Animal care training and experience (Sec. 58.29(a) & 300 5 1,500 .25 375
(d))..................................................... (15 minutes)
--all persons are qualified for multisite studies (Sec. 300 500 150,000 .25 37,500
58.31(i))................................................ (15 minutes)
--Periodic review of GLP Quality System (Sec. 58.31(b)). 300 .25 75 .5 37.5
(30 minutes)
--Periodic review of QAU (Sec. 58.31(r))................ 300 1 300 .5 150
(30 minutes)
--Appointment of management representative (Sec. 300 .1 30 .25 7.5
58.31(e))................................................ (15 minutes)
--all test sites have master schedule (Sec. 58.31(j))... 300 15 4,500 .25 1,125
(15 minutes)
--appointment of person to manage master schedule (Sec. 300 0.1 30 .25 7.5
58.31(k))................................................ (15 minutes)
--selection of lead QAU for multisite studies (Sec. 300 5 1,500 .25 375
58.31(p)).................................................... (15 minutes)
--QAU review of protocols, SOPs, & their amendments (Sec. 300 5 1,500 .25 375
58.31(q)).................................................... (15 minutes)
QAU:
--review of study protocols + amendments (Sec. 300 17 5,100 1.5 7,650
58.35(b)3))..............................................
--SOPs review + amendments (Sec. 58.35(b)(4))........... 300 17 5,100 1.5 7,650
--facility and process-based inspections (Sec. 150 5 750 .25 187.5
58.35(b)(5))............................................. (15 minutes)
--audits of final reports of contributing scientists (Sec. 300 600 180,000 .5 90,000
58.35(b)(9))........................................... (30 minutes)
--audits of principal investigator (reports (Sec. 300 120 36,000 .5 18,000
58.35(b)(9))............................................. (30 minutes)
--audits of final study reports for multisite studies 300 60 18,000 .5 9,000
(Sec. 58.35(b)(10)).................................... (30 minutes)
Study Director
--Multisite study need for PIs (Sec. 58.33(b)(7)(ii))... 300 180 54,000 1 54,000
--communications (Sec. 58.33(b)(12)).................... 300 180 54,000 .25 13,500
(15 minutes)
--protocol followed (Sec. 58.33(b)(1)).................. 300 60 18,000 1 18,000
--QAU review of protocol & SOPs (Sec. 58.33(b)(2))...... 300 17 5,100 .25 1,275
(15 minutes)
[[Page 58366]]
--management provided adequate resources (Sec. 300 5 1,500 .5 750
58.33(b)(3))............................................. (30 minutes)
--computerized systems validated (Sec. 58.33(b)(4))..... 300 5 1,500 .25 375
(15 minutes)
--Committee review 58.33(b)(5)............................ 300 17 5,100 .25 1,275
(15 minutes)
--multisite study personnel qualified (Sec. 300 15 4,500 1 4,500
58.33(b)(7)(i))..........................................
--test system as required (Sec. 58.33(b)(10))........... 300 5 1,500 .25 375
(15 minutes)
--GLP compliance (Sec. 58.33(b)(11)).................... 300 60 18,000 1 18,000
--test article accountability when containers disposed of 300 6 1,800 .25 450
(Sec. 58.105(d))....................................... (15 minutes)
Independent contributing scientists:
--Education, training, and experience (Sec. 58.37(b)(2)) 30 1 30 .25 7.5
(15 minutes)
--Archive location (Sec. 58.37(b)(4))................... 30 1 30 .25 7.5
(15 minutes)
--Appropriate animal care (Sec. 58.37(b)(3))............ 2 1 2 .5 1
(30 minutes)
PIs:
--Protocol + amendment acceptance (Sec. 58.39(a))....... 200 5 1,000 .25 250
(15 minutes)
--Study deviations (Sec. 58.39(c))...................... 200 10 2,000 .5 1,000
(30 minutes)
--Archive location (Sec. 58.39((e))..................... 200 40 8,000 .25 2,000
(15 minutes)
Recordkeeping (Sec. 58.195)............................. 300 251.5 75,450 3.9 294,255
-----------------------------------------------------------------------------------------
Total................................................. ................ ................ 1,188,031 ................ 906,289.5
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
Table 5 shows the estimated recurring recordkeeping burden
associated with the proposed rule. Together, this results in a total of
1,013,689.5 hours and 1,195,231 records.
To ensure that comments on information collection are received, OMB
recommends that written comments be faxed to the Office of Information
and Regulatory Affairs, OMB (see ADDRESSES). All comments should be
identified with the title of the information collection.
In compliance with the Paperwork Reduction Act of 1995 (44 U.S.C.
3407(d)), the Agency has submitted the information collection
provisions of this proposed rule to OMB for review. These requirements
will not be effective until FDA obtains OMB approval. FDA will publish
a notice concerning OMB approval of these requirements in the Federal
Register.
X. Federalism
FDA has analyzed this proposed rule according to the principles set
forth in Executive Order 13132. FDA has determined that the proposed
rule, if finalized, would not contain policies that would have
substantial direct effects on the States, on the relationship between
the National Government and the States, or on the distribution of power
and responsibilities among the various levels of government.
Accordingly, the Agency tentatively concludes that the proposed rule
does not contain policies that have federalism implications as defined
in the Executive order and, consequently, a federalism summary impact
statement is not required.
XI. References
The following references are on display in the Division of Dockets
Management (see ADDRESSES and are available for viewing by interested
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also
available electronically at https://www.regulations.gov. FDA has
verified the Web site addresses, as of the date this document publishes
in the Federal Register, but Web sites are subject to change over time.
1. ``OECD Series on Principles of Good Laboratory Practice (GLP)
and Compliance Monitoring,'' (the link provided is to an index of
all OECD documents related to GLPs, with links to each of the
individual documents) (https://www.oecd.org/chemicalsafety/testingofchemicals/oecdseriesonprinciplesofgoodlaboratorypracticeglpandcompliancemonitoring.htm).
2. ``Mutual Acceptance of Data (MAD),'' (https://www.oecd.org/env/ehs/mutualacceptanceofdatamad.htm).
3. FDA, ``FDA Announces New Initiative to Modernize the
Regulation of Clinical Trials and Bioresearch Monitoring,'' FDA News
Release, June 26, 2006 (https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108677.htm).
4. FDA, ``Nonclinical Laboratory Studies; Proposed Regulations
for Good Laboratory Practice Regulations'' 41 FR 51206 (November 19,
1976).
5. MOU 225-06-4000. ``Memorandum of Understanding Among the
Animal and Plant Health Inspection Service, U.S. Department of
Agriculture, and the Food and Drug Administration, U.S. Department
of Health and Human Services, and the National Institutes of Health,
U.S. Department of
[[Page 58367]]
Health and Human Services, Concerning Laboratory Animal Welfare,''
(https://www.fda.gov/AboutFDA/PartnershipsCollaborations/MemorandaofUnderstandingMOUs/DomesticMOUs/ucm247294.htm).
6. ``OECD Series on Principles of Good Laboratory Practice and
Compliance Monitoring Number 13,'' The Application of the OECD
Principles of GLP to the Organisation and Management of Multi-Site
Studies; Consensus Document of the Working Group on Good Laboratory
Practice (https://search.oecd.org/officialdocuments/displaydocumentpdf/?doclanguage=en&cote=env/jm/mono(2002)9).
7. ``OECD Series on Principles of Good Laboratory Practice and
Compliance Monitoring Number 4 (Revised),'' Consensus Document;
Quality Assurance and GLP (https://search.oecd.org/officialdocuments/displaydocumentpdf/?doclanguage=en&cote=env/jm/mono(99)20).
8. ``OECD Series on Principles of Good Laboratory Practice and
Compliance Monitoring Number 1,'' The OECD Principles on Good
Laboratory Practice (https://search.oecd.org/officialdocuments/displaydocumentpdf/?doclanguage=en&cote=env/mc/chem(98)17).
9. ``OECD Series on Principles of Good Laboratory Practice and
Compliance Monitoring Number 11,'' Advisory Document of the Panel on
Good Laboratory Practices, The Role and Responsibilities of the
Sponsor in the Application of the Principles of GLP (https://search.oecd.org/officialdocuments/displaydocumentpdf/?doclanguage=en&cote=env/mc/chem(98)16).
10. Council for International Organization of Medical Sciences
and The International Council for Laboratory Animal Science,
International Guiding Principles for Biomedical Research Involving
Animals, December 2012 (revised) (https://www.cioms.ch/images/stories/CIOMS/IGP2012.pdf).
11. Institute for Laboratory Animal Research, Guide for the Care
and Use of Laboratory Animals, Eighth Edition, 2011 (https://grants.nih.gov/grants/olaw/Guide-for-the-Care-and-Use-of-Laboratory-Animals.pdf).
12. FDA, ``Nonclinical Laboratory Studies, Good Laboratory
Practice Regulations,'' Final Rule, 43 FR 59986 (December 22, 1978).
13. Compliance Policy Guide (CPG 7151.02), Sec. 130.300--FDA
Access to Results of Quality Assurance Program Audits and
Inspections (https://www.fda.gov/ICECI/ComplianceManuals/CompliancePolicyGuidanceManual/ucm073841.htm).
14. ``OECD Series on Principles of Good Laboratory Practice and
Compliance Monitoring Number 8 (Revised),'' Consensus Document, The
Role and Responsibilities of the Study Director in GLP Studies
(https://search.oecd.org/officialdocuments/displaydocumentpdf/?doclanguage=en&cote=env/jm/mono(99)24).
15. ``OECD Series on Principles of Good Laboratory Practice and
Compliance Monitoring Number 7 (Revised),'' Consensus Document, The
Application of the GLP Principles to Short Term Studies (https://search.oecd.org/officialdocuments/displaydocumentpdf/?doclanguage=en&cote=env/jm/mono(99)23).
16. Bioanalytical Method Validation Draft Guidance for Industry
(https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM368107.pdf).
17. Pesticide Registration Notice 2011-3 ``Standard Format for
Data Submitted Under the Federal Insecticide, Fungicide, and
Rodenticide Act and Certain Provisions of the Federal Food, Drug,
and Cosmetic Act'' (https://www.epa.gov/sites/production/files/2014-04/documents/pr2011-3.pdf) (Study profile templates available at
https://www.epa.gov/pesticide-registration/study-profile-templates).
