Agency Information Collection Activities; Submission for Office of Management and Budget Review; Comment Request; Guidance for Industry on Adverse Event Reporting for Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act, 45999-46005 [2015-18911]
Download as PDF
Federal Register / Vol. 80, No. 148 / Monday, August 3, 2015 / Notices
will also be available in either hard
copy or on CD–ROM, after submission
of a Freedom of Information request.
Written requests are to be sent to
Division of Freedom of Information
(ELEM–1029), Food and Drug
Administration, 12420 Parklawn Dr.,
Element Bldg., Rockville, MD 20857.
Dated: July 29, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015–18969 Filed 7–31–15; 8:45 am]
BILLING CODE 4164–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
[Docket No. FDA–2015–N–0001]
Surrogate Endpoints for Clinical Trials
in Kidney Transplantation; Public
Workshop
Food and Drug Administration,
HHS.
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ACTION:
Notice of public workshop.
The Food and Drug Administration
(FDA) is announcing a public workshop
entitled ‘‘Surrogate Endpoints for
Clinical Trials in Kidney
Transplantation.’’ The purpose of the
public workshop is to discuss potential
surrogate endpoints for clinical trials for
drugs and therapeutic biologics used in
kidney transplantation, with a focus on
endpoints in conditions that represent
unmet medical needs. This public
workshop is intended to provide
information and gain perspective from
health care providers, academia, and
industry on the role of various
laboratory, histologic, and other
endpoints used to evaluate patient and
allograft outcome in clinical trials for
kidney transplantation.
Date and Time: The public workshop
will be held on September 28, 2015,
from 8 a.m. to 6 p.m.
Location: The public workshop will
be held at the Residence Inn Marriott,
2850 South Potomac Ave., Arlington,
VA 22202. Web site: https://
www.marriott.com/hotels/travel/wasryresidence-inn-arlington-capital-view/.
(FDA has verified the Web site address,
but FDA is not responsible for any
subsequent changes to the Web site after
this document publishes in the Federal
Register.) Seating will be available on a
first-come, first-served basis.
Contact Person: Ramou Pratt, Center
for Drug Evaluation and Research, Food
and Drug Administration, 10903 New
Hampshire Ave., Bldg. 22, Rm. 6193,
Silver Spring, MD 20993–0002, 301–
796–3928 or 301–796–1600.
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FDA is
announcing a public workshop entitled
‘‘Surrogate Endpoints for Clinical Trials
in Kidney Transplantation.’’ The
purpose of the workshop is to discuss
potential clinical or surrogate endpoints
and biomarkers for clinical trials for
drugs and therapeutic biologics in
kidney transplantation. The input from
this public workshop will help in
developing topics for further discussion
and may serve to inform
recommendations on potential surrogate
endpoints in clinical trials for kidney
transplantation. The Agency encourages
individuals, patient advocates, industry,
consumer groups, health care
professionals, researchers, and other
interested persons to attend this public
workshop.
This workshop is part of the Agency’s
program to facilitate the development of
surrogate endpoints, clinical endpoints,
and other scientific methods for
predicting clinical benefit, in
accordance with section 901 of the Food
and Drug Administration Safety and
Innovation Act, titled ‘‘Enhancement of
Accelerated Patient Access to New
Medical Treatments,’’ which was signed
into law on July 9, 2012. During the
workshop, there will be a discussion on
potential surrogate endpoints and their
ability to predict clinical benefit.
This public workshop will include
discussion of allograft histology and
biomarkers, laboratory measures of
outcome, and other endpoints that may
serve as surrogates for patient
morbidity, graft function, and patient
and graft survival. Related topics for
discussion will include clinically
relevant risk factors and prognostic
factors in the kidney transplant
population. Patient selection and
enrichment strategies (inclusion/
exclusion criteria) will be considered.
The public workshop will include
scientific discussion on the following
topics:
SUPPLEMENTARY INFORMATION:
Food and Drug Administration
AGENCY:
Registration: Mail or fax your
registration information (including
name, title, firm name, address,
telephone and fax numbers) to Ramou
Pratt (see Contact Person) by September
25, 2015. Registration is free for the
public workshop. Early registration is
recommended because seating is
limited. Registration on the day of the
public workshop will be provided on a
space-available basis beginning at 8 a.m.
If you need special accommodations
because of a disability, please contact
Ramou Pratt (see Contact Person) at
least 7 days in advance.
• Surrogate endpoints and accelerated
approval
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45999
• Unmet medical need in kidney
transplant patients
• Histology: Findings on kidney biopsy
(including protocol biopsies)
• Laboratory measurements and
outcomes, surrogates and biomarkers
• Patient selection criteria and
enrichment strategies
• Risk factors and prognostic factors
• Medication adherence
Transcripts: Please be advised that as
soon as possible after a transcript of the
public workshop is available, it will be
accessible at https://
www.regulations.gov. It may be viewed
at the Division of Dockets Management
(HFA–305), Food and Drug
Administration, 5630 Fishers Lane, Rm.
1061, Rockville, MD 20852. A transcript
will also be available in either hard
copy or on CD–ROM, after submission
of a Freedom of Information request.
Send written requests to the Division of
Freedom of Information, U.S. Food &
Drug Administration, 5630 Fishers
Lane, Rm. 1033, Rockville, MD 20857.
Transcripts will also be available on the
Internet at https://wcms.fda.gov/FDAgov/
Drugs/NewsEvents/ucm449248.htm
approximately 45 days after the
workshop.
Dated: July 29, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015–18957 Filed 7–31–15; 8:45 am]
BILLING CODE 4164–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA–2014–D–2138]
Agency Information Collection
Activities; Submission for Office of
Management and Budget Review;
Comment Request; Guidance for
Industry on Adverse Event Reporting
for Outsourcing Facilities Under
Section 503B of the Federal Food,
Drug, and Cosmetic Act
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Notice.
The Food and Drug
Administration (FDA) is announcing
that a proposed collection of
information has been submitted to the
Office of Management and Budget
(OMB) for review and clearance under
the Paperwork Reduction Act of 1995.
DATES: Fax written comments on the
collection of information by September
2, 2015.
SUMMARY:
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Federal Register / Vol. 80, No. 148 / Monday, August 3, 2015 / Notices
To ensure that comments on
the information collection are received,
OMB recommends that written
comments be faxed to the Office of
Information and Regulatory Affairs,
OMB, Attn: FDA Desk Officer, FAX:
202–395–7285, or emailed to oira_
submission@omb.eop.gov. All
comments should be identified with the
OMB control number 0910—NEW and
title ‘‘Guidance for Industry on Adverse
Event Reporting for Outsourcing
Facilities Under Section 503B of the
Federal Food, Drug, and Cosmetic Act.’’
Also include the FDA docket number
found in brackets in the heading of this
document.
FOR FURTHER INFORMATION CONTACT: FDA
PRA Staff, Office of Operations,Food
and Drug Administration, 8455
Colesville Rd., COLE–14526, Silver
Spring, MD 20993–0002, PRAStaff@
fda.hhs.gov.
SUPPLEMENTARY INFORMATION: In
compliance with 44 U.S.C. 3507, FDA
has submitted the following proposed
collection of information to OMB for
review and clearance.
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ADDRESSES:
Guidance for Industry on Adverse
Event Reporting for Outsourcing
Facilities Under Section 503B of the
Federal Food, Drug, and Cosmetic Act
OMB Control Number 0910—NEW
In the Federal Register of February
19, 2015 (80 FR 8872), FDA announced
the availability of a draft guidance for
industry entitled ‘‘Adverse Event
Reporting for Outsourcing Facilities
Under Section 503B of the Federal
Food, Drug, and Cosmetic Act.’’ On
November 27, 2013, President Obama
signed the Drug Quality and Security
Act (DQSA) into law (Pub. L. 113–54).
The DQSA added a new section 503B to
the FD&C Act (21 U.S.C. 353b). Under
section 503B(b), a compounder can
register as an outsourcing facility with
FDA. If the conditions outlined in
section 503B(a) of the FD&C Act are
satisfied, a drug compounded by or
under the direct supervision of a
licensed pharmacist in an outsourcing
facility is exempt from certain sections
of the FD&C Act, including section
502(f)(1) (21 U.S.C. 352(f)(1))
(concerning the labeling of drugs with
adequate directions for use) and section
505 (21 U.S.C. 355) (concerning the
approval of human drug products under
new drug applications (NDAs) or
abbreviated new drug applications
(ANDAs)). Drugs compounded in
outsourcing facilities are not exempt
from the requirements of section
501(a)(2)(B) of the FD&C Act (21 U.S.C.
351(a)(2)(B)) (concerning current good
manufacturing practice for drugs).
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Under section 503B(b)(5), an
outsourcing facility must submit
adverse event reports to FDA in
accordance with the content and format
requirements established through
guidance or regulation under 21 CFR
310.305 (or any successor regulations).
This guidance explains electronic
reporting of adverse events in
accordance with § 310.305 with respect
to outsourcing facilities.
Under § 310.305(c)(1), manufacturers,
packers, and distributors of marketed
prescription drug products that are not
the subject of an approved new drug or
abbreviated new drug application,
including, as set forth in the guidance,
outsourcing facilities must submit to
FDA adverse event reports within 15
calendar days of receiving the
information and must submit followup
reports within 15 calendar days of
receipt of new information about the
adverse event, or as requested by FDA.
