Postmarketing Safety Reporting for Combination Products, 92603-92626 [2016-30485]
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Federal Register / Vol. 81, No. 244 / Tuesday, December 20, 2016 / Rules and Regulations
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the claims that have been proved to the
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Dated: December 15, 2016.
Thomas J. Curry,
Comptroller of the Currency.
[FR Doc. 2016–30666 Filed 12–19–16; 8:45 am]
BILLING CODE 4810–33–P
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DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
21 CFR Part 4
[Docket No. FDA–2008–N–0424]
RIN 0910–AF82
Postmarketing Safety Reporting for
Combination Products
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Final rule.
The Food and Drug
Administration (FDA or Agency) is
issuing regulations to set forth
postmarketing safety reporting
requirements for combination products.
Specifically, this final rule describes the
postmarketing safety reporting
requirements that apply when two or
more different types of regulated
medical products (drugs, devices, and/
or biological products, which are
referred to as ‘‘constituent parts’’ of a
combination product) comprise a
combination product and the
combination product or its constituent
parts have received FDA marketing
authorization. The rule is intended to
promote and protect the public health
by setting forth the requirements for
postmarketing safety reporting for these
combination products, and is part of
FDA’s ongoing effort to ensure the
consistency and appropriateness of the
regulatory requirements for combination
products.
DATES: Effective date: This rule is
effective on January 19, 2017.
Compliance dates: Some provisions of
the rule have a compliance date that is
the same as the effective date of this
rule, and other provisions of the rule
have a later compliance date as
discussed in section III.I, Effective Date
and Compliance Dates.
FOR FURTHER INFORMATION CONTACT: John
Barlow Weiner, Associate Director for
Policy, Office of Combination Products,
Food and Drug Administration, 10903
New Hampshire Ave., Bldg. 32, Rm.
5129, Silver Spring, MD 20933, 301–
796–8930, john.weiner@fda.hhs.gov.
SUPPLEMENTARY INFORMATION:
SUMMARY:
Table of Contents
Executive Summary
I. Background
A. Rationale for Rulemaking
B. The Proposed Rule
II. Overview of the Final Rule
A. Section 4.100—What is the scope of this
subpart?
B. Section 4.101—How does FDA define
key terms and phrases in this subpart?
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C. Section 4.102—What reports must you
submit to FDA for your combination
product or constituent part?
D. Section 4.103—What information must
you share with other constituent part
applicants for the combination product?
E. Section 4.104—How and where must
you submit postmarketing safety reports
for your combination product or
constituent part?
F. Section 4.105—What are the
postmarketing safety reporting
recordkeeping requirements for your
combination product or constituent part?
III. Comments on the Proposed Rule
A. Section 4.100—What is the scope of this
subpart?
B. Section 4.101—How does FDA define
key terms and phrases in this subpart?
C. Section 4.102—What reports must you
submit to FDA for your combination
product or constituent part?
D. Section 4.103—What information must
you share with other constituent part
applicants for the combination product?
E. Section 4.104—How and where must
you submit postmarketing safety reports
for your combination product or
constituent part?
F. Section 4.105—What are the
postmarketing safety reporting
recordkeeping requirements for your
combination product or constituent part?
G. Alternate Approaches
H. Guidance and Agency Internal
Coordination and Training
I. Effective Date and Compliance Dates
J. Miscellaneous
IV. Legal Authority
V. Analysis of Environmental Impact
VI. Paperwork Reduction Act of 1995
VII. Federalism
VIII. Economic Analysis of Impacts
A. Introduction
B. Summary of Costs and Benefits
IX. References
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Executive Summary
Purpose of the Final Rule
The Agency has not previously issued
regulations on postmarketing safety
reporting specifically for combination
products, which are products comprised
of: (1) A drug and a device; (2) a device
and a biological product; (3) a biological
product and a drug; or (4) a drug, a
device, and a biological product.
Instead, the Agency has applied
provisions to combination products
from the postmarketing safety reporting
regulations applicable to the constituent
parts (i.e., reporting requirements
specific to drugs, devices, and biological
products). These regulations for drugs,
devices, and biological products share
many similarities; however, each set of
regulations has certain unique reporting
requirements, standards, and
timeframes based in part on the
characteristics of the type of product.
These variations among the regulations
and lack of clarity on how to apply
these requirements to combination
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products can result in inconsistent and
incomplete postmarketing safety
reporting for combination products and
their constituent parts.
The purpose of this final rule is to
ensure consistent, complete
postmarketing safety reporting
requirements for combination products
that have received FDA marketing
authorization, while avoiding
duplicative reporting. The term
‘‘postmarketing safety’’ is used in this
rule because this rule concerns certain
postmarket events, including
manufacturing events, device
malfunctions, and events causing injury
to users, and the reporting requirements
that relate to product and patient safety
arising from these events. The final rule
supports the underlying purpose of
postmarketing safety reporting for all
medical products, namely to protect the
public health by ensuring continued
safety and effectiveness of the product
once it is placed on the market.
Summary of the Major Provisions of the
Final Rule
This final rule requires that a
‘‘combination product applicant’’ (an
entity holding the application(s), as the
term ‘‘application’’ is defined in 21 CFR
4.101 of this rule, for a combination
product) and a ‘‘constituent part
applicant’’ (an entity holding the
application to market a drug, device, or
biological product as a constituent part
of a combination product the
constituent parts of which are marketed
under applications held by different
applicants) comply with postmarketing
safety reporting requirements applicable
to the product based on the application
type (e.g., new drug application,
premarket approval application,
biologics license application) under
which the combination product or
constituent part received marketing
authorization. In addition to these
application-type based reporting
requirements, the final rule requires
combination product applicants to
submit additional specified reports
based on the constituent parts included
in the combination product (e.g.,
malfunction reports if the combination
product includes a device, field alert
reports if it includes a drug, and
biological product deviation reports if it
includes a biological product). The final
rule requires constituent part applicants
to share certain postmarketing safety
information they receive with one
another. The rule also specifies how
combination product and constituent
part applicants must submit
postmarketing safety reporting
information to the Agency and what
records they must maintain.
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The Agency received 16 sets of
comments on the proposed rule.
Commenters largely sought clarification
of the scope of the proposed rule, how
reporting requirements, timelines, and
reporting standards from the underlying
regulations for drugs, devices, and
biological products apply, and how and
what information must be shared
between constituent part applicants.
Several commenters, while supporting
rulemaking to address postmarketing
safety reporting for combination
products, recommended alternative
approaches. After considering the
comments received on the proposed
rule, the Agency has made clarifications
and other revisions in the final rule to,
among other things: (1) Clarify that the
final rule applies only to combination
product and constituent part applicants;
(2) clarify when a single report may
suffice to comply with more than one
reporting requirement; and (3)
incorporate biological product deviation
reporting and device correction and
removal reporting requirements
applicable to combination product
applicants.
Legal Authority
The legal framework underlying this
final rule is twofold. The first aspect is
that drugs, devices, and biological
products do not lose their discrete
regulatory identities when they become
constituent parts of a combination
product. In general, the postmarketing
safety reporting requirements specific to
each constituent part of a combination
product also apply to the combination
product itself. Although the constituent
parts of combination products retain
their regulatory identities, the Federal
Food, Drug, and Cosmetic Act (FD&C
Act) also recognizes combination
products as a category of products that
are distinct from products that are solely
drugs, devices, or biological products.
FDA has the authority to develop
regulations to ensure sufficient and
appropriate ongoing assessment of the
risks associated with combination
products.
The second aspect of the framework is
founded on the postmarketing safety
reporting regulatory scheme associated
with the application under which the
combination product received
marketing authorization, plus any
applicable requirements associated with
the additional six specified report types
listed in this rule. Although similar in
effect to the first aspect of the
framework, this aspect is based on the
legal authority FDA used to issue each
of its existing regulations for
postmarketing safety reporting for drugs,
devices, and biological products.
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Costs and Benefits
The final rule will generate one-time
administrative costs from reading and
understanding the rule, assessing
current compliance, modifying existing
standards of practice, changing storage
and reporting software, and training
personnel on the requirements under
this rule. Firms that do not currently
comply with the reporting requirements
identified in 21 CFR 4.102(c) of this rule
will also incur annual reporting costs
from the submission of field alert
reports, 5-day reports, 15-day reports,
malfunction reports, correction or
removal reports, and biological product
deviation reports. The annualized total
costs of the rule are between $1.36 and
$2.68 million at a 7 percent discount
rate and between $1.35 and $2.65
million at a 3 percent discount rate.
The final rule will benefit firms
through reduced uncertainty about the
reporting requirements for their specific
combination product and through
decreased duplicative reporting. The
final rule will also benefit public health
by helping to ensure that important
safety information is submitted and
directed to the appropriate Agency
components, so that the Agency may
receive and review this information in
a timely manner.
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I. Background
As set forth in 21 CFR part 3, a
combination product is a product
comprised of a drug and a device; a
device and a biological product; a
biological product and a drug; or a drug,
a device, and a biological product. A
combination product includes the
following: (1) A product comprised of
two or more regulated components, i.e.,
drug/device, biologic/device, drug/
biologic, or drug/device/biologic, that
are physically, chemically, or otherwise
combined or mixed and produced as a
single entity (‘‘single-entity’’
combination products); (2) two or more
separate products packaged together in
a single package or as a unit and
comprised of drug and device products,
device and biological products, or
biological and drug products (‘‘copackaged’’ combination products); (3) a
drug, device, or biological product
packaged separately that, according to
its investigational plan or proposed
labeling, is intended for use only with
an approved individually specified
drug, device, or biological product
where both are required to achieve the
intended use, indication, or effect and
where upon approval of the proposed
product the labeling of the approved
product would need to be changed; e.g.,
to reflect a change in intended use,
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dosage form, strength, route of
administration, or significant change in
dose (a type of ‘‘cross-labeled’’
combination product); or (4) any
investigational drug, device, or
biological product packaged separately
that, according to its proposed labeling,
is for use only with another individually
specified investigational drug, device, or
biological product where both are
required to achieve the intended use,
indication, or effect (another type of
‘‘cross-labeled’’ combination product).1
For purposes of this rulemaking and
consistent with 21 CFR 4.2, the drugs,
devices, and/or biological products
included in a combination product are
referred to as ‘‘constituent parts’’ of the
combination product.
A. Rationale for Rulemaking
In the proposed rule (74 FR 50744 at
50745 to 50751, October 1, 2009), FDA
described its rationale and goals for the
proposed rulemaking. To date, the
Agency has not issued regulations on
postmarketing safety reporting (PMSR)
specifically for combination products.
Instead, the Agency has applied
provisions to combination products
from the PMSR regulations applicable to
the constituent parts of the combination
product (i.e., the reporting requirements
specific to drugs, devices, and biological
products). These requirements for drugs,
devices, and biological products share
many similarities and have a common
underlying purpose, namely to protect
the public health by ensuring a
product’s continued safety and
effectiveness once placed on the market.
However, each set of regulations has
certain reporting standards and
timeframes with unique requirements
based in part on the characteristics of
the type of product.
FDA held a public hearing on
November 25, 2002, entitled ‘‘FDA
Regulation of Combination Products’’
(Ref. 1) and a public workshop on July
8, 2003, entitled ‘‘Innovative Systems
for Delivery of Drugs and Biologics:
Scientific, Clinical and Regulatory
Challenges’’ (Ref. 2) to discuss
postmarketing safety reporting, among
other issues pertaining to combination
products. In developing the proposed
rule, we carefully considered the
comments offered by stakeholders,
including written comments submitted
to the docket that we opened to
facilitate further input on combination
product issues. Two common themes
1 As discussed in response to Comment 1, this
rule addresses only PMSR requirements for
combination products that have received marketing
authorization. It does not describe reporting
requirements for investigational combination
products.
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from the comments were the need for
consistency in postmarketing safety
reporting requirements for combination
products and the importance of
avoiding unnecessarily duplicative
reporting. Some stakeholders suggested
that FDA consider developing an
entirely new postmarketing safety
reporting scheme for combination
products, but we concluded that
because of the broad similarities in the
postmarketing safety reporting
regulations for drugs, devices, and
biological products and industry’s
familiarity and experience with current
postmarketing safety reporting
requirements, the most appropriate
approach would be to rely on existing
rules and to explain how to comply
with them.
FDA is issuing this final rule to
ensure appropriate and consistent
PMSR requirements for combination
products that have received FDA
marketing authorization by describing
how combination product applicants
and constituent part applicants must
comply with the PMSR regulations for
drugs, devices, and biological products,
and also to eliminate unnecessary PMSR
requirements for such combination
products.
B. The Proposed Rule
Entities subject to the proposed rule
included those subject to PMSR duties
under 21 CFR parts 314, 600, 606, and
803, except for user facilities and
distributors as defined under part 803.
Those four sets of regulations
expressly address PMSR for: (1) Drugs
(part 314); (2) biological products (parts
600 and 606); and (3) devices (part 803).
These sets of regulations have certain
similarities. For example, the PMSR
regulations for biological products,
devices, and drugs each requires reports
of death and other serious adverse
events; each provides for expedited
reporting for certain types of safety
events; and each provides for followup
and non-expedited reports. However,
there are also certain significant
differences in these sets of regulations
designed, in part, to address the distinct
characteristics and potential safety
issues related to a particular type of
product (i.e., drug, device, and
biological product).
Accordingly, we proposed to require
that entities comply with the PMSR
requirements associated with the
combination product’s application type
(e.g., requirements under part 314 for a
combination product approved under a
new drug application (NDA), or under
part 803 for a combination product
approved under a premarket approval
application (PMA)) and also comply
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with certain specified additional
reporting provisions that are not
associated with that application type
but are associated with a constituent
part(s) of the combination product. The
additional reporting requirements
specified in the proposed rule were: (1)
5-Day reports under § 803.53; (2) device
malfunction reports under § 803.50; (3)
15-day ‘‘alert reports’’ for drugs and
biological products under §§ 314.80 and
600.80; (4) field alert reports for drugs
under § 314.81; and (5) expedited blood
fatality reports under § 606.170. The
Agency identified these five types of
reports as addressing particular safety
issues related to the type of article
(drug, biological product, and device)
and, therefore, appropriate to apply to
combination products that include that
type of article regardless of the
application type for the combination
product, to ensure consistent and
appropriate PMSR for the combination
product.
The proposed rule also addressed
circumstances in which the constituent
parts of a combination product are
marketed under separate applications,
or are legally marketed by different
reporters without separate applications.
For constituent parts marketed under
separate applications, we proposed that
the reporter must comply with the
reporting requirements associated with
that application type. In addition, we
proposed for constituent parts marketed
under separate applications held by
different entities or legally marketed by
separate entities without an approved or
cleared marketing application, that each
of these entities would have a duty to
share within 5 calendar days
information it receives about the event,
either with the other entity or entities
for the combination product or with
FDA. We further proposed that entities
that receive postmarketing safety
information from another such entity,
would have to investigate the event and
comply with applicable reporting
obligations under the rule.
We proposed that reporters submit
their reports and maintain records for
them in accordance with the
requirements of the underlying
regulations from which the reporting
duty arises (parts 314, 600, 606, or 803).
Following publication of the proposed
rule, FDA participated in a workshop on
January 21, 2010, entitled
‘‘Understanding Implications of the
Postmarket Safety for Combination
Products Proposed Rule,’’ sponsored by
the Advanced Medical Technology
Association, the Combination Products
Coalition, and the Regulatory Affairs
Professional Society. At this workshop,
the Agency provided a summary of the
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proposed rule, and stakeholders then
worked in groups to identify issues on
which to comment.
II. Overview of the Final Rule
The final rule follows the approach
presented in the proposed rule, with
certain simplifications, clarifications,
additions, and other changes, generally
made in light of comments received, as
described in sections II.A through II.F.
The goal of the final rule remains the
same as for the proposed rule, to ensure
consistent and appropriate
postmarketing safety reporting for
combination products, while enabling
this reporting to be as efficient as
possible. Accordingly, this rulemaking
seeks to apply those postmarketing
safety reporting requirements to
combination products necessary to
ensure their safety and effectiveness,
clarify how to comply with reporting
requirements applicable to combination
products, and enable efficiencies
including submission of a single report
if multiple reporting duties apply to an
event. Following is a section-by-section
overview of the final rule, and then a
summary chart of the requirements
presented in the rule.
A. Section 4.100—What is the scope of
this subpart?
The scope of the rule remains largely
the same as proposed. As in the
proposed rule, § 4.100(a) reflects that
the rule describes PMSR requirements
for combination products. We have
revised § 4.100(a) to clarify that the rule
only applies to ‘‘combination product
applicants’’ and ‘‘constituent part
applicants’’ (as defined in § 4.101); this
rule does not apply to any other entities.
We have also revised § 4.100(b) to
clarify that the rule does not apply to
investigational combination products or
to combination products that have not
received marketing authorization. We
have eliminated proposed § 4.102 as
that section was largely duplicative of
proposed § 4.100.
B. Section 4.101—How does FDA define
key terms and phrases in this subpart?
We eliminated unnecessary
definitions, including terms not used in
this final rule. We also simplified
certain definitions, using crossreferences to definitions provided in
other provisions of Title 21 of the CFR
without restating those definitions. We
made these changes for clarity and to
minimize the need for amendments to
this rule if a change is made in the
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future to the terminology or definitions
in the cross-referenced provisions.2
The final rule newly includes
definitions for ‘‘biological product
deviation report’’ (BPDR) (by reference
to §§ 600.14 and 606.171), and
‘‘correction or removal report’’ (by
reference to 21 CFR 806.10), because the
final rule incorporates these reporting
requirements as discussed in relation to
§ 4.102(c) in section III.C. Similarly, we
added a definition for ‘‘Product
Development Protocol’’ (PDP) (by
reference to section 515(f) of the FD&C
Act (21 U.S.C. 360e(f))) and de novo
classification request (by reference to
section 513(f)(2) of the FD&C Act (21
U.S.C. 360c(f)(2))) because the final rule
addresses these types of applications.
In addition, we included definitions
for ‘‘applicant’’, ‘‘combination product
applicant’’, ‘‘constituent part
applicant’’, and ‘‘device application’’ to
help clarify which entities are subject to
which duties under this rule.
Specifically, we clarified that an
applicant is the person holding an
application under which a combination
product or constituent part has received
marketing authorization, and that there
is a combination product applicant if
there is one applicant that either holds
the application for a combination
product or, holds the applications for
each constituent part if the constituent
parts of the combination product are
marketed under separate applications
(as could be the case for the constituent
parts of a cross-labeled combination
product). We also clarified that a
constituent part applicant is the
applicant for a constituent part of a
combination product the constituent
parts of which marketed under
applications held by different
applicants. We defined the term ‘‘device
application’’ to mean a PMA, PDP,
humanitarian device exemption (HDE),
de novo classification request (request
for classification under section 513(f)(2)
of the FD&C Act), or premarket
notification (510(k)) submission, so that
we could simplify and clarify the rule
by using this term to refer to all such
submission types, rather than listing
them each, where appropriate in the
rule.
2 We understand that provisions cross-referenced
in this rule may be revised in the future, and we
want to ensure that it is clear that those provisions
as revised continue apply to combination products
under this rule, without having to amend this rule
each time to provide such clarity. However, if the
Agency determines that a future revision to a crossreferenced provision is not appropriate to apply to
combination products under this rule, or its
application to combination products is unclear
under this rule, we intend to amend this rule or
otherwise clarify.
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C. Section 4.102—What reports must
you submit to FDA for your combination
product or constituent part?
The requirements listed in § 4.102
include those that were in § 4.103 of the
proposed rule with certain adjustments
and additional requirements to address,
in part, comments received on the
proposed rule.
Specifically, we have eliminated the
requirement to comply with blood
fatality reporting requirements as
described in § 606.170 for combination
products that received marketing
authorization under an application
other than a biologics license
application (BLA). We have also revised
the requirement for all combination
product applicants to submit 15-day
reports as described in §§ 314.80 and
600.80, to permit these reports to be
submitted within 30 days rather than 15
days for combination products that
received marketing authorization under
a device application.
In addition, we have incorporated
BPDR and correction and removal
reporting requirements for combination
product applicants to ensure that the
issues addressed by these reporting
requirements, for biological products
and devices, respectively, are also
addressed for combination products that
include these types of constituent parts.
We have also made other adjustments in
§ 4.102 for clarity.
Following is a description of § 4.102
as finalized, including explanations of
changes from § 4.103 of the proposed
rule.
1. Section 4.102(a)
A new § 4.102(a) clarifies that all
applicants must comply with the
applicable PMSR requirements with
respect to their product. A constituent
part applicant must comply with
applicable requirements for the
constituent part it is marketing, and a
combination product applicant must
comply with applicable requirements
for the combination product it is
marketing.