18. Full Analysis of Economic Impacts (Docket Number FDA-2010-N-
0548). Preliminary Regulatory Impact Analysis, Initial Regulatory
Flexibility Analysis, and Unfunded Mandates Reform Act Analysis for
Good Laboratory Practice for Nonclinical Laboratory Studies;
Proposed Rule, available at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.
List of Subjects
21 CFR Part 16
Administrative practice and procedure.
21 CFR Part 58
Laboratories, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR parts 16 and 58 be amended as follows:
PART 16--REGULATORY HEARING BEFORE THE FOOD AND DRUG ADMINISTRATION
0
1. The authority citation for part 16 continues to read as follows:
Authority: 15 U.S.C. 1451-1461; 21 U.S.C. 141-149, 321-394,
467f, 679, 821, 1034; 28 U.S.C. 2112; 42 U.S.C. 201-262, 263b, 364.
0
2. In Sec. 16.1, amend paragraph (b)(2) by removing the entry for
Sec. 58.204(b) and adding an entry for Sec. Sec. 58.200 through
58.219 to read as follows:
Sec. 16.1 Scope.
* * * * *
(b) * * *
(2) * * *
Sec. Sec. 58.200 through 58.219 (see part 58, subpart K of this
chapter), relating to disqualifying any person conducting a phase of a
nonclinical laboratory study of FDA-regulated products.
* * * * *
PART 58--GOOD LABORATORY PRACTICE FOR NONCLINICAL LABORATORY
STUDIES
0
3. The authority citation for part 58 is revised to read as follows:
Authority: 21 U.S.C. 342, 346, 346a, 348, 351, 352, 353, 355,
360, 360b-360f, 360h-360j, 360ccc, 371, 379e, 381, 387e, 387j, 387k;
42 U.S.C. 216, 262, 263b-263n.
0
4. In Sec. 58.1, revise paragraph (a) and add paragraph (c) to read as
follows:
Sec. 58.1 Scope.
(a) This part prescribes good laboratory practices (GLPs) for
conducting nonclinical laboratory studies of safety or toxicity or both
that support or are intended to support an application or submission
for products regulated by the Food and Drug Administration (FDA),
including food and color additives, animal food additives, human and
animal drugs, devices, biological products, electronic products, and
tobacco products. Applications and submissions to FDA affected by these
regulations include those listed in Sec. 58.3. Compliance with this
part is intended to assure the quality and integrity of data from
nonclinical laboratory studies filed or submitted pursuant to sections
402, 406, 408, 409, 501, 502, 503, 505, 510, 512-516, 518-520, 571,
701, 721, 801, 905, 910, and 911 of the Federal Food, Drug, and
Cosmetic Act and sections 351 and 354-360F of the Public Health Service
Act.
* * * * *
(c) In this part the term ``where appropriate'' is used several
times. When a requirement is qualified by ``where appropriate,'' it is
deemed to be ``appropriate'' unless justification can be otherwise
documented. A requirement is ``appropriate'' if non-implementation
could reasonably be expected to result in a nonclinical laboratory
study whose results lack the required reliability.
0
5. Revise Sec. 58.3 to read as follows:
Sec. 58.3 Definitions.
As used in this part, the following terms have the meanings
specified:
Applications and Submissions to FDA include:
(1) A color additive petition, described in section 721 of the
Federal Food, Drug, and Cosmetic Act, and as described in part 71 of
this chapter.
(2) A food additive petition, described in section 409 of the
Federal Food, Drug and Cosmetic Act, and as described in parts 171 and
571 of this chapter.
(3) Data and information regarding a substance submitted as part of
the procedures for establishing that a substance is generally
recognized as safe for use, which use results or may reasonably be
expected to result, directly or indirectly, in its becoming a component
or otherwise affecting the characteristics of any food, described in
Sec. Sec. 170.35 and 570.25 of this chapter.
[[Page 58368]]
(4) Data and information regarding a food additive submitted as
part of the procedures regarding food additives permitted to be used on
an interim basis pending additional study, described in Sec. 180.1 of
this chapter.
(5) A petition for a nutrient content claim, described in section
403 of the Federal Food, Drug, and Cosmetic Act, and as described in
subpart D of part 101 of this chapter.
(6) A petition for a health claim, described in section 403 of the
Federal Food, Drug, and Cosmetic Act, and as described in subpart E of
part 101 of this chapter.
(7) An investigational new drug application, described in section
505(i) of the Federal Food, Drug, and Cosmetic Act, and as described in
part 312 of this chapter.
(8) Applications for FDA approval to market a new drug, described
in section 505 of the Federal Food, Drug, and Cosmetic Act, and as
described in part 314 of this chapter.
(9) Data and information regarding an over-the-counter drug for
human use, submitted as part of the procedures for classifying such
drugs as generally recognized as safe and effective and not misbranded,
described in part 330 of this chapter.
(10) Data and information about a substance submitted as part of
the procedures for establishing a tolerance for unavoidable
contaminants in food and food-packaging materials, described in
sections 406, 408, and 409 of the Federal Food, Drug, and Cosmetic Act,
and as described in parts 109 and 509 of this chapter.
(11) A notice of claimed investigational exemption for a new animal
drug, section 512(j) of the Federal Food, Drug, and Cosmetic Act, and
as described in described in part 511 of this chapter.
(12) New animal drug applications, described in section 512 of the
Federal Food, Drug, and Cosmetic Act, and as described in part 514 of
this chapter.
(13) An abbreviated application for a new animal drug, described in
section 512(b) of the Federal Food, Drug, and Cosmetic Act.
(14) An application for conditional approval of new animal drugs
for minor use and minor species, described in section 571(a)(2) of the
Federal Food, Drug, and Cosmetic Act, and as described in part 516 of
this chapter.
(15) Authorization to market edible products from experimental
animals as described in parts 170 and 570 of this chapter.
(16) A request to establish or amend an import tolerance described
in section 512 of the Federal Food, Drug, and Cosmetic Act.
(17) [Reserved]
(18) An application for a biologics license, described in section
351 of the Public Health Service Act, and as described in part 601 of
this chapter.
(19) An application for an investigational device exemption,
described in section 520(g) of the Federal Food, Drug, and Cosmetic
Act, and as described in part 812 of this chapter.
(20) An application for premarket approval of a medical device,
described in section 515 of the Federal Food, Drug, and Cosmetic Act,
and as described in part 814 of this chapter.
(21) An application for humanitarian device exemption, authorized
under section 520(m) of the Federal Food, Drug, and Cosmetic Act, and
as described in part 814, subpart H of this chapter.
(22) A product development protocol for a medical device, described
in section 515 of the Federal Food, Drug, and Cosmetic Act, and as
described in part 814 of this chapter.
(23) A premarket notification submission for a medical device as
authorized under section 510(k) of the Federal Food, Drug, and Cosmetic
Act, and as described in part 807, subpart E of this chapter.
(24) Data and information regarding a medical device submitted as
part of the procedures for classifying such devices described in part
860, subpart B of this chapter, reclassification petitions described in
part 860, subpart C of this chapter, and requests associated with the
evaluation of automatic class III designations, authorized under
section 513(f)(2) of the Federal Food, Drug, and Cosmetic Act.
(25) Data and information regarding a medical device submitted as
part of the procedures for establishing, amending, or revoking a
performance standard for such devices, described in section 514 of the
Federal Food, Drug, and Cosmetic Act, and as described in part 861 of
this chapter.
(26) Data and information regarding an electronic product submitted
as part of the procedures for obtaining an exemption from notification
of a radiation safety defect or failure of compliance with a radiation
safety performance standard, described in subpart D of part 1003 of
this chapter.
(27) Data and information regarding an electronic product submitted
as part of the procedures for establishing, amending, or repealing a
standard for such product, described in section 358 of the Public
Health Service Act.
(28) Data and information regarding an electronic product submitted
as part of the procedures for obtaining a variance from any electronic
product performance standard as described in Sec. 1010.4 of this
chapter.
(29) Data and information regarding an electronic product submitted
as part of the procedures for granting, amending, or extending an
exemption from any electronic product performance standard, as
described in Sec. 1010.5 of this chapter.
(30) A premarket notification for a food contact substance,
described in section 409 of the Federal Food, Drug, and Cosmetic Act,
and as described in part 170, subpart D of this chapter.
(31) [Reserved]
(32) A premarket application for a new tobacco product, as
described in section 910(b)(1) of the Federal Food, Drug, and Cosmetic
Act.
(33) A substantial equivalence report as described in section
905(j) of the Federal Food, Drug, and Cosmetic Act.
(34) A request for exemption under section 905(j)(3) of the Federal
Food, Drug, and Cosmetic Act, and as described in part 1107 of this
chapter.
(35) An application or submission related to a modified risk
tobacco product, as described in section 911of the Federal Food, Drug,
and Cosmetic Act.
Attending veterinarian means a veterinarian who has training or
experience or both in the care and management of the species being
attended and who has direct or delegated authority for activities
involving animals.
Batch means a specific quantity or lot of a test, control, or
reference article that has been characterized according to Sec. 58.105
and handled according to Sec. 58.107.
Contracted person means a person who assumes, either directly or
indirectly as an independent contractor, one or more responsibilities
for the conduct of a nonclinical laboratory study.
Contributing scientist means an individual responsible for the
conduct, interpretation, analysis, or any other service for a phase of
a nonclinical laboratory study. An individual expert or specialist who
is an independently employed contracted person, as defined in this
section, is an independent contributing scientist.
Control article means any food additive, color additive, drug,
biological product, electronic product, device, tobacco product, or any
article other than a test article, reference article, feed, or water
that is administered to the test system in the course of a nonclinical
[[Page 58369]]
laboratory study for the purpose of establishing a basis for comparison
with the test article.
Establish means define, document (in writing or electronically),
and implement.
Facility-based inspection means an inspection which is not based on
specific studies but covers general facilities and activities, for
example, installations, support systems, computer systems, training,
environmental monitoring, and equipment maintenance and calibration.
GLP Quality System means the organizational structure,
responsibilities, procedures, processes, and resources for implementing
quality management in the conduct of a nonclinical laboratory study.