Outsourcing facilities must submit the
adverse event report in an electronic
format that FDA can process, review,
and archive (collection of information is
approved by OMB control number
0910–0291). A copy of the current
labeling of the compounded drug
product must be provided.
Under § 310.305(f), entities subject to
the regulation must maintain for 10
years the records of all adverse events
required to be reported under § 310.305.
The outsourcing facility should also
maintain records of its efforts to obtain
the data elements described in the draft
guidance for each adverse event report.
In the Federal Register of February
19, 2015 (80 FR 8872), FDA published
a 60-day notice requesting public
comment on the proposed collection of
information. FDA received seven
comments on the draft guidance, several
of which raised issues pertaining to the
information collection provisions in the
draft guidance. The issues raised are
addressed below.
Issue One: Several individuals
submitted comments related to the
requirement described in the guidance
that outsourcing facilities report adverse
events that are both serious and
unexpected and the recommendation in
the guidance that outsourcing facilities
report all serious adverse events,
regardless of whether they are
unexpected. Specifically:
• One commenter noted that the
applicable regulation, § 310.305, defines
an ‘‘unexpected’’ adverse drug
experience as an adverse drug
experience ‘‘that is not listed in the
current labeling for the drug product.’’
The commenter indicated that this
definition is not easily applied to
unapproved drugs, as such products
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lack uniform FDA-reviewed language,
meaning products with the same active
ingredient may list different adverse
events in the labeling, or no adverse
events at all.
• One commenter indicated that
instead of strongly recommending that
outsourcing facilities report all serious
adverse drug experiences to the FDA,
the FDA should require such reporting.
• One commenter stated that
reporting all serious adverse drug
experiences (not just those that are both
serious and unexpected) should be
required, rather than ‘‘strongly
recommended,’’ and because reporting
all serious adverse events is not
currently required under § 310.305, FDA
should amend this regulation.
• Several commenters noted that
§ 310.305 only requires reporting of
serious, unexpected adverse events, but
the draft guidance suggests that
outsourcing facilities should report all
serious adverse events. They stated that
FDA is reaching beyond what the
regulations allow, and this suggestion
will lead to confusion to what must be
reported and what is suggested. FDA
should narrow reporting to unexpected
adverse events.
FDA Response to Issue One: FDA
responds as follows:
• FDA has clarified the guidance with
regard to reporting adverse events that
are considered ‘‘unexpected.’’
Specifically, the guidance now includes
the following language to clarify the
meaning of the term ‘‘unexpected’’ in
the context of adverse events associated
with compounded drugs: ‘‘For example,
if current labeling for a compounded
drug product does not list any adverse
drug experiences, all adverse drug
experiences associated with the
compounded drug product would be
considered ‘unexpected.’ ’’
• With regard to the recommendation
that outsourcing facilities be required to
report all serious adverse events, rather
than just those that are considered both
serious and unexpected, § 310.305, the
regulation applicable to reporting of
adverse events by all manufacturers of
unapproved drugs, does not require
reporting of all serious adverse drug
experiences to FDA. Therefore,
requiring outsourcing facilities to report
all serious adverse events would be
inconsistent with § 310.305.
• Amending the regulation § 310.305
would require a separate rulemaking,
which is beyond the scope of this
guidance document.
• With regard to the concern about
possible confusion caused by FDA’s
recommendation that outsourcing
facilities report all serious adverse
events, the draft guidance states the
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regulations require reporting of all
adverse events that are both serious and
unexpected, and that FDA is
recommending that outsourcing
facilities report all serious adverse
events. Specifically, the draft guidance
states that ‘‘FDA strongly recommends
that outsourcing facilities submit all
serious adverse drug experiences’’ (lines
128–131) and that ‘‘the regulations
require reporting of each adverse drug
experience received or otherwise
obtained that is both serious and
unexpected . . . .’’ (lines 103–104).
FDA will further clarify this by adding
the following italicized language: ‘‘In
addition, although they are not required
to do so, FDA strongly recommends that
outsourcing facilities report all serious
adverse events. . . .’’
Issue Two: Several commenters noted
that FDA encourages, as appropriate, the
outsourcing facility to attach to the
report: (1) Hospital discharge
summaries, (2) autopsy reports/death
certificates, (3) relevant laboratory data,
and (4) other critical clinical data, and
that in case of a death, an outsourcing
facility should also provide any
available information on the event(s)
that led to the death. The commenters
stated it is unlikely that an outsourcing
facility will be given access to the
elements voluntarily by the healthcare
facility where the serious adverse event
occurred without being legally
compelled to do so. A commenter also
asked how a manufacturer, distributor,
and/or supplier can obtain this
information under the Health Insurance
Portability and Accountability Act
(HIPAA).
FDA Response to Issue Two: With
regard to HIPAA, 45 CFR 164.512
describes situations under which a
covered entity, e.g., a healthcare
provider, may use or disclose protected
health information without the written
authorization of the individual or the
opportunity for the individual to agree
or object. One of these situations is ‘‘to
collect or report adverse events’’ to FDA
(45 CFR 164.512(b)(1)(iii)(A)). However,
although information about adverse
events can be obtained under HIPAA,
the guidance does not state that an
outsourcing facility must obtain this
information. Rather, the guidance states
that attaching this information is
encouraged. It should be provided if the
outsourcing facility has the information,
but the outsourcing facility is not
specifically required to obtain this
information. FDA has clarified in the
guidance that the information should be
provided to FDA if it is available.
Specifically, the guidance now reads:
‘‘In addition, as part of the adverse
event report, we encourage, as
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appropriate, attachment of the
following, if available: (1) Hospital
discharge summaries, (2) autopsy
reports/death certificates, (3) relevant
laboratory data, and (4) other critical
clinical data. In the case of a death,
outsourcing facilities should also
provide any available information on
the event(s) that led to the death.’’
Issue Three: One commenter noted
that the period of 15 calendar days to
submit an initial report of an adverse
event and the 15 calendar days to
submit a followup report is too long;
that during this period illnesses,
injuries, or deaths can result. The
commenter also stated that this would
likely also delay initiation of recall
procedures, and that the time period for
reporting should be no more than 48 or
72 hours, followed by an equally
prompt followup and investigation
period, and an immediate decision on a
recall.
FDA Response to Issue Three: The
applicable regulation, § 310.305,
provides a 15-day timeframe for
reporting an adverse event and an
additional 15-day timeframe to submit a
followup report. This is the maximum
amount of time permitted. The guidance
states that the regulations require
reporting ‘‘as soon as possible, but in no
case later than 15 calendar days . . . .’’
The preamble to § 310.305 notes that the
manufacturer must usually obtain
additional information about the
product (e.g., followup with the
reporting physician or patient), and that
reducing the time for submitting these
reports would increase the number of
incomplete reports. (51 FR 24478).
Issue Four: FDA should immediately
share all adverse events reported with
the home State regulator, so the State
agency is also aware of potential
problems at one of its licensee’s
facilities.
FDA Response to Issue Four: FDA
intends to continue to work closely with
its State partners on oversight of
compounding, including improving and
streamlining information sharing as
much as possible. However, this
recommendation is not relevant to this
guidance document, which focuses on
how outsourcing facilities should
submit adverse event reports to FDA.
Issue Five: Two commenters asked
how the reporting requirements
proposed by the draft guidance
interplay with reporting requirements
imposed by State boards of pharmacy.
The commenters asked whether, in the
event a State board of pharmacy has
adverse event reporting requirements
that apply to an outsourcing facility,
satisfying the adverse event reporting
requirements described by the draft
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46001
guidance ‘‘preempt’’ the requirement to
comply with a State reporting
requirement. They asked whether an
outsourcing facility must report to both
Federal and State regulators and noted
that this could result in duplicate
reporting.
FDA Response to Issue Five: This
guidance addresses requirements under
the FD&C Act and FDA regulations.
Outsourcing facilities may have
independent responsibilities to report to
State boards of pharmacy. FDA will
clarify in the guidance that in addition
to complying with federal adverse event
reporting requirements, outsourcing
facilities must comply with any
applicable State adverse event reporting
requirements. Specifically, FDA will
add the following language: ‘‘Certain
state boards of pharmacy may also
require outsourcing facilities licensed in
their states to report adverse events.
Outsourcing facilities must comply with
any applicable state reporting
requirements independent of and in
addition to reporting adverse events as
described in this guidance.’’
Issue Six: One commenter proposed
language clarifying that the regulations
described in the guidance apply to
products without an ANDA.
FDA Response to Issue Six: This
additional language is unnecessary
because the guidance cites the
regulation § 310.305 and makes clear
that it applies to manufacturers of
prescription drug products that are not
the subject of an approved drug
application.
Issue Seven: With regard to the
following statement in the draft
guidance: ‘‘Reports should be submitted
as long as the outsourcing facility has
information on at least the suspect drug
and the adverse event’’, one commenter
recommended that FDA clarify that if a
report lacks the four minimum data
elements, the outsourcing facility
should review the report for any
potential safety issue.
FDA Response to Issue Seven: FDA
believes that the draft guidance is clear
that if the report lacks the four data
elements, the outsourcing facility
should continue investigating. The
guidance states, ‘‘If the outsourcing
facility was not able to include all four
of the data elements in its initial report,
it should exercise due diligence to
obtain information about any of the
remaining elements.’’