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2. Section 4.102(b)
As in § 4.103(a) of the proposed rule,
§ 4.102(b) lists the PMSR requirements
that apply based on the application type
for the product. Section 4.102(b)
clarifies that combination product
applicants and constituent part
applicants must comply with the
requirements identified under
§ 4.102(b)(1) through (3) that are
applicable based on their product’s
application type. In addition, § 4.102
clarifies that this rule does not require
a combination product applicant to
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submit multiple reports relating to the
same event when one report could be
used to satisfy both § 4.102(b) and (c).
Specifically, if the applicant has
submitted one type of report and that
report: Includes all of the information
that would also be required in another
type of report; is required to be
submitted in the same manner under
this rule as that other report; and is
submitted within applicable deadlines,
the submission of the single report will
be considered to satisfy both reporting
obligations.
The requirements of § 4.102(b) are as
follows:
a. Section 4.102(b)(1). Combination
product applicants and constituent part
applicants must comply with the PMSR
requirements under parts 803 and 806 if
their product received marketing
authorization under a device
application.
b. Section 4.102(b)(2). Combination
product applicants and constituent part
applicants must comply with the PMSR
requirements under part 314 if their
product received marketing
authorization under an NDA or
abbreviated new drug application
(ANDA).
c. Section 4.102(b)(3). Combination
product applicants and constituent part
applicants must comply with the PMSR
requirements under parts 600 and 606 if
their product received marketing
authorization under a BLA.
3. Section 4.102(c)
This provision applies only to
combination product applicants, not to
constituent part applicants. It states
which requirements combination
product applicants must meet in
addition to those associated with the
product’s application type, to ensure
consistent and appropriate PMSR for
combination products. Like § 4.102(b), it
also states how applicants can submit a
single report to comply with multiple
reporting requirements.
As indicated previously, § 4.102(c)
does not require blood fatality reporting
for combination products that received
marketing authorization under a device
application, NDA, or ANDA, and
permits combination product applicants
for combination products that received
marketing authorization under a device
application to submit 15-day reports
within 30 days rather than 15 days.
We removed the requirement under
this rule to make blood fatality reports
for combination products that received
marketing authorization under a device
application, NDA, or ANDA, because
facilities at which such events occur are
currently required to make blood fatality
reports irrespective of the type of
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92607
application under which the product
received marketing authorization.
Because these facilities must make such
reports, we concluded that it would be
unnecessary for a combination product
applicant (who is not also the operator
of the facility) to report the same
information as well.
In light of comments received (as
discussed more fully in response to
Comments 7, 8, 10), we modified the 15day report requirement to permit these
reports to be made within 30 days for
combination products that received
marketing authorization under a device
application. We made this change based
on several factors, including the
following. We determined that the
Agency would continue to be able to
respond in a timely manner to these
reports if submitted within 30 days
rather than 15 days for such
combination products. Further, we
determined that permitting such reports
to be made within 30 days would enable
better alignment of reporting for deviceled combination products because this
timing would be consistent with the
timing for submission of medical device
reports. This alignment could be
expected to improve the efficiency,
clarity and completeness of reports for
this class of combination products and
to eliminate unnecessary complexity
and potential for confusion.3
Section 4.102(c) includes additional
reporting requirements not in the
proposed rule to address specific safety
concerns related to medical devices and
biological products. Combination
product applicants must submit
correction and removal reports as
described in § 806.10 and comply with
related recordkeeping requirements as
described in § 806.20 for combination
products that include a device
constituent part; and combination
product applicants must submit BPDRs
3 We considered whether to make a
corresponding change for combination products
that received marketing authorization under an
NDA or ANDA (drug-led combination products) or
under a BLA (biologic-led combination products),
to require that malfunction reports be submitted
within 15 days to align with the deadline for 15day reports, in the interest of simplifying and
clarifying requirements for such combination
product applicants as well. However, we
determined that the nature of events triggering, and
the information required for, malfunction reports
might make it difficult to provide a meaningful
report within 15 days in some cases. As indicated
in the final rule, if an event triggers both a 15-day
report and a malfunction report for such a
combination product, the combination product
applicant can opt to comply with both reporting
requirements in a single report submitted within 15
days. If the applicant determines that additional
time is needed to investigate the device
malfunction, the applicant can submit a followup
report to the initial 15-day report with the
additional information.
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Federal Register / Vol. 81, No. 244 / Tuesday, December 20, 2016 / Rules and Regulations
as described in §§ 600.14 and 606.171
for combination products that include a
biological product constituent part.
Having considered the unique safety
issues that these additional
requirements address in light of
comments received, we concluded that
this rule should ensure that these
additional requirements are addressed
by all combination product applicants
for combination products that include
constituent parts to which these
requirements relate.
In many cases, correction and removal
reporting requirements arise in relation
to manufacturers’ recalls in response to
adverse events that may also trigger
medical device reporting requirements
under part 803. In such cases,
submission of a medical device report
(MDR) that contains all the information
required by part 806 will suffice to
comply with both sets of reporting
requirements. Under § 806.10(f), no
separate correction or removal report is
required to be submitted if a report of
the correction or removal has been
submitted under part 803. However, in
some instances, a correction or removal
will not be associated with a reportable
adverse event, or the action that a
manufacturer takes in response will not
trigger a 5-day reporting requirement,
but the action must still be reported as
described in part 806 to ensure, in part,
appropriate coordination between the
manufacturer and the Agency. In such
cases, the correction or removal report
currently should be submitted to the
appropriate Agency field office.
Further, some corrections and
removals may not trigger reporting
requirements under part 803 or part 806,
but may trigger recordkeeping
requirements under part 806, and these
recordkeeping requirements must be
satisfied for combination products that
include a device constituent part.
Accordingly, we have incorporated the
correction and removal reporting and
recordkeeping requirements under
§ 4.102(c) to ensure that combination
product applicants comply with these
requirements.
With respect to BPDRs, as discussed
more fully in response to Comment 13
in section III, we concluded that these
reports are akin to field alert reports for
drugs, and that it was important for
BPDRs to be submitted for combination
products that include biological product
constituent parts to enable the applicant
and the Agency to address the deviation
in a timely, appropriate manner.
Further, we note that in most instances,
a biological product deviation that is
reportable under §§ 600.14 and 606.171
is not associated with an adverse
experience. Accordingly, we have
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included in § 4.102(c) BDPR
requirements for all combination
product applicants whose combination
products contain a biological product
constituent part.
The requirements applicable to
combination products applicants under
§ 4.102(c) are now specified as follows:
a. Section 4.102(c)(1). Combination
product applicants whose combination
products received marketing
authorization under a BLA, NDA, or
ANDA and include a device constituent
part must also submit: (i) 5-Day reports
as described in §§ 803.3 and 803.53 and
supplemental or followup reports as
described in § 803.56; (ii) Malfunction
reports as described in § 803.50 and
supplemental or followup reports as
described in § 803.56; and (iii)
Correction or removal reports as
described in § 806.10 and comply with
recordkeeping requirements as
described in § 806.20.
b. Section 4.102(c)(2). Combination
product applicants whose combination
products received marketing
authorization under a BLA or a device
application and include a drug
constituent part must also submit: (i)
Field alert reports as described in
§ 314.81 and (ii) 15-day reports and
followup reports as described in
§ 314.80, within 30 calendar days
instead of 15 calendar days if the
combination product received
marketing authorization under a device
application.
c. Section 4.102(c)(3). Combination
product applicants whose combination
products received marketing
authorization under an NDA, ANDA, or
device application, and include a
biological product constituent part must
also submit: (i) BPDRs as described in
§§ 600.14 and 606.171 and (ii) 15-day
reports and followup reports as
described in § 600.80, within 30
calendar days instead of 15 calendar
days if the combination product
received marketing authorization under
a device application.
4. Section 4.102(d)
This provision replaces and has been
revised as compared to proposed
§ 4.103(c) to: (a) Clarify that it applies
only to combination product applicants;
(b) identify the content expected in
periodic safety reports for combination
products that received marketing
authorization under an NDA, ANDA, or
BLA; and (c) provide that additional
reporting is required for combination
products that received marketing
authorization under a device
application only upon notification by
the Agency if the Agency determines
additional or clarifying safety
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information is required to protect the
public health. Section 4.102(d) has two
paragraphs stating the following
requirements:
a. Section 4.102(d)(1). Combination
product applicants for combination
products that received marketing
authorization under an NDA, ANDA, or
BLA must include in their periodic
safety reports, in addition to
information required under § 314.80 or
600.80, respectively, a summary and
analysis of reports that the applicant
submitted in accordance with
§ 4.102(c)(1)(i) and/or (ii) (5-day and
malfunction reporting requirements).
b. Section 4.102(d)(2). Combination
product applicants for combination
products that received marketing
authorization under a device
application do not have to make
periodic reports under this rule but
must submit additional reports
regarding postmarketing safety events in
accordance with written requests by the
Agency that will be made only if the
Agency determines that protection of
the public health requires additional or
clarifying safety information. Any such
written request will specify the safety
information to include in such reports
and the reason or purpose for the
request.
D. Section 4.103—What information
must you share with other constituent
part applicants for the combination
product?
As discussed more fully in response
to Comment 18 in section III, the final
rule makes clear that the duties to share
information within 5 calendar days
under § 4.103 (replacing § 4.104 in the
proposed rule) apply only to constituent
part applicants. In addition, we clarified
and simplified these requirements.
Constituent part applicants must share
only information they receive regarding
events that involve a death or serious
injury within the meaning of § 803.3 or
an adverse experience within the
meaning of § 314.80(a) or § 600.80(a),
and must share this information only
with each other; we have eliminated the
alternative of sharing the information
with FDA as unnecessary and
inefficient. Also, we have removed as
unnecessary the content of proposed
§ 4.104(b) regarding how to respond to
information received from another
constituent part applicant. Section
4.102(b) states which PMSR
requirements apply to constituent part
applicants, and those PMSR
requirements prescribe under what
circumstances an entity subject to them
must submit a report regarding
information that the entity receives.
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We have added a new § 4.103(b)
addressing recordkeeping for this
information sharing duty. This
provision has been added to provide
constituent part applicants appropriate
clarity and certainty regarding what
records to keep and what
documentation the Agency will
consider adequate to demonstrate
compliance with the informationsharing requirement.
E. Section 4.104—How and where must
you submit postmarketing safety reports
for your combination product or
constituent part?
This section has been revised as
compared to proposed § 4.105, to clarify
where and how to submit postmarketing
safety reports for constituent part
applicants (§ 4.104(a)) and combination
product applicants (§ 4.104(b)).
1. Section 4.104(a)
Constituent part applicants must
make all reports in accordance with the
existing regulations applicable to that
type of product (for example, making
reports in accordance with the
requirements of part 314 if the
constituent part is a drug). Like an
applicant for a non-combination
product, a constituent part applicant
holds an application for a single type of
article (drug, device, or biological
product) and is required to make
postmarketing safety reports to FDA
only for events concerning its product.
Accordingly, these reports are most
appropriately submitted to the same
Agency components in the same manner
as they would be by any applicant
holding an application for the same type
of product.
2. Section 4.104(b)
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Combination product applicants are
required to submit postmarketing safety
reports concerning the combination
product, including each of that
combination product’s constituent parts.
The nature of the events and the
appropriate Agency component to
contact regarding them can vary
however. In light of these
considerations, § 4.104(b) draws a
distinction between individual case
study reports (ICSRs) (Ref. 3) for safety
events experienced by individual users
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of combination products 4 and other
safety reports.
Section 4.104(b) requires that
combination product applicants must
submit all ICSRs (15-day reports,
malfunction reports, serious injury or
death reports, and 5-day reports)
applicable to the combination product
in the manner specified in the PMSR
regulations associated with the
application type for the combination
product. See §§ 4.104(b)(1) and (2).
This approach to submission of ICSRs
by combination product applicants best
assures the clarity, completeness, and
efficiency of such reporting. Having all
ICSRs submitted in the same manner to
the Center with the lead for the
application enables multiple reporting
requirements for an event to be satisfied
by submitting a single report and
ensures that all such reports relating to
the same event will be captured in a
single series (see also response to
Comment 24).
In addition, under § 4.104(b), all
BPDRs, field alert reports, and
correction and removal reports must be
submitted as described in the
regulations from which these reporting
requirements arise. The Agency
currently receives these reports through
differing mechanisms and Agency
components based on such factors as
logistical considerations and expertise
to take the lead in assessing and
addressing the issues raised in the
report. For example, field alert reports
for drugs currently must be submitted to
FDA district offices as described in part
314, and BPDRs currently must be
submitted to the Center for Biologics
Evaluation and Research (CBER) or the
Center for Drug Evaluation and Research
(CDER) as appropriate based on which
of these two Centers would ordinarily
have jurisdiction over the type of
biological product included in the
combination product, as described in
parts 600 and 606. These existing
reporting systems are designed to assure
4 ‘‘Individual case study report’’ or ICSR is the
internationally recognized term of art referring to
reports of an adverse event, including a
malfunction, experienced by an individual user of
the product. This term is used to refer to such
reports in international standards, and FDA
implementing materials, regarding proper methods
for submitting ICSRs to regulatory bodies for drugs,
biologics, and devices.
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92609
timely, effective resolution of the
matters raised in these reports.
As discussed in response to Comment
28 and in section III.A., the Agency
anticipates issuing a guidance to
provide recommendations on how
applicants may adopt more streamlined,
effective approaches to making reports
under this rule.
F. Section 4.105—What are the
postmarketing safety reporting
recordkeeping requirements for your
combination product or constituent
part?
As discussed more fully in section III,
response to Comment 26, we revised
this section (replacing § 4.106 in the
proposed rule) to clarify and simplify
the recordkeeping requirements
associated with PMSR obligations for
combination product applicants and
constituent part applicants. Section
4.105(a) describes the recordkeeping
requirements for constituent part
applicants and § 4.105(b) describes the
requirements for combination product
applicants, as follows:
1. Section 4.105(a)
Constituent part applicants must
comply with the recordkeeping
requirements prescribed in the
underlying PMSR regulations identified
in § 4.102(b) as applicable to the
product based on its application type. In
addition, they must retain the records
required in § 4.103 (information sharing)
for the longest retention period (if more
than one period applies) required for
records under the PMSR regulations
applicable to their constituent part (as
explained in response to Comment 26).
2. Section 4.105(b)
Combination product applicants must
maintain records relating to their
postmarketing safety reports for
whichever is the longest required
record-keeping period under the PMSR
requirements applicable to the
combination product applicant under
§ 4.102. Because both parts 314 and 600
currently require recordkeeping for 10
years, at this time the recordkeeping
period for combination product
applicant PMSR records would be at
least 10 years.
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Federal Register / Vol. 81, No. 244 / Tuesday, December 20, 2016 / Rules and Regulations
TABLE 1—REQUIREMENTS FOR BOTH CONSTITUENT PART APPLICANTS AND COMBINATION PRODUCT APPLICANTS 1
[See § 4.102(b) of this rule]
Application Types
Source of PMSR requirements
ANDA/NDA
Part
Part
Part
Part
Part
314
600
606
803
806
.......................................................................................................................................
.......................................................................................................................................
.......................................................................................................................................
.......................................................................................................................................
.......................................................................................................................................
BLA
Device
application
X
........................
........................
........................
........................
........................
X
X
........................
........................
........................
........................
........................
X
X
1 In addition to the requirements in table 1, constituent part applicants must share certain adverse event information with other constituent part
applicant(s) for the combination product. (See § 4.103 of this rule).
TABLE 2—ADDITIONAL REQUIREMENTS ONLY FOR COMBINATION PRODUCT APPLICANTS 1
[See § 4.102(c) of this rule]
Application Type
Combination product includes
Reporting requirement
ANDA/NDA
Drug ........................................
Biologic ...................................
Device .....................................
§ 314.81, Field Alert Reports ..................................................
§ 314.80, 15-Day Reports (initial and followup) .....................
§§ 600.14 and 606.171, Biological Product Deviation Reports.
§ 600.80, 15-day Reports (initial and followup) ......................
§§ 803.53 and 803.56, 5-Day Reports (initial and supplemental or followup).
§§ 803.50 and 803.56, Malfunction Reports (initial and supplemental or followup).
Part 806, Correction or Removal Reports and Records ........
BLA
Device
application
See table 1
........................
X
X
X
See table 1
X
X
X
X
X
........................
X
X
See table 1
X
X
........................
X
X
........................
1 In
addition to the requirements in table 2, the rule addresses other reporting requirements for combination product applicants as follows: (1)
Combination products that received marketing authorization under an NDA, ANDA, or BLA: Include a summary and analysis of malfunction
(§§ 803.50 and 803.56) and 5-day (§§ 803.53 and 803.56) reports submitted during the report interval in the periodic safety reports (see
§ 4.102(d)(1)) and (2) combination products that received marketing authorization under a device application: Submit additional reports when notified by the Agency because FDA has determined the information is required to protect the public health (see § 4.102(d)(2)).
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III. Comments on the Proposed Rule
We received comments from 15
entities and one individual on the
proposed rule. Commenters included
trade organizations and manufacturers
of drugs, devices, biological products,
and combination products. Many
commenters sought clarification on
particular points or recommended
adjustments to specific aspects of the
proposed rule. Several commenters,
while supporting rulemaking to address
PMSR for combination products,
recommended alternative approaches as
discussed in Comment 27.
To make it easier to identify
comments and our responses, the word
‘‘Comment’’ appears before the
descriptions of the comments, and the
word ‘‘Response’’ appears before our
response. We have also numbered
comments to help distinguish among
them. The number assigned to each
comment is purely for organizational
purposes and does not signify relative
value or importance of comments or the
order in which they were received.
Certain comments are grouped together
under a single number because the
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subject matter of the comments was
similar.
A. Section 4.100—What is the scope of
this subpart?
(Comment 1) Some commenters
sought clarification of safety reporting
requirements for investigational
combination products through guidance
or expansion of the scope of the rule,
including for investigational
combination products that contain a
legally marketed article as a constituent
part. One commenter asked if the
Agency is planning to publish guidance
on this issue. One commenter asked that
the Agency clearly lay out the
responsibilities of the manufacturer of
an approved product in the
investigational setting.
(Response 1) Safety reporting for
investigational products is an important
issue for combination products, just as
it is for drugs, devices, and biological
products. However, this rule only
discusses the PMSR requirements for
combination products that have
received marketing authorization. As
stated in § 4.100(b), this rule does not
apply to investigational combination
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products. The safety reporting
requirements for investigational new
drugs are in 21 CFR 312.32, and the
safety reporting requirements for
investigational devices are in 21 CFR
812.150. The Agency intends to
continue developing guidance relating
to this topic for combination products.
If you have questions regarding how to
comply with the reporting requirements
for your investigational combination
product, please raise them with the
review division in CDER, CBER, or the
Center for Devices and Radiological
Health (CDRH) that is responsible for
reviewing your application, or with the
Office of Combination Products (OCP)
as needed.
(Comment 2) Some commenters
requested that the Agency clarify which
entities and products are subject to this
rule. Some commenters proposed
clarifying that this rule applies only to
application holders. Other commenters
sought clarification of the rule’s
applicability to devices marketed under
a 510(k) clearance and to nonapplicants, including contract
manufacturers. One commenter asked
for clarification of whether the rule
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would apply to component suppliers.
One commenter sought clarification of
which entities have reporting
requirements under this rule for
combination products composed of
constituent parts marketed under
separate applications. One commenter
proposed that the Agency prepare a
comprehensive list of products by class,
product code or other designations that
are subject to this rule.
(Response 2) As also discussed in
section II (discussions of §§ 4.100 and
4.101), in light of comments received,
we have amended this rule to clarify
which entities it addresses and what
PMSR requirements apply to them. We
have clarified that this rule applies only
to ‘‘combination product applicants’’
and ‘‘constituent part applicants,’’ as
those terms are defined in § 4.101. We
also have clarified the final rule to state
which requirements apply to
combination product applicants and
which apply to constituent part
applicants.