Lead quality assurance unit (lead QAU) means the QAU responsible
for quality assurance (QA) in a multisite nonclinical laboratory study.
Testing facility management with executive responsibility selects the
lead QAU.
Management with executive responsibility means those senior
employees of a testing facility or test site who have the authority to
establish or make changes to the quality policy and GLP Quality System
at the testing facility and test site, respectively.
Master schedule means a compilation of information used for
assessment of workload and the tracking of nonclinical laboratory
studies.
Multisite study means any study that has phases conducted at more
than one site.
Nonclinical laboratory study means in vivo or in vitro experiments
in which test articles are studied prospectively in test systems under
laboratory conditions or in the applicable environment to determine
their safety or toxicity or both. The term does not include studies
involving human subjects, clinical studies, or clinical investigational
use in animals. The term does not include basic exploratory studies
carried out to determine whether a test article has any potential
utility or basic exploratory studies to determine the physical or
chemical characteristics of a test article.
Person includes an individual, partnership, corporation,
association, scientific or academic establishment, government agency,
or organizational unit thereof, and any other legal entity.
Phase means a defined activity or set of activities in the conduct
of a nonclinical laboratory study.
Principal investigator means an individual who has specific
responsibilities for one or more phases of a nonclinical laboratory
study as delegated by the study director.
Process-based inspection means an inspection conducted to monitor
procedures or processes of a repetitive nature that are very frequently
performed. Process-based inspections are conducted on a prearranged
schedule, which is not connected to the timing of any particular
nonclinical laboratory study. Performance of process-based inspections
covering processes or procedures that occur with a very high frequency
(for example, certain mutagenicity studies) may cause some studies to
be uninspected during the in-life period of the study, as defined in
this section within the definition of Short-term study.
Quality means the totality of features and characteristics that
bear on the ability of a nonclinical laboratory study to provide data
that can be relied upon.
Quality assurance unit (QAU) means any person or organizational
element designated to perform the duties relating to quality assurance
(QA) of nonclinical laboratory studies. For any given study, the QAU
must be entirely separate from and independent of the personnel engaged
in the direction and conduct of the study.
Quality policy means the overall intentions and direction of an
organization with respect to quality, as established by management with
executive responsibility.
Raw data means all original nonclinical laboratory study records
and documentation or exact copies that maintain the original intent and
meaning and are made according to the person's certified copy
procedures. Raw data includes any laboratory worksheets,
correspondence, notes, and other documentation (regardless of capture
medium) that are the result of original observations and activities of
a nonclinical laboratory study and are necessary for the reconstruction
and evaluation of the report of that study. Raw data also includes the
signed and dated pathology report.
Reference article means any chemical substance or mixture, or
analytical standard, or material other than a test article, control
article, feed, or water that is administered to or used in analyzing
the test system in the course of a study for the purposes of
establishing the basis for comparison with the test article for known
chemical or biological measurements.
Short-term study means a study for which the in-life period is
completed within several days or a week at most. The in-life period of
a study is that period during which data are collected.
Specimen means any material derived from a test system for
examination, analysis, or retention.
Sponsor means: (1) A person that initiates and supports, by
provision of financial or other resources, a nonclinical laboratory
study; or
(2) A person that submits a nonclinical laboratory study in support
of an application or submission to FDA; or
(3) A person that initiates a nonclinical laboratory study and
functions as, and has the same responsibilities as, a testing facility,
test site, or contributing scientist, as those terms are defined in
this section.
Standard operating procedures (SOPs) means documented procedures
which describe how to perform tests or activities normally not
specified in detail in study protocols.
Study-based inspection means an inspection of a critical operation
of the study which is scheduled according to the chronology of the
given study. Management with executive responsibility at the testing
facility and/or test site identifies which operations are critical
before initiation of the study.
Study completion date means the date the final report is signed by
the study director.
Study director means the individual responsible for the overall
conduct of a nonclinical laboratory study.
Study initiation date means the date the protocol is signed by the
study director.
Test article means any food additive, color additive, drug,
biological product, electronic product, device, tobacco product, or any
other article subject to regulation under the Federal Food, Drug, and
Cosmetic Act or under sections 351 and 354-360F of the Public Health
Service Act.
Test site means a person who is responsible for one or more phases
of a multisite nonclinical laboratory study. A test site includes
management with executive responsibility and supporting SOPs relevant
to the conduct of nonclinical laboratory studies.
Test system means any animal, plant, microorganism, or subparts
thereof to which the test, control, or reference article is
administered or added for study. Test system also includes appropriate
groups or components of the system not treated with the test, control,
or reference articles.
Testing facility means the person responsible for coordinating,
conducting, or completing a nonclinical laboratory study, or any
combination thereof. The testing facility designates the study
director.
Validation means confirmation by examination and provision of
objective evidence that the particular
[[Page 58370]]
requirements for a specific intended use can be consistently fulfilled.
Vehicle means any agent which serves as a carrier and is used to
mix, disperse, or solubilize the test, control, or reference article
for administration or application to the test system.
0
6. Add Sec. 58.5 to subpart A to read as follows:
Sec. 58.5 Sponsor responsibilities.
For each nonclinical laboratory study, the sponsor must:
(a) Ensure the nonclinical laboratory study protocol (the study
protocol) meets the requirements in Sec. 58.120.
(b) Ensure that the study protocol provides for humane care and
ethical treatment of animals.
(c) Sign and date the study protocol to indicate approval.
(d) Contract with persons accredited as following appropriate
animal welfare procedures for phases of a nonclinical laboratory study
that include the use of animals. If these contracted persons are not
accredited, document this fact, the reason for using a non-accredited
person, and the qualifications of the non-accredited person. This
information must be included in the compliance statement required in
paragraph (k) in this section.
(e) Document that any contracted person conducting a phase of a
nonclinical laboratory study is qualified according to the provisions
in this part.
(f) Ensure that appropriate lines of communication are established
among all persons conducting a phase of the nonclinical laboratory
study and document all study-related communications that involve the
sponsor.
(g) Document that test, control, and reference articles are
prepared, characterized, and labeled according to subpart F of this
part, and are appropriately shipped. Obtain, and provide to the study
director as soon as available, information regarding test, control, and
reference article characterization as specified in Sec. 58.105.
(h) Inform the study director of any known potential risks of the
test article to human health or the environment and any measures
necessary to protect study personnel and the environment.
(i) Review, approve, sign, and date each protocol amendment before
implementation.
(j) Document and update as necessary the archive location of all
raw data and records as described in Sec. Sec. 58.190 and 58.195.
(k) Include, in any application or submission to FDA that includes
the results of a nonclinical laboratory study, the final study report
and all amendments. If a summary report of the nonclinical laboratory
study is included in such applications or submissions, a copy of the
final study report, as described in Sec. 58.185, must be appended or
provided elsewhere within the application or submission. Also, include
either a statement that the study was conducted in compliance with the
requirements set forth in this part, or, if the study was not conducted
in compliance with these regulations, a brief statement of the reason
for the noncompliance.
0
7. Revise Sec. 58.10 to read as follows:
Sec. 58.10 Transfer of responsibilities.
(a) Any person utilizing the services of a contracted person (as
defined in Sec. 58.3) to perform a phase (as defined in Sec. 58.3) of
a nonclinical laboratory study may transfer to the contracted person
any regulatory responsibility in this chapter, unless delegation of
such responsibility is expressly prohibited. Any such transfer must be
described in writing. Any responsibility not covered by the written
description is deemed not transferred.
(b) Any person transferring to a contracted person any
responsibility for a phase of a nonclinical laboratory study must
inform that contracted person that the transferred responsibility must
be performed in compliance with the provisions in this part.
(c) A contracted person assuming any responsibility for a phase of
a nonclinical laboratory study must comply with the regulations in this
chapter applicable to the transferred responsibility and is subject to
the same regulatory actions as those transferring the responsibility.
0
8. Revise Sec. 58.15 to read as follows:
Sec. 58.15 Inspection of any person conducting a phase of a
nonclinical laboratory study.
(a) Any person conducting a phase of a nonclinical laboratory study
must permit, at reasonable times and in a reasonable manner, an
authorized employee of FDA to inspect and copy all records and inspect
all specimens required to be maintained for nonclinical laboratory
studies within the scope of this part and, where applicable, to collect
reserve samples for such studies. The records inspection and copying
requirements do not routinely apply to QAU records of findings and
problems or to actions recommended and taken. However, FDA retains the
authority to inspect all QAU records when necessary to ensure
compliance with this part.
(b) FDA will not consider a nonclinical laboratory study submitted
in support of an application or submission to FDA if any person
conducting a phase of the nonclinical laboratory study refuses to
permit inspection. The determination that a nonclinical laboratory
study will not be considered in support of an application or submission
to FDA does not, however, relieve the applicant of any obligation under
any other applicable statute or regulation to submit the results of the
study to FDA.
0
9. Revise Sec. 58.29 to read as follows:
Sec. 58.29 Personnel.
(a) Each individual engaged in the conduct of, or responsible for
the supervision of, a nonclinical laboratory study must have education,
training, and experience, or a combination thereof, to enable that
individual to perform the assigned functions. This must include
training and experience with GLP requirements. Personnel who work with
animals must have both general and species-specific training and
experience.
(b) All study personnel must have access to and comply with the
protocol and all applicable protocol amendments and SOPs. Any deviation
must be reported to the study director.
(c) All study personnel must record raw data, as defined in Sec.
58.3, promptly and accurately as required by Sec. 58.180.
(d) Any person conducting a phase of a nonclinical laboratory study
must maintain a current summary of training and experience and a job
description for each individual in the person's employment engaged in
or supervising the phase of the study for which the person is
responsible.
(e) There must be a sufficient number of personnel for the timely
and proper conduct of the study according to the protocol.
(f) Personnel must take necessary personal sanitation and health
precautions designed to avoid contamination of test, control, and
reference articles and test systems.
(g) Personnel engaged in a nonclinical laboratory study must wear
clothing appropriate for the duties they perform. Such clothing must be
changed as often as necessary to prevent microbiological, radiological,
or chemical contamination of test systems and test, control, and
reference articles.