Issue Eight: One commenter suggested
that FDA clarify that if an adverse event
reporter does not identify a suspect
drug, the outsourcing facility should
submit a report that lists all drugs that
the patient was taking as suspect.
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FDA Response to Issue Eight: FDA
does not agree with this suggestion. The
guidance states that for an adverse event
to be reportable to FDA, the outsourcing
facility must have information on at
least two data elements: An adverse
event and a suspect drug. A suspect
drug product is one that the initial
reporter suspected was associated with
the adverse event. If the reporter does
not identify a suspect drug, the adverse
event is not reportable. The outsourcing
facility should not submit a report that
lists each of the drugs the patient was
taking as suspect drugs, as the comment
suggests, if none of the drugs was
identified as suspect by the reporter. In
most cases, we believe that a reporter
that contacts an outsourcing facility will
be able to identify the suspect drug. It
is unlikely that the reporter would have
notified the outsourcing facility of the
adverse event if it did not believe the
compounded drug manufactured by the
outsourcing facility caused the adverse
event.
Issue Nine: Several commenters noted
that under the draft guidance, when an
adverse event cannot be directly
determined to be associated with a
specific drug, the outsourcing facility
should identify and list all other
medications to which the identified
patient may have been exposed
including information related to all
compounded prescription preparations,
brand and generic manufactured drug
products, dietary supplements, and
over-the counter medications that may
have been taken by the patient. The
commenters stated that requiring
information on all drug products taken
by a patient that may be ‘‘suspect’’ is
unduly burdensome, especially when a
compounded preparation is distributed
to a medical center where multiple
treatments and therapies are provided at
any given time to an individual. An
outsourcing facility may therefore have
an incomplete picture of the
circumstances under which the drug
was administered. In addition, the
outsourcing facility would also have no
control over how a drug is administered,
and improper administration may be
material to the cause of the adverse
event.
FDA Response to Issue Nine: FDA
will clarify that the outsourcing facility
should only include information on
suspect drug products that the
outsourcing facility is aware of from the
reporter and the outsourcing facility’s
due diligence to obtain additional
information. The outsourcing facility is
not expected to report information that
it does not have. Specifically, FDA will
add the italicized language: ‘‘In all
cases, including those where not all of
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the drug products were made by the
outsourcing facility, the report should
include information on all suspect drug
products of which the outsourcing
facility is aware.’’
FDA will also clarify that FDA will
consider how the drug was
administered, the patient’s medical
history, and any other relevant facts
when investigating the adverse event.
Specifically, FDA will add the following
language: ‘‘The outsourcing facility
should include the information
described in this guidance on suspect
drug products and concomitant
medications of which it is aware after
exercising due diligence. For example,
although an outsourcing facility should
exercise due diligence to determine any
concomitant medical products, FDA
only expects that it report information
about concomitant products that it is
able to obtain from the reporter.
Furthermore, as noted previously, the
report or information submitted by an
outsourcing facility issued in § 310.305
(and any release by FDA of that report
or information) does not necessarily
reflect a conclusion that the report or
information constitutes an admission
that the drug caused or contributed to
an adverse effect.1 When investigating
the adverse event, FDA considers how
the drug was administered, the patient’s
medical history, and any other relevant
information.’’
Issue 10: Two commenters asked how,
given that a compounded product
contains more than one component,
could an outsourcing facility or the
healthcare provider know which
component of the compounded product,
or which component of which product,
is suspect. Compounded products have
a number of components and active
pharmaceutical ingredients (API), so it
may be difficult for an outsourcing
facility to tie a serious, unexpected
adverse event to a specific component
or API. A commenter also noted that
FDA should require that an adverse
event report identify all the APIs
contained in a compounded drug and
the APIs’ manufacturer(s).
FDA Response to Issue 10: The
guidance makes clear that the minimum
data element for reporting is the suspect
drug product, and not a suspect
component. (See section III.B.3 of the
draft guidance.) We agree with the
suggestion that the outsourcing facility
should identify in its adverse event
report all of the APIs contained in a
compounded drug and the APIs’
manufacturer. The guidance states that
all known components of a suspect drug
product should be reported. It states
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§ 310.305(g).
Frm 00071
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that, ‘‘[i]f the compounded drug product
contains multiple components (e.g.,
excipients, drug substances, finished
dosage forms), the outsourcing facility
should list each component and its
manufacturer. . .’’
Issue 11: One commenter noted that
as indicated within the guidance
document, FDA is not prepared nor has
the necessary infrastructure in place to
receive electronic reports of adverse
events despite having such a system
already available for other registered
entities including manufacturers. The
commenter asked that the FDA provide
an implementation schedule to all
currently registered outsourcing
facilities outlining the anticipated date
of an electronic adverse event reporting
system as soon as possible.
FDA Response to Issue 11: This final
guidance describes the process for
outsourcing facilities to report adverse
events to FDA electronically. The
electronic reporting system is ready for
outsourcing facilities to use, and,
therefore, the issue raised by this
comment is now moot.
Issue 12: Two commenters stated that
this draft guidance imposes uneven
reporting requirements on similarlysituated facilities (i.e., outsourcing
facilities operating under section 503B
and pharmacies operating under section
503A of the FD&C Act) engaging in the
same activities. Because outsourcing
facilities can compound drugs issued in
individual prescriptions, they are
permitted to do the same kind of
activities as facilities compounding
under section 503A of the FD&C Act.
Holding facilities that engage in the
same conduct to different standards is
‘‘illogical and arbitrary and capricious.’’
If FDA determines that section 503A
facilities should not be required to
adhere to the same adverse event
reporting requirements as outsourcing
facilities, an outsourcing facility that
compounds issued in individual
prescriptions should not have to report
adverse events associated with
individual preparations.
FDA Response to Issue 12: FDA does
not agree with this comment. The
purpose of this guidance is to
implement section 503B(b)(5) of the
FD&C Act, which requires adverse event
reporting for outsourcing facilities and
does not address adverse reporting for
compounding conducted under section
503A. Adverse event reporting for
entities operating under section 503A of
the FD&C Act is beyond the scope of
this guidance. We also note that section
503B of the FD&C Act requires
outsourcing facilities to report adverse
events associated with all of their
compounded drugs to FDA and does not
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distinguish between patient specific and
non-patient specific compounded
products.
Issue 13: One commenter noted that
FDA may have written this guidance
because it may be interested in knowing
the sheer number of adverse events that
occurred at each outsourcing facility. If
this is the case, this kind of information
could be collected by reporting the
number of adverse events without the
need for extensive detail about the
affected patient or the components of
the compounded product. This
information could be collected through
the recordkeeping and facility
inspections that are already required of
outsourcing facilities. Further, it may be
more efficient to collect this information
at regular intervals (e.g., quarterly or
biannually) rather than in relation to
when the adverse event occurred.
FDA Response to Issue 13: FDA is not
interested only in the number of adverse
events associated with compounded
drug products from a particular
outsourcing facility, as the comment
suggests. A single report of an adverse
event can signal a serious public health
concern, such as an outbreak resulting
from drug contamination, or could
signal serious quality problems at the
outsourcing facility that if corrected
promptly could prevent an outbreak.
FDA evaluates each adverse event report
to determine what followup action is
appropriate. Collecting adverse events at
longer intervals would conflict with the
15-calendar day submission timeline
required under § 310.305 and would not
be sufficient for FDA’s need to evaluate
adverse event reports in a timely way.
Whether to require additional reporting
or collect additional information is
beyond the scope of the current
guidance.
Issue 14: One commenter noted that
an outsourcing facility would not
necessarily know which patient
received which drug, unless it was
compounded issued in an individual
prescription. Most outsourcing facilities
make the majority of their preparations
to be supplied to healthcare providers
rather than issued in a prescription, so
the only way an outsourcing facility
would learn of the adverse event is if it
is reported to the outsourcing facility by
a patient or a healthcare provider.
Healthcare providers are in a better
position to know about the occurrence
of adverse events. Therefore, it may be
advantageous for FDA to seek to collect
this information from healthcare
providers with better access to the
information, through submitting reports
to FDA and supplying copies of those
reports to the outsourcing facility. The
outsourcing facility could then submit
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the adverse event report to FDA,
reference the fact that the occurrence
was already reported, and provide
additional information about the
product.
FDA Response to Issue 14: Reporting
by healthcare providers is not
mandatory under the FD&C Act or its
implementing regulations. Section 503B
of the FD&C Act requires outsourcing
facilities, and not healthcare providers,
to report adverse events to FDA. We
agree with the comment that healthcare
providers have useful information on a
patient, and for this reason encourage
outsourcing facilities to contact the
healthcare provider to obtain additional
information on the patient. The
guidance makes clear that outsourcing
facilities must report adverse events that
they are aware of; if they do not learn
of an adverse event, there would be
nothing for them to report.
Issue 15: Two commenters asked what
the consequences are if a practitioner
reports a serious, unexpected adverse
event but the outsourcing facility did
not because it was not aware of the
adverse event. The commenters
indicated that an outsourcing facility
should be permitted to refer to a
previously submitted adverse event
report instead of being required to
prepare a separate, duplicative report.