Under § 4.101 of this rule, the term
‘‘applicant’’ is defined to mean a person
holding an application (BLA, NDA,
ANDA, PMA, HDE, PDP, de novo
classification request or premarket
notification (510(k)) submission) under
which a combination product or
constituent part has received marketing
authorization (see also definitions for
‘‘application’’ and ‘‘device
application’’); ‘‘combination product’’ is
defined to mean a product meeting the
definition for this term under § 3.2(e);
and the term ‘‘constituent part’’ is
defined as in § 4.2 to mean a drug,
device, or biological product that is part
of a combination product. The term
‘‘combination product applicant’’ is
defined to mean an applicant holding
the application(s) for a combination
product (i.e., either holding the
application for the entire combination
product or the applications for each
constituent part—in some cases the
constituent parts of a combination
product are marketed under their own
marketing authorizations, as might be
the case for a cross-labeled combination
product for example), and ‘‘constituent
part applicant’’ is defined to mean an
applicant for a constituent part of a
combination product the constituent
parts of which are marketed under
applications held by different
applicants. In other words, if a single
entity holds the application(s) under
which a combination product is
marketed, that entity is the combination
product applicant; there are no
constituent part applicants for that
combination product. If instead, one
applicant receives marketing
authorization to market a constituent
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part of a combination product and
another applicant receives marketing
authorization to market another
constituent part of that combination
product, each of those entities is a
constituent part applicant for their
constituent part of that combination
product. Importers, component
manufacturers and suppliers, and any
other entities that do not meet the
definition of combination product
applicant or constituent part applicant,
are not subject to this rule.5
To illustrate how these definitions are
used to determine who is subject to this
rule, take the example of a prefilled
syringe that received marketing
authorization under an NDA or ANDA
held by entity A, which purchases the
syringe components for this product
from entity B, which manufactures the
syringe components. Entity A is the
only applicant for the combination
product, and, therefore, is the
combination product applicant and
must comply with the provisions of this
rule applicable to combination product
applicants. There are no constituent part
applicants for the combination product.
Entity B has no reporting duties under
this rule (nor does it have any under
part 803 or 806 for the syringe
components 6). (It bears noting that
entity A is responsible not only for
reporting but also for conducting any
necessary quality investigations for the
combination product as a whole and
may need to coordinate with entity B for
5 We note that all entities that are not subject to
this rule but that have reporting requirements under
other regulations must comply with those
requirements, including, as appropriate, with
respect to events relating to a combination product.
For example, although they are not applicants
under this rule, entities marketing unapproved
combination products must comply with all
applicable PMSR requirements, for instance under
21 CFR part 310, for their products. Similarly, all
entities subject to PMSR requirements under parts
314, 600, 606, 803, and 806 must comply with those
requirements including for events relating to a
combination product.
We note that non-applicants subject to reporting
requirements under 314.80 and 600.80 may provide
their reports to the applicant rather than the
Agency. Similarly, non-applicants subject to
reporting requirements under part 803 may request
a reporting exemption from CDRH under § 803.19.
Accordingly, entities that are not combination
product applicants or constituent part applicants, as
those terms are defined under this rule (importers,
for example), who have reporting duties under part
803 in relation to a combination product may
request a reporting exemption, subject to § 803.19.
We intend to provide further information on these
topics for combination products in guidance.
6 Parts 803 and 806 apply to, among others,
device ‘‘manufacturers,’’ and under §§ 803.3 and
806.2, device ‘‘manufacturers’’ include entities that
manufacture components which are devices that are
ready to be used and are intended to be
commercially distributed and intended to be used
as is, or are processed by a licensed practitioner or
other qualified person to meet the needs of a
particular patient.
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such investigations and to address
safety issues relating to the device
constituent part for the combination
product.) If entity B were also to
manufacture and separately market
under a 510(k) complete, finished,
empty syringes, not as part of a
combination product, entity B would be
subject to reporting requirements under
parts 803 and 806, but would not be
subject to this rule for this device. Entity
A would remain the sole applicant for
the combination product, i.e., the
combination product applicant.
Similarly, if entity B manufactured
syringes to supply to entity A for
inclusion in kits for which entity A
received marketing authorization under
an NDA or ANDA, entity A would still
be the sole applicant for the
combination product, i.e., the
combination product applicant, since it
holds the NDA or ANDA under which
the kits received marketing
authorization, and, therefore, only entity
A would be subject to this rule.
To take another example, if entity C
receives marketing authorization under
a PMA or 510(k) to market an imaging
device as a constituent part of a crosslabeled combination product, and entity
D receives marketing authorization
under an NDA or ANDA to market a
contrast agent drug as a constituent part
of that same cross-labeled combination
product, then entities C and D are both
constituent part applicants, and both are
subject to the provisions of this rule
applicable to constituent part
applicants. There is no combination
product applicant for this product.
Regarding one commenter’s request
for the Agency to develop a
comprehensive list of products subject
to this rule, we note that combination
products are marketed for diverse
medical purposes and include a wide
variety of constituent parts, making a
comprehensive listing impractical to
compile. The definition of combination
product is provided at § 3.2(e), and
additional information regarding
product classification is available on the
Web page for OCP. In addition,
regulated entities may seek feedback
from OCP regarding the classification of
their products, including by submitting
a request for designation (RFD) in
accordance with part 3 to obtain a
formal decision from the Agency of
whether their product is a drug, device,
biological product, or combination
product. Guidance for how to prepare
an RFD is available on OCP’s Web page
(https://www.fda.gov/
CombinationProducts/default.htm).
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B. Section 4.101—How does FDA define
key terms and phrases in this subpart?
(Comment 3) One commenter thought
we should clarify what we mean by
‘‘combination product,’’ and in
particular whether we mean to include
products that combine only two or more
of the same type of article, such as a
drug and a drug.
(Response 3) This rule defines
combination products as those products
falling within the scope of § 3.2(e).
Under § 3.2(e), a combination product
must include: A drug and either a
device or biological product; a device
and either a drug or biological product;
a biological product and either a drug or
device; or a drug, device, and a
biological product. A product that
includes only multiple drugs, multiple
devices, or multiple biological products
is not a combination product as defined
in § 3.2(e).
(Comment 4) Some commenters
proposed that we clarify what products
fall within the scope of ‘‘cross-labeled’’
combination products as described in
§ 3.2(e)(3), with some noting that the
preamble to the part 3 regulation (56 FR
58754, November 21, 1991) states that
most drugs, devices, and biological
products intended for concomitant use
are not combination products. One
commenter stated that the Agency must
issue ‘‘guidance on cross-labeled
combination products’’ before the
effective date of this rule ‘‘for
meaningful implementation of this
rule.’’
(Response 4) While we disagree that
we must issue guidance on cross-labeled
combination products prior to the
effective date for this final rule, we
agree that clarifying when separately
distributed articles constitute a
combination product would be helpful.
This issue may be relevant not only for
purposes of postmarketing safety
reporting, but to all aspects of the
regulation of such combination
products. Whether a drug, device, and/
or biological product together constitute
a cross-labeled combination product
generally would be determined during
the premarket review process, but
sponsors may, for example, wish to
clarify the matter earlier in product
development. If sponsors have questions
regarding whether a drug, device, and/
or biological product that are intended
to be separately distributed, but
intended to be used with one another
constitute a cross-labeled combination
product, we encourage them to contact
OCP. If sponsors wish to obtain a formal
classification determination from the
Agency, they may submit an RFD to
OCP (see Comment 2).
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FDA intends to publish a guidance
that provides recommendations on how
to comply with the requirements under
this rule for combination products,
including cross-labeled combination
products.
(Comment 5) Two commenters noted
that the definition of ‘‘constituent part’’
incorrectly cited § 3.1(e), a non-existent
provision, rather than § 3.2(e), which is
the citation for the ‘‘combination
product’’ definition.
(Response 5) We have corrected this
error by revising the definition to cite to
§ 4.2 as ‘‘constituent part’’ is defined in
that section.
(Comment 6) Some commenters
expressed concerns regarding the
definition of ‘‘constituent part’’ for this
rule and asked how constituent parts of
combination products compare to
components of devices. Some
commenters specifically raised concerns
that the definition of constituent part
would result in certain entities, which
are currently not subject to reporting
requirements, becoming subject to
PMSR requirements under this rule.
Some commenters proposed revising the
definition for ‘‘constituent part’’ and
adding a definition for ‘‘component’’ in
this rule to clarify that components of
drugs, devices, and biological products
are not constituent parts.
(Response 6) The purpose of the term
‘‘constituent part’’ is to identify the
drug, device, and/or biological products
that are part of a combination product.
We believe the questions and concerns
raised in these comments are fully
addressed by the revisions we have
made to the rule. As discussed in
sections II.A and B (discussions of
§§ 4.100 and 4.101) and in response to
Comment 2, we have included
definitions of ‘‘combination product
applicant’’ and ‘‘constituent part
applicant,’’ and clarified that this rule
applies only to these two categories of
entities.
The term ‘‘component’’ is defined
elsewhere in Title 21 for drugs and
devices (see 21 CFR parts 210, 212, and
820). Because the term ‘‘component’’ is
not used in this rule, we determined it
is not necessary to define the term as
part of this rulemaking.
C. Section 4.102—What reports must
you submit to FDA for your combination
product or constituent part?
(Comment 7) Several commenters
requested that the Agency clarify under
what circumstances this rule might
require the submission of multiple
reports in relation to the same event. In
this regard, some commenters sought
clarification of what reports
‘‘supersede’’ others and under what
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circumstances the submission of one
type of report applicable to a
combination product would obviate the
need to submit a second type of report
for the same event. Another commenter
sought clarification of reporting
requirements for combination products
comprised of constituent parts marketed
under separate constituent part
applications.
(Response 7) Under this rule,
combination product applicants and
constituent part applicants must submit
reports as required by the PMSR
requirements applicable to that
applicant under § 4.102. Constituent
part applicants are subject to only one
set of PMSR requirements under this
rule (in addition to the duty to share
information with other constituent part
applicants for the combination product,
in accordance with § 4.103 as discussed
in section II.D). Specifically, constituent
part applicants must comply only with
the PMSR requirements listed under
§ 4.102(b) based on the application type
for their constituent part (e.g., parts 803
and 806 PMSR requirements if the
constituent part received marketing
authorization under a device
application). Combination product
applicants also must comply with the
PMSR requirements applicable to their
combination product under § 4.102(b)
based on the application type for their
combination product. In addition,
combination product applicants must
comply with the PMSR requirements
identified in § 4.102(c) as applicable
based on the types of constituent parts
(drug, device, and/or biological product)
that the combination product includes.
We have clarified when a single
report may suffice to comply with more
than one reporting requirement for
combination product applicants.7 If a
combination product applicant submits
a report that satisfies multiple
applicable reporting requirements,
including all submission deadlines, for
reports required to be submitted in the
same manner, then the applicant does
not need to submit any additional
reports to satisfy those reporting
requirements. As an example, a
combination product applicant who
holds an NDA for a drug-device
combination product must submit both
7 Constituent part applicants are subject only to
the PMSR regulations applicable to their type of
constituent part (drug, device, or biological
product) (in addition to the duty to share
information with other constituent part applicants
for the combination product, in accordance with
§ 4.103 of this rule, as discussed elsewhere in this
preamble). Accordingly, any circumstances under
which they may be able to comply with more than
one reporting requirement through a single report
are identified in those PMSR regulations (see, e.g.,
§ 806.10(f)).
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15-day reports as described in § 314.80
and malfunction reports as described in
§ 803.50, for an event that triggers both
duties. That applicant could satisfy both
requirements by submitting a single
report within 15 days that includes all
of the information that would be
required in both types of reports for the
event.
(Comment 8) Some commenters
sought clarification of the standards for
submitting a report under this rule. One
commenter requested clarification of
whether limitations established under
§§ 314.80 and 600.80 for 15-day
reporting requirements with respect to
postmarketing studies apply to
combination products under this rule.
Other commenters sought clarification
of the standard for when to submit an
expedited report under § 314.80 or
§ 600.80, which state that events must
be reported if ‘‘associated with’’ the use
of the product, ‘‘whether or not
considered’’ drug or biologic related.
Other commenters requested
clarification of how to interpret aspects
of the device reporting standards in part
803, such as the meaning of ‘‘reasonably
suggests’’ in relation to whether the
event is reportable, the meaning of
‘‘unreasonable risk of substantial harm
to the public health’’ in relation to 5-day
reports, and the meaning of ‘‘caused or
contributed,’’ a term defined under
§ 803.3.
(Response 8) The standards in this
rule for when to submit a report are
those established in the underlying
PMSR regulations listed in § 4.102(b)
and (c), including any exceptions
provided in those underlying
regulations. The standards and
definitions for the underlying PMSR
requirements, such as the definition of
‘‘caused or contributed’’ in § 803.3,
remain applicable for combination
products and their constituent parts.
For instance, if you are a combination
product applicant for a drug-device
combination product, in deciding
whether you must submit a 15-day
report for a serious, unlabeled adverse
event, you must determine if the event
was ‘‘associated with’’ the use of the
combination product, and if so, you
must submit the report regardless of
whether you believe the combination
product caused or contributed to the
event. Similarly, in deciding whether
you must submit a malfunction report,
you must assess, among other things,
whether the information ‘‘reasonably
suggests’’ that the product
malfunctioned. If the information does
not ‘‘reasonably suggest’’ that a
malfunction occurred, then a
malfunction report would not be
required.
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If you are a combination product
applicant and your combination product
received marketing authorization under
a device application, in deciding
whether you must submit a serious
injury or death report, you must
consider whether the information
‘‘reasonably suggests’’ that the
combination product may have caused
or contributed to the death or serious
injury in which case you must submit
a report even if the event does not
trigger submittal of a 15-day report.
In some cases, a report required under
§ 4.102(c) for a combination product
applicant may address a constituent
part; in others, it may address the
combination product as a whole. For
example, correction or removal that
triggers a correction or removal report
may involve the entire combination
product. Bacteriological contamination
or a significant change or deterioration
to the drug constituent part that triggers
a field alert report may relate to an
aspect of manufacturing for the drug
alone, or may also relate to an aspect of
the manufacture of the combination
product as a whole that is affecting the
drug constituent part. A manufacturing
deviation or other event that may affect
the safety, purity, or potency of a
biological product constituent part and
trigger a BPDR may involve the
biological product alone, or the
combination product as a whole. In all
cases, the report should fully present
the issues, including with respect to
each constituent part and the
combination product as a whole, as
applicable, to ensure an appropriate
response to the event.
(Comment 9) One commenter sought
clarification of what adverse events
would be considered ‘‘unexpected,’’ for
purposes of §§ 314.80 and 600.80 with
regard to combination products.
Another commenter asked whether a
serious adverse event that is expected
under the drug labeling for a
combination product and that does not
involve a device malfunction should be
reported in an expedited manner. In
relation to these issues, other
commenters also raised whether this
rule will ‘‘require labeling specific to
the combination product,’’ and whether
a distinct understanding of
‘‘expectedness’’ would need to be
developed with respect to combination
products marketed under a device
application as opposed to an NDA or
BLA due to differences in product
review and labeling.
(Response 9) Under this rule, a
serious adverse event could trigger a
requirement for submission of a 15-day
report as described in § 314.80 or
§ 600.80 by a combination product
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92613
applicant or a drug or biological product
constituent part applicant if the event is
not listed in the current FDA-approved
labeling for the combination product.
While this rule does not establish any
labeling requirements, we recognize that
there is a question of what labeling is
relevant to a determination of whether
an adverse event is unexpected for
purposes of 15-day reports described in
§§ 314.80 and 600.80, if the constituent
parts of the combination product have
their own labeling.
Our goal is to ensure timely, complete
reporting without creating unnecessary
redundancy of reporting. Combination
product labeling must meet the labeling
requirements for each constituent part,
including all required information
regarding the risks associated with the
use of the combination product. The
term ‘‘expectedness’’ for purposes of
§ 314.80 or § 600.80 should be
interpreted in the same manner
regardless of the type of application(s)
under which the combination product
received marketing authorization.
Accordingly, in determining whether
an adverse experience is unexpected, it
is appropriate to consider all of the
FDA-approved labeling for the
combination product. For example, if
the constituent parts of a cross-labeled
combination product have their own
labeling, and the event is addressed in
the labeling for either constituent part,
the event is expected for the
combination product.
(Comment 10) One commenter
proposed that the requirements for
submitting postmarketing 15-day reports
and MDRs be consolidated for
combination products, arguing that this
would eliminate duplicative reporting
as much as possible and improve
efficiency. Other commenters proposed
applying only the reporting
requirements associated with the
application type if it is unclear which
constituent part or parts contributed to
the event.
(Response 10) We agree with the goal
of consolidating requirements and
avoiding unnecessary redundancy in
reporting for combination products. To
this end, we have not required
submission of serious injury and death
reports under part 803 for combination
products that received marketing
authorization under a BLA, NDA, or
ANDA and that include a device
constituent part, based on the premise
that the requirements of §§ 600.80 and
314.80, respectively, ensure timely
reporting of such events for such
combination products. In addition, as
discussed in section II.C, discussion of
§ 4.102(c), we have revised the
requirement for combination product
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applicants to submit 15-day reports to
permit these reports to be submitted
within 30 days for combination
products that received marketing
authorization under a device
application, so that the timing for these
reports corresponds to the timing for
related MDRs for such combination
products, specifically serious injury,
death, and malfunction reports. Further,
we have clarified that applicants need
not submit multiple types of reports for
the same event if they are able to satisfy
the requirements of each in a single
report.
As discussed in the preamble to the
proposed rule, there are certain
significant differences in the PMSR
regulations for drugs, devices, and
biological products, that address
distinct characteristics and potential
safety issues associated with the
particular type of product, and the
public health benefit of these unique
provisions would be lost if the
combination product were subject solely
to the reporting requirements associated
with the application type (74 FR 50744
at 50746). For example, malfunction
reports can address distinct issues that
are not captured by other reporting
requirements and need to be submitted
for all combination products that
include a device constituent part.
Specifically, malfunction reports ensure
that the Agency receives notice of
malfunctions of combination products
and device constituent parts if that
product or a similar one marketed by
that applicant would be likely to cause
or contribute to a death or serious injury
if the malfunction were to recur.
(Comment 11) One commenter argued
that the proposed rule included
provisions that could result in
inconsistent reporting requirements.
This commenter stated that an applicant
for a drug-device combination product
marketed under a single application
would have a duty to address adverse
events caused by the device under 15day reporting requirements while, if a
drug-device combination product were
marketed under separate applications
for the drug and device, the 15-day
reporting requirements would extend
only to the adverse events caused by the
drug.
(Response 11) This final rule clarifies
these reporting requirements, which we
do not consider to be inconsistent. As
the commenter indicates, 15-day reports
are required for combination product
applicants and for drug and biological
product constituent part applicants. The
scope of these reporting requirements
depends on the type of product (drug,
biological product, device, combination
product) that is marketed by the
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applicant. A combination product
applicant must report unexpected
serious adverse events associated with
its product, i.e., the combination
product. A drug or biological product
constituent part applicant must report
unexpected serious adverse events
associated with its product, i.e., the drug
or biological product, and also must
share information it receives with the
other constituent part applicant(s) for
that combination product in accordance
with § 4.103. The other constituent part
applicant(s) then must comply with any
applicable PMSR requirements for its
product with respect to that event,
including preparation and submission
of reports as appropriate.
(Comment 12) One commenter sought
clarification of when the clock starts for
a 5-day report (as described in §§ 803.3
and 803.53).
(Response 12) This rule does not
affect or change when the clock starts
for reporting requirements. The clock
starts for a 5-day report for a
combination product as it would for a
device. As required under § 803.53(a),
the clock begins when you become
aware that a reportable event
necessitates remedial action to prevent
an unreasonable risk of substantial harm
to the public health. Or, as required
under § 803.53(b), the clock begins
when you receive a written request from
FDA for the submission of a 5-day
report. Additional information on the
timing requirements associated with 5day reports is in the CDRH guidance
document ‘‘Medical Device Reporting
for Manufacturers’’ available at https://
www.fda.gov/downloads/
MedicalDevices/
DeviceRegulationandGuidance/
GuidanceDocuments/ucm359566.pdf.
(Comment 13) One commenter
proposed BPDRs as an additional type
of required report to include among the
specified required reports listed in
proposed § 4.103(b), arguing that BPDRs
serve a purpose similar to field alert
reports and, therefore, would be
appropriate to include as well.
(Response 13) We agree with this
comment. To ensure the completeness
of postmarketing safety reports for
combination products that include a
biological product constituent part,
including combination products that
received marketing authorization under
an NDA, ANDA, or device application,
we are explicitly including BPDRs
under § 4.102(c). Similar to field alert
reports for drugs, BPDRs address events
associated with manufacturing that
represent a deviation from current good
manufacturing practice, applicable
regulations, applicable standards or
established specifications, or represent
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an unexpected or unforeseeable event
that may affect the safety, purity, or
potency of the product. Therefore, we
are adding BPDRs to the list of types of
reports under § 4.102(c) that a
combination product applicant must
submit if the combination product
includes a biological product
constituent part.