(h) Any individual found at any time to have an illness that may
adversely affect the quality and integrity of the nonclinical
laboratory study must be excluded from direct contact with test
systems; test, control, and reference articles; and any other operation
or function that may adversely affect the study until the condition is
corrected.
[[Page 58371]]
All personnel must be instructed to report to their immediate
supervisors any health or medical conditions that may reasonably be
considered to have an adverse effect on a nonclinical laboratory study.
0
10. Revise Sec. 58.31 to read as follows:
Sec. 58.31 Testing facility management with executive responsibility.
Management with executive responsibility is ultimately responsible
for the GLP Quality System and must establish policy and objectives for
a GLP Quality System and a commitment to quality, as defined in Sec.
58.3. Management with executive responsibility must ensure that the
quality policy, as defined in Sec. 58.3, is implemented and maintained
at all levels of the organization. Management with executive
responsibility must:
(a) Establish and update written SOPs, as required in Sec.
58.81(b)(2) for a GLP Quality System.
(b) Review the suitability and effectiveness of the GLP Quality
System at defined intervals and with sufficient frequency according to
established procedures, to be included in SOPs for the GLP Quality
System (Sec. 58.81(b)(2)), to ensure that the GLP Quality System
satisfies the established quality policy and objectives and the
requirements of this part. The dates and results of these reviews must
be documented.
(c) Establish and maintain an adequate organizational structure
(personnel, resources, facilities, equipment, materials, and
methodologies) to ensure that all testing complies with the established
GLP Quality System, according to the requirements of this part.
(d) Establish procedures, to be included in SOPs for the GLP
Quality System (Sec. 58.81(b)(2)), for the appropriate responsibility,
authority, and interrelationship among all personnel who manage,
perform, and assess work affecting quality, and provide the
independence and authority necessary to perform these tasks.
(e) Appoint and document the appointment of, according to
procedures to be included in SOPs for the GLP Quality System (Sec.
58.81(b)(2)), a management representative who is a member of the
testing facility management with authority over and responsibility for:
(1) Documenting that GLP Quality System requirements are
effectively established and effectively maintained; and
(2) Reporting on the performance of the GLP Quality System to
management with executive responsibility for review, including all
reports from the QAU.
(f) Establish SOPs for equipment, as required in Sec.
58.81(b)(14), including standards for appropriate documentation of
equipment validation, as defined in Sec. 58.3. For multisite studies,
document that any person conducting a phase of the nonclinical
laboratory study follows adequate equipment-related SOPs.
(g) Establish SOPs to ensure that computerized systems are suitable
for their intended purposes and are appropriately validated, operated,
and maintained as required in Sec. 58.81(b)(15).
(h) Document that all study personnel are trained to perform their
assigned functions.
(i) Establish SOPs, as required in Sec. 58.81(b)(18), for ensuring
and documenting the qualifications of any person conducting a phase of
a nonclinical laboratory study.
(j) Establish SOPs for the development and maintenance of the
master schedule as required in Sec. 58.81(b)(13).
(k) Appoint and document the appointment of a person to maintain
the master schedule. The master schedule must be indexed by test
article and contain the identification of the test system, the nature
of the study, the date the study was initiated, the current status of
each study, the identity of the sponsor, and the name of the study
director. For multisite studies, the master schedule of each person
conducting a phase of a nonclinical laboratory study must also include
the specific phases that person conducts.
(l) Establish procedures, to be included in SOPs for multisite
studies required in Sec. 58.81(b)(18), for the transfer of data,
specimens, and samples among all persons conducting phases of the
nonclinical laboratory study; verification of the accuracy and
completeness of any translations of SOPs and protocols, when
applicable; and storage, return, or disposal of test, control, and
reference articles, as applicable.
(m) Review all protocols to determine that there are no
environmental, animal welfare, or work resource issues or issues with
scientific methodology that might affect or bias any phase of the
conduct of the proposed study. Document the review and acceptance of
each protocol.
(n) Establish SOPs, as required in Sec. 58.81(b)(3), for
designation of a study director, as described in Sec. 58.33, before
the study is initiated and prompt replacement of the study director if
it becomes necessary to do so during the conduct of a study.
(o) Establish procedures, to be included in SOPs for the GLP
Quality System (Sec. 58.81(b)(2)), to ensure a clear line of
communication among the study director, principal investigator(s),
QAU(s), the sponsor, and all study personnel, as applicable.
(p) Provide for a QAU as described in Sec. 58.35. Before
initiating a multisite study, as defined in Sec. 58.3, designate and
document the designation of the lead QAU with overall responsibility
for the entire study. Provide the information described in Sec.
58.35(a) of the lead QAU to all persons involved in the conduct of the
study and all QAUs serving those persons.
(q) Establish procedures, to be included in SOPs for the GLP
Quality System (Sec. 58.81(b)(2)), to ensure QAU review of SOPs and
study protocols to verify that they meet GLP requirements. This review
must be documented.
(r) Review the suitability and effectiveness of the QAU or lead
QAU, as applicable, at defined intervals and with sufficient frequency,
according to established SOPs as required in Sec. 58.81(b)(17), to
ensure that the QAU satisfies established quality policy and objectives
and the requirements of this part. For multisite studies, testing
facility management with executive responsibility must periodically
review the suitability and effectiveness of the lead QAU. The dates and
results of reviews of the QAU must be documented.
(s) Establish SOPs, as required in Sec. 58.81(b)(6), for the
receipt of information regarding the characterization of all test,
control, and reference articles or mixtures, including data on their
identity, strength, purity, stability, and uniformity, as applicable.
(t) Establish SOPs, with appropriate timeframes, for the conduct of
QAU inspections and for the receipt, review, and followup of all
concerns, problems, and regulatory deviations reported by the QAU.
These SOPs must include procedures for correcting reported problems
and, as necessary, for modification of relevant SOPs to prevent a
recurrence of any problems, as required in Sec. 58.81(b)(20) and (21).
(u) Establish SOPs, as required in Sec. 58.81(b)(13), for the
development and maintenance of an archive system, including the
designation and replacement of the archivist and any supporting staff.
(v) Establish procedures to ensure maintenance of a historical file
of all SOPs as required in Sec. 58.81(b)(1).
0
11. Add Sec. 58.32 to subpart B to read as follows:
Sec. 58.32 Test site management with executive responsibility.
For multisite studies, each test site participating in the study
must have
[[Page 58372]]
management with executive responsibility for the test site who must:
(a) Comply with responsibilities delineated for testing facility
management with executive responsibility, as described in section Sec.
58.31, where appropriate.
(b) Develop and maintain SOPs as specified in Sec. 58.81, where
appropriate.
0
12. Revise Sec. 58.33 to read as follows:
Sec. 58.33 Study director.
(a) For each nonclinical laboratory study, a scientist or other
professional of appropriate education, training, and experience, or
combination thereof, must be identified as the study director. The
study director represents the single point of study control and has
overall responsibility, which cannot be delegated, for:
(1) The technical conduct of the entire study;
(2) The implementation of procedures to ensure adequate
communication among all study personnel and with the study sponsor, as
applicable; and
(3) The interpretation, analysis, documentation, and reporting of
results and study compliance.
(b) The study director must:
(1) Approve the protocol, including any changes, as provided by
Sec. 58.120, and document that it is followed.
(2) Document that the QAU has reviewed the protocol and all
applicable SOPs, and any amendments, before study initiation and
implementation of applicable amendments to ensure that they are
compliant with GLP requirements.
(3) Document that testing facility management with executive
responsibility has committed adequate resources for the conduct of the
specific study.
(4) Document that computerized systems are validated and fit for
use in the specific study.
(5) For studies requiring the use of animals, document that the
initial protocol and any amendments that impact the use of animals are
reviewed and approved, as required in Sec. 58.120(b) and (e), by a
committee whose function is to ensure that the care and use of animals
in studies is appropriate and humane, before study initiation and the
implementation of applicable amendments.
(6) Consult with the attending veterinarian, as defined in Sec.
58.3, during review of proposed study protocols to determine potential
animal welfare concerns and appropriate responses to likely
contingencies. Defer to the attending veterinarian when decisions
regarding animal welfare arise, particularly when animals are in pain
or distress.
(7) For multisite studies:
(i) Document the qualifications of any person conducting a phase of
the nonclinical laboratory study.
(ii) Determine and document the need for principal investigators.
(8) Document that all experimental data, including observations of
unanticipated responses of the test system, are accurately recorded and
verified.
(9) Document unforeseen circumstances that may affect the quality
and integrity of the nonclinical laboratory study when they occur and
the corrective action taken.
(10) Document that test systems are as specified in the approved
study protocol.
(11) Document that all applicable GLP regulations are followed and
include a study compliance statement in the final study report.
(12) Document all communications with all persons conducting a
phase of the nonclinical laboratory study and with the sponsor, as
applicable.
(13) Sign and date the final study report.
(14) Archive all raw data, documentation, protocols, specimens,
reserve samples, and final reports no later than 2 weeks after the
study completion date.
0
13. Revise Sec. 58.35 to read as follows:
Sec. 58.35 Quality assurance unit (QAU).
(a)(1) Function. A QAU must monitor each study to assure management
that the facilities, equipment, personnel, methods, practices, records,
and controls are in conformance with the regulations in this part. For
any given study, the QAU must be entirely separate from and independent
of the personnel engaged in the direction and conduct of the study.
(2) Location and identity. (i) For studies conducted entirely at
the testing facility, the QAU can consist of personnel at the facility
itself or be a separately contracted unit.
(ii) For multisite studies, a lead QAU must be designated by
testing facility management with executive responsibility and must have
responsibility for the QA of the entire study. The lead QAU can consist
of personnel at the testing facility, be a QAU for another person
conducting a phase of the study, or be a separately contracted unit.
QAUs for persons conducting a phase of the study must coordinate with
the lead QAU as specified in SOPs as described in Sec. 58.81(b)(17)
and (20). The lead QAU has direct QA responsibility for any person
lacking a QAU.
(b) QAUs must: (1) Maintain access to the master schedule (defined
in Sec. 58.3) of all nonclinical laboratory studies conducted by the
person employing the QAU or contracting for QA services. For multisite
studies, the lead QAU must maintain access to the master schedule of
any person lacking a QAU.
(2) Maintain access to copies of all protocols pertaining to all
nonclinical laboratory studies for which the QAU is responsible.