FDA Response to Issue 15:
Outsourcing facilities are required to
report serious unexpected adverse
events that they are aware of, regardless
of whether anyone else voluntarily
reported them. The guidance states that
‘‘failure to report adverse events by an
entity that is registered in accordance
with section 503B(b) is a prohibited act
under section 301(ccc)(3) of the FD&C
Act. Violations relating to this provision
are subject to regulatory and
enforcement action.’’ If an adverse event
associated with an outsourcing facility’s
product is submitted to the FDA
voluntarily by an entity other than the
outsourcing facility (a healthcare
provider), the outsourcing facility,
under section 503B of the FD&C Act, is
still required to submit an adverse event
report if it also became aware of the
same adverse event report and it is
reportable. During the review and
analysis of case reports from the FDA
Adverse Event Reporting System, FDA
reviewers identify duplicate cases and
treat them as one case report in their
evaluation.
Issue 16: One commenter asked if
there would be a consequence to an
outsourcing facility that does not report
an adverse event because another
individual or entity reported it directly
to FDA.
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46003
FDA Response to Issue 16: The
outsourcing facility is required to report
any adverse events of which it becomes
aware, regardless of whether anyone
else voluntarily reported it. The
guidance states that ‘‘failure to report
adverse events by an entity that is
registered in accordance with section
503B(b) is a prohibited act under section
301(ccc)(3) of the FD&C Act. Violations
relating to this provision are subject to
regulatory and enforcement action.’’
Issue 17: Two commenters stated that
the draft guidance fails to account for
compounded drug products being used
for off-label treatment. By failing to
address this issue, the reporting
requirements detailed in the draft
guidance may not provide FDA with the
information it seeks. Additionally, an
outsourcing facility may not know how
the compounded drug is to be used,
thereby limiting its ability to provide a
full and accurate accounting of the
adverse event. The patient’s healthcare
provider may be in a better position to
provide this information.
FDA Response to Issue 17: FDA
disagrees with this comment. The
concept of ‘‘off-label treatment’’ is not
applicable to compounded drugs
because compounded drugs are not
approved and do not have approved
labeling. FDA evaluates adverse event
reports associated with compounded
drug products for quality issues.
Furthermore, section 503B of the FD&C
Act requires outsourcing facilities to
report adverse events. Reporting by
healthcare providers is voluntary and
not the subject of this guidance.
Issue 18: Two commenters asked if,
after complying with the reporting
requirement, FDA will require any
additional information or followup
activity by the outsourcing facility that
submits the report. They asked if the
outsourcing facility will be required to
provide information about the adverse
event to healthcare providers or others
who purchased the same or similar
product, and if the adverse event does
not trigger reporting requirements
imposed by the applicable State board
of pharmacy, whether the outsourcing
facility must notify the State board.
FDA Response to Issue 18: The draft
guidance describes the requirement
under § 310.305(c)(2) that all serious,
unexpected adverse drug experiences
shall be promptly investigated by the
outsourcing facility and a followup
report must be submitted within 15
calendar days of receipt of new
information ‘‘or as requested by FDA.’’
The guidance does not direct the
outsourcing facility to provide
information about adverse events to any
other entities. Whether the outsourcing
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facility must also notify the State is a
question of State law. The guidance
makes clear that the outsourcing facility
must comply with any State
requirements. As described above, for
clarification, FDA added the following
language to the guidance: ‘‘Certain state
boards of pharmacy may also require
outsourcing facilities licensed in their
states to report adverse events.
Outsourcing facilities must comply with
any applicable state reporting
requirements independent of and in
addition to reporting adverse events as
described in this guidance.’’
Issue 19: Two commenters asked what
action, if any, FDA will take following
the reporting of an adverse event. They
asked if such reporting will trigger
inspections or additional scrutiny by
FDA, whether the filing of an adverse
event report automatically means FDA
will undertake any kind of formal
enforcement action or any other
followup, and whether FDA will notify
the State board, or otherwise disclose
the adverse event to the public,
healthcare providers, purchasers, or
others. A commenter also noted that if
the purpose of the guidance is to
monitor and identify issues with
particular outsourcing facilities, the
disclosure requirements go too far
because information such as patient
information, a reporter, or drug
information would not be needed by
FDA and can be addressed through
recordkeeping and inspections.
FDA Response to Issue 19: When FDA
receives a report of an adverse event
associated with a compounded drug,
FDA evaluates the report for appropriate
action. In appropriate cases, FDA will
contact the outsourcing facility or
reporter for additional information, and
if the report suggests a quality issue,
FDA may initiate an inspection of the
outsourcing facility and/or the reporter’s
facility, as appropriate. FDA may also
contact such an outsourcing facility
about initiating a recall or ceasing sterile
operations if, for example, there is
evidence that the firm may have
released adulterated or misbranded drug
products (e.g., contaminated drug
products) that could cause patient harm,
or pursue regulatory action. In other
cases, FDA may be able to determine
that the adverse event resulted from the
patient’s underlying condition,
improper administration, or
concomitant product and not from a
drug product compounded by the
outsourcing facility. In the guidance,
FDA has provided additional
information about the actions that it
takes upon receiving an adverse event
report and why adverse event reporting
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is important. Specifically, FDA added
the following language:
‘‘Adverse event reporting for drug
products compounded by outsourcing
facilities is a critical mechanism by
which FDA identifies signals of
potential quality problems that may be
associated with a particular drug or drug
component, and which may have been
caused by substandard conditions or
processes at a facility where the drug or
its components were made or handled.
FDA needs to distinguish such cases
from cases of medication error, hospital
or clinic procedural problems, or quality
issues associated with ingredients such
as active pharmaceutical ingredients
(APIs) or excipients. For example,
several reports of adverse events in
patients who received compounded
drug products from the same
outsourcing facility may be a signal of
a quality issue resulting from a
deficiency in the outsourcing facility’s
manufacturing processes. However, if
several different outsourcing facilities
report adverse events in patients who
received drug products that contained
the same API, this may suggest a quality
problem associated with the API used in
the compounded drug product.
An adverse event may be reported for
reasons other than a quality problem.
For example, it may be a side effect of
taking the drug product, or may have
resulted from lack of efficacy of the drug
product, the patient’s underlying
medical condition, or use of a
concomitant medication. To address the
reported adverse event appropriately,
FDA reviews information provided by
the outsourcing facilities, such as the
description of the circumstances
associated with the adverse event such
as the source of the drug and its
ingredients, concomitant medications
that the patient was taking, and relevant
information reflected in hospital
discharge summaries, autopsy reports/
death certificates, relevant laboratory
data, and other critical clinical data
used to determine the cause of the
adverse event.’’
Issue 20: One commenter noted that
the draft guidance requires that
outsourcing facilities maintain for 10
years the records of all adverse events
required to be reported, including
certain specific information. The
commenter asked when this 10-year
period begins: From the date of the
occurrence of the adverse event, the
date the adverse event is reported to
FDA, or another date, whether there are
any requirements concerning how or
where these records must be
maintained, and whether FDA expects
to provide additional guidance on the
maintenance of such records
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Sfmt 4703
FDA Response to Issue 20: FDA
clarified the guidance by adding the
following language: ‘‘The ten-year
retention period for a particular record
begins from the time that an outsourcing
facility receives information (e.g., a
document with information about one of
the four data elements).’’ FDA does not
feel that additional recordkeeping
guidance is necessary.
Issue 21: One commenter requested
clarification regarding the specific
information that an outsourcing facility
should keep in its records of an adverse
event report. The commenter stated that
if specific data are not available at the
time of the report, FDA should specify
that it is acceptable for those data to be
missing from the record of the adverse
event. In addition, FDA should clarify
how outsourcing facilities should
document their efforts to obtain the four
data elements.
FDA Response to Issue 21: FDA has
clarified this in the guidance.
Specifically, FDA added the following
italicized language: ‘‘If the outsourcing
facility was not able to include all four
of the data elements in its initial report,
it should exercise due diligence to
obtain information about any of the
remaining elements and should keep
records of its efforts to obtain this and
other relevant information (e.g., dates of
discussions with the reporter to
determine how many patients
experienced a particular adverse event
or dates of discussions with a healthcare
facility to obtain contact information for
an identifiable person who purports to
have knowledge about the patient,
adverse event, or drug involved).’’
Issue 22: One commenter asked
whether FDA anticipates requiring
outsourcing facilities to adopt common
standard operating procedures (SOPs)
governing the reporting of adverse
events. The commenter noted that
having standardized SOPs issued by
FDA may help ensure consistency in the
frequency of reporting, the information
reported, and how this information is
provided. The commenter asked
whether FDA will provide additional
guidance or standards clarifying the
‘‘written processes for the surveillance,
receipt, evaluation, and reporting of
adverse events for the drug products it
compounds as described in 21 CFR
310.305(a) and 211.198’’ that it
anticipates reviewing during
inspections of outsourcing facilities.
FDA Response to Issue 22:
Outsourcing facilities are required to
develop and implement written
procedures for the surveillance, receipt,
evaluation, and reporting of
postmarketing adverse drug experiences
as described in §§ 310.305(a) and
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211.198. FDA will consider whether to
provide additional guidance on SOPs,
but outsourcing facilities are required to
develop written procedures that enable
them to fulfill their review, reporting,
and recordkeeping obligations even if
FDA does not provide such guidance.
Issue 23: One commenter suggests
using the MedWatch Form FDA 3500
voluntary reporting instead of the
mandatory Form FDA 3500A reporting
form.