(Comment 14) One commenter sought
clarification of the application of part
806 device correction and removal
reporting requirements within the
proposed PMSR system for combination
products. The commenter also sought
confirmation that part 806 reporting
requirements can be met for
combination products through part 803
reporting, as they can for devices that
are not constituent parts of combination
products.
(Response 14) To address this
comment, we have expressly
incorporated under § 4.102(c) correction
and removal reporting described in
§ 806.10 and associated recordkeeping
requirements described in § 806.20. We
have made this change to provide
clarity, promote efficiency, and ensure
the completeness of postmarketing
safety reports for combination products
that include a device constituent part.
Part 806 implements, in part, section
519(g) of the FD&C Act (21 U.S.C. 360i),
which was enacted due to Congressional
concern that device manufacturers were
carrying out product corrections or
removals without notifying FDA or not
doing so in a timely fashion (H.R. Rep.
No. 101–808, at 29 (1990); S. Rep. No.
101–513, at 23 (1990)). Congress
explained that industry’s failure to
report corrections and removals,
particularly those undertaken to reduce
risks associated with the use of a device,
‘‘denies the agency the opportunity to
fulfill its public health responsibilities
by evaluating device-related problems
and the adequacy of corrective actions’’
(S. Rep. No. 101–513, at 23), and ‘‘has
seriously interfered with the FDA’s
ability to take prompt action against
potentially dangerous devices’’ (H. R.
Rep. No. 101–808, at 29).
FDA believes that correction and
removal reporting and recordkeeping for
combination products containing a
device constituent part is necessary to
protect the public health as envisioned
by Congress, by ensuring that the
Agency has current and complete
information regarding those actions
taken by applicants to reduce risks to
health caused by their products. Reports
of such actions will improve the
Agency’s ability to evaluate problems
and to take prompt action against
potentially dangerous combination
products, regardless of the type of
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application under which the
combination product received
marketing authorization.
As for all of the PMSR requirements
incorporated into this rule by reference,
the standards for how to report under
§ 806.10 and for recordkeeping under
§ 806.20 are not affected by this rule,
including not having to submit an 806
report if the correction or removal is
addressed in a report submitted under
part 803 (§ 806.10(f)). To enable efficient
reporting and avoid unnecessarily
redundant reports, this rule provides
that part 803 reporting requirements can
be satisfied through submission of drug
or biological product reports, as
explained in response to comment 7.
Similarly, part 806 reporting
requirements also can be satisfied
through submission of an MDR or 15day report, so long as the report
includes all of the information needed
to comply with the requirements of part
806 and is filed within 10 working days
of initiating the correction or removal,
as described in § 806.10.
In circumstances in which a 15-day
report or MDR is not triggered but
reporting under part 806 is required,
reports of corrections or removals
should be sent to the FDA in the same
manner as for other such reports unless
otherwise specified by the Agency.
Currently, reports required under part
806 are submitted to the district office
for the district in which the reporting
facility is located, on the basis that the
district office can best monitor the
firm’s removal or corrections activities
in a timely fashion. Combination
product applicants for combination
products with a device constituent part
who initiate a correction or removal that
is not required to be reported to FDA
under 806.10, must maintain a record of
the correction or removal as described
in § 806.20.
(Comment 15) Some commenters
sought clarification of the applicability
of section 227 of the Food and Drug
Administration Amendments Act of
2007 (FDAAA) concerning the reporting
of malfunctions to FDA, including the
use of summary reporting, for Class I
devices and for Class II devices that are
not permanently implantable, life
supporting, or life sustaining. Some
commentators sought clarification of
how the status of ‘‘life-supporting’’ or
‘‘life-sustaining’’ would apply to
combination products, and whether the
intended use of the combination
product would determine the status of
the device constituent part. One
commenter sought clarification of how
such a class-based approach would be
applied to combination products
approved under NDA or BLA, for which
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no express classification may have been
made for the device constituent part.
(Response 15) FDA issued a notice in
the Federal Register (76 FR 12743,
March 8, 2011) clarifying that Class I
and II device manufacturers and
importers must continue to submit
malfunction reports in accordance with
part 803, pending future action by FDA
to address the malfunction reporting
requirements for Class I and Class II
devices addressed in FDAAA.
Accordingly, combination product
applicants for combination products
that include a device constituent part,
and constituent part applicants for
device constituent parts, must comply
with part 803 requirements as described
in this rule pending such further
Agency action. At this time, therefore,
malfunction reporting duties are the
same for all combination products that
include a device constituent part,
regardless of whether the combination
product or device constituent part
would be considered life-supporting or
life-sustaining, and regardless of
whether the device constituent part
would be considered a Class I, II, or III
device.
(Comment 16) One commenter sought
clarification of whether the periodic
reports addressed in proposed § 4.103(c)
should be considered ‘‘expedited’’
reports for purposes of this rule.
(Response 16) FDA has retitled this
provision to ‘‘Other reporting
requirements for combination product
applicants’’ for clarity because it
addresses periodic safety reports for
drug and biologic-led combination
products and also addresses under what
circumstances additional reports for
device-led combination products are
required upon Agency request. This rule
does not modify the timing of periodic
safety reports. The purpose of § 4.102(d)
is to clarify which combination product
applicants must submit periodic safety
reports and other safety reports, and
what information they must include in
such reports. The intent of § 4.102(d), in
conjunction with § 4.102(a), (b), and (c)
is to ensure that the Agency obtains
complete, timely postmarketing safety
information regarding combination
products while avoiding unnecessary
burden to applicants.
(Comment 17) One commenter
proposed the reorganization of proposed
4.103(b) to parallel the structure of
§ 4.103(a).
(Response 17) We have not adopted
this approach because § 4.102(c) is
intended to address a different issue
than § 4.102(b). Section 4.102(b) (like
proposed § 4.103(a)) addresses
requirements that constituent part
applicants and combination product
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92615
applicants must satisfy for their
marketed products depending upon the
type of application under which it
received marketing authorization, and
structuring the provision based on the
type of application that the applicant
holds provides a clear, efficient way to
identify such requirements. In contrast,
the purpose of § 4.102(c) (like proposed
§ 4.103(b)) is to state which additional
requirements a combination product
applicant must satisfy based on the
types of constituent parts included in
the combination product, which are
most clearly and efficiently listed by
constituent part type (drug, biological
product, or device).
D. Section 4.103—What information
must you share with other constituent
part applicants for the combination
product?
(Comment 18) Some commenters
requested clarification of whether
proposed § 4.104(a) applied if there
were a single application holder for the
combination product but the
combination product included an article
approved under another application
held by another entity for independent
marketing not related to the
combination product. Other
commenters asked for clarification of
which applicants for constituent parts of
combination products could be subject
to proposed § 4.104(a) and (b) if the
combination product were not approved
under a single application. Some
commenters proposed an approach
under which, if there is a single
application for the combination
product, the holder of that application
would report to FDA in accordance with
proposed § 4.103, and FDA would then
decide whether any other application
holders for articles included in the
combination product should be notified
and whether to seek additional reports
from them.
(Response 18) As reflected in the
preamble to the proposed rule (see 74
FR 50744 at 50749 to 50750), proposed
§ 4.104(a) was intended to apply if the
constituent parts of the combination
product were being marketed by
different entities, including when the
constituent parts received marketing
authorization under separate
applications held by different
applicants. As explained in the response
to Comment 2, we have revised the rule
to apply to combination product
applicants and constituent part
applicants, in part to clarify which
entities are subject to it. Accordingly,
we have revised this provision to clarify
that it applies solely to constituent part
applicants. Section 4.103 of this final
rule is not intended to establish any
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duties for entities who hold a marketing
authorization to market a product not as
part of a combination product, even if
the same article is part of a combination
product for which another entity
received marketing authorization (e.g.,
the second entity might have combined
the article with another product to make
a co-packaged or single-entity
combination product, or market the
article for a new use with another
product as a cross-labeled combination
product).
For example, if entity A holds an
approved application to market a crosslabeled combination product that
includes a device and a drug, and entity
B holds an approved application to
market the drug for a different use (i.e.,
not as part of the combination product),
then entity A would be the combination
product applicant for that combination
product, and neither entity A nor B
would be a constituent part applicant
for that combination product. Therefore,
§ 4.103 would not require either entity
A or B to share information with the
other.
In contrast, if entity A holds an
approved PMA to market a device as
one constituent part of a cross-labeled
combination product (i.e., entity A is the
constituent part applicant for the device
constituent part of the combination
product), and entity B holds an
approved NDA to market a drug as the
other constituent part of that
combination product (i.e., entity B is the
constituent part applicant for the drug
constituent part of the combination
product), then § 4.103 would require
both entities A and B to share
postmarketing safety information with
each other for the specified types of
events relating to that combination
product.
Regarding the issue of which entities
would be subject to proposed § 4.104(b),
we have decided to eliminate the
provision as unnecessary. Constituent
part applicants that receive information
from another constituent part applicant
must comply with the same duties
under § 4.102(b) with respect to this
information as they must with respect to
any information they receive regarding
a postmarketing safety issue for their
product, including the duty to submit
postmarketing safety reports as required.
(Comment 19) Some commenters
argued that the 5-day deadline under
proposed § 4.104(a) for information
sharing was too short. Some
commenters recommended instead tying
the timeframe to the nature of the event.
Some argued that it is not warranted or
useful to share information
automatically within a 5-day timeframe
because it leaves entities little time to
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evaluate the information before sharing
it and could result in unnecessary
redundancy of reporting.
(Response 19) We disagree with these
comments. The provision calls for
sharing information that the constituent
part applicant receives regarding an
adverse event relating to the
combination product, and does not
require the applicant to prepare a report
in accordance with any of the regulatory
reporting requirements established
under parts 314, 600, 606, 803, or 806.
The duty under § 4.103 does not require
a constituent part applicant to analyze,
investigate, or organize the information
or take any other actions beyond
forwarding the information as received
to the other constituent part applicant(s)
for the combination product and
maintaining certain records.
Accordingly, we believe 5 calendar days
is a reasonable deadline that does not
impose undue burden, while enabling
timely reporting by the constituent part
applicant(s) with whom the information
is shared.
Such an expedited sharing of
information is important to ensure
timely, complete reporting with regard
to adverse events that may have been
brought to the attention of only one
constituent part applicant for a
combination product. Enabling each
constituent part applicant to review in
a timely manner the information related
to the combination product enhances
efficiency and thoroughness of reporting
because each constituent part applicant
evaluates the information with respect
to its own constituent part and with
regard to the reporting requirements
applicable to that type of constituent
part.
(Comment 20) Some commenters
stated that the information sharing
requirements of proposed § 4.104
should be eliminated; some said these
requirements are unnecessary
depending on the nature of the event,
and likely to produce unnecessary,
duplicative reporting. Some
commenters proposed that the
information sharing requirements under
proposed § 4.104 should apply only if
the event is potentially reportable and
that proposed § 4.104(a) should not
apply if the applicant determines that
the event does not concern the other
constituent part(s) of the combination
product. Other commenters proposed
that if it can be determined that the
event is attributable to only one
constituent part, then reporting
requirements should apply only to the
application holder for that constituent
part. Some commenters proposed that
the rule be revised such that, in the
event that constituent parts of a
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combination product are being marketed
under separate applications, and it is
unclear which constituent part(s)
contributed to the event, the rule would
require compliance only with the
reporting requirements for the
constituent part providing the primary
mode of action for the combination
product.8 One commenter argued that
requiring separate reporting to the
centers responsible for each constituent
part would be overly burdensome. Some
commenters sought clarification for
when an applicant should report to
another applicant or to FDA under
proposed § 4.104(a). Some commenters
requested clarification regarding when
FDA would notify application holder(s)
for the constituent part(s) of a
combination product if FDA receives
information from another application
holder for that combination product.
One commenter proposed eliminating
the option of sharing the information
with FDA arguing that including FDA in
the process would slow
communications and not provide any
benefit. One commenter proposed that
subsequent information received
relating to the same event be shared
only with FDA or with another
applicant in the same time-frame as a
report would be required to be
submitted to FDA.
(Response 20) The best way for the
Agency to receive complete reports for
combination products is to ensure that
each constituent part applicant has an
opportunity to review the information
received regarding the specified types of
events (serious injuries, deaths, and
other adverse events) for the
combination product. Accordingly, we
disagree with the proposals to narrow or
eliminate the information sharing
requirement. We do not agree this
requirement will produce unnecessarily
duplicative reporting. The trigger for a
constituent part applicant to submit a
report to the Agency is not the mere act
of receiving information but a
determination that the event is
reportable under the PMSR
requirements applicable to that
applicant. The Agency may receive
multiple reports regarding the same
event because of § 4.103 (formerly
§ 4.104 in the proposed rule), but this
approach ensures that the Agency has
the benefit of each constituent part
applicant’s expertise and familiarity
regarding its own constituent part in
8 The term ‘‘primary mode of action’’ is defined
at § 3.2 as the mode of action that provides the most
important therapeutic action of the combination
product, i.e., that is expected to make the greatest
contribution to the overall therapeutic effects of the
combination product.
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assessing the information with respect
to that constituent part.
Regarding the issue of sharing
information with FDA as opposed to
other constituent part applicants, we
have eliminated the option of sharing
information with FDA as unnecessary
and inefficient. We agree that timely,
complete reporting by each constituent
part applicant is best assured by having
constituent part applicants share
information they receive directly with
one another.
We also agree that when any
constituent part applicant shares
information relating to an event with the
other constituent part applicant(s), the
information sharing duty ends with
respect to that event. When information
is shared, each constituent part
applicant must investigate and report to
the Agency, under the applicable PMSR
requirements, regarding the event as
they would for any event for which they
receive information. The constituent
part applicants may find it helpful to
share with one another additional and
followup information they receive or
develop relating to the event, but this is
not required by this rule.
(Comment 21) Some commenters
stated that disclosure of event
information to another company might
involve disclosure of confidential and
proprietary information. One
commenter proposed that the
information be shared with the other
applicant if practicable and if it does not
raise concerns regarding confidentiality
or proprietary information.
(Response 21) Section 4.103 does not
require the sharing of trade secret or
confidential commercial information
with other constituent part applicants.
Further, we have revised this section to
specify that the information required to
be shared concern events that involve a
death or serious injury as described in
§ 803.3, or an adverse experience as
described in § 314.80(a) or § 600.80(a).
Such information is likely to be received
from health care facilities, consumers,
and other sources, and therefore,
unlikely to contain trade secret or
confidential commercial information.
In regard to the Federal Health
Insurance Portability and
Accountability Act (HIPAA), we note
that HIPAA only applies to covered
entities (i.e., health plans, covered
health care providers, and health care
clearinghouses), and their business
associates, and thus is unlikely to apply
to constituent part applicants.
Moreover, even if a constituent part
applicant is a HIPAA covered entity or
business associate, we note that HIPAA
permits the disclosure of protected
health information (PHI), such as
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information that identifies a particular
patient, if such disclosures are required
by other law. The HIPAA Privacy Rule
permits the use or disclosure of PHI ‘‘to
the extent that such use or disclosure is
required by law and the use or
disclosure complies with and is limited
to the relevant requirements of such
law.’’ 45 CFR 164.512(a)(1). Because
§ 4.103 of this rule requires constituent
part applicants to share with each other
information received, including PHI,
regarding certain events related to the
combination product, a constituent part
applicant, which is subject to HIPAA,
would be permitted by HIPAA to make
such disclosure.
(Comment 22) Some commenters
sought clarification of the start time for
meeting the reporting deadlines under
proposed § 4.104(b). One commenter
recommended that it be the day the
information is received from the
reporter subject to proposed § 4.104(a).
(Response 22) While the content of
proposed § 4.104(b) has been removed
from the rule as unnecessary, we note
that the start time for determining the
submission deadline for postmarketing
safety reports is the same as for
information received from any other
source, and depends on the type of
report and the regulation from which
the requirement for the report arises.
(Comment 23) Some commenters
asked for the Agency to provide
examples of the application of proposed
§ 4.104, including guidance on what
information to include in reports under
this provision. One commenter asked
for guidance on the process for
submitting information to the Agency
under proposed § 4.104.
(Response 23) Section 4.103 requires
the transmittal of information received.
Constituent part applicants do not need
to modify, organize, or evaluate the
information; they must only forward the
information to the other constituent part
applicant(s) for the combination
product. As discussed in Comment 18,
we have eliminated the alternative of
sharing the information with FDA as
unnecessary and inefficient. We intend
to provide additional information
regarding how to comply with § 4.103 in
guidance.
E. Section 4.104—How and where must
you submit postmarketing safety reports
for your combination product or
constituent part?
(Comment 24) Some commenters
sought clarification of how to comply
with the submission requirements for
different types of reports for a
combination product. One commenter
proposed that the rule expressly state
reports be submitted to ‘‘the approved
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92617
application’’ if there is only one reporter
for the combination product. Another
proposed that reports for a combination
product marketed under one application
be submitted to the lead center, while
those for combination products
marketed under separate applications
for different constituent parts in some,
but not all, cases be submitted to the
center responsible for the particular
constituent part’s application. One
commenter noted a need to clarify how
to make electronic submissions for
combination products.
(Response 24) As discussed in section
II.E (discussion of § 4.104), we have
revised the rule to clarify how and
where to submit postmarketing safety
reports for constituent part applicants
and for combination product applicants.
In keeping with comments received,
§ 4.104(a) requires constituent part
applicants to submit their reports in the
same manner as any other applicant
holding the same kind of application for
a product (e.g., a constituent part
applicant holding a PMA for a device
constituent part must submit reports in
the same manner as any other applicant
holding a PMA for a device).
We have drawn a distinction between
types of postmarketing safety reports
submitted by combination product
applicants. With regard to ICSRs, we
have adopted an approach consistent
with comments suggesting that reports
be submitted to the lead center and in
accordance with the procedures
associated with the application type for
the combination product. Specifically,
§ 4.104(b) requires such combination
product applicants to submit 5-day, 15day, and malfunction reports, if
required for their product, in the
manner described in the PMSR
regulations associated with the
application type for the combination
product. For example, if the
combination product received
marketing authorization under an NDA,
then 5-day, 15-day, and malfunction
reports, and all followup reports, would
be submitted how and where described
in part 314 for 15-day reports and
followup reports to them. This approach
promotes efficiency and ensures that all
such reports relating to the same event
are pooled together, and that multiple
ICSR reporting requirements for the
same event can be satisfied through a
single submission (so long as that
submission meets the content and
deadlines for each reporting
requirement).
At the same time, it is appropriate for
specific components of the Agency to
have the lead for addressing certain
distinct types of reports, in light of such
factors as the issues raised in the
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reports, logistical considerations for
Agency response, and efficient
engagement of appropriate Agency
expertise. Specifically, correction or
removal reports, field alert reports, and
BPDRs are currently directed to specific
Agency offices to ensure efficient,
effective assessment and response.
Accordingly, under § 4.104(b), all
combination product applicants must
direct field alert reports and BPDRs to
the same Agency components that
currently receive them, in accordance
with the underlying regulations for
these reports. For example, if the
combination product includes a
biological product, BPDRs must be
submitted to the appropriate component
within CDER or CBER in accordance
with parts 600 and 606, based upon
which of these two Centers would
ordinarily have jurisdiction over the
biological product included in the
combination product. Part 806 does not
specify where to submit correction or
removal reports. Accordingly, neither
does this rule, but applicants currently
should submit them to the appropriate
FDA district office, unless the
information is included in an ICSR for
the event, as explained in response to
Comment 14. See Recalls, Corrections
and Removals (Devices) (https://
www.fda.gov/medicaldevices/
deviceregulationandguidance/
postmarketrequirements/
recallscorrectionsandremovals/
default.htm).
The Agency intends to provide
guidance concerning procedural and
technical details of complying with
these requirements, including how to
comply with the Centers’ electronic
reporting requirements. We seek to take
best advantage of information
technology and other resources to
maximize the benefit of PMSR while
minimizing the burden.
(Comment 25) Several commenters
sought guidance regarding the content,
format, and completeness of applicable
forms, and appropriate terminology to
use with respect to different types of
events and constituent parts for
combination products.
(Response 25) Applicants should
provide relevant information in as
complete and clear a manner as
possible, consistent with the parameters
of the FDA form. Also, we intend to
update relevant FDA forms, if
appropriate, including the instructions
for how to complete them, and to
develop guidance that provides
recommendations for meeting PMSR
requirements under this rule.
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F. Section 4.105—What are the
postmarketing safety reporting
recordkeeping requirements for your
combination product or constituent
part?
(Comment 26) A commenter proposed
that the same recordkeeping
requirements apply to all types of
reports for a combination product.
(Response 26) We agree with the
premise that a uniform set of record
retention requirements apply to all
reports relating to a combination
product marketed by a single applicant,
i.e., a combination product applicant.