(3) Review all protocols before study initiation, and all protocol
amendments before implementation, to ensure that they can be conducted
in compliance with this part. This review must be documented.
(4) Review all SOPs to be used for the conduct of all phases of a
nonclinical laboratory study to assess their clarity and compliance
with this part. This review must be documented.
(5) Inspect each nonclinical laboratory study for which the QAU is
responsible at intervals adequate to ensure the integrity of the
specific study. Inspections must determine compliance with the
protocol, applicable SOPs, and the requirements of this part. These can
include study-based, process-based, and facility-based inspections as
defined in Sec. 58.3 and as specified in SOPs as required in Sec.
58.81(b)(20). For multisite studies, the lead QAU must coordinate the
conduct of study inspections with any other existing QAUs, as specified
in SOPs as required in Sec. 58.81(b)(20). Upon discovery, any problems
found during an inspection which are likely to affect study integrity
must be reported to the study director and management with executive
responsibility for the study or studies affected.
(6) Maintain written and properly signed records of all inspections
that include the date of the inspection, the individual performing the
inspection, findings and problems, action recommended and taken to
resolve existing problems, and any scheduled date for reinspection. For
study-specific inspections, reports must also include the identity of
the study and the phase of the study inspected.
(7) Periodically submit to management with executive responsibility
and the study director written status reports on each study that
discuss the overall progress and compliance status of the study and
that include any problems observed and the corrective actions taken.
The content and frequency of these reports must be specified in SOPs,
as described in Sec. 58.81(b)(21).
(8) Determine that no deviations from approved protocols or SOPs
were made without proper authorization and
[[Page 58373]]
documentation. For multisite studies, the lead QAU is responsible for
identifying all deviations that occur across the entire study,
including deviations identified by all other QAUs participating in the
study, as described in SOPs in Sec. 58.81(b)(17).
(9) Audit the reports of all contributing scientists, and any
amendments to such reports, to ensure such reports reflect the protocol
and all amendments, accurately describe the methods and SOPs, and
report all of the raw data of the specific phases covered by each
report. For multisite studies, QAUs for persons conducting a phase of
the study must audit the reports of any principal investigators and all
contributing scientists for whom they are responsible, and any
amendments to such reports, as specified in SOPs as described in Sec.
58.81(b)(17). The lead QAU must audit the reports, and any amendments
to such reports, of any principal investigators and all contributing
scientists for any person lacking a QAU and of any independent
contributing scientists.
(10) Audit the final study report, and any amendments to this
report, to ensure that such report accurately describes the methods and
SOPs, all raw data of the nonclinical laboratory study are reported,
and that all original and amended signed and dated reports from all
contributing scientists are appended. For multisite studies, this is
the responsibility of the lead QAU.
(11) Prepare, sign, and date a statement to be included with the
final study report that specifies:
(i) The dates of study-specific inspections, process-based
inspections if applicable, and facility-based inspections;
(ii) Findings reported to management with executive responsibility
and to the study director; and
(iii) The dates of QAU audits of the reports of all contributing
scientists (including any independent contributing scientists), any
principal investigators, and of the final study report and all
amendments to such. For multisite studies, this is the responsibility
of the lead QAU. When other persons conducting a phase of the study
have QAUs, those QAUs must provide to the lead QAU such statements
regarding the audits they conducted, for appending to the final study
report.
(c) The responsibilities and procedures applicable to the QAU, the
records maintained by the QAU, and the method of indexing such records
must be in writing and must be maintained as specified in SOPs as
required in Sec. 58.81(b)(17). For multisite studies, the lead QAU and
all other QAUs participating in the study must maintain those documents
relevant to their oversight. These SOPs as well as documentation of the
dates of all QAU inspections, the study or process or procedure, or
facility inspected as applicable, the phase or segment of the study
inspected for study-specific inspections, and the name of the
individual performing the inspection must be made available for
inspection to authorized employees of FDA.
(d) A designated representative of FDA must, upon request, be given
access to the written SOPs established for QAU inspections. If
requested by FDA, the person inspected must certify that inspections
are being implemented, performed, documented, and followed up according
to this part.
(e) If a person conducting a phase of a nonclinical laboratory
study chooses to conduct process-based inspections, that person must
prepare a written certification, as specified in SOPs as required in
Sec. 58.81(b)(21), whenever a process-based inspection reveals
problems. This certification must document actions taken to properly
inform and, when applicable, modify reports for all studies impacted by
the results of the process or procedure in question.
0
14. Add Sec. 58.37 to subpart B to read as follows:
Sec. 58.37 Contributing scientist.
(a) Each contributing scientist must:
(1) Conduct, oversee, analyze, and provide any other service for
the conduct of all phases of the nonclinical laboratory study for which
the contributing scientist is responsible according to the requirements
of this part.
(2) Provide a signed and dated report of all phases for which the
contributing scientist is responsible, to be included in the final
study report. When there are amendments to the original report, provide
a signed and dated copy of the amended report, to be included in the
final study report along with the original report. Provide the report,
and all amendments, to the study director or, when a multisite study
employs principal investigators, through the principal investigator.
(3) Permit oversight by the designated QAU.
(b) In addition to the requirements in paragraphs (a)(1) through
(3) of this section, an independent contributing scientist must:
(1) Date and sign the study protocol to indicate agreement to
comply with protocol requirements for all phases of the nonclinical
laboratory study the independent contributing scientist will conduct
and the applicable requirements of this part. Date and sign any
protocol amendments applicable to the phases of the nonclinical
laboratory study conducted by the independent contributing scientist to
indicate agreement.
(2) Maintain and update documentation of education, training, and
experience pertinent to those phases of the nonclinical laboratory
studies for which the independent contributing scientist is
responsible.
(3) If conducting phases of a nonclinical laboratory study that
include the use of animals:
(i) Document that housing, feeding, handling, and care of the
animals as specified in Sec. 58.90 are available.
(ii) Document that an attending veterinarian is available for
consult and deferred to as necessary, particularly when animals are in
pain or distress.
(iii) Document corrective actions required to assure the humane
care and ethical treatment of animals.
(4) Archive all materials pertinent to all phases of the
nonclinical laboratory the independent contributing scientist
conducted, as required by the protocol and Sec. 58.195; document when
and where archiving was completed.
0
15. Add Sec. 58.39 to subpart B to read as follows:
Sec. 58.39 Principal investigator.
The study director can delegate to principal investigators
responsibility for phases of a nonclinical laboratory study but not
responsibility for an entire study. For all phases of the nonclinical
laboratory study for which the principal investigator is responsible, a
principal investigator must:
(a) Sign and date the study protocol, and any applicable
amendments, to document agreement to comply with the protocol
requirements and the applicable requirements of this part.
(b) Verify that the study is conducted according to the
requirements of this part.
(c) Document all deviations noted during the conduct of the study,
report those deviations to the study director as soon as possible after
discovery, and document that the information was forwarded to the study
director.
(d) Submit to the study director either:
(1) The signed and dated reports from all contributing scientists
for whom the principal investigator is responsible and any amendments
to such reports, any raw data not covered by such reports, and a signed
compliance statement indicating any areas of noncompliance; or
[[Page 58374]]
(2) Signed and dated report of all phases for inclusion in the
final study report. The signed report must include the original
principal investigator's report and any amendments, reports of all
contributing scientists for whom the principal investigator is
responsible and any amendments to such reports, and a signed compliance
statement indicating any areas of noncompliance.
(e) Document that all materials and records are appropriately
archived, as required by the protocol and Sec. 58.195.
0
16. Revise Sec. 58.41 to read as follows:
Sec. 58.41 General.
Any person conducting a phase of a nonclinical laboratory study
must have facilities of suitable size and construction to facilitate
the proper conduct of nonclinical laboratory studies. Facilities must
be designed so that there is a degree of separation that will prevent
any function or activity from having an adverse effect on the study.
0
17. In Sec. 58.43, revise paragraphs (a), (b), and (d) to read as
follows:
Sec. 58.43 Animal care facilities.
(a) Any person conducting a phase of a nonclinical laboratory study
that utilizes animals must have a sufficient number of animal rooms or
areas, as needed, to assure proper:
(1) Separation of species or test systems,
(2) Isolation of individual projects,
(3) Quarantine of animals, and
(4) Routine or specialized housing of animals.
(b) Any person conducting a phase of a nonclinical laboratory study
that utilizes animals must have a number of animal rooms or areas
separate from those described in paragraph (a) of this section to
ensure isolation of studies being done with test systems or test,
control, or reference articles known to be biohazardous, including
volatile substances, aerosols, radioactive materials, and infectious
agents.
* * * * *
(d) When animals are housed, facilities must exist for the
collection and disposal of all animal waste and refuse or for safe
sanitary storage of waste before removal from any facility at which a
phase of a nonclinical laboratory study that utilizes animals is
conducted. Disposal facilities must be so provided and operated as to
minimize vermin infestation, odors, disease hazards, and environmental
contamination.
0
18. Revise Sec. 58.47 to read as follows:
Sec. 58.47 Facilities for handling test, control, and reference
articles.
(a) As necessary to prevent contamination or mixups, there must be
separate areas for:
(1) Receipt and storage of the test, control, and reference
articles.
(2) Mixing of the test, control, and reference articles with a
carrier, e.g., feed.
(3) Storage of the test, control, and reference article mixtures.
(b) Storage areas for the test, control, and reference articles and
test, control, and reference article mixtures must be separate from
areas housing the test systems and must be adequate to preserve the
characteristics of the articles and mixtures, including their identity,
strength, purity, and stability, as applicable.
0
19. Revise Sec. 58.61 to read as follows:
Sec. 58.61 Equipment design.
Equipment, including computerized systems, used in the generation,
measurement, maintenance, archiving, retrieval, or assessment of data
(or any combination thereof) and equipment used for facility
environmental control must be of appropriate design and adequate
capacity to function according to the protocol and must be suitably
located for operation, inspection, cleaning, and maintenance.
0
20. In Sec. 58.63, revise paragraphs (a) and (b) to read as follows:
Sec. 58.63 Maintenance and calibration of equipment.
(a) Equipment must be adequately inspected, cleaned, and
maintained. Equipment used for the generation, measurement,
maintenance, archiving, retrieval, or assessment of data (or any
combination thereof) must be adequately tested, calibrated, and
standardized, as applicable.