FDA Response to Issue 23: FDA
disagrees with this comment. Section
503B of the FD&C Act requires that
outsourcing facilities report adverse
events. Therefore, voluntary reporting
mechanisms such as the Form FDA
3500 would not be appropriate for
outsourcing facility adverse event
reporting.
Issue 24: One commenter asked for
clarification about the type of products
about which adverse event reports must
be submitted, noting that outsourcing
facilities often do more than
compounding. The commenter asked
whether the reporting requirements
apply to other activities such as
repackaging.
FDA Response to Issue 24: The
guidance states that ‘‘for purposes of
reporting adverse drug experiences, the
term prescription drug products
includes any compounded drug product
subject to the prescription requirements
in section 503(b)(1) of the FD&C Act.’’
Reporting for other activities such as
repackaging will be addressed in
separate guidance documents. For
example, when finalized, FDA’s draft
guidance, ‘‘Repackaging of Certain
Human Drug Products by Pharmacies
and Outsourcing Facilities,’’ will
describe adverse event reporting for
drug products repackaged by
outsourcing facilities, if they will be
expected to report adverse events
associated with their repackaged
products, as contemplated by the draft
guidance.
46005
Burden Estimates:
The total estimated reporting and
recordkeeping burdens for the guidance
are as follows:
We estimate that approximately 55
outsourcing facilities (‘‘Number of
Respondents’’ and ‘‘Total Annual
Responses’’ in table 1) will annually
submit adverse event reports to FDA as
specified in the guidance, and that
preparing and submitting this
information will take approximately 1.1
hours per registrant (‘‘Average Burden
per Response’’ in table 1).
We estimate that approximately 55
outsourcing facilities (‘‘Number of
Recordkeepers’’ in table 2) will annually
maintain records of adverse events as
specified in the guidance, and that
preparing and maintaining the records
will take approximately 16 hours per
registrant (‘‘average burden per
recordkeeping’’ in table 2).
FDA estimates the burden of this
collection of information as follows:
TABLE 1—ESTIMATED ANNUAL REPORTING BURDEN 1
Compounding outsourcing facility
Number of
respondents
Number of
responses per
respondent
Total annual
responses
Average burden
per response
Total hours
Submission of adverse event reports including copy of labeling and other information as described in the guidance ....................................................
55
1
55
1.1
61
1 There
are no capital costs or operating and maintenance costs associated with this collection of information.
TABLE 2—ESTIMATED ANNUAL RECORDKEEPING BURDEN 1
Type of recordkeeping
Number of
recordkeepers
Number of records
per recordkeeper
Total annual
records
Average burden
per recordkeeping
Total hours
Records of adverse events, including
records of efforts to obtain the data
elements for each adverse event report .....................................................
55
1
55
16
880
1 There
are no capital costs or operating and maintenance costs associated with this collection of information.
Dated: July 28, 2015.
Leslie Kux,
Associate Commissioner for Policy.
ACTION:
BILLING CODE 4164–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
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Food and Drug Administration
[Docket No. FDA–2015–N–0007]
Biosimilar User Fee Rates for Fiscal
Year 2016
Food and Drug Administration,
HHS.
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The Food and Drug
Administration (FDA) is announcing the
rates for biosimilar user fees for fiscal
year (FY) 2016. The Federal Food, Drug,
and Cosmetic Act (the FD&C Act), as
amended by the Biosimilar User Fee Act
of 2012 (BsUFA), authorizes FDA to
assess and collect user fees for certain
activities in connection with biosimilar
biological product development, certain
applications and supplements for
approval of biosimilar biological
products, establishments where
approved biosimilar biological products
are made, and a biosimilar biological
product fee for each biosimilar
biological product approved in a
SUMMARY:
[FR Doc. 2015–18911 Filed 7–31–15; 8:45 am]
AGENCY:
Notice.
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biosimilar biological product
application.
BsUFA directs FDA to establish,
before the beginning of each fiscal year,
the initial and annual biosimilar
biological product development (BPD)
fees, the reactivation fee, and the
biosimilar biological product
application, establishment, and product
fees. These fees are effective on October
1, 2015, and will remain in effect
through September 30, 2016.
FOR FURTHER INFORMATION CONTACT:
Rachel Richter, Office of Financial
Management, Food and Drug
Administration, 8455 Colesville Rd.,
COLE–14216, Silver Spring, MD 20993–
0002, 301–796–7111.
SUPPLEMENTARY INFORMATION:
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Agencies
[Federal Register Volume 80, Number 148 (Monday, August 3, 2015)]
[Notices]
[Pages 45999-46005]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-18911]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2014-D-2138]
Agency Information Collection Activities; Submission for Office
of Management and Budget Review; Comment Request; Guidance for Industry
on Adverse Event Reporting for Outsourcing Facilities Under Section
503B of the Federal Food, Drug, and Cosmetic Act
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is announcing that a
proposed collection of information has been submitted to the Office of
Management and Budget (OMB) for review and clearance under the
Paperwork Reduction Act of 1995.
DATES: Fax written comments on the collection of information by
September 2, 2015.
[[Page 46000]]
ADDRESSES: To ensure that comments on the information collection are
received, OMB recommends that written comments be faxed to the Office
of Information and Regulatory Affairs, OMB, Attn: FDA Desk Officer,
FAX: 202-395-7285, or emailed to oira_submission@omb.eop.gov. All
comments should be identified with the OMB control number 0910--NEW and
title ``Guidance for Industry on Adverse Event Reporting for
Outsourcing Facilities Under Section 503B of the Federal Food, Drug,
and Cosmetic Act.'' Also include the FDA docket number found in
brackets in the heading of this document.
FOR FURTHER INFORMATION CONTACT: FDA PRA Staff, Office of
Operations,Food and Drug Administration, 8455 Colesville Rd., COLE-
14526, Silver Spring, MD 20993-0002, PRAStaff@fda.hhs.gov.
SUPPLEMENTARY INFORMATION: In compliance with 44 U.S.C. 3507, FDA has
submitted the following proposed collection of information to OMB for
review and clearance.
Guidance for Industry on Adverse Event Reporting for Outsourcing
Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic
Act OMB Control Number 0910--NEW
In the Federal Register of February 19, 2015 (80 FR 8872), FDA
announced the availability of a draft guidance for industry entitled
``Adverse Event Reporting for Outsourcing Facilities Under Section 503B
of the Federal Food, Drug, and Cosmetic Act.'' On November 27, 2013,
President Obama signed the Drug Quality and Security Act (DQSA) into
law (Pub. L. 113-54). The DQSA added a new section 503B to the FD&C Act
(21 U.S.C. 353b). Under section 503B(b), a compounder can register as
an outsourcing facility with FDA. If the conditions outlined in section
503B(a) of the FD&C Act are satisfied, a drug compounded by or under
the direct supervision of a licensed pharmacist in an outsourcing
facility is exempt from certain sections of the FD&C Act, including
section 502(f)(1) (21 U.S.C. 352(f)(1)) (concerning the labeling of
drugs with adequate directions for use) and section 505 (21 U.S.C. 355)
(concerning the approval of human drug products under new drug
applications (NDAs) or abbreviated new drug applications (ANDAs)).
Drugs compounded in outsourcing facilities are not exempt from the
requirements of section 501(a)(2)(B) of the FD&C Act (21 U.S.C.
351(a)(2)(B)) (concerning current good manufacturing practice for
drugs).
Under section 503B(b)(5), an outsourcing facility must submit
adverse event reports to FDA in accordance with the content and format
requirements established through guidance or regulation under 21 CFR
310.305 (or any successor regulations). This guidance explains
electronic reporting of adverse events in accordance with Sec. 310.305
with respect to outsourcing facilities.
Under Sec. 310.305(c)(1), manufacturers, packers, and distributors
of marketed prescription drug products that are not the subject of an
approved new drug or abbreviated new drug application, including, as
set forth in the guidance, outsourcing facilities must submit to FDA
adverse event reports within 15 calendar days of receiving the
information and must submit followup reports within 15 calendar days of
receipt of new information about the adverse event, or as requested by
FDA. Outsourcing facilities must submit the adverse event report in an
electronic format that FDA can process, review, and archive (collection
of information is approved by OMB control number 0910-0291). A copy of
the current labeling of the compounded drug product must be provided.
Under Sec. 310.305(f), entities subject to the regulation must
maintain for 10 years the records of all adverse events required to be
reported under Sec. 310.305. The outsourcing facility should also
maintain records of its efforts to obtain the data elements described
in the draft guidance for each adverse event report.
In the Federal Register of February 19, 2015 (80 FR 8872), FDA
published a 60-day notice requesting public comment on the proposed
collection of information. FDA received seven comments on the draft
guidance, several of which raised issues pertaining to the information
collection provisions in the draft guidance. The issues raised are
addressed below.
Issue One: Several individuals submitted comments related to the
requirement described in the guidance that outsourcing facilities
report adverse events that are both serious and unexpected and the
recommendation in the guidance that outsourcing facilities report all
serious adverse events, regardless of whether they are unexpected.
Specifically:
One commenter noted that the applicable regulation, Sec.
310.305, defines an ``unexpected'' adverse drug experience as an
adverse drug experience ``that is not listed in the current labeling
for the drug product.'' The commenter indicated that this definition is
not easily applied to unapproved drugs, as such products lack uniform
FDA-reviewed language, meaning products with the same active ingredient
may list different adverse events in the labeling, or no adverse events
at all.