Accordingly, § 4.105(b) requires that
combination product applicants
maintain all PMSR records for the
longest time period established in the
recordkeeping requirements associated
with the PMSR provisions applicable to
the combination product. This approach
allows combination product applicants
to maintain all these PMSR records for
a product under one record retention
scheme, and helps ensure that
potentially interrelated records all
remain available for events and for the
combination product. Because both
parts 314 and 600 currently require
record retention for 10 years, at this
time, all combination product
applicants must retain PMSR records for
at least 10 years.
In contrast to combination product
applicants, constituent part applicants
market only a drug, device, or biological
product rather than a complete
combination product. This distinction is
acknowledged and reflected in the
approach taken throughout the rule in
establishing PMSR requirements for
constituent part applicants. The
requirements for record retention by
constituent part applicants align with
the overall approach of the rule.
Specifically, § 4.105(a)(1) requires that
constituent part applicants comply with
the underlying recordkeeping
requirements, including timeframes,
established in the PMSR requirements
identified in § 4.102(b) as applicable
based on their product’s application
type. This ensures that constituent part
applicants comply with the same
requirements as any other applicant
marketing a drug, device, or biological
product.
The essential difference between
constituent part applicants and other
applicants for drugs, devices, and
biological products is the distinct
relationship of constituent part
applicants’ products to one another as
parts of a combination product. The
information sharing requirements of
§ 4.103 reflect this distinct relationship
and the overarching need for
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coordination between constituent part
applicants to ensure the safety and
effectiveness of the combination
product. As explained in section II
(discussion of § 4.103), § 4.103(b)
includes an explicit recordkeeping
requirement in relation to the
information constituent part applicants
are required to share with one another
under § 4.103(a). Section 4.103 is
intended to ensure complete, timely
reporting for the combination product as
a whole. To support this goal, while at
the same time aligning the record
retention requirement for the records
required under § 4.103(b) with the
overall approach of this rule for
constituent part applicants, § 4.105(a)(2)
requires constituent part applicants to
maintain the specified records of
information shared for the retention
period established in the PMSR
recordkeeping requirements for that
constituent part applicant’s constituent
part if there is only one period
established, and the longest
recordkeeping requirement established
in those requirements if those
requirements establish more than one
record retention period. We believe that
this retention period will ensure that the
information remains available to the
applicants and the Agency for a
sufficiently long period to inform
investigation of events and responses to
them for the combination product, and
enable the Agency to assess compliance
with § 4.103, without imposing undue
burden on constituent part applicants.
This approach also avoids the
complexities of tying the retention
period for records relating to the
information sharing provision to the
record retention requirements
applicable to the other constituent part
applicant(s).
G. Alternate Approaches
(Comment 27) Several commenters
proposed that the Agency adopt a
wholly different PMSR approach for
combination products, with some
supporting the Agency’s proposed
approach as an interim measure until a
unified framework is developed either
for combination products in particular
or for all FDA-regulated medical
products. Some commenters proposed
adopting the most stringent set of PMSR
requirements applicable to the
combination product. Others called for
developing a harmonized approach for
combination products, with one
commenter calling for a public meeting
to address the issue and another for
such a system to be put in place after
a single reporting porthole is established
for all regulated products. One
commenter called for FDA to develop a
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PMSR system for combination products
consistent with Global Harmonization
Task Force guidelines, International
Organization for Standardization
standards, and European Commission
guidelines. This comment emphasized
that such other approaches rely on the
‘‘primary intended action’’ of the
combination product to determine what
PMSR requirements should apply. Some
commenters recommended applying
only the reporting requirements
applicable to the application type. One
commenter emphasized challenges of
complying with multiple reporting
systems.
(Response 27) The Agency has
considered alternate approaches to
PMSR for combination products,
including in relation to the public
hearing held on November 25, 2002, and
the workshop held on July 8, 2003. We
have considered such options and
presented in the preamble (74 FR 50744
at 50745 to 50747) the Agency’s reasons
for pursuing the approach described in
the proposed rule. In finalizing this rule,
FDA again determined that the
approach described in this rule allows
FDA to receive complete, timely
postmarketing safety information
regarding combination products, which
is necessary to assure the continued
safety and effectiveness of such
products, using established standards
and systems, while minimizing
unnecessary duplication and burdens
on combination product and constituent
part applicants.
H. Guidance and Agency Internal
Coordination and Training
(Comment 28) Various commenters
requested that the Agency address
implementation of this rule through
guidance. Commenters noted the
importance of ensuring that this rule is
as clear as possible. Most commenters
requested that the guidance present how
the rule would apply to different types
of combination products and different
types of events. Several commenters
requested that this guidance include a
decision tree, flow charts, tables,
algorithm, or other organizational and
explanatory tools to clarify how to
comply with the reporting requirements
applicable to a combination product.
One commenter asked for guidance on
whether to cross-reference reports
submitted to different locations, such as
field alert reports and 15-day reports.
Some commenters proposed that the
Agency issue guidance prior to
publication of this rule. One commenter
called for the guidance to address how
Agency personnel will coordinate to
ensure compliance and how the Agency
will monitor implementation of this
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rule’s requirements. One commenter
called for the Agency to ensure that the
lead center has appropriate expertise to
address adverse event reports for a
combination product and that training,
guidance, and cross-assignment of staff
might be helpful in this regard. Another
commenter proposed that the Agency
take appropriate measures to ensure
timely, effective communication
between Agency components with
respect to postmarketing safety reports
for combination products. Some
commenters also noted the importance
of appropriate training and other
Agency personnel considerations.
(Response 28) We intend to publish
guidance that provides
recommendations on how to comply
with the requirements under this rule
for combination product applicants and
constituent part applicants, including
such matters as cross-referencing of
reports. We appreciate the comments
received on this issue and look forward
to further feedback in response to the
publication of this final rule and of the
draft guidance we may issue. With
regard to the requests that we issue
guidance prior to issuance of this final
rule, we clarified and revised the rule in
certain respects, and we did not believe
it would be appropriate to anticipate the
content of this final rule by publishing
guidance concerning its content prior to
its finalization.
We agree that appropriate training of
Agency staff and timely, effective
coordination among Agency
components to address postmarketing
safety reports for combination products
are important efforts that the Agency
continues to address.
I. Effective Date and Compliance Dates
(Comment 29) Some commenters
proposed that the Agency delay the
effective date for this rule, arguing that
180 days would not provide sufficient
time to take steps to come into
compliance, including to develop,
validate, and implement new systems,
alter procedures and commercial
arrangements, and train staff as needed
to comply with this rule’s requirements.
Some proposed making the effective
date 1 year after issuance. One
commenter proposed 2 years.
(Response 29) We do not agree that it
would be appropriate to delay the
effective date of this rule. However, in
light of these comments, and in
consideration of the costs of this rule as
discussed in section VIII, we have
decided to extend the compliance date
with respect to certain provisions of the
rule for combination product applicants
and constituent part applicants, for a
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period of 18 months following the
effective date of this rule.
The duties for both combination
product and constituent part applicants
under § 4.102(a) and (b), and for
constituent part applicants under
§§ 4.104(a) and 4.105(a)(1) are generally
the same as for any other entity holding
such an application for its product, and
we expect all applicants subject to this
rule already to be in compliance with
these provisions for their products as
these provisions generally refer to
existing regulations that such applicants
have generally followed (see 74 FR
50744 at 50745). Accordingly, the
effective date for the rule is 30 days after
the date of its publication and the
compliance date for these provisions is
the same as the effective date for this
rule. However, with respect to the
requirements of § 4.102(c) and (d) for
combination product applicants, the
requirements of §§ 4.103 and 4.105(a)(2)
for constituent part applicants, and the
requirements of §§ 4.104(b) and 4.105(b)
for combination product applicants, the
compliance date will be 18 months
following the effective date of this rule.
J. Miscellaneous
(Comment 30) Some comments
concerned coordination of various
Agency activities related to adverse
events including then pending Agency
rulemakings concerning electronic
reporting, adverse event report database
management and searchability, forms
referenced in this and other
rulemakings, and harmonization efforts
with foreign regulatory agencies.
(Response 30) The Agency has taken
into account such coordination
considerations. Pending FDA
rulemakings were one consideration in
deciding to streamline this rule by using
cross-references to requirements of the
underlying regulations listed in § 4.102,
without repeating the substance of those
requirements. As noted in section II (see
discussion of § 4.101), this approach
will minimize the need to revise this
regulation should the underlying
regulations be amended. Similar
considerations have informed our
determination to reference in § 4.104 the
reporting procedures required in the
underlying regulations. As discussed in
Response 25, we intend to update
relevant FDA forms, if appropriate,
including the instructions for how to
complete them, and to develop guidance
that provides recommendations for
meeting PMSR requirements under this
rule.
With respect to international
harmonization, we remain committed to
such efforts, including with respect to
PMSR requirements for combination
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products. A practical challenge for
combination products in particular is
that international collaboration and
harmonization efforts are at an early
stage for these products. At the same
time, there is a current need to clarify
FDA’s PMSR requirements for this class
of products. We have taken an approach
that integrates underlying PMSR
approaches for drugs, devices, and
biological products, which have
benefited in various respects from
international harmonization efforts. We
are committed to continuing to work
with our foreign counterparts on PMSR
and other issues for combination
products.
IV. Legal Authority
The Agency derives its authority to
issue the regulations in proposed part 4
subpart B from 21 U.S.C. 321, 331, 351,
352, 353, 355, 360, 360b–360f, 360h–
360j, 360l, 360hh–360ss, 360aaa–
360bbb, 371(a), 372–374, 379e, 381, 383,
and 394, and 42 U.S.C. 216, 262, 263a,
264, and 271. For a drug approved
under an NDA or an ANDA, section
505(k) of the FD&C Act (21 U.S.C. 355)
requires the applicant to submit reports
concerning clinical experience and
other data or information with respect to
the drug to FDA and to establish and
maintain related records. Section 505(k)
provides the Agency with authority to
specify by regulation which data or
information must be submitted in such
reports. FDA used this statutory
authority, among others, in issuing the
Agency’s regulation concerning
postmarketing reporting of adverse drug
experiences and other postmarketing
reports including field alert reports. The
regulations for postmarketing reporting
of adverse drug experiences and for
field alert reports are set forth in
§ 314.80 and § 314.81, respectively.
For a device, section 519 of the FD&C
Act requires manufacturers and
importers to establish and maintain
records, make reports, and provide
information, as FDA may reasonably
require to assure that such device is not
adulterated or misbranded and to
otherwise assure its safety and
effectiveness. FDA utilized this
statutory authority, in addition to other
authorities, in issuing the MDR
regulation and the correction and
removal regulation, found in parts 803
and 806, respectively.
For a biological product, section 351
of the Public Health Service Act (PHS
Act) (42 U.S.C. 262) requires FDA to
approve a BLA on the basis of a
demonstration that the product is safe,
pure, and potent (section 351(a)(2)(C) of
the PHS Act). Section 351(a)(2)(A) of the
PHS Act requires FDA to establish by
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regulation requirements for the
approval, suspension, and revocation of
BLAs. Section 351(b) of the PHS Act
also prohibits falsely labeling a
biological product. FDA used section
351of the PHS Act as statutory
authority, along with other sources of
statutory authority, in issuing the
postmarketing reporting of adverse
experiences regulation for biological
products. This regulation is found in
§ 600.80. In proposing § 600.80, FDA
indicated that information made
available to the Agency through the
adverse experience reports
contemplated under § 600.80 could
establish that a biological product is not
safe or properly labeled and that the
license should be revoked (55 FR 11611
at 11613, March 29, 1990). FDA used
section 351 of the PHS Act as statutory
authority, along with other sources of
statutory authority, in issuing the BPDR
regulations for biological products.
These regulations are found in §§ 600.14
and 606.171. In issuing these
regulations, FDA stated that these
reports would enable FDA to respond
when public health may be at risk,
provide FDA with uniform data to track
trends that may indicate broader threats
to the public health, and help ensure
facilities are taking appropriate actions
to investigate and correct biological
product deviations. (65 FR 66621 at
66623, November 7, 2000).
There is considerable overlap in the
PMSR requirements for drugs, devices,
and biological products. The regulatory
schemes for adverse event reporting for
drugs and biological products are
identical in most respects. The MDR
regulation has many similarities to the
drug and biological product PMSR
regulations. Overall, the regulatory
framework governing PMSR for each
type of product is intended to achieve
the same general goals.
Nevertheless, these three sets of
regulations differ somewhat because
each is tailored to the characteristics of
the types of products for which it was
designed. For instance, each set of
regulations contains certain specific
requirements pertaining to particular
products or types of postmarketing
safety events that are not found in the
other sets of regulations. The additional
requirements for combination product
applicants that FDA considers necessary
are as follows: 5-day reports, 15-day
reports, malfunction reports, correction
or removal reports, field alert reports,
and BPDRs. As set forth in this rule, it
is crucial that these additional
requirements be met if they apply.
The legal framework underlying this
proposed rule is twofold. The first is
that drugs, devices, and biological
PO 00000
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products do not lose their discrete
regulatory identities when they become
constituent parts of a combination
product. In general, the PMSR
requirements specific to each
constituent part of a combination
product also apply to the combination
product itself. Therefore, all
combination products are subject to at
least two sets of PMSR requirements.
For example, in the case of a device and
biological product combination product,
the PMSR requirements applicable to
devices and to biological products
would apply to the combination
product. However, this rule is intended
to clarify that a combination product
applicant may comply only with the
PMSR requirements associated with the
application under which the
combination product received
marketing authorization and certain,
specified PMSR requirements associated
with the other constituent part(s).
Taking the example of a device-biologic
combination product, if the combination
product has an approved BLA, the
combination product applicant (holder
of the BLA) would use parts 600 and
606 to make postmarketing safety
reports for the combination product. In
addition, as explained in this rule, the
combination product applicant must
also comply with all of the specified
requirements that apply to the product.
Thus, in this case, the combination
product applicant must also comply
with the reporting requirements for 5day reports, correction or removal
reports, and malfunction reports if the
criteria for such reports are met. Under
this legal framework, if you demonstrate
compliance with the applicable
requirements of the set of regulations
(e.g., biological product PMSR)
associated with the approved
application (e.g., BLA), and comply
with any applicable specified additional
provisions (e.g., 5-day reports,
correction or removal reports, and
malfunction reports), you will be
considered to have satisfied all
applicable PMSR requirements
associated with the combination
product, including its constituent parts.
The legal authority for this
streamlining approach is based on the
following. Although combination
products retain the regulatory identities
of their constituent parts, the FD&C Act
also recognizes combination products as
a category of products that are distinct
from products that are solely drugs,
devices, or biological products. For
example, section 503(g)(4)(A) of the
FD&C Act (21 U.S.C. 353b(g)(4)(A))
requires OCP to ‘‘designate’’ a product
as a combination product as well as to
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ensure ‘‘consistent and appropriate
postmarket regulation of like products
subject to the same statutory
requirements.’’ Further, section 563 of
the FD&C Act (21 U.S.C. 360bbb–2)
governs the ‘‘classification’’ of products
as ‘‘drug, biological product, device, or
a combination product subject to section
503(g)’’ (emphasis added). In this
respect, the FD&C Act identifies a
combination product as a distinct type
of product that could be subject to
specialized regulatory controls. In
addition, for the efficient enforcement of
the FD&C Act under section 701 (21
U.S.C. 371), FDA has the authority to
develop regulations to ensure sufficient
and appropriate ongoing assessment of
the risks associated with combination
products.
The second legal framework for this
rule is founded on the postmarket safety
reporting regulatory scheme associated
with the application under which the
combination product is approved, plus
any applicable requirements associated
with the additional six specified report
types listed in this rule. Although
similar in effect to the previously
discussed framework, this approach is
based on the legal authority FDA used
to issue each of its three existing
regulations for postmarketing safety
reporting for drugs, devices, and
biological products. In the context of
this rule, such authority would include,
but not be limited to, sections 505(k)
and 519 of the FD&C Act, and section
351 of the PHS Act. Under this authority
FDA is now issuing additional
requirements based on the six
additional specified report types. This
means that in the case, for example, of
a device-biologic combination product,
approved under a BLA, section 351 of
the PHS Act (in addition to other
applicable authorities) would provide
the authority for FDA to require
postmarketing safety reporting in
accordance with parts 600 and 606.
Furthermore, section 351 of the PHS Act
also would provide the authority for the
Agency to require additional reporting
for the device-biologic combination
product (5-day reports, malfunction
reports, and correction or removal
reports) if the criteria for such reports
are met.
V. Analysis of Environmental Impact
FDA has determined under 21 CFR
25.30(a), 25.30(h), and 25.31(a) through
(c) that this action is of a type that does
not individually or cumulatively have a
significant effect on the human
environment. Therefore, neither an
environmental assessment nor an
environmental impact statement is
required.
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VI. Paperwork Reduction Act of 1995
This final rule contains information
collection provisions that are subject to
review by the Office of Management and
Budget (OMB) under the Paperwork
Reduction Act of 1995 (44 U.S.C. 3501–
3520). The title, description and
respondent description of the
information collection provisions are
shown in the following paragraphs with
an estimate of the annual reporting and
recordkeeping burdens. Included in the
estimate is the time for reviewing
instructions, searching existing data
sources, gathering and maintaining the
data needed, and completing and
reviewing each collection of
information.
Title: Postmarketing Safety Reporting
for Combination Products.
Description: This final rule describes
the PMSR requirements for combination
products. In the development of this
final rule, the Agency considered the
fact that a combination product is
subject to the PMSR provisions
applicable to its constituent parts (drug,
device, and/or biological product). The
Agency reviewed each set of regulations
governing PMSR for new drugs (part
314), biological products (parts 600 and
606), and devices (parts 803 and 806).
The review determined that each set of
regulations contains many substantially
similar requirements.
Given the broad similarities in the
PMSR regulations, the Agency
determined that, to ensure consistent,
appropriate PMSR for combination
products that received marketing
authorization under a single
application, we need only require that
combination product applicants comply
with the regulatory requirements for
PMSR associated with the application,
and with additional, specified
provisions from the other set(s) of PMSR
requirements applicable to the other
constituent part(s) of the combination
product. This approach recognizes and
addresses PMSR considerations relevant
to each type of constituent part of a
combination product while avoiding
unnecessary redundancy and burden.
Specifically, the additional reporting
requirements specified in this rule,
along with any associated followup
reports, are: (1) Submission of a ‘‘5-day
report’’ as described in § 803.53 if the
combination product contains a device
constituent part; (2) submission of a
‘‘malfunction report’’ as described in
§ 803.50 if the combination product
contains a device constituent part; (3)
submission of a ‘‘correction or removal
report’’ as described in § 806.10 if the
combination product contains a device
constituent part; (4) submission of a
PO 00000
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Fmt 4700
Sfmt 4700
92621
‘‘field alert report’’ as described in
§ 314.81 if the combination product
contains a drug constituent part; (5)
submission of a 15-day report as
described in § 314.80 or § 600.80 if the
combination product contains a drug or
biological product constituent part,
respectively; and (6) submission of a
‘‘BPDR’’ as described in §§ 600.14 and
606.171 if the combination product
contains a biological product
constituent part.
For combination products for which
the constituent parts received marketing
authorization under separate
applications held by different entities,
the Agency has determined that
compliance with the PMSR
requirements associated with the
application type for the constituent part
is sufficient. In addition, constituent
part applicants must share safety
information they receive related to
certain events with the other constituent
part applicant(s).
We note that the PMSR information
collections for drugs, biological
products, and devices found in
§§ 314.80, 314.81, 600.80, 600.81,
606.170, 606.171, 803.50, 803.53,
803.56, 806.10, and 806.20 have already
been approved and are in effect. The
pertinent PMSR information collection
provisions for § 314.80(c) and (e), as
well as for § 314.81(b) are approved
under OMB control numbers 0910–
0001, 0910–0230, and 0910–0291. The
information collection provisions for
§§ 600.80 and 600.81 are approved
under OMB control number 0910–0308.
Those for § 606.170 are approved under
OMB control number 0910–0116. Those
for § 606.171 are approved under OMB
control number 0910–0458. The
information collection provisions for
§§ 803.50, 803.53, and 803.56 are
approved under OMB control numbers
0910–0291 and 0910–0437. The
information collection provisions for
§§ 806.10 and 806.20 are approved
under OMB control number 0910–0359.
While this rule serves to permit
combination product applicants to
comply with a streamlined subset of the
PMSR requirements applicable to all of
their constituent parts, we recognize
that some combination product
applicants have been complying with
only the reporting requirements
associated with their application type.
As a result, the information collection
described here refers to the reporting
and recordkeeping requirements for the
six additional report types specified in
this rule. It also refers to the new
information sharing and related
recordkeeping requirement applicable to
constituent parts marketed under
separate applications.