(b) The written SOPs required under Sec. 58.81(b)(14) and (15)
must set forth in sufficient detail the methods, materials, and
schedules to be used in the routine inspection, cleaning, maintenance,
testing, calibration, and standardization of equipment, as applicable,
and must specify, when appropriate, remedial action to be taken in the
event of failure or malfunction of equipment. The written SOPs must
designate the person responsible for the performance of each operation.
* * * * *
0
21. Revise the heading of subpart E to read as follows:
Subpart E--Nonclinical Laboratory Study Operations
0
22. Revise Sec. 58.81 to read as follows:
Sec. 58.81 Standard operating procedures (SOPs).
(a) The testing facility and all test sites must have SOPs in
writing setting forth nonclinical laboratory study procedures that
management with executive responsibility is satisfied are adequate to
ensure the quality and integrity of the data generated in the course of
a study. All deviations from SOPs in a study must be authorized by the
study director and must be documented in the raw data. Significant
changes in established SOPs must be properly authorized in writing by
management with executive responsibility.
(b) The testing facility and all test sites must establish SOPs for
all applicable phases of a nonclinical laboratory study. Where
appropriate, SOPs must include the following:
(1) Preparation, modification, and administration of all SOPs.
These must include procedures for developing and maintaining a
historical file of SOPs and all revisions, including the dates of such
revisions.
(2) Establishment and periodic review of a GLP Quality System.
(3) Designation and replacement of the study director.
(4) Animal room preparation.
(5) Animal care.
(6) Receipt, identification, storage, handling, mixing, and method
of sampling of the test, control, and reference articles.
(7) Test system observations for in vivo and in vitro testing, as
applicable.
(8) Laboratory tests.
(9) Handling of animals found moribund or dead during study.
(10) Necropsy of animals or post mortem examination of animals.
(11) Collection and identification of specimens.
(12) Histopathology.
(13) Data handling, storage, and retrieval, including maintenance
of the master schedule and all study protocols, and the establishment
and maintenance of an archive system.
(14) Validation, maintenance, and calibration of equipment.
(15) Ensuring computerized systems are suitable for their intended
purpose and are appropriately validated, operated, and maintained and
that electronic records from computerized systems are readily available
for review and assessment.
(16) Transfer, proper placement, and identification of animals.
(17) QAU functions, including QA oversight for multisite studies.
(18) Multisite studies.
(19) Designation and replacement of a principal investigator.
[[Page 58375]]
(20) Planning, performing, documenting, and reporting inspections
conducted by the QAU.
(21) Receipt, review, and followup of all concerns, problems, and
regulatory deviations reported by the QAU, including the frequency and
content of periodic study reports required by Sec. 58.35(b)(7), and
for modifying relevant SOPs when necessary to prevent recurrence.
(22) Certifying copies of study records as true copies of the
original that maintain the original intent and meaning.
(c) Each laboratory area must have immediately available laboratory
manuals and SOPs relative to the laboratory procedures being performed.
Published literature may be used as a supplement to SOPs.
0
23. In Sec. 58.90, revise paragraphs (b) through (e) to read as
follows:
Sec. 58.90 Animal care.
* * * * *
(b) All newly received animals from outside sources must be
isolated and their health status must be evaluated according to
acceptable veterinary medical practices. Also, throughout the study,
all test animals must be evaluated for their health status according to
acceptable veterinary medical practices.
(c) At the initiation of a nonclinical laboratory study, animals
must be free of any disease or condition that might interfere with the
purpose or conduct of the study. If, during the course of the study,
the animals contract such a disease or condition, the diseased animals
must be isolated, if necessary. These animals may be treated for
disease or signs of disease as deemed necessary by the study's
attending veterinarian. The diagnosis, treatment authorizations,
treatment description, and each treatment date must be documented and
must be retained as part of the study raw data.
(d) Warm-blooded animals, except nursing neonates, used in
laboratory procedures that require manipulations and observations over
an extended period of time or in studies that require the animals to be
removed from and returned to their home cages for any reason (e.g.,
cage cleaning, treatment, etc.), must receive appropriate
identification. All information needed to specifically identify each
animal within an animal-housing unit must appear on the outside of that
unit.
(e) Animals of different species must be housed in separate rooms
when necessary. Animals of the same species, but used in different
studies, should not ordinarily be housed in the same room when
inadvertent exposure to control, reference, or test articles or animal
mixup could affect the outcome of either study. If such mixed housing
is necessary, adequate differentiation by space and identification must
be made.
* * * * *
0
24. Revise the heading of subpart F to read as follows:
Subpart F--Test, Control, and Reference Articles
0
25. Revise Sec. 58.105 to read as follows:
Sec. 58.105 Test, control, and reference article characterization.
(a) For all test, control, and reference articles other than
tobacco products, the identity, strength, purity, and composition or
other characteristics which will appropriately define the test,
control, or reference article must be determined for each batch and
must be documented. For test, control, and reference articles for
tobacco products, the chemical composition (including mainstream or
aerosol smoke composition, when applicable), microbiological
characterization (fermented tobacco products), and design parameters
which will appropriately define the test, control, or reference article
must be determined for each batch and must be documented. These
analyses must be performed by the sponsor or by a contracted person
either:
(1) Before study initiation, or
(2) Concomitantly according to written SOPs as required in Sec.
58.81(b)(6). The results of such analyses must be provided to the study
director as soon as available. In those cases where marketed products
are used as control or reference articles, with the exception of
tobacco products, such products can be characterized by their labeling.
(b) Methods of synthesis, fabrication, or derivation of the test,
control, and reference articles must be documented by the person who
conducts the analyses.
(c) The stability of each test, control, and reference article must
be determined as required by the conditions of the study either:
(1) Before study initiation, or
(2) Concomitantly according to written SOPs, as required in Sec.
58.81(b)(6), which provide for periodic analysis of each batch. The
results of such testing must be provided to the study director as soon
as available.
(d) Each storage container for a test, control, or reference
article must be labeled by name; Chemical Abstract Service (CAS) number
or code number, where such identification exists; batch number;
expiration date, if any; and, where applicable, storage conditions
necessary to maintain the identity, strength, purity, and composition
of the test, control, or reference article, other than tobacco
products. For tobacco product test, control, and reference articles,
labeling must include storage conditions necessary to maintain the
chemical composition (including mainstream smoke composition),
microbiological composition, and design parameters, where applicable.
Storage containers must be assigned to a particular test article for
the duration of the study. Empty test article containers may be
disposed of once the study director verifies and documents the
distribution and final disposition of the test article. Approval for
the disposal of empty containers must be in writing and signed and
dated by the study director.
(e) For studies of more than 4 weeks duration, reserve samples from
each batch of test, control, and reference article must be retained for
the period of time provided by Sec. 58.195.
0
26. In Sec. 58.107, revise the heading and introductory text to read
as follows:
Sec. 58.107 Test, control, and reference article handling.
Procedures must be established, as required in Sec. 58.81(b)(6),
for a system for the handling of the test, control, and reference
articles to ensure that:
* * * * *
0
27. Revise Sec. 58.113 to read as follows:
Sec. 58.113 Mixtures of articles with carriers.
(a) For each test, control, and reference article that is mixed
with a carrier, tests by appropriate analytical methods must be
conducted:
(1) To determine the uniformity of the mixture and to determine,
periodically, the concentration of the test, control, or reference
article in the mixture; and
(2) To determine the stability of the test, control, and reference
articles in the mixture as required by the conditions of the study.
(b) Determination of uniformity, concentration, and stability must
be conducted either:
(1) Before study initiation; or
(2) Concomitantly according to written SOPs, as required by Sec.
58.81(b)(6), which provide for periodic analysis of the test, control,
or reference articles in the mixture.
(c) The results of such testing, performed by the sponsor or by a
contracted person, must be provided to the study director as soon as
available.
(d) Where any of the components of the test, control, or reference
article carrier mixture has an expiration date,
[[Page 58376]]
that date must be clearly shown on the container. If more than one
component has an expiration date, the earliest expiration date must be
shown.
0
28. Revise Sec. 58.120 to read as follows:
Sec. 58.120 Protocol.
(a) Each study must have an approved written protocol that clearly
indicates the specific objectives and all methods for the conduct of
the study. The protocol must contain, where appropriate, the following
information:
(1) A descriptive title and statement of the purpose of the study.
(2) Identification of test, control, and reference articles by:
(i) Name;
(ii) Chemical Abstract Service (CAS) number or code number, where
such identification exists;
(iii) The name and address of the manufacturer(s); and
(iv) The person(s) determining their characteristics, as
applicable.
(3) The name and contact information (including address, phone
number, email address, and facsimile number) for the sponsor and the
testing facility and the name and affiliation of the study director.
Also, for multisite studies, the contact information for all persons
conducting a phase of the nonclinical laboratory study, including all
principal investigators and independent contributing scientists.
(4) The number, body weight range, sex, source of supply, species,
strain, substrain, and age of the test system.
(5) The procedure for identification of the test system.
(6) A description of the experimental design, including the methods
for the control of bias in the conduct of the study and the analysis
and reporting of study test results and procedures to be followed when
a study includes a peer review of any phase. For multisite studies,
identification of which phases of the nonclinical laboratory study will
be conducted by which person or persons.
(7) A description or identification, as applicable, of the diet
used in the study as well as solvents, emulsifiers, and/or other
materials used to solubilize or suspend the test, control, or reference
articles, as applicable, before mixing with the carrier. The
description must include specifications for acceptable levels of
contaminants that are reasonably expected to be present in the dietary
materials and are known to be capable of interfering with the purpose
or conduct of the study if present at levels greater than established
by the specifications.
(8) Each dosage level, expressed in milligrams per kilogram of body
weight or other appropriate units, of the test, control, or reference
article to be administered and the method and frequency of
administration. For each test, control, or reference article that is
mixed with a carrier for administration, limits for the results of
concentration, uniformity, and stability testing and the name and
address of the person conducting the testing.
(9) The type and frequency of tests, analyses, and measurements to
be made.
(10) A list or description of the records to be maintained for the
specific study. For multisite studies, the archive location(s) of study
materials and records from all phases of the nonclinical laboratory
study.