One commenter indicated that instead of strongly
recommending that outsourcing facilities report all serious adverse
drug experiences to the FDA, the FDA should require such reporting.
One commenter stated that reporting all serious adverse
drug experiences (not just those that are both serious and unexpected)
should be required, rather than ``strongly recommended,'' and because
reporting all serious adverse events is not currently required under
Sec. 310.305, FDA should amend this regulation.
Several commenters noted that Sec. 310.305 only requires
reporting of serious, unexpected adverse events, but the draft guidance
suggests that outsourcing facilities should report all serious adverse
events. They stated that FDA is reaching beyond what the regulations
allow, and this suggestion will lead to confusion to what must be
reported and what is suggested. FDA should narrow reporting to
unexpected adverse events.
FDA Response to Issue One: FDA responds as follows:
FDA has clarified the guidance with regard to reporting
adverse events that are considered ``unexpected.'' Specifically, the
guidance now includes the following language to clarify the meaning of
the term ``unexpected'' in the context of adverse events associated
with compounded drugs: ``For example, if current labeling for a
compounded drug product does not list any adverse drug experiences, all
adverse drug experiences associated with the compounded drug product
would be considered `unexpected.' ''
With regard to the recommendation that outsourcing
facilities be required to report all serious adverse events, rather
than just those that are considered both serious and unexpected, Sec.
310.305, the regulation applicable to reporting of adverse events by
all manufacturers of unapproved drugs, does not require reporting of
all serious adverse drug experiences to FDA. Therefore, requiring
outsourcing facilities to report all serious adverse events would be
inconsistent with Sec. 310.305.
Amending the regulation Sec. 310.305 would require a
separate rulemaking, which is beyond the scope of this guidance
document.
With regard to the concern about possible confusion caused
by FDA's recommendation that outsourcing facilities report all serious
adverse events, the draft guidance states the
[[Page 46001]]
regulations require reporting of all adverse events that are both
serious and unexpected, and that FDA is recommending that outsourcing
facilities report all serious adverse events. Specifically, the draft
guidance states that ``FDA strongly recommends that outsourcing
facilities submit all serious adverse drug experiences'' (lines 128-
131) and that ``the regulations require reporting of each adverse drug
experience received or otherwise obtained that is both serious and
unexpected . . . .'' (lines 103-104). FDA will further clarify this by
adding the following italicized language: ``In addition, although they
are not required to do so, FDA strongly recommends that outsourcing
facilities report all serious adverse events. . . .''
Issue Two: Several commenters noted that FDA encourages, as
appropriate, the outsourcing facility to attach to the report: (1)
Hospital discharge summaries, (2) autopsy reports/death certificates,
(3) relevant laboratory data, and (4) other critical clinical data, and
that in case of a death, an outsourcing facility should also provide
any available information on the event(s) that led to the death. The
commenters stated it is unlikely that an outsourcing facility will be
given access to the elements voluntarily by the healthcare facility
where the serious adverse event occurred without being legally
compelled to do so. A commenter also asked how a manufacturer,
distributor, and/or supplier can obtain this information under the
Health Insurance Portability and Accountability Act (HIPAA).
FDA Response to Issue Two: With regard to HIPAA, 45 CFR 164.512
describes situations under which a covered entity, e.g., a healthcare
provider, may use or disclose protected health information without the
written authorization of the individual or the opportunity for the
individual to agree or object. One of these situations is ``to collect
or report adverse events'' to FDA (45 CFR 164.512(b)(1)(iii)(A)).
However, although information about adverse events can be obtained
under HIPAA, the guidance does not state that an outsourcing facility
must obtain this information. Rather, the guidance states that
attaching this information is encouraged. It should be provided if the
outsourcing facility has the information, but the outsourcing facility
is not specifically required to obtain this information. FDA has
clarified in the guidance that the information should be provided to
FDA if it is available. Specifically, the guidance now reads: ``In
addition, as part of the adverse event report, we encourage, as
appropriate, attachment of the following, if available: (1) Hospital
discharge summaries, (2) autopsy reports/death certificates, (3)
relevant laboratory data, and (4) other critical clinical data. In the
case of a death, outsourcing facilities should also provide any
available information on the event(s) that led to the death.''
Issue Three: One commenter noted that the period of 15 calendar
days to submit an initial report of an adverse event and the 15
calendar days to submit a followup report is too long; that during this
period illnesses, injuries, or deaths can result. The commenter also
stated that this would likely also delay initiation of recall
procedures, and that the time period for reporting should be no more
than 48 or 72 hours, followed by an equally prompt followup and
investigation period, and an immediate decision on a recall.
FDA Response to Issue Three: The applicable regulation, Sec.
310.305, provides a 15-day timeframe for reporting an adverse event and
an additional 15-day timeframe to submit a followup report. This is the
maximum amount of time permitted. The guidance states that the
regulations require reporting ``as soon as possible, but in no case
later than 15 calendar days . . . .'' The preamble to Sec. 310.305
notes that the manufacturer must usually obtain additional information
about the product (e.g., followup with the reporting physician or
patient), and that reducing the time for submitting these reports would
increase the number of incomplete reports. (51 FR 24478).
Issue Four: FDA should immediately share all adverse events
reported with the home State regulator, so the State agency is also
aware of potential problems at one of its licensee's facilities.
FDA Response to Issue Four: FDA intends to continue to work closely
with its State partners on oversight of compounding, including
improving and streamlining information sharing as much as possible.
However, this recommendation is not relevant to this guidance document,
which focuses on how outsourcing facilities should submit adverse event
reports to FDA.
Issue Five: Two commenters asked how the reporting requirements
proposed by the draft guidance interplay with reporting requirements
imposed by State boards of pharmacy. The commenters asked whether, in
the event a State board of pharmacy has adverse event reporting
requirements that apply to an outsourcing facility, satisfying the
adverse event reporting requirements described by the draft guidance
``preempt'' the requirement to comply with a State reporting
requirement. They asked whether an outsourcing facility must report to
both Federal and State regulators and noted that this could result in
duplicate reporting.
FDA Response to Issue Five: This guidance addresses requirements
under the FD&C Act and FDA regulations. Outsourcing facilities may have
independent responsibilities to report to State boards of pharmacy. FDA
will clarify in the guidance that in addition to complying with federal
adverse event reporting requirements, outsourcing facilities must
comply with any applicable State adverse event reporting requirements.
Specifically, FDA will add the following language: ``Certain state
boards of pharmacy may also require outsourcing facilities licensed in
their states to report adverse events. Outsourcing facilities must
comply with any applicable state reporting requirements independent of
and in addition to reporting adverse events as described in this
guidance.''
Issue Six: One commenter proposed language clarifying that the
regulations described in the guidance apply to products without an
ANDA.
FDA Response to Issue Six: This additional language is unnecessary
because the guidance cites the regulation Sec. 310.305 and makes clear
that it applies to manufacturers of prescription drug products that are
not the subject of an approved drug application.
Issue Seven: With regard to the following statement in the draft
guidance: ``Reports should be submitted as long as the outsourcing
facility has information on at least the suspect drug and the adverse
event'', one commenter recommended that FDA clarify that if a report
lacks the four minimum data elements, the outsourcing facility should
review the report for any potential safety issue.
FDA Response to Issue Seven: FDA believes that the draft guidance
is clear that if the report lacks the four data elements, the
outsourcing facility should continue investigating. The guidance
states, ``If the outsourcing facility was not able to include all four
of the data elements in its initial report, it should exercise due
diligence to obtain information about any of the remaining elements.''
Issue Eight: One commenter suggested that FDA clarify that if an
adverse event reporter does not identify a suspect drug, the
outsourcing facility should submit a report that lists all drugs that
the patient was taking as suspect.
[[Page 46002]]
FDA Response to Issue Eight: FDA does not agree with this
suggestion. The guidance states that for an adverse event to be
reportable to FDA, the outsourcing facility must have information on at
least two data elements: An adverse event and a suspect drug. A suspect
drug product is one that the initial reporter suspected was associated
with the adverse event. If the reporter does not identify a suspect
drug, the adverse event is not reportable. The outsourcing facility
should not submit a report that lists each of the drugs the patient was
taking as suspect drugs, as the comment suggests, if none of the drugs
was identified as suspect by the reporter. In most cases, we believe
that a reporter that contacts an outsourcing facility will be able to
identify the suspect drug. It is unlikely that the reporter would have
notified the outsourcing facility of the adverse event if it did not
believe the compounded drug manufactured by the outsourcing facility
caused the adverse event.
Issue Nine: Several commenters noted that under the draft guidance,
when an adverse event cannot be directly determined to be associated
with a specific drug, the outsourcing facility should identify and list
all other medications to which the identified patient may have been
exposed including information related to all compounded prescription
preparations, brand and generic manufactured drug products, dietary
supplements, and over-the counter medications that may have been taken
by the patient. The commenters stated that requiring information on all
drug products taken by a patient that may be ``suspect'' is unduly
burdensome, especially when a compounded preparation is distributed to
a medical center where multiple treatments and therapies are provided
at any given time to an individual. An outsourcing facility may
therefore have an incomplete picture of the circumstances under which
the drug was administered. In addition, the outsourcing facility would
also have no control over how a drug is administered, and improper
administration may be material to the cause of the adverse event.