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These requirements are necessary to
ensure: (1) Consistent PMSR for
combination products and constituent
parts, (2) that the Agency receives
necessary information to promote and
protect the public health, (3)
appropriate ongoing assessment of risks,
and (4) consistent and appropriate
postmarketing regulation of
combination products. This rule enables
applicants to comply with these
requirements while avoiding
unnecessary duplicative reporting, for
example, by limiting the number of
PMSR requirements with which
combination product applicants must
comply and by authorizing applicants to
submit only a single, complete report for
an event even if multiple reporting
duties apply to the same event.
Description of Respondents: This rule
applies to combination product
applicants and constituent part
applicants. Any person holding the
application(s) under which a
combination product received
marketing authorization is a
combination product applicant. Any
person holding an application under
which a constituent part (drug, device,
or biological product) of a combination
product received marketing
authorization is a constituent part
applicant if the other constituent part
received marketing authorization under
an application held by a different
person.
FDA estimates the burden for this
information collection as follows:
TABLE 3—ESTIMATED ANNUAL REPORTING BURDEN
Number of
respondents
21 CFR section
Number of
responses per
respondent
Total annual
responses
Average
burden per
response
Total hours
4.102(c)(1)(i) Submitting 5-day reports ................................
4.102(c)(1)(ii) Submitting malfunction reports .....................
4.102(c)(1)(iii) Submitting correction or removal reports .....
4.102(c)(2)(i) Submitting field alerts ....................................
4.102(c)(2)(ii) and (3)((ii) Submitting 15-day reports ...........
4.102(c)(3) Submitting BPDRs ............................................
4.102(d) ................................................................................
15
15
20
92
1
24
1
98
98
1
10.8
1
6
1
1,470
1,470
20
994
1
144
1
1.21
1.21
10
8
1
2
1
1,779
1,779
200
7,949
1
288
1
Totals * ..........................................................................
........................
........................
........................
........................
11,709
TABLE 4—ESTIMATED ANNUAL RECORDKEEPING BURDEN
Number of
recordkeepers
21 CFR section
4.103(b)/4.105(a)(2) Records of information shared
by constituent part applicants.
4.105(b) additional record-keeping by device-led
combination products.
4.105(b) additional recordkeeping by drug and biologic-led combination products.
Totals ................................................................
Number of
records per
recordkeeper
Total annual
records
Average burden per
recordkeeping
Total hours
33
18
594
.1 (6 minutes) ............
59
279
.45
126
.5 (30 minutes) ..........
63
186
6
1,116
.5 (30 minutes) ..........
558
........................
........................
........................
....................................
680
TABLE 5—ESTIMATED ANNUAL THIRD PARTY DISCLOSURE BURDEN
Number of
respondents
21 CFR section
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4.103 Sharing information with other constituent
part applicants.
Based on FDA’s experience regarding
receipt of postmarketing safety reports
for combination products, the Agency
estimates that there will be 401
reporters (who will keep corresponding
records) submitting a total of 11,709
reports annually under § 4.102(c) and
(d) and 33 reporters (who will keep
corresponding records) sharing
information eighteen times annually
under § 4.103. Further, FDA estimates,
based on its experience with
information collection regarding
postmarketing safety reporting
provisions for drugs, biological
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Number of
disclosures
per
respondent
33
Total annual
disclosures
18
products, and devices, that each report
(or information sharing event under
§ 4.103) may take from approximately
20 minutes to 10 hours, depending on
report type, to prepare and submit, and
from approximately 6 to 30 minutes to
fulfill the corresponding recordkeeping
requirements. FDA believes that there
are no significant new operating and
maintenance costs associated with this
collection of information because, in
order to legally market their products,
all applicants are required to develop
and maintain systems for reporting and
maintaining records of postmarketing
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594
Average burden per
disclosure
.35 (21 minutes) ........
Total hours
208
safety events. Therefore, appropriate
mechanisms for PMSR should already
be in place, and combination product
applicants and constituent part
applicants will accrue no significant
additional costs to fulfill the
requirements set forth here.
In addition, we estimate that there
will no significant new costs for 15-day
reporting (§ 4.102(c)(2)(ii) and (3)(ii))
and periodic reporting (§ 4.102(d)(1))
under the rule because there is
significant overlap between the types of
events that trigger a 15-day report for
drugs and biological products and the
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events that trigger expedited reporting
for devices. We also estimate there will
be no significant new costs for other
non-expedited reporting (§ 4.102(d)(2))
because of the expected rarity of the
agency seeking such additional
information.
Before the effective date of this final
rule, FDA will publish a notice in the
Federal Register announcing OMB’s
decision to approve, modify, or
disapprove the information collection
provisions in this final rule. An Agency
may not conduct or sponsor, and a
person is not required to respond to, a
collection of information unless the
Agency displays a currently valid OMB
control number.
VII. Federalism
FDA has analyzed this final rule in
accordance with the principles set forth
in Executive Order 13132. FDA has
determined that the rule does not
contain policies that have substantial
direct effects on the States, on the
relationship between the National
Government and the States, or on the
distribution of power and
responsibilities among the various
levels of government. Accordingly, the
Agency has concluded that the final rule
does not contain policies that have
federalism implications as defined in
the Executive order and, consequently,
a federalism summary impact statement
is not required.9
VIII. Economic Analysis of Impacts
A. Introduction
We have examined the impacts of the
final rule under Executive Order 12866,
Executive Order 13563, the Regulatory
Flexibility Act (5 U.S.C. 601–612), and
the Unfunded Mandates Reform Act of
1995 (Pub. L. 104–4). Executive Orders
12866 and 13563 direct us to assess all
costs and benefits of available regulatory
alternatives and, when regulation is
necessary, to select regulatory
approaches that maximize net benefits
(including potential economic,
environmental, public health and safety,
and other advantages; distributive
impacts; and equity). We have
developed a comprehensive Economic
Analysis of Impacts that assesses the
impacts of the final rule. We believe that
this final rule is not a significant
regulatory action as defined by
Executive Order 12866.
The Regulatory Flexibility Act
requires us to analyze regulatory options
that would minimize any significant
impact of a rule on small entities.
Because the final rule essentially
describes the application of existing
postmarketing safety reporting
regulations to certain combination
products, we certify that the final rule
will not have a significant economic
impact on a substantial number of small
entities.
The Unfunded Mandates Reform Act
of 1995 (section 202(a)) requires us to
prepare a written statement, which
includes an assessment of anticipated
costs and benefits, before issuing ‘‘any
rule that includes any Federal mandate
that may result in the expenditure by
State, local, and tribal governments, in
the aggregate, or by the private sector, of
$100,000,000 or more (adjusted
annually for inflation) in any one year.’’
The current threshold after adjustment
for inflation is $146 million, using the
most current (2015) Implicit Price
Deflator for the Gross Domestic Product.
92623
This final rule would not result in an
expenditure in any year that meets or
exceeds this amount.
The full analysis of economic impacts
is available in the docket for this final
rule at https://www.fda.gov/AboutFDA/
ReportsManualsForms/Reports/
EconomicAnalyses/default.htm.
B. Summary of Costs and Benefits
The final rule will generate one-time
administrative costs from reading and
understanding the rule, assessing
current compliance, modifying existing
standards of practice, changing storage
and reporting software, and training
personnel on the requirements under
this rule. Firms that do not currently
comply with the reporting requirements
specified by the final rule will also
incur annual reporting costs from the
submission of field alert reports, 5-day
reports, malfunction reports, correction
or removal reports, and biological
product deviation reports, as applicable.
The annualized total costs of the rule
are between $1.36 and $2.68 million at
a 7 percent discount rate and between
$1.35 and $2.65 million at a 3 percent
discount rate.
The final rule will benefit firms
through reduced uncertainty about the
reporting requirements for their specific
combination product and through
decreased potentially duplicative
reporting. The final rule will also
benefit public health by helping to
ensure that important safety information
is submitted and directed to the
appropriate components within the
Agency, so that we may receive and
review this important information in a
timely manner for the protection of
public health.
TABLE 6—SUMMARY OF BENEFITS, COSTS, AND DISTRIBUTIONAL EFFECTS OF FINAL RULE
Units
Category
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Benefits:
Annualized ............
Monetized
($millions/year) ..
Annualized ............
Quantified ..............
Primary
estimate
Low
estimate
High
estimate
........................
........................
........................
2016
7
10
........................
........................
........................
........................
........................
........................
........................
........................
........................
2016
2016
2016
3
7
3
10
10
10
9 The rule clarifies which PMSR requirements
apply when drugs, devices, and biological products
are used to create combination products. The
Agency notes that there are no express preemption
provisions of the FD&C act applicable to
prescription drugs or biological products. Section
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Year
dollars
521 of the FD&C Act (21 U.S.C. 360k) contains an
express preemption provision that applies to
devices; nonetheless, the Supreme Court concluded
in Medtronic, Inc. v. Lohr, 581 U.S. 470, 500–01
(1996), that requirements not applicable to a
particular device do not preempt State law under
PO 00000
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Fmt 4700
Sfmt 4700
Discount rate
(%)
Period
covered
(years)
Notes
section 521. Device adverse event reporting
requirements, like the good manufacturing practice
requirements at issue in the Medtronic case, are
general requirements that do not preempt under
section 521 of the FD&C Act.
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TABLE 6—SUMMARY OF BENEFITS, COSTS, AND DISTRIBUTIONAL EFFECTS OF FINAL RULE—Continued
Units
Category
Qualitative .............
Costs:
Annualized ............
Monetized
($millions/year) ..
Annualized ............
Quantified ..............
Primary
estimate
Low
estimate
High
estimate
Year
dollars
Discount rate
(%)
Period
covered
(years)
Notes
Firms will benefit from reduced uncertainty about
reporting requirements. The rule will benefit
public health by helping to ensure Agency
components’ timely receipt of postmarketing
safety reports.
........................
$1.36
$2.68
2016
7
10
........................
........................
........................
$1.35
........................
........................
$2.65
........................
........................
2016
2016
2016
3
7
3
10
10
10
........................
........................
........................
........................
........................
........................
2016
2016
7
3
10
10
2016
2016
7
3
10
10
Qualitative .............
Transfers:
Federal ..................
Annualized ............
Monetized
($millions/year) ..
From:
Other .....................
Annualized ............
........................
........................
Monetized
($millions/year) ..
From:
To:
........................
........................
........................
........................
To:
Effects:
State, Local or Tribal Government:
Small Business:
Wages:
Growth:
IX. References
mstockstill on DSK3G9T082PROD with RULES
The following references are on
display in the Division of Dockets
Management, Food and Drug
Administration, 5630 Fishers Lane, Rm.
1061, Rockville, MD 20852, and are
available for viewing by interested
persons between 9 a.m. and 4 p.m.,
Monday through Friday; they are also
available electronically at https://
www.regulations.gov. FDA has verified
the Web site addresses, as of the date
this document publishes in the Federal
Register, but Web sites are subject to
change over time.
1. FDA Regulation of Combination
Products, November 25, 2002, accessed at:
https://www.fda.gov/downloads/Combination
Products/MeetingsConferencesWorkshops/
UCM117123.pdf.
2. Innovative Systems for Delivery of Drugs
and Biologics: Scientific, Clinical and
Regulatory Challenges, July 8, 2003, accessed
at: https://www.fda.gov/ohrms/dockets/
dockets/03n0203/03n0203.htm.
3. Individual Case Study Reports, accessed
at: (https://www.fda.gov/ForIndustry/
DataStandards/IndividualCaseSafetyReports/
default.htm).
VerDate Sep<11>2014
19:50 Dec 19, 2016
Jkt 241001
List of Subjects in 21 CFR Part 4
Biological products, Combination
products, Drugs, Medical devices,
Regulation of combination products,
Reporting and recordkeeping
requirements, Safety.
Therefore, under the Federal Food,
Drug, and Cosmetic Act, the Public
Health Service Act, and under authority
delegated to the Commissioner of Food
and Drugs, 21 CFR part 4 is amended as
follows:
PART 4—REGULATION OF
COMBINATION PRODUCTS
1. The authority citation for part 4
continues to read as follows:
■
Authority: 21 U.S.C. 321, 331, 351, 352,
353, 355, 360, 360b–360f, 360h–360j, 360l,
360hh–360ss, 360aaa–360bbb, 371(a), 372–
374, 379e, 381, 383, 394; 42 U.S.C. 216, 262,
263a, 264, 271.
2. Add subpart B, consisting of
§§ 4.100 through 4.105, to read as
follows:
■
Subpart B—Postmarketing Safety Reporting
for Combination Products
Sec.
PO 00000
Frm 00076
Fmt 4700
Sfmt 4700
4.100 What is the scope of this subpart?
4.101 How does FDA define key terms and
phrases in this subpart?
4.102 What reports must you submit to FDA
for your combination product or
constituent part?
4.103 What information must you share
with other constituent part applicants for
the combination product?
4.104 How and where must you submit
postmarketing safety reports for your
combination product or constituent part?
4.105 What are the postmarketing safety
reporting recordkeeping requirements for
your combination product or constituent
part?
Subpart B—Postmarketing Safety
Reporting for Combination Products
§ 4.100
What is the scope of this subpart?
(a) This subpart identifies
postmarketing safety reporting
requirements for combination product
applicants and constituent part
applicants.
(b) This subpart does not apply to
investigational combination products,
combination products that have not
received marketing authorization, or to
persons other than combination product
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Federal Register / Vol. 81, No. 244 / Tuesday, December 20, 2016 / Rules and Regulations
applicants and constituent part
applicants.
(c) This subpart supplements and
does not supersede other provisions of
this chapter, including the provisions in
parts 314, 600, 606, 803, and 806 of this
chapter, unless a regulation explicitly
provides otherwise.
mstockstill on DSK3G9T082PROD with RULES
§ 4.101 How does the FDA define key
terms and phrases in this subpart?
Abbreviated new drug application
(ANDA) has the same meaning given the
term ‘‘abbreviated application’’ in
§ 314.3(b) of this chapter.
Agency or we means Food and Drug
Administration.
Applicant means, for the purposes of
this subpart, a person holding an
application under which a combination
product or constituent part of a
combination product has received
marketing authorization (such as
approval, licensure, or clearance). For
the purposes of this subpart, applicant
is used interchangeably with the term
‘‘you.’’
Application means, for purposes of
this subpart, a BLA, an NDA, an ANDA,
or a device application, including all
amendments and supplements to them.
Biological product has the meaning
given the term in section 351 of the
Public Health Service Act (42 U.S.C.
262).
Biological product deviation report
(BPDR) is a report as described in
§§ 600.14 and 606.171 of this chapter.
Biologics license application (BLA)
has the meaning given the term in
section 351 of the Public Health Service
Act (42 U.S.C. 262) and § 601.2 of this
chapter.
Combination product has the meaning
given the term in § 3.2(e) of this chapter.
Combination product applicant
means an applicant that holds the
application(s) for a combination
product.
Constituent part has the meaning
given the term in § 4.2.
Constituent part applicant means the
applicant for a constituent part of a
combination product the constituent
parts of which are marketed under
applications held by different
applicants.
Correction or removal report is a
report as described in § 806.10 of this
chapter.
De novo classification request is a
submission requesting de novo
classification under section 513(f)(2) of
the Federal Food, Drug, and Cosmetic
Act.
Device has the meaning given the
term in section 201(h) of the Federal
Food, Drug, and Cosmetic Act.
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19:50 Dec 19, 2016
Jkt 241001
Device application means a PMA,
PDP, premarket notification submission,
de novo classification request, or HDE.
Drug has the meaning given the term
in section 201(g)(1) of the Federal Food,
Drug, and Cosmetic Act.
Field alert report is a report as
described in § 314.81 of this chapter.
Fifteen-day report is a report required
to be submitted within 15 days as
described in § 314.80 of this chapter or
§ 600.80 of this chapter, as well as
followup reports to such a report.
Five-day report is a report as
described in §§ 803.3 and 803.53 of this
chapter, as well as supplemental or
followup reports to such a report as
described in § 803.56 of this chapter.
Humanitarian device exemption
(HDE) has the meaning given the term
in § 814.3 of this chapter.
Malfunction report is a report as
described in § 803.50 of this chapter as
well as supplemental or followup
reports to such a report as described in
§ 803.56 of this chapter.
New drug application (NDA) has the
meaning given the term ‘‘application’’ in
§ 314.3(b) of this chapter.
Premarket approval application
(PMA) has the meaning given the term
in § 814.3 of this chapter.
Premarket notification submission is a
submission as described in § 807.87 of
this chapter.
Product Development Protocol (PDP)
is a submission as set forth in section
515(f) of the Federal Food, Drug, and
Cosmetic Act.
§ 4.102 What reports must you submit to
FDA for your combination product or
constituent part?
(a) In general. If you are a constituent
part applicant, the reporting
requirements applicable to you that are
identified in this section apply to your
constituent part, and if you are a
combination product applicant, the
reporting requirements applicable to
you that are identified in this section
apply to your combination product as a
whole.
(b) Reporting requirements applicable
to both combination product applicants
and constituent part applicants. If you
are a combination product applicant or
constituent part applicant, you must
comply with the reporting requirements
identified in paragraphs (b)(1), (b)(2), or
(b)(3) of this section for your product
based on its application type. If you are
a combination product applicant, you
are required to submit a report as
specified in this paragraph unless you
have already submitted a report in
accordance with paragraph (c) of this
section for the same event that: Includes
the information required under the
PO 00000
Frm 00077
Fmt 4700
Sfmt 4700
92625
applicable regulations identified in this
paragraph, is required to be submitted
in the same manner under § 4.104, and
meets the deadlines under the
applicable regulations identified in this
paragraph.
(1) If your combination product or
device constituent part received
marketing authorization under a device
application, you must comply with the
requirements for postmarketing safety
reporting described in parts 803 and 806
of this chapter with respect to your
product.
(2) If your combination product or
drug constituent part received
marketing authorization under an NDA
or ANDA, you must comply with the
requirements for postmarketing safety
reporting described in part 314 of this
chapter with respect to your product.
(3) If your combination product or
biological product constituent part
received marketing authorization under
a BLA, you must comply with the
requirements for postmarketing safety
reporting described in parts 600 and 606
of this chapter with respect to your
product.
(c) Reporting requirements applicable
only to combination product applicants.
If you are a combination product
applicant, in addition to compliance
with paragraph (a) of this section, you
must also comply with the reporting
requirements identified under this
paragraph as applicable to your product
based on its constituent parts. If you are
a combination product applicant, you
are required to submit a report as
specified in this paragraph unless you
have already submitted a report in
accordance with paragraph (b) of this
section for the same event that: Includes
the information required under the
applicable regulations for the report
identified in this paragraph; is required
to be submitted in the same manner
under § 4.104 of this chapter; and,
unless otherwise specified in this
paragraph, meets the deadlines under
the applicable regulations for the report
identified in this paragraph.
(1) If your combination product
contains a device constituent part, you
must submit:
(i) Five-day reports;
(ii) Malfunction reports; and
(iii) Correction or removal reports,
and maintain records as described in
§ 806.20 of this chapter for corrections
and removals not required to be
reported.
(2) If your combination product
contains a drug constituent part, you
must submit:
(i) Field alert reports; and
(ii) Fifteen-day reports as described in
§ 314.80 of this chapter, which must be
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Federal Register / Vol. 81, No. 244 / Tuesday, December 20, 2016 / Rules and Regulations
submitted within 30 calendar days
instead of 15 calendar days if your
combination product received
marketing authorization under a device
application.
(3) If your combination product
contains a biological product
constituent part, you must submit:
(i) Biological product deviation
reports; and
(ii) Fifteen-day reports as described in
§ 600.80 of this chapter, which must be
submitted within 30 calendar days
instead of 15 calendar days if your
combination product received
marketing authorization under a device
application.
(d) Other reporting requirements for
combination product applicants. (1) If
you are the combination product
applicant for a combination product that
contains a device constituent part and
that received marketing authorization
under an NDA, ANDA, or BLA, in
addition to the information otherwise
required in the periodic safety reports
you submit under § 314.80 or § 600.80 of
this chapter, your periodic safety reports
must also include a summary and
analysis of the reports identified in
paragraphs (c)(1)(i) and (ii) of this
section that were submitted during the
report interval.
(2) If you are the combination product
applicant for a combination product that
received marketing authorization under
a device application, in addition to the
reports required under paragraphs (b)
and (c) of this section, you must submit
reports regarding postmarketing safety
events if notified by the Agency in
writing that the Agency requires
additional information. We will specify
what safety information is needed and
will require such information if we
determine that protection of the public
health requires additional or clarifying
safety information for the combination
product. In any request under this
section, we will state the reason or
purpose for the safety information
request, specify the due date for
submitting the information, and clearly
identify the reported event(s) related to
our request.
mstockstill on DSK3G9T082PROD with RULES
§ 4.103 What information must you share
with other constituent part applicants for
the combination product?