(11) The dated signature of the study sponsor, the study director,
independent contributing scientists, principal investigators, and any
other person conducting a phase of the nonclinical laboratory study, as
applicable.
(12) A statement of the proposed statistical methods to be used.
(b) For studies that include the use of animals, a committee whose
function is to ensure that the care and use of animals is appropriate
and humane must review and approve the study before initiation of the
study and approval must be documented.
(c) A statement that the study must be conducted in compliance with
the provisions of this part, to be signed and dated by the study
sponsor and testing facility management with executive responsibility,
must be appended to the protocol.
(d) All changes in or revisions of an approved protocol and the
reasons for the changes must be documented. These amendments to the
protocol must be signed and dated by the study sponsor and the study
director. For multisite studies, these amendments must also be signed
and dated by all independent contributing scientists, principal
investigators, and any other person conducting a phase of the
nonclinical laboratory study affected by the amendment. Signed and
dated amendments must be maintained with the protocol.
(e) A committee whose function is to ensure that the care and use
of animals in studies is appropriate and humane must review and approve
any protocol changes that would impact animal welfare before
implementation and approval must be documented.
0
29. Revise Sec. 58.130 to read as follows:
Sec. 58.130 Conduct of a nonclinical laboratory study.
(a) The analytical methods used for all phases of a nonclinical
laboratory study must be demonstrated to be accurate and of sufficient
sensitivity to measure, with appropriate precision, the analytes in
question.
(b) Test, control, and reference article characterization testing
must be conducted as described in subpart F of this part.
(c) Humane care and ethical treatment of test animals must be
considered in advance and upheld in conjunction with achieving study
objectives. The attending veterinarian must be included in
consultations regarding the impact of a given protocol on the welfare
of test animals, in particular the recognition and alleviation of
species-specific pain or distress and methods of euthanasia. The
attending veterinarian must be deferred to when decisions regarding
animal welfare arise, particularly when animals are in pain or
distress.
(d) The nonclinical laboratory study must be conducted according to
the protocol. The person responsible for a given phase of a nonclinical
laboratory study must sign and date the protocol, as required in Sec.
58.120(a)(11), before initiation of that phase of the study.
(e) Any change to the protocol must be approved as an amendment, as
required in Sec. 58.120(d), before implementation.
(f) The test systems must be monitored in conformity with the
protocol.
(g) Specimens must be identified by test system, study, nature, and
date of collection. This information must be located on the specimen
container or must accompany the specimen in a manner that precludes
error in the recording and storage of data.
(h) Records of gross findings for a specimen from post mortem
observations must be available to a pathologist when examining that
specimen histopathologically, unless specified otherwise in the study
protocol.
0
30. Add Sec. 58.180 to subpart J to read as follows:
Sec. 58.180 Data quality and integrity.
(a) All data generated during the conduct of a nonclinical
laboratory study must be accurate, legible, contemporaneous, original,
and attributable (ALCOA). Also, data must be credible, internally
consistent, and corroborated.
(b) All data must be recorded indelibly, directly, and promptly to
a permanent medium at the time of observation and must identify
unambiguously the person entering the data. Any change to any entry
must be made so as not to obscure the original entry, must indicate the
reason for such
[[Page 58377]]
change, must indicate when the change was made, and must identify who
made the change. When data are either captured or maintained, or both
captured and maintained electronically, these requirements are
fulfilled by the use of an electronic records system fully compliant
with applicable regulations.
(c) All data accrued as required in paragraphs (a) and (b) of this
section must be included in the final study report.
0
31. Revise Sec. 58.185 to read as follows:
Sec. 58.185 Reporting of nonclinical laboratory study results.
(a) A final study report must be prepared for each nonclinical
laboratory study and must include the following:
(1) Name and address of the testing facility and the dates on which
the study was initiated and completed. For multisite studies,
additionally the name and address of any person conducting a phase of
the nonclinical laboratory study, including the location of all
independent contributing scientists.
(2) Names of the attending veterinarians for all phases of the
nonclinical laboratory study that included the use of animals.
(3) Objectives and procedures stated in the approved protocol,
including any changes in the original protocol.
(4) Statistical methods employed for analyzing the data.
(5) Test, control, and reference articles identified by:
(i) Name;
(ii) Chemical Abstract Service (CAS) number or code number, where
such identification exists;
(iii) Strength, purity, and composition or other appropriate
characteristics, and for tobacco products as described in Sec.
58.105(a);
(iv) The name and address of the manufacturer(s); and
(v) The name and address of the person(s) conducting the testing to
define their characteristics, as applicable.
(6) Stability of test, control, and reference articles under the
conditions of administration, including the name and address of the
person(s) conducting the testing.
(7) A description of the methods used, including methods for the
control of bias in the conduct of the study and the analysis and
reporting of test results.
(8) A description of the test system used. Where applicable, the
final study report must include the number of animals used, sex, body
weight range, source of supply, species, strain and substrain, age, and
procedure used for identification.
(9) A description of the dosage, dosage regimen, route of
administration, and duration, including the results of testing
conducted to determine the concentration, uniformity, and stability of
mixtures of articles with carriers, as applicable, and the name and
address of the person conducting the testing.
(10) A description of all circumstances that may have affected the
quality or integrity of the data, including those documented by the
study director as described in Sec. 58.33(b)(9) and all health-related
issues reported by an attending veterinarian or appropriately
designated personnel during the course of the study as described in
Sec. 58.90(b) and (c).
(11) The name and affiliation of the study director, the names of
all contributing scientists, principal investigators, and other
professionals, the sponsor, and all supervisory personnel who were
involved in the study or in the preparation or review of the final
study report.
(12) A description of the transformations, calculations, or
operations performed on the data, a summary and analysis of the data,
and a statement of the conclusions drawn from the analysis.
(13) The original, and any amended, signed and dated reports of
each of the contributing scientists, principal investigators, or any
other person involved in the study, including each person who conducted
an analysis or evaluation of data or specimens from the study after
data generation was completed. These reports must contain all data
generated.
(14) The locations where all specimens, reserve samples, raw data,
and the final study report are to be stored.
(15) The statement prepared and signed by the responsible QAU as
described in Sec. 58.35(b)(11).
(16) A statement by the study director of the study's extent of
compliance with this part, including a discussion of any study
deviations found to impact the integrity of the study as described in
Sec. 58.185(a)(10).
(b) The final report must be signed and dated by the study
director.
(c) Corrections or additions to a final report must be in the form
of an amendment by the study director. The amendment must clearly
identify that part of the final report that is being added to or
corrected and the reasons for the correction or addition, and must be
signed and dated by the person responsible.
(d) If for any reason a study is discontinued before completion,
the study director must write, sign, and date a short summary report
closing the study. This report must discuss the reasons for closure and
must be archived, along with all study material, as described in Sec.
58.190.
0
32. Revise Sec. 58.190 to read as follows:
Sec. 58.190 Storage and retrieval of records and data.
(a) All raw data, documentation, protocols, final reports, reserve
samples, and specimens (except those specimens obtained from
mutagenicity tests and wet specimens of blood, urine, feces, and
biological fluids) generated as a result of a nonclinical laboratory
study must be retained. Correspondence and other documents relating to
interpretation and evaluation of data, other than those documents
contained in the final study report, must also be retained.
(b) There must be archives for orderly storage and expedient
retrieval of all raw data, documentation, protocols, specimens, and
interim and final reports. Conditions of storage must minimize
deterioration of the documents or specimens in accordance with the
requirements for the time period of their retention and the nature of
the documents or specimens. A testing facility may contract with
commercial archives to provide a repository for all material to be
retained. Raw data and specimens may be retained elsewhere provided
that the archives have specific reference to those other locations.
(c) Material retained or referred to in the archives must be
indexed to permit expedient retrieval.
(d) All study material described in paragraph (a) of this section
must be archived no later than 2 weeks after the study completion date
(as defined in Sec. 58.3).
(e) If a sponsor delays completion of the final study report, the
study director must complete, sign, and date the final study report and
archive all study material no later than 6 months after completion of
the last draft of the final study report.
(f) If a study sponsor halts a nonclinical laboratory study before
all protocol-required testing is completed, a decision that the study
is discontinued must be made no later than 6 months after the study was
stopped. Once the study has been determined to be discontinued, the
study director must prepare a summary report, as required by Sec.
58.185(d). The summary report and all study material must be archived
no later than 2 weeks after the study director signs the summary
report.
(g) An individual must be identified as responsible for the
archives. Archiving specifications for multisite
[[Page 58378]]
studies must also be included in the approved study protocol.
(h) Only authorized personnel can have access to the archives.
(i) SOPs regarding archiving, required in Sec. 58.81(b)(13), must
include specific procedures for removal of study materials from the
archives, including maximum timeframes material can remain outside of
the archives.
0
33. Revise Sec. 58.195 to read as follows:
Sec. 58.195 Retention of records.
(a) Record retention requirements set forth in this section do not
supersede the record retention requirements of any other regulations in
this chapter nor do they supersede any other legal requirements
elsewhere in applicable statutes or regulations.
(b) Except as provided in paragraph (c) of this section, all raw
data, documentation, protocols, final study reports, reserve samples,
and specimens pertaining to a nonclinical laboratory study and required
to be made by this part must be retained in the archive(s) for
whichever of the following periods is shortest:
(1) A period of at least 2 years following the date on which an
application or submission to FDA, in support of which the results of
the nonclinical laboratory study were submitted, is approved or cleared
by FDA, a premarket authorization is issued, or the application or
submission is administratively closed. This requirement does not apply
to studies supporting investigational new drug applications (INDs) or
applications for investigational device exemptions (IDEs), records of
which are governed by the provisions of paragraph (b)(2) of this
section.
(2) A period of at least 5 years following the date on which the
results of the nonclinical laboratory study are submitted to FDA in
support of an application or submission.
(3) In other situations (e.g., where the nonclinical laboratory
study does not result in the submission of the study in support of an
application or submission to FDA), a period of at least 2 years
following the study completion date or the date on which the study is
terminated or discontinued.