FDA Response to Issue Nine: FDA will clarify that the outsourcing
facility should only include information on suspect drug products that
the outsourcing facility is aware of from the reporter and the
outsourcing facility's due diligence to obtain additional information.
The outsourcing facility is not expected to report information that it
does not have. Specifically, FDA will add the italicized language: ``In
all cases, including those where not all of the drug products were made
by the outsourcing facility, the report should include information on
all suspect drug products of which the outsourcing facility is aware.''
FDA will also clarify that FDA will consider how the drug was
administered, the patient's medical history, and any other relevant
facts when investigating the adverse event. Specifically, FDA will add
the following language: ``The outsourcing facility should include the
information described in this guidance on suspect drug products and
concomitant medications of which it is aware after exercising due
diligence. For example, although an outsourcing facility should
exercise due diligence to determine any concomitant medical products,
FDA only expects that it report information about concomitant products
that it is able to obtain from the reporter. Furthermore, as noted
previously, the report or information submitted by an outsourcing
facility issued in Sec. 310.305 (and any release by FDA of that report
or information) does not necessarily reflect a conclusion that the
report or information constitutes an admission that the drug caused or
contributed to an adverse effect.\1\ When investigating the adverse
event, FDA considers how the drug was administered, the patient's
medical history, and any other relevant information.''
---------------------------------------------------------------------------
\1\ See Sec. 310.305(g).
---------------------------------------------------------------------------
Issue 10: Two commenters asked how, given that a compounded product
contains more than one component, could an outsourcing facility or the
healthcare provider know which component of the compounded product, or
which component of which product, is suspect. Compounded products have
a number of components and active pharmaceutical ingredients (API), so
it may be difficult for an outsourcing facility to tie a serious,
unexpected adverse event to a specific component or API. A commenter
also noted that FDA should require that an adverse event report
identify all the APIs contained in a compounded drug and the APIs'
manufacturer(s).
FDA Response to Issue 10: The guidance makes clear that the minimum
data element for reporting is the suspect drug product, and not a
suspect component. (See section III.B.3 of the draft guidance.) We
agree with the suggestion that the outsourcing facility should identify
in its adverse event report all of the APIs contained in a compounded
drug and the APIs' manufacturer. The guidance states that all known
components of a suspect drug product should be reported. It states
that, ``[i]f the compounded drug product contains multiple components
(e.g., excipients, drug substances, finished dosage forms), the
outsourcing facility should list each component and its manufacturer. .
.''
Issue 11: One commenter noted that as indicated within the guidance
document, FDA is not prepared nor has the necessary infrastructure in
place to receive electronic reports of adverse events despite having
such a system already available for other registered entities including
manufacturers. The commenter asked that the FDA provide an
implementation schedule to all currently registered outsourcing
facilities outlining the anticipated date of an electronic adverse
event reporting system as soon as possible.
FDA Response to Issue 11: This final guidance describes the process
for outsourcing facilities to report adverse events to FDA
electronically. The electronic reporting system is ready for
outsourcing facilities to use, and, therefore, the issue raised by this
comment is now moot.
Issue 12: Two commenters stated that this draft guidance imposes
uneven reporting requirements on similarly-situated facilities (i.e.,
outsourcing facilities operating under section 503B and pharmacies
operating under section 503A of the FD&C Act) engaging in the same
activities. Because outsourcing facilities can compound drugs issued in
individual prescriptions, they are permitted to do the same kind of
activities as facilities compounding under section 503A of the FD&C
Act. Holding facilities that engage in the same conduct to different
standards is ``illogical and arbitrary and capricious.'' If FDA
determines that section 503A facilities should not be required to
adhere to the same adverse event reporting requirements as outsourcing
facilities, an outsourcing facility that compounds issued in individual
prescriptions should not have to report adverse events associated with
individual preparations.
FDA Response to Issue 12: FDA does not agree with this comment. The
purpose of this guidance is to implement section 503B(b)(5) of the FD&C
Act, which requires adverse event reporting for outsourcing facilities
and does not address adverse reporting for compounding conducted under
section 503A. Adverse event reporting for entities operating under
section 503A of the FD&C Act is beyond the scope of this guidance. We
also note that section 503B of the FD&C Act requires outsourcing
facilities to report adverse events associated with all of their
compounded drugs to FDA and does not
[[Page 46003]]
distinguish between patient specific and non-patient specific
compounded products.
Issue 13: One commenter noted that FDA may have written this
guidance because it may be interested in knowing the sheer number of
adverse events that occurred at each outsourcing facility. If this is
the case, this kind of information could be collected by reporting the
number of adverse events without the need for extensive detail about
the affected patient or the components of the compounded product. This
information could be collected through the recordkeeping and facility
inspections that are already required of outsourcing facilities.
Further, it may be more efficient to collect this information at
regular intervals (e.g., quarterly or biannually) rather than in
relation to when the adverse event occurred.
FDA Response to Issue 13: FDA is not interested only in the number
of adverse events associated with compounded drug products from a
particular outsourcing facility, as the comment suggests. A single
report of an adverse event can signal a serious public health concern,
such as an outbreak resulting from drug contamination, or could signal
serious quality problems at the outsourcing facility that if corrected
promptly could prevent an outbreak. FDA evaluates each adverse event
report to determine what followup action is appropriate. Collecting
adverse events at longer intervals would conflict with the 15-calendar
day submission timeline required under Sec. 310.305 and would not be
sufficient for FDA's need to evaluate adverse event reports in a timely
way. Whether to require additional reporting or collect additional
information is beyond the scope of the current guidance.
Issue 14: One commenter noted that an outsourcing facility would
not necessarily know which patient received which drug, unless it was
compounded issued in an individual prescription. Most outsourcing
facilities make the majority of their preparations to be supplied to
healthcare providers rather than issued in a prescription, so the only
way an outsourcing facility would learn of the adverse event is if it
is reported to the outsourcing facility by a patient or a healthcare
provider. Healthcare providers are in a better position to know about
the occurrence of adverse events. Therefore, it may be advantageous for
FDA to seek to collect this information from healthcare providers with
better access to the information, through submitting reports to FDA and
supplying copies of those reports to the outsourcing facility. The
outsourcing facility could then submit the adverse event report to FDA,
reference the fact that the occurrence was already reported, and
provide additional information about the product.
FDA Response to Issue 14: Reporting by healthcare providers is not
mandatory under the FD&C Act or its implementing regulations. Section
503B of the FD&C Act requires outsourcing facilities, and not
healthcare providers, to report adverse events to FDA. We agree with
the comment that healthcare providers have useful information on a
patient, and for this reason encourage outsourcing facilities to
contact the healthcare provider to obtain additional information on the
patient. The guidance makes clear that outsourcing facilities must
report adverse events that they are aware of; if they do not learn of
an adverse event, there would be nothing for them to report.
Issue 15: Two commenters asked what the consequences are if a
practitioner reports a serious, unexpected adverse event but the
outsourcing facility did not because it was not aware of the adverse
event. The commenters indicated that an outsourcing facility should be
permitted to refer to a previously submitted adverse event report
instead of being required to prepare a separate, duplicative report.
FDA Response to Issue 15: Outsourcing facilities are required to
report serious unexpected adverse events that they are aware of,
regardless of whether anyone else voluntarily reported them. The
guidance states that ``failure to report adverse events by an entity
that is registered in accordance with section 503B(b) is a prohibited
act under section 301(ccc)(3) of the FD&C Act. Violations relating to
this provision are subject to regulatory and enforcement action.'' If
an adverse event associated with an outsourcing facility's product is
submitted to the FDA voluntarily by an entity other than the
outsourcing facility (a healthcare provider), the outsourcing facility,
under section 503B of the FD&C Act, is still required to submit an
adverse event report if it also became aware of the same adverse event
report and it is reportable. During the review and analysis of case
reports from the FDA Adverse Event Reporting System, FDA reviewers
identify duplicate cases and treat them as one case report in their
evaluation.
Issue 16: One commenter asked if there would be a consequence to an
outsourcing facility that does not report an adverse event because
another individual or entity reported it directly to FDA.
FDA Response to Issue 16: The outsourcing facility is required to
report any adverse events of which it becomes aware, regardless of
whether anyone else voluntarily reported it. The guidance states that
``failure to report adverse events by an entity that is registered in
accordance with section 503B(b) is a prohibited act under section
301(ccc)(3) of the FD&C Act. Violations relating to this provision are
subject to regulatory and enforcement action.''
Issue 17: Two commenters stated that the draft guidance fails to
account for compounded drug products being used for off-label
treatment. By failing to address this issue, the reporting requirements
detailed in the draft guidance may not provide FDA with the information
it seeks. Additionally, an outsourcing facility may not know how the
compounded drug is to be used, thereby limiting its ability to provide
a full and accurate accounting of the adverse event. The patient's
healthcare provider may be in a better position to provide this
information.
FDA Response to Issue 17: FDA disagrees with this comment. The
concept of ``off-label treatment'' is not applicable to compounded
drugs because compounded drugs are not approved and do not have
approved labeling. FDA evaluates adverse event reports associated with
compounded drug products for quality issues. Furthermore, section 503B
of the FD&C Act requires outsourcing facilities to report adverse
events. Reporting by healthcare providers is voluntary and not the
subject of this guidance.
Issue 18: Two commenters asked if, after complying with the
reporting requirement, FDA will require any additional information or
followup activity by the outsourcing facility that submits the report.