(a) When you receive information
regarding an event that involves a death
or serious injury as described in § 803.3
of this chapter, or an adverse experience
as described in § 314.80(a) of this
chapter or § 600.80(a) of this chapter,
associated with the use of the
combination product, you must provide
the information to the other constituent
part applicant(s) for the combination
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19:50 Dec 19, 2016
Jkt 241001
product no later than 5 calendar days of
your receipt of the information.
(b) With regard to information you
must provide to the other constituent
part applicant(s) for the combination
product, you must maintain records that
include:
(1) A copy of the information you
provided,
(2) The date the information was
received by you,
(3) The date the information was
provided to the other constituent part
applicant(s), and
(4) The name and address of the other
constituent part applicant(s) to whom
you provided the information.
accordance with the longest time period
required for records under the
regulations applicable to your product
under § 4.102.
Dated: December 14, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016–30485 Filed 12–19–16; 8:45 am]
BILLING CODE 4164–01–P
DEPARTMENT OF HOUSING AND
URBAN DEVELOPMENT
24 CFR Parts 5, 92, 93, 570, 574, 578,
880, 881, 883, 884, 886, 891, 905, 983
§ 4.104 How and where must you submit
postmarketing safety reports for your
combination product or constituent part?
[Docket No. FR 5890–F–02]
(a) If you are a constituent part
applicant, you must submit
postmarketing safety reports in
accordance with the regulations
identified in § 4.102(b) that are
applicable to your product based on its
application type.
(b) If you are a combination product
applicant, you must submit
postmarketing safety reports required
under § 4.102 in the manner specified in
the regulation applicable to the type of
report, with the following exceptions:
(1) You must submit the
postmarketing safety reports identified
in § 4.102(c)(1)(i) and (ii) in accordance
with § 314.80(g) of this chapter if your
combination product received
marketing authorization under an NDA
or ANDA or in accordance with
§ 600.80(h) of this chapter if your
combination product received
marketing authorization under a BLA.
(2) You must submit the
postmarketing safety reports identified
in § 4.102(c)(2)(ii) and (c)(3)(ii) in
accordance with § 803.12(a) of this
chapter if your combination product
received marketing authorization under
a device application.
Narrowing the Digital Divide Through
Installation of Broadband
Infrastructure in HUD-Funded New
Construction and Substantial
Rehabilitation of Multifamily Rental
Housing
§ 4.105 What are the postmarketing safety
reporting recordkeeping requirements for
your combination product or constituent
part?
(a) If you are a constituent part
applicant:
(1) You must maintain records in
accordance with the recordkeeping
requirements in the applicable
regulation(s) described in § 4.102(b).
(2) You must maintain records
required under § 4.103(b) for the longest
time period required for records under
the postmarketing safety reporting
regulations applicable to your product
under § 4.102(b).
(b) If you are a combination product
applicant, you must maintain records in
PO 00000
Frm 00078
Fmt 4700
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RIN 2501–AD75
Office of the Secretary, HUD.
Final rule.
AGENCY:
ACTION:
Through this rule, HUD
continues its efforts to narrow the
digital divide in low-income
communities served by HUD by
providing, where feasible and with HUD
funding, broadband infrastructure to
communities in need of such
infrastructure. In this final rule, HUD
requires installation of broadband
infrastructure at the time of new
construction or substantial
rehabilitation of multifamily rental
housing that is funded or supported by
HUD, the point at which such
installation is generally easier and less
costly than when undertaken as a standalone effort. The rule, however,
recognizes that installation of
broadband infrastructure may not be
feasible for all new construction or
substantial rehabilitation, and,
therefore, it allows limited exceptions to
the installation requirements. Installing
unit-based broadband infrastructure in
multifamily rental housing that is newly
constructed or substantially
rehabilitated with or supported by HUD
funding will provide a platform for
individuals and families residing in
such housing to participate in the digital
economy and increase their access to
economic opportunities.
DATES: Effective date: January 19, 2017.
FOR FURTHER INFORMATION CONTACT: If
you have any questions, please contact
the following people (the telephone
numbers are not toll-free):
Office of Community Planning and
Development programs: Clifford Taffet,
SUMMARY:
E:\FR\FM\20DER1.SGM
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]]>Agencies
[Federal Register Volume 81, Number 244 (Tuesday, December 20, 2016)]
[Rules and Regulations]
[Pages 92603-92626]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-30485]
=======================================================================
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 4
[Docket No. FDA-2008-N-0424]
RIN 0910-AF82
Postmarketing Safety Reporting for Combination Products
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA or Agency) is issuing
regulations to set forth postmarketing safety reporting requirements
for combination products. Specifically, this final rule describes the
postmarketing safety reporting requirements that apply when two or more
different types of regulated medical products (drugs, devices, and/or
biological products, which are referred to as ``constituent parts'' of
a combination product) comprise a combination product and the
combination product or its constituent parts have received FDA
marketing authorization. The rule is intended to promote and protect
the public health by setting forth the requirements for postmarketing
safety reporting for these combination products, and is part of FDA's
ongoing effort to ensure the consistency and appropriateness of the
regulatory requirements for combination products.
DATES: Effective date: This rule is effective on January 19, 2017.
Compliance dates: Some provisions of the rule have a compliance
date that is the same as the effective date of this rule, and other
provisions of the rule have a later compliance date as discussed in
section III.I, Effective Date and Compliance Dates.
FOR FURTHER INFORMATION CONTACT: John Barlow Weiner, Associate Director
for Policy, Office of Combination Products, Food and Drug
Administration, 10903 New Hampshire Ave., Bldg. 32, Rm. 5129, Silver
Spring, MD 20933, 301-796-8930, john.weiner@fda.hhs.gov.
SUPPLEMENTARY INFORMATION:
Table of Contents
Executive Summary
I. Background
A. Rationale for Rulemaking
B. The Proposed Rule
II. Overview of the Final Rule
A. Section 4.100--What is the scope of this subpart?
B. Section 4.101--How does FDA define key terms and phrases in
this subpart?
[[Page 92604]]
C. Section 4.102--What reports must you submit to FDA for your
combination product or constituent part?
D. Section 4.103--What information must you share with other
constituent part applicants for the combination product?
E. Section 4.104--How and where must you submit postmarketing
safety reports for your combination product or constituent part?
F. Section 4.105--What are the postmarketing safety reporting
recordkeeping requirements for your combination product or
constituent part?
III. Comments on the Proposed Rule
A. Section 4.100--What is the scope of this subpart?
B. Section 4.101--How does FDA define key terms and phrases in
this subpart?
C. Section 4.102--What reports must you submit to FDA for your
combination product or constituent part?
D. Section 4.103--What information must you share with other
constituent part applicants for the combination product?
E. Section 4.104--How and where must you submit postmarketing
safety reports for your combination product or constituent part?
F. Section 4.105--What are the postmarketing safety reporting
recordkeeping requirements for your combination product or
constituent part?
G. Alternate Approaches
H. Guidance and Agency Internal Coordination and Training
I. Effective Date and Compliance Dates
J. Miscellaneous
IV. Legal Authority
V. Analysis of Environmental Impact
VI. Paperwork Reduction Act of 1995
VII. Federalism
VIII. Economic Analysis of Impacts
A. Introduction
B. Summary of Costs and Benefits
IX. References
Executive Summary
Purpose of the Final Rule
The Agency has not previously issued regulations on postmarketing
safety reporting specifically for combination products, which are
products comprised of: (1) A drug and a device; (2) a device and a
biological product; (3) a biological product and a drug; or (4) a drug,
a device, and a biological product. Instead, the Agency has applied
provisions to combination products from the postmarketing safety
reporting regulations applicable to the constituent parts (i.e.,
reporting requirements specific to drugs, devices, and biological
products). These regulations for drugs, devices, and biological
products share many similarities; however, each set of regulations has
certain unique reporting requirements, standards, and timeframes based
in part on the characteristics of the type of product. These variations
among the regulations and lack of clarity on how to apply these
requirements to combination products can result in inconsistent and
incomplete postmarketing safety reporting for combination products and
their constituent parts.
The purpose of this final rule is to ensure consistent, complete
postmarketing safety reporting requirements for combination products
that have received FDA marketing authorization, while avoiding
duplicative reporting. The term ``postmarketing safety'' is used in
this rule because this rule concerns certain postmarket events,
including manufacturing events, device malfunctions, and events causing
injury to users, and the reporting requirements that relate to product
and patient safety arising from these events. The final rule supports
the underlying purpose of postmarketing safety reporting for all
medical products, namely to protect the public health by ensuring
continued safety and effectiveness of the product once it is placed on
the market.
Summary of the Major Provisions of the Final Rule
This final rule requires that a ``combination product applicant''
(an entity holding the application(s), as the term ``application'' is
defined in 21 CFR 4.101 of this rule, for a combination product) and a
``constituent part applicant'' (an entity holding the application to
market a drug, device, or biological product as a constituent part of a
combination product the constituent parts of which are marketed under
applications held by different applicants) comply with postmarketing
safety reporting requirements applicable to the product based on the
application type (e.g., new drug application, premarket approval
application, biologics license application) under which the combination
product or constituent part received marketing authorization. In
addition to these application-type based reporting requirements, the
final rule requires combination product applicants to submit additional
specified reports based on the constituent parts included in the
combination product (e.g., malfunction reports if the combination
product includes a device, field alert reports if it includes a drug,
and biological product deviation reports if it includes a biological
product). The final rule requires constituent part applicants to share
certain postmarketing safety information they receive with one another.
The rule also specifies how combination product and constituent part
applicants must submit postmarketing safety reporting information to
the Agency and what records they must maintain.
The Agency received 16 sets of comments on the proposed rule.
Commenters largely sought clarification of the scope of the proposed
rule, how reporting requirements, timelines, and reporting standards
from the underlying regulations for drugs, devices, and biological
products apply, and how and what information must be shared between
constituent part applicants. Several commenters, while supporting
rulemaking to address postmarketing safety reporting for combination
products, recommended alternative approaches. After considering the
comments received on the proposed rule, the Agency has made
clarifications and other revisions in the final rule to, among other
things: (1) Clarify that the final rule applies only to combination
product and constituent part applicants; (2) clarify when a single
report may suffice to comply with more than one reporting requirement;
and (3) incorporate biological product deviation reporting and device
correction and removal reporting requirements applicable to combination
product applicants.
Legal Authority
The legal framework underlying this final rule is twofold. The
first aspect is that drugs, devices, and biological products do not
lose their discrete regulatory identities when they become constituent
parts of a combination product. In general, the postmarketing safety
reporting requirements specific to each constituent part of a
combination product also apply to the combination product itself.
Although the constituent parts of combination products retain their
regulatory identities, the Federal Food, Drug, and Cosmetic Act (FD&C
Act) also recognizes combination products as a category of products
that are distinct from products that are solely drugs, devices, or
biological products. FDA has the authority to develop regulations to
ensure sufficient and appropriate ongoing assessment of the risks
associated with combination products.
The second aspect of the framework is founded on the postmarketing
safety reporting regulatory scheme associated with the application
under which the combination product received marketing authorization,
plus any applicable requirements associated with the additional six
specified report types listed in this rule. Although similar in effect
to the first aspect of the framework, this aspect is based on the legal
authority FDA used to issue each of its existing regulations for
postmarketing safety reporting for drugs, devices, and biological
products.
[[Page 92605]]
Costs and Benefits
The final rule will generate one-time administrative costs from
reading and understanding the rule, assessing current compliance,
modifying existing standards of practice, changing storage and
reporting software, and training personnel on the requirements under
this rule. Firms that do not currently comply with the reporting
requirements identified in 21 CFR 4.102(c) of this rule will also incur
annual reporting costs from the submission of field alert reports, 5-
day reports, 15-day reports, malfunction reports, correction or removal
reports, and biological product deviation reports. The annualized total
costs of the rule are between $1.36 and $2.68 million at a 7 percent
discount rate and between $1.35 and $2.65 million at a 3 percent
discount rate.
The final rule will benefit firms through reduced uncertainty about
the reporting requirements for their specific combination product and
through decreased duplicative reporting. The final rule will also
benefit public health by helping to ensure that important safety
information is submitted and directed to the appropriate Agency
components, so that the Agency may receive and review this information
in a timely manner.
I. Background
As set forth in 21 CFR part 3, a combination product is a product
comprised of a drug and a device; a device and a biological product; a
biological product and a drug; or a drug, a device, and a biological
product. A combination product includes the following: (1) A product
comprised of two or more regulated components, i.e., drug/device,
biologic/device, drug/biologic, or drug/device/biologic, that are
physically, chemically, or otherwise combined or mixed and produced as
a single entity (``single-entity'' combination products); (2) two or
more separate products packaged together in a single package or as a
unit and comprised of drug and device products, device and biological
products, or biological and drug products (``co-packaged'' combination
products); (3) a drug, device, or biological product packaged
separately that, according to its investigational plan or proposed
labeling, is intended for use only with an approved individually
specified drug, device, or biological product where both are required
to achieve the intended use, indication, or effect and where upon
approval of the proposed product the labeling of the approved product
would need to be changed; e.g., to reflect a change in intended use,
dosage form, strength, route of administration, or significant change
in dose (a type of ``cross-labeled'' combination product); or (4) any
investigational drug, device, or biological product packaged separately
that, according to its proposed labeling, is for use only with another
individually specified investigational drug, device, or biological
product where both are required to achieve the intended use,
indication, or effect (another type of ``cross-labeled'' combination
product).\1\ For purposes of this rulemaking and consistent with 21 CFR
4.2, the drugs, devices, and/or biological products included in a
combination product are referred to as ``constituent parts'' of the
combination product.
---------------------------------------------------------------------------
\1\ As discussed in response to Comment 1, this rule addresses
only PMSR requirements for combination products that have received
marketing authorization. It does not describe reporting requirements
for investigational combination products.
---------------------------------------------------------------------------
A. Rationale for Rulemaking
In the proposed rule (74 FR 50744 at 50745 to 50751, October 1,
2009), FDA described its rationale and goals for the proposed
rulemaking. To date, the Agency has not issued regulations on
postmarketing safety reporting (PMSR) specifically for combination
products. Instead, the Agency has applied provisions to combination
products from the PMSR regulations applicable to the constituent parts
of the combination product (i.e., the reporting requirements specific
to drugs, devices, and biological products). These requirements for
drugs, devices, and biological products share many similarities and
have a common underlying purpose, namely to protect the public health
by ensuring a product's continued safety and effectiveness once placed
on the market. However, each set of regulations has certain reporting
standards and timeframes with unique requirements based in part on the
characteristics of the type of product.
FDA held a public hearing on November 25, 2002, entitled ``FDA
Regulation of Combination Products'' (Ref. 1) and a public workshop on
July 8, 2003, entitled ``Innovative Systems for Delivery of Drugs and
Biologics: Scientific, Clinical and Regulatory Challenges'' (Ref. 2) to
discuss postmarketing safety reporting, among other issues pertaining
to combination products. In developing the proposed rule, we carefully
considered the comments offered by stakeholders, including written
comments submitted to the docket that we opened to facilitate further
input on combination product issues. Two common themes from the
comments were the need for consistency in postmarketing safety
reporting requirements for combination products and the importance of
avoiding unnecessarily duplicative reporting. Some stakeholders
suggested that FDA consider developing an entirely new postmarketing
safety reporting scheme for combination products, but we concluded that
because of the broad similarities in the postmarketing safety reporting
regulations for drugs, devices, and biological products and industry's
familiarity and experience with current postmarketing safety reporting
requirements, the most appropriate approach would be to rely on
existing rules and to explain how to comply with them.
FDA is issuing this final rule to ensure appropriate and consistent
PMSR requirements for combination products that have received FDA
marketing authorization by describing how combination product
applicants and constituent part applicants must comply with the PMSR
regulations for drugs, devices, and biological products, and also to
eliminate unnecessary PMSR requirements for such combination products.
B. The Proposed Rule
Entities subject to the proposed rule included those subject to
PMSR duties under 21 CFR parts 314, 600, 606, and 803, except for user
facilities and distributors as defined under part 803.
Those four sets of regulations expressly address PMSR for: (1)
Drugs (part 314); (2) biological products (parts 600 and 606); and (3)
devices (part 803). These sets of regulations have certain
similarities. For example, the PMSR regulations for biological
products, devices, and drugs each requires reports of death and other
serious adverse events; each provides for expedited reporting for
certain types of safety events; and each provides for followup and non-
expedited reports. However, there are also certain significant
differences in these sets of regulations designed, in part, to address
the distinct characteristics and potential safety issues related to a
particular type of product (i.e., drug, device, and biological
product).
Accordingly, we proposed to require that entities comply with the
PMSR requirements associated with the combination product's application
type (e.g., requirements under part 314 for a combination product
approved under a new drug application (NDA), or under part 803 for a
combination product approved under a premarket approval application
(PMA)) and also comply
[[Page 92606]]
with certain specified additional reporting provisions that are not
associated with that application type but are associated with a
constituent part(s) of the combination product. The additional
reporting requirements specified in the proposed rule were: (1) 5-Day
reports under Sec. 803.53; (2) device malfunction reports under Sec.
803.50; (3) 15-day ``alert reports'' for drugs and biological products
under Sec. Sec. 314.80 and 600.80; (4) field alert reports for drugs
under Sec. 314.81; and (5) expedited blood fatality reports under
Sec. 606.170. The Agency identified these five types of reports as
addressing particular safety issues related to the type of article
(drug, biological product, and device) and, therefore, appropriate to
apply to combination products that include that type of article
regardless of the application type for the combination product, to
ensure consistent and appropriate PMSR for the combination product.
The proposed rule also addressed circumstances in which the
constituent parts of a combination product are marketed under separate
applications, or are legally marketed by different reporters without
separate applications. For constituent parts marketed under separate
applications, we proposed that the reporter must comply with the
reporting requirements associated with that application type. In
addition, we proposed for constituent parts marketed under separate
applications held by different entities or legally marketed by separate
entities without an approved or cleared marketing application, that
each of these entities would have a duty to share within 5 calendar
days information it receives about the event, either with the other
entity or entities for the combination product or with FDA. We further
proposed that entities that receive postmarketing safety information
from another such entity, would have to investigate the event and
comply with applicable reporting obligations under the rule.
We proposed that reporters submit their reports and maintain
records for them in accordance with the requirements of the underlying
regulations from which the reporting duty arises (parts 314, 600, 606,
or 803).
Following publication of the proposed rule, FDA participated in a
workshop on January 21, 2010, entitled ``Understanding Implications of
the Postmarket Safety for Combination Products Proposed Rule,''
sponsored by the Advanced Medical Technology Association, the
Combination Products Coalition, and the Regulatory Affairs Professional
Society. At this workshop, the Agency provided a summary of the
proposed rule, and stakeholders then worked in groups to identify
issues on which to comment.
II. Overview of the Final Rule
The final rule follows the approach presented in the proposed rule,
with certain simplifications, clarifications, additions, and other
changes, generally made in light of comments received, as described in
sections II.A through II.F. The goal of the final rule remains the same
as for the proposed rule, to ensure consistent and appropriate
postmarketing safety reporting for combination products, while enabling
this reporting to be as efficient as possible. Accordingly, this
rulemaking seeks to apply those postmarketing safety reporting
requirements to combination products necessary to ensure their safety
and effectiveness, clarify how to comply with reporting requirements
applicable to combination products, and enable efficiencies including
submission of a single report if multiple reporting duties apply to an
event. Following is a section-by-section overview of the final rule,
and then a summary chart of the requirements presented in the rule.
A. Section 4.100--What is the scope of this subpart?
The scope of the rule remains largely the same as proposed. As in
the proposed rule, Sec. 4.100(a) reflects that the rule describes PMSR
requirements for combination products. We have revised Sec. 4.100(a)
to clarify that the rule only applies to ``combination product
applicants'' and ``constituent part applicants'' (as defined in Sec.
4.101); this rule does not apply to any other entities. We have also
revised Sec. 4.100(b) to clarify that the rule does not apply to
investigational combination products or to combination products that
have not received marketing authorization. We have eliminated proposed
Sec. 4.102 as that section was largely duplicative of proposed Sec.
4.100.
B. Section 4.101--How does FDA define key terms and phrases in this
subpart?