(c) Wet specimens (except those specimens obtained from
mutagenicity tests and wet specimens of blood, urine, feces, and
biological fluids), samples of test, control, and reference articles,
and specially prepared material, which are relatively fragile and
differ markedly in stability and quality during storage, must be
retained only as long as the quality of the preparation affords
evaluation. In no case is retention required for longer periods than
those set forth in paragraphs (a) and (b) of this section.
(d) Management with executive responsibility must ensure
maintenance of the master schedule and copies of study protocols, as
specified in SOPs as described in Sec. 58.81(b)(13) and as specified
in paragraphs (a) and (b) of this section. QAUs must maintain records
of QAU inspections, as required by Sec. 58.35(c) for the period of
time specified in paragraphs (a) and (b) of this section.
(e) Summaries of training and experience and job descriptions
required to be maintained by Sec. 58.29(d) may be retained along with
all other employment records for the length of time specified in
paragraphs (a) and (b) of this section.
(f) Records and reports of the maintenance and calibration and
inspection of equipment, as required by Sec. 58.63(b) and (c), must be
retained for the length of time specified in paragraph (b) of this
section.
(g) Records required by this part may be retained either as
original records or as true copies that maintain the original intent
and meaning and are made according to the person's SOPs as described in
Sec. 58.81(b)(22).
(h) If a facility conducting nonclinical laboratory testing goes
out of business or for any reason can no longer serve as the archive
site for a particular study, all raw data, documentation, and other
material specified in this section must be transferred to the archives
of the sponsor of the study or to another appropriate archive facility.
The facility must notify FDA in writing (and the study sponsor if not
the recipient of the study material) of the transfer no later than 10
working days after the transfer occurs.
(i) A copy of the notification of change of archive site, as
required by paragraph (h) of this section, can serve as the amendment
to the final study report required in Sec. 58.185(c) when appended to
that report.
0
34. Revise the heading of subpart K to read as follows:
Subpart K--Disqualification of Any Person Conducting a Phase of a
Nonclinical Laboratory Study
0
35. Revise Sec. 58.200 to read as follows:
Sec. 58.200 Purpose.
(a) The purposes of disqualification are:
(1) To permit the exclusion from consideration of completed studies
for which a phase was conducted by any person failing to comply with
the requirements of the GLP regulations until it can be adequately
demonstrated that such noncompliance did not occur during, or did not
affect the validity or acceptability of data generated by, a particular
study; and
(2) To exclude from consideration all studies completed after the
date of disqualification until the disqualified person can satisfy the
Commissioner that it will conduct studies in compliance with such
regulations.
(b) The determination that a nonclinical laboratory study may not
be considered in support of an application or submission to FDA does
not, however, relieve the applicant of any obligation under any other
applicable regulation to submit the results of the study to FDA.
0
36. Revise Sec. 58.202 to read as follows:
Sec. 58.202 Grounds for disqualification.
FDA may disqualify any person conducting a phase of a nonclinical
laboratory study upon finding that person repeatedly or deliberately
failed to comply with one or more of the regulations set forth in this
part (or any other regulations regarding such facilities in this
chapter) or repeatedly or deliberately submitted false information in
any required report.
0
37. In Sec. 58.204, revise paragraph (a) to read as follows:
Sec. 58.204 Notice of and opportunity for hearing on proposed
disqualification.
(a) Whenever FDA has information indicating that grounds exist
under Sec. 58.202, which justifies disqualification of any person
conducting a phase of a nonclinical laboratory study, FDA may issue to
that person a written notice proposing that person be disqualified.
* * * * *
0
38. Revise Sec. 58.206 to read as follows:
Sec. 58.206 Final order on disqualification.
(a) If the Commissioner, after the regulatory hearing, or after the
time for requesting a hearing expires without a request being made,
upon an evaluation of the administrative record of the disqualification
proceeding, makes the findings required in Sec. 58.202, the
Commissioner issues a final order disqualifying that person. Such order
must include a statement of the basis for that determination. Upon
issuing a final order, the Commissioner notifies (with a copy of the
order) the disqualified person of the action. The notification also
will explain that a person who is disqualified under this part will be
ineligible to receive a test article under part 511 of this chapter. A
clinical investigator ineligible to receive a test article under part
511 of this chapter
[[Page 58379]]
will be ineligible to conduct any nonclinical laboratory study intended
to support an application for a research or marketing permit for a new
animal drug.
(b) If the Commissioner, after a regulatory hearing or after the
time for requesting a hearing expires without a request being made,
upon an evaluation of the administrative record of the disqualification
proceeding, does not make the findings required in Sec. 58.202, the
Commissioner issues a final order terminating the disqualification
proceeding. Such order must include a statement of the basis for that
determination. Upon issuing a final order the Commissioner notifies
that person and provides a copy of the order.
0
39. Revise Sec. 58.210 to read as follows:
Sec. 58.210 Actions upon disqualification.
(a) Once a person has been disqualified, each application and
submission to FDA containing or relying upon any nonclinical laboratory
study for which a phase was conducted by the disqualified person may be
examined to determine whether such study was or would be essential to a
decision. If it is determined that a study was or would be essential,
FDA must also determine whether the study is acceptable,
notwithstanding the disqualification of that person. Any study for
which a phase was conducted by the disqualified person before
disqualification may be presumed to be unacceptable, and the person
relying on the study may be required to establish that the study was
not affected by the circumstances that led to the disqualification,
e.g., by submitting validating information. If the study is then
determined to be unacceptable, such data will be eliminated from
consideration in support of the application or submission to FDA and
such elimination may serve as new information justifying appropriate
regulatory action.
(b) No nonclinical laboratory study for which any phase was begun
by a disqualified person after the date of that person's
disqualification can be considered in support of any application or
submission to FDA, unless the disqualified person has been reinstated
under Sec. 58.219. The determination that a study may not be
considered in support of an application or submission to FDA does not,
however, relieve the applicant of any obligation under any other
applicable regulation to submit the results of the study to FDA.
0
40. Revise Sec. 58.213 to read as follows:
Sec. 58.213 Public disclosure of information regarding
disqualification.
(a) Upon issuance of a final order disqualifying a person under
Sec. 58.206(a), the Commissioner may notify all or any interested
persons. Such notice may be given at the discretion of the Commissioner
whenever the Commissioner believes that such disclosure would further
the public interest or would promote compliance with the GLP
regulations set forth in this part. Such notice, if given, must include
a copy of the final order issued under Sec. 58.206(a) and must state
that the disqualification constitutes a determination by FDA that
nonclinical laboratory studies for which a phase was performed by the
disqualified person will not be considered by FDA in support of any
application or submission to FDA. If such notice is sent to another
Federal Government agency, FDA will recommend that the agency also
consider whether or not it should accept nonclinical laboratory studies
for which a phase was performed by the disqualified person. If such
notice is sent to any other person, it states that it is given because
of the relationship between the disqualified person and the person
being notified and that FDA is not advising or recommending that any
action be taken by the person notified.
(b) A determination that a person has been disqualified and the
administrative record regarding such determination are disclosable to
the public under part 20 of this chapter.
0
41. Revise Sec. 58.215 to read as follows:
Sec. 58.215 Alternative or additional actions to disqualification.
(a) Disqualification of any person under this subpart is
independent of, and neither in lieu of nor a precondition to, other
proceedings or actions authorized by the Federal Food, Drug, and
Cosmetic Act. FDA may, at any time, institute against a disqualified
person or against the sponsor of a nonclinical laboratory study that
has been submitted to FDA, or both, any appropriate judicial
proceedings (civil or criminal) and any other appropriate regulatory
action, including civil money penalties, in addition to or in lieu of,
and before, simultaneously with, or subsequent to, disqualification.
FDA may also refer the matter to another Federal, State, or local
government law enforcement or regulatory agency for such action as that
agency deems appropriate.
(b) FDA may refuse to consider any particular nonclinical
laboratory study in support of an application or submission to FDA, if
it finds that the study was not conducted according to the GLP
regulations set forth in this part, without disqualifying any person
that conducted one or more phases of the study or undertaking other
regulatory action.
0
42. Revise Sec. 58.217 to read as follows:
Sec. 58.217 Suspension or termination of any person conducting a
phase of a nonclinical laboratory study by a sponsor.
Termination of any person conducting a phase of a nonclinical
laboratory study by a sponsor is independent of, and neither in lieu of
nor a precondition to, proceedings or actions authorized by this
subpart. If a sponsor terminates or suspends any person conducting a
phase of a nonclinical laboratory study from further participation in a
study that is being conducted as part of any application or submission
to FDA that has been submitted to any Center of FDA (whether approved
or cleared, premarket authorization issued, or administratively
closed), the sponsor must notify that Center in writing within 15
working days of the action; the notice must include a statement of the
reasons for such action. Suspension or termination of any person
conducting a phase of a nonclinical laboratory study by a sponsor does
not relieve the sponsor of any obligation under any other applicable
regulation to submit the results of the study to FDA.
0
43. Revise Sec. 58.219 to read as follows:
Sec. 58.219 Reinstatement of a disqualified person.
Any person that has been disqualified may be reinstated as an
acceptable source of data for a phase of a nonclinical laboratory study
to be submitted to FDA if the Commissioner determines, upon an
evaluation of materials submitted by that person, as well as the
results from an FDA inspection of that person, that procedures are in
place that would allow that person to conduct a phase of future
nonclinical laboratory studies in compliance with the GLP regulations
set forth in this part. As noted in Sec. 58.210(b), no nonclinical
laboratory study for which a phase was begun by a disqualified person
after the date of that person's disqualification is considered in
support of any application or submission to FDA, unless that person has
been reinstated. A disqualified person that wishes to be so reinstated
must present in writing to the Commissioner reasons why it believes it
should be reinstated and a detailed description of the corrective
actions it has taken or intends to take to assure that the acts or
omissions which led to its disqualification will not recur.
[[Page 58380]]
The disqualified person must also state its availability for
inspection. If a disqualified person is reinstated, the Commissioner
must so notify that person and all organizations and persons who were
notified, under Sec. 58.213 of the disqualification of that person. A
determination that a disqualified person has been reinstated is
disclosable to the public under part 20 of this chapter.
Dated: August 16, 2016.
Peter Lurie,
Associate Commissioner for Public Health Strategy and Analysis.
[FR Doc. 2016-19875 Filed 8-23-16; 8:45 am]
BILLING CODE 4164-01-P