They asked if the outsourcing facility will be required to provide
information about the adverse event to healthcare providers or others
who purchased the same or similar product, and if the adverse event
does not trigger reporting requirements imposed by the applicable State
board of pharmacy, whether the outsourcing facility must notify the
State board.
FDA Response to Issue 18: The draft guidance describes the
requirement under Sec. 310.305(c)(2) that all serious, unexpected
adverse drug experiences shall be promptly investigated by the
outsourcing facility and a followup report must be submitted within 15
calendar days of receipt of new information ``or as requested by FDA.''
The guidance does not direct the outsourcing facility to provide
information about adverse events to any other entities. Whether the
outsourcing
[[Page 46004]]
facility must also notify the State is a question of State law. The
guidance makes clear that the outsourcing facility must comply with any
State requirements. As described above, for clarification, FDA added
the following language to the guidance: ``Certain state boards of
pharmacy may also require outsourcing facilities licensed in their
states to report adverse events. Outsourcing facilities must comply
with any applicable state reporting requirements independent of and in
addition to reporting adverse events as described in this guidance.''
Issue 19: Two commenters asked what action, if any, FDA will take
following the reporting of an adverse event. They asked if such
reporting will trigger inspections or additional scrutiny by FDA,
whether the filing of an adverse event report automatically means FDA
will undertake any kind of formal enforcement action or any other
followup, and whether FDA will notify the State board, or otherwise
disclose the adverse event to the public, healthcare providers,
purchasers, or others. A commenter also noted that if the purpose of
the guidance is to monitor and identify issues with particular
outsourcing facilities, the disclosure requirements go too far because
information such as patient information, a reporter, or drug
information would not be needed by FDA and can be addressed through
recordkeeping and inspections.
FDA Response to Issue 19: When FDA receives a report of an adverse
event associated with a compounded drug, FDA evaluates the report for
appropriate action. In appropriate cases, FDA will contact the
outsourcing facility or reporter for additional information, and if the
report suggests a quality issue, FDA may initiate an inspection of the
outsourcing facility and/or the reporter's facility, as appropriate.
FDA may also contact such an outsourcing facility about initiating a
recall or ceasing sterile operations if, for example, there is evidence
that the firm may have released adulterated or misbranded drug products
(e.g., contaminated drug products) that could cause patient harm, or
pursue regulatory action. In other cases, FDA may be able to determine
that the adverse event resulted from the patient's underlying
condition, improper administration, or concomitant product and not from
a drug product compounded by the outsourcing facility. In the guidance,
FDA has provided additional information about the actions that it takes
upon receiving an adverse event report and why adverse event reporting
is important. Specifically, FDA added the following language:
``Adverse event reporting for drug products compounded by
outsourcing facilities is a critical mechanism by which FDA identifies
signals of potential quality problems that may be associated with a
particular drug or drug component, and which may have been caused by
substandard conditions or processes at a facility where the drug or its
components were made or handled. FDA needs to distinguish such cases
from cases of medication error, hospital or clinic procedural problems,
or quality issues associated with ingredients such as active
pharmaceutical ingredients (APIs) or excipients. For example, several
reports of adverse events in patients who received compounded drug
products from the same outsourcing facility may be a signal of a
quality issue resulting from a deficiency in the outsourcing facility's
manufacturing processes. However, if several different outsourcing
facilities report adverse events in patients who received drug products
that contained the same API, this may suggest a quality problem
associated with the API used in the compounded drug product.
An adverse event may be reported for reasons other than a quality
problem. For example, it may be a side effect of taking the drug
product, or may have resulted from lack of efficacy of the drug
product, the patient's underlying medical condition, or use of a
concomitant medication. To address the reported adverse event
appropriately, FDA reviews information provided by the outsourcing
facilities, such as the description of the circumstances associated
with the adverse event such as the source of the drug and its
ingredients, concomitant medications that the patient was taking, and
relevant information reflected in hospital discharge summaries, autopsy
reports/death certificates, relevant laboratory data, and other
critical clinical data used to determine the cause of the adverse
event.''
Issue 20: One commenter noted that the draft guidance requires that
outsourcing facilities maintain for 10 years the records of all adverse
events required to be reported, including certain specific information.
The commenter asked when this 10-year period begins: From the date of
the occurrence of the adverse event, the date the adverse event is
reported to FDA, or another date, whether there are any requirements
concerning how or where these records must be maintained, and whether
FDA expects to provide additional guidance on the maintenance of such
records
FDA Response to Issue 20: FDA clarified the guidance by adding the
following language: ``The ten-year retention period for a particular
record begins from the time that an outsourcing facility receives
information (e.g., a document with information about one of the four
data elements).'' FDA does not feel that additional recordkeeping
guidance is necessary.
Issue 21: One commenter requested clarification regarding the
specific information that an outsourcing facility should keep in its
records of an adverse event report. The commenter stated that if
specific data are not available at the time of the report, FDA should
specify that it is acceptable for those data to be missing from the
record of the adverse event. In addition, FDA should clarify how
outsourcing facilities should document their efforts to obtain the four
data elements.
FDA Response to Issue 21: FDA has clarified this in the guidance.
Specifically, FDA added the following italicized language: ``If the
outsourcing facility was not able to include all four of the data
elements in its initial report, it should exercise due diligence to
obtain information about any of the remaining elements and should keep
records of its efforts to obtain this and other relevant information
(e.g., dates of discussions with the reporter to determine how many
patients experienced a particular adverse event or dates of discussions
with a healthcare facility to obtain contact information for an
identifiable person who purports to have knowledge about the patient,
adverse event, or drug involved).''
Issue 22: One commenter asked whether FDA anticipates requiring
outsourcing facilities to adopt common standard operating procedures
(SOPs) governing the reporting of adverse events. The commenter noted
that having standardized SOPs issued by FDA may help ensure consistency
in the frequency of reporting, the information reported, and how this
information is provided. The commenter asked whether FDA will provide
additional guidance or standards clarifying the ``written processes for
the surveillance, receipt, evaluation, and reporting of adverse events
for the drug products it compounds as described in 21 CFR 310.305(a)
and 211.198'' that it anticipates reviewing during inspections of
outsourcing facilities.
FDA Response to Issue 22: Outsourcing facilities are required to
develop and implement written procedures for the surveillance, receipt,
evaluation, and reporting of postmarketing adverse drug experiences as
described in Sec. Sec. 310.305(a) and
[[Page 46005]]
211.198. FDA will consider whether to provide additional guidance on
SOPs, but outsourcing facilities are required to develop written
procedures that enable them to fulfill their review, reporting, and
recordkeeping obligations even if FDA does not provide such guidance.
Issue 23: One commenter suggests using the MedWatch Form FDA 3500
voluntary reporting instead of the mandatory Form FDA 3500A reporting
form.
FDA Response to Issue 23: FDA disagrees with this comment. Section
503B of the FD&C Act requires that outsourcing facilities report
adverse events. Therefore, voluntary reporting mechanisms such as the
Form FDA 3500 would not be appropriate for outsourcing facility adverse
event reporting.
Issue 24: One commenter asked for clarification about the type of
products about which adverse event reports must be submitted, noting
that outsourcing facilities often do more than compounding. The
commenter asked whether the reporting requirements apply to other
activities such as repackaging.
FDA Response to Issue 24: The guidance states that ``for purposes
of reporting adverse drug experiences, the term prescription drug
products includes any compounded drug product subject to the
prescription requirements in section 503(b)(1) of the FD&C Act.''
Reporting for other activities such as repackaging will be addressed in
separate guidance documents. For example, when finalized, FDA's draft
guidance, ``Repackaging of Certain Human Drug Products by Pharmacies
and Outsourcing Facilities,'' will describe adverse event reporting for
drug products repackaged by outsourcing facilities, if they will be
expected to report adverse events associated with their repackaged
products, as contemplated by the draft guidance.
Burden Estimates:
The total estimated reporting and recordkeeping burdens for the
guidance are as follows:
We estimate that approximately 55 outsourcing facilities (``Number
of Respondents'' and ``Total Annual Responses'' in table 1) will
annually submit adverse event reports to FDA as specified in the
guidance, and that preparing and submitting this information will take
approximately 1.1 hours per registrant (``Average Burden per Response''
in table 1).
We estimate that approximately 55 outsourcing facilities (``Number
of Recordkeepers'' in table 2) will annually maintain records of
adverse events as specified in the guidance, and that preparing and
maintaining the records will take approximately 16 hours per registrant
(``average burden per recordkeeping'' in table 2).
FDA estimates the burden of this collection of information as
follows:
Table 1--Estimated Annual Reporting Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number of
Compounding outsourcing facility Number of responses per Total annual Average burden per Total hours
respondents respondent responses response
--------------------------------------------------------------------------------------------------------------------------------------------------------
Submission of adverse event reports including copy 55 1 55 1.1 61
of labeling and other information as described in
the guidance.......................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
Table 2--Estimated Annual Recordkeeping Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number of Number of records Total annual Average burden per
Type of recordkeeping recordkeepers per recordkeeper records recordkeeping Total hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
Records of adverse events, including records of 55 1 55 16 880
efforts to obtain the data elements for each
adverse event report...............................
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
Dated: July 28, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-18911 Filed 7-31-15; 8:45 am]
BILLING CODE 4164-01-P