We eliminated unnecessary definitions, including terms not used in
this final rule. We also simplified certain definitions, using cross-
references to definitions provided in other provisions of Title 21 of
the CFR without restating those definitions. We made these changes for
clarity and to minimize the need for amendments to this rule if a
change is made in the future to the terminology or definitions in the
cross-referenced provisions.\2\
---------------------------------------------------------------------------
\2\ We understand that provisions cross-referenced in this rule
may be revised in the future, and we want to ensure that it is clear
that those provisions as revised continue apply to combination
products under this rule, without having to amend this rule each
time to provide such clarity. However, if the Agency determines that
a future revision to a cross-referenced provision is not appropriate
to apply to combination products under this rule, or its application
to combination products is unclear under this rule, we intend to
amend this rule or otherwise clarify.
---------------------------------------------------------------------------
The final rule newly includes definitions for ``biological product
deviation report'' (BPDR) (by reference to Sec. Sec. 600.14 and
606.171), and ``correction or removal report'' (by reference to 21 CFR
806.10), because the final rule incorporates these reporting
requirements as discussed in relation to Sec. 4.102(c) in section
III.C. Similarly, we added a definition for ``Product Development
Protocol'' (PDP) (by reference to section 515(f) of the FD&C Act (21
U.S.C. 360e(f))) and de novo classification request (by reference to
section 513(f)(2) of the FD&C Act (21 U.S.C. 360c(f)(2))) because the
final rule addresses these types of applications.
In addition, we included definitions for ``applicant'',
``combination product applicant'', ``constituent part applicant'', and
``device application'' to help clarify which entities are subject to
which duties under this rule. Specifically, we clarified that an
applicant is the person holding an application under which a
combination product or constituent part has received marketing
authorization, and that there is a combination product applicant if
there is one applicant that either holds the application for a
combination product or, holds the applications for each constituent
part if the constituent parts of the combination product are marketed
under separate applications (as could be the case for the constituent
parts of a cross-labeled combination product). We also clarified that a
constituent part applicant is the applicant for a constituent part of a
combination product the constituent parts of which marketed under
applications held by different applicants. We defined the term ``device
application'' to mean a PMA, PDP, humanitarian device exemption (HDE),
de novo classification request (request for classification under
section 513(f)(2) of the FD&C Act), or premarket notification (510(k))
submission, so that we could simplify and clarify the rule by using
this term to refer to all such submission types, rather than listing
them each, where appropriate in the rule.
[[Page 92607]]
C. Section 4.102--What reports must you submit to FDA for your
combination product or constituent part?
The requirements listed in Sec. 4.102 include those that were in
Sec. 4.103 of the proposed rule with certain adjustments and
additional requirements to address, in part, comments received on the
proposed rule.
Specifically, we have eliminated the requirement to comply with
blood fatality reporting requirements as described in Sec. 606.170 for
combination products that received marketing authorization under an
application other than a biologics license application (BLA). We have
also revised the requirement for all combination product applicants to
submit 15-day reports as described in Sec. Sec. 314.80 and 600.80, to
permit these reports to be submitted within 30 days rather than 15 days
for combination products that received marketing authorization under a
device application.
In addition, we have incorporated BPDR and correction and removal
reporting requirements for combination product applicants to ensure
that the issues addressed by these reporting requirements, for
biological products and devices, respectively, are also addressed for
combination products that include these types of constituent parts. We
have also made other adjustments in Sec. 4.102 for clarity.
Following is a description of Sec. 4.102 as finalized, including
explanations of changes from Sec. 4.103 of the proposed rule.
1. Section 4.102(a)
A new Sec. 4.102(a) clarifies that all applicants must comply with
the applicable PMSR requirements with respect to their product. A
constituent part applicant must comply with applicable requirements for
the constituent part it is marketing, and a combination product
applicant must comply with applicable requirements for the combination
product it is marketing.
2. Section 4.102(b)
As in Sec. 4.103(a) of the proposed rule, Sec. 4.102(b) lists the
PMSR requirements that apply based on the application type for the
product. Section 4.102(b) clarifies that combination product applicants
and constituent part applicants must comply with the requirements
identified under Sec. 4.102(b)(1) through (3) that are applicable
based on their product's application type. In addition, Sec. 4.102
clarifies that this rule does not require a combination product
applicant to submit multiple reports relating to the same event when
one report could be used to satisfy both Sec. 4.102(b) and (c).
Specifically, if the applicant has submitted one type of report and
that report: Includes all of the information that would also be
required in another type of report; is required to be submitted in the
same manner under this rule as that other report; and is submitted
within applicable deadlines, the submission of the single report will
be considered to satisfy both reporting obligations.
The requirements of Sec. 4.102(b) are as follows:
a. Section 4.102(b)(1). Combination product applicants and
constituent part applicants must comply with the PMSR requirements
under parts 803 and 806 if their product received marketing
authorization under a device application.
b. Section 4.102(b)(2). Combination product applicants and
constituent part applicants must comply with the PMSR requirements
under part 314 if their product received marketing authorization under
an NDA or abbreviated new drug application (ANDA).
c. Section 4.102(b)(3). Combination product applicants and
constituent part applicants must comply with the PMSR requirements
under parts 600 and 606 if their product received marketing
authorization under a BLA.
3. Section 4.102(c)
This provision applies only to combination product applicants, not
to constituent part applicants. It states which requirements
combination product applicants must meet in addition to those
associated with the product's application type, to ensure consistent
and appropriate PMSR for combination products. Like Sec. 4.102(b), it
also states how applicants can submit a single report to comply with
multiple reporting requirements.
As indicated previously, Sec. 4.102(c) does not require blood
fatality reporting for combination products that received marketing
authorization under a device application, NDA, or ANDA, and permits
combination product applicants for combination products that received
marketing authorization under a device application to submit 15-day
reports within 30 days rather than 15 days.
We removed the requirement under this rule to make blood fatality
reports for combination products that received marketing authorization
under a device application, NDA, or ANDA, because facilities at which
such events occur are currently required to make blood fatality reports
irrespective of the type of application under which the product
received marketing authorization. Because these facilities must make
such reports, we concluded that it would be unnecessary for a
combination product applicant (who is not also the operator of the
facility) to report the same information as well.
In light of comments received (as discussed more fully in response
to Comments 7, 8, 10), we modified the 15-day report requirement to
permit these reports to be made within 30 days for combination products
that received marketing authorization under a device application. We
made this change based on several factors, including the following. We
determined that the Agency would continue to be able to respond in a
timely manner to these reports if submitted within 30 days rather than
15 days for such combination products. Further, we determined that
permitting such reports to be made within 30 days would enable better
alignment of reporting for device-led combination products because this
timing would be consistent with the timing for submission of medical
device reports. This alignment could be expected to improve the
efficiency, clarity and completeness of reports for this class of
combination products and to eliminate unnecessary complexity and
potential for confusion.\3\
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\3\ We considered whether to make a corresponding change for
combination products that received marketing authorization under an
NDA or ANDA (drug-led combination products) or under a BLA
(biologic-led combination products), to require that malfunction
reports be submitted within 15 days to align with the deadline for
15-day reports, in the interest of simplifying and clarifying
requirements for such combination product applicants as well.
However, we determined that the nature of events triggering, and the
information required for, malfunction reports might make it
difficult to provide a meaningful report within 15 days in some
cases. As indicated in the final rule, if an event triggers both a
15-day report and a malfunction report for such a combination
product, the combination product applicant can opt to comply with
both reporting requirements in a single report submitted within 15
days. If the applicant determines that additional time is needed to
investigate the device malfunction, the applicant can submit a
followup report to the initial 15-day report with the additional
information.
---------------------------------------------------------------------------
Section 4.102(c) includes additional reporting requirements not in
the proposed rule to address specific safety concerns related to
medical devices and biological products. Combination product applicants
must submit correction and removal reports as described in Sec. 806.10
and comply with related recordkeeping requirements as described in
Sec. 806.20 for combination products that include a device constituent
part; and combination product applicants must submit BPDRs
[[Page 92608]]
as described in Sec. Sec. 600.14 and 606.171 for combination products
that include a biological product constituent part. Having considered
the unique safety issues that these additional requirements address in
light of comments received, we concluded that this rule should ensure
that these additional requirements are addressed by all combination
product applicants for combination products that include constituent
parts to which these requirements relate.
In many cases, correction and removal reporting requirements arise
in relation to manufacturers' recalls in response to adverse events
that may also trigger medical device reporting requirements under part
803. In such cases, submission of a medical device report (MDR) that
contains all the information required by part 806 will suffice to
comply with both sets of reporting requirements. Under Sec. 806.10(f),
no separate correction or removal report is required to be submitted if
a report of the correction or removal has been submitted under part
803. However, in some instances, a correction or removal will not be
associated with a reportable adverse event, or the action that a
manufacturer takes in response will not trigger a 5-day reporting
requirement, but the action must still be reported as described in part
806 to ensure, in part, appropriate coordination between the
manufacturer and the Agency. In such cases, the correction or removal
report currently should be submitted to the appropriate Agency field
office.
Further, some corrections and removals may not trigger reporting
requirements under part 803 or part 806, but may trigger recordkeeping
requirements under part 806, and these recordkeeping requirements must
be satisfied for combination products that include a device constituent
part. Accordingly, we have incorporated the correction and removal
reporting and recordkeeping requirements under Sec. 4.102(c) to ensure
that combination product applicants comply with these requirements.
With respect to BPDRs, as discussed more fully in response to
Comment 13 in section III, we concluded that these reports are akin to
field alert reports for drugs, and that it was important for BPDRs to
be submitted for combination products that include biological product
constituent parts to enable the applicant and the Agency to address the
deviation in a timely, appropriate manner. Further, we note that in
most instances, a biological product deviation that is reportable under
Sec. Sec. 600.14 and 606.171 is not associated with an adverse
experience. Accordingly, we have included in Sec. 4.102(c) BDPR
requirements for all combination product applicants whose combination
products contain a biological product constituent part.
The requirements applicable to combination products applicants
under Sec. 4.102(c) are now specified as follows:
a. Section 4.102(c)(1). Combination product applicants whose
combination products received marketing authorization under a BLA, NDA,
or ANDA and include a device constituent part must also submit: (i) 5-
Day reports as described in Sec. Sec. 803.3 and 803.53 and
supplemental or followup reports as described in Sec. 803.56; (ii)
Malfunction reports as described in Sec. 803.50 and supplemental or
followup reports as described in Sec. 803.56; and (iii) Correction or
removal reports as described in Sec. 806.10 and comply with
recordkeeping requirements as described in Sec. 806.20.
b. Section 4.102(c)(2). Combination product applicants whose
combination products received marketing authorization under a BLA or a
device application and include a drug constituent part must also
submit: (i) Field alert reports as described in Sec. 314.81 and (ii)
15-day reports and followup reports as described in Sec. 314.80,
within 30 calendar days instead of 15 calendar days if the combination
product received marketing authorization under a device application.
c. Section 4.102(c)(3). Combination product applicants whose
combination products received marketing authorization under an NDA,
ANDA, or device application, and include a biological product
constituent part must also submit: (i) BPDRs as described in Sec. Sec.
600.14 and 606.171 and (ii) 15-day reports and followup reports as
described in Sec. 600.80, within 30 calendar days instead of 15
calendar days if the combination product received marketing
authorization under a device application.
4. Section 4.102(d)
This provision replaces and has been revised as compared to
proposed Sec. 4.103(c) to: (a) Clarify that it applies only to
combination product applicants; (b) identify the content expected in
periodic safety reports for combination products that received
marketing authorization under an NDA, ANDA, or BLA; and (c) provide
that additional reporting is required for combination products that
received marketing authorization under a device application only upon
notification by the Agency if the Agency determines additional or
clarifying safety information is required to protect the public health.
Section 4.102(d) has two paragraphs stating the following requirements:
a. Section 4.102(d)(1). Combination product applicants for
combination products that received marketing authorization under an
NDA, ANDA, or BLA must include in their periodic safety reports, in
addition to information required under Sec. 314.80 or 600.80,
respectively, a summary and analysis of reports that the applicant
submitted in accordance with Sec. 4.102(c)(1)(i) and/or (ii) (5-day
and malfunction reporting requirements).
b. Section 4.102(d)(2). Combination product applicants for
combination products that received marketing authorization under a
device application do not have to make periodic reports under this rule
but must submit additional reports regarding postmarketing safety
events in accordance with written requests by the Agency that will be
made only if the Agency determines that protection of the public health
requires additional or clarifying safety information. Any such written
request will specify the safety information to include in such reports
and the reason or purpose for the request.
D. Section 4.103--What information must you share with other
constituent part applicants for the combination product?
As discussed more fully in response to Comment 18 in section III,
the final rule makes clear that the duties to share information within
5 calendar days under Sec. 4.103 (replacing Sec. 4.104 in the
proposed rule) apply only to constituent part applicants. In addition,
we clarified and simplified these requirements. Constituent part
applicants must share only information they receive regarding events
that involve a death or serious injury within the meaning of Sec.
803.3 or an adverse experience within the meaning of Sec. 314.80(a) or
Sec. 600.80(a), and must share this information only with each other;
we have eliminated the alternative of sharing the information with FDA
as unnecessary and inefficient. Also, we have removed as unnecessary
the content of proposed Sec. 4.104(b) regarding how to respond to
information received from another constituent part applicant. Section
4.102(b) states which PMSR requirements apply to constituent part
applicants, and those PMSR requirements prescribe under what
circumstances an entity subject to them must submit a report regarding
information that the entity receives.
[[Page 92609]]
We have added a new Sec. 4.103(b) addressing recordkeeping for
this information sharing duty. This provision has been added to provide
constituent part applicants appropriate clarity and certainty regarding
what records to keep and what documentation the Agency will consider
adequate to demonstrate compliance with the information-sharing
requirement.
E. Section 4.104--How and where must you submit postmarketing safety
reports for your combination product or constituent part?
This section has been revised as compared to proposed Sec. 4.105,
to clarify where and how to submit postmarketing safety reports for
constituent part applicants (Sec. 4.104(a)) and combination product
applicants (Sec. 4.104(b)).
1. Section 4.104(a)
Constituent part applicants must make all reports in accordance
with the existing regulations applicable to that type of product (for
example, making reports in accordance with the requirements of part 314
if the constituent part is a drug). Like an applicant for a non-
combination product, a constituent part applicant holds an application
for a single type of article (drug, device, or biological product) and
is required to make postmarketing safety reports to FDA only for events
concerning its product. Accordingly, these reports are most
appropriately submitted to the same Agency components in the same
manner as they would be by any applicant holding an application for the
same type of product.
2. Section 4.104(b)
Combination product applicants are required to submit postmarketing
safety reports concerning the combination product, including each of
that combination product's constituent parts. The nature of the events
and the appropriate Agency component to contact regarding them can vary
however. In light of these considerations, Sec. 4.104(b) draws a
distinction between individual case study reports (ICSRs) (Ref. 3) for
safety events experienced by individual users of combination products
\4\ and other safety reports.
---------------------------------------------------------------------------
\4\ ``Individual case study report'' or ICSR is the
internationally recognized term of art referring to reports of an
adverse event, including a malfunction, experienced by an individual
user of the product. This term is used to refer to such reports in
international standards, and FDA implementing materials, regarding
proper methods for submitting ICSRs to regulatory bodies for drugs,
biologics, and devices.
---------------------------------------------------------------------------
Section 4.104(b) requires that combination product applicants must
submit all ICSRs (15-day reports, malfunction reports, serious injury
or death reports, and 5-day reports) applicable to the combination
product in the manner specified in the PMSR regulations associated with
the application type for the combination product. See Sec. Sec.
4.104(b)(1) and (2).
This approach to submission of ICSRs by combination product
applicants best assures the clarity, completeness, and efficiency of
such reporting. Having all ICSRs submitted in the same manner to the
Center with the lead for the application enables multiple reporting
requirements for an event to be satisfied by submitting a single report
and ensures that all such reports relating to the same event will be
captured in a single series (see also response to Comment 24).
In addition, under Sec. 4.104(b), all BPDRs, field alert reports,
and correction and removal reports must be submitted as described in
the regulations from which these reporting requirements arise. The
Agency currently receives these reports through differing mechanisms
and Agency components based on such factors as logistical
considerations and expertise to take the lead in assessing and
addressing the issues raised in the report. For example, field alert
reports for drugs currently must be submitted to FDA district offices
as described in part 314, and BPDRs currently must be submitted to the
Center for Biologics Evaluation and Research (CBER) or the Center for
Drug Evaluation and Research (CDER) as appropriate based on which of
these two Centers would ordinarily have jurisdiction over the type of
biological product included in the combination product, as described in
parts 600 and 606. These existing reporting systems are designed to
assure timely, effective resolution of the matters raised in these
reports.
As discussed in response to Comment 28 and in section III.A., the
Agency anticipates issuing a guidance to provide recommendations on how
applicants may adopt more streamlined, effective approaches to making
reports under this rule.
F. Section 4.105--What are the postmarketing safety reporting
recordkeeping requirements for your combination product or constituent
part?
As discussed more fully in section III, response to Comment 26, we
revised this section (replacing Sec. 4.106 in the proposed rule) to
clarify and simplify the recordkeeping requirements associated with
PMSR obligations for combination product applicants and constituent
part applicants. Section 4.105(a) describes the recordkeeping
requirements for constituent part applicants and Sec. 4.105(b)
describes the requirements for combination product applicants, as
follows:
1. Section 4.105(a)
Constituent part applicants must comply with the recordkeeping
requirements prescribed in the underlying PMSR regulations identified
in Sec. 4.102(b) as applicable to the product based on its application
type. In addition, they must retain the records required in Sec. 4.103
(information sharing) for the longest retention period (if more than
one period applies) required for records under the PMSR regulations
applicable to their constituent part (as explained in response to
Comment 26).
2. Section 4.105(b)
Combination product applicants must maintain records relating to
their postmarketing safety reports for whichever is the longest
required record-keeping period under the PMSR requirements applicable
to the combination product applicant under Sec. 4.102. Because both
parts 314 and 600 currently require recordkeeping for 10 years, at this
time the recordkeeping period for combination product applicant PMSR
records would be at least 10 years.
[[Page 92610]]
Table 1--Requirements for BOTH Constituent Part Applicants and Combination Product Applicants \1\
[See Sec. 4.102(b) of this rule]
----------------------------------------------------------------------------------------------------------------
Application Types
--------------------------------------------------
Source of PMSR requirements Device
ANDA/NDA BLA application
----------------------------------------------------------------------------------------------------------------
Part 314..................................................... X ............... ...............
Part 600..................................................... ............... X ...............
Part 606..................................................... ............... X ...............
Part 803..................................................... ............... ............... X
Part 806..................................................... ............... ............... X
----------------------------------------------------------------------------------------------------------------
\1\ In addition to the requirements in table 1, constituent part applicants must share certain adverse event
information with other constituent part applicant(s) for the combination product. (See Sec. 4.103 of this
rule).
Table 2--Additional Requirements ONLY for Combination Product Applicants \1\
[See Sec. 4.102(c) of this rule]
----------------------------------------------------------------------------------------------------------------
Application Type
--------------------------------------------------
Combination product includes Reporting requirement Device
ANDA/NDA BLA application
----------------------------------------------------------------------------------------------------------------
Drug.............................. Sec. 314.81, Field See table 1 X X
Alert Reports.
Sec. 314.80, 15-Day ............... X X
Reports (initial and
followup).
Biologic.......................... Sec. Sec. 600.14 and X See table 1 X
606.171, Biological
Product Deviation
Reports.
Sec. 600.80, 15-day X ............... X
Reports (initial and
followup).
Device............................ Sec. Sec. 803.53 and X X See table 1
803.56, 5-Day Reports
(initial and
supplemental or
followup).
Sec. Sec. 803.50 and X X ...............
803.56, Malfunction
Reports (initial and
supplemental or
followup).
Part 806, Correction or X X ...............
Removal Reports and
Records.
----------------------------------------------------------------------------------------------------------------
\1\ In addition to the requirements in table 2, the rule addresses other reporting requirements for combination
product applicants as follows: (1) Combination products that received marketing authorization under an NDA,
ANDA, or BLA: Include a summary and analysis of malfunction (Sec. Sec. 803.50 and 803.56) and 5-day (Sec.
Sec. 803.53 and 803.56) reports submitted during the report interval in the periodic safety reports (see
Sec. 4.102(d)(1)) and (2) combination products that received marketing authorization under a device
application: Submit additional reports when notified by the Agency because FDA has determined the information
is required to protect the public health (see Sec. 4.102(d)(2)).
III. Comments on the Proposed Rule
We received comments from 15 entities and one individual on the
proposed rule. Commenters included trade organizations and
manufacturers of drugs, devices, biological products, and combination
products. Many commenters sought clarification on particular points or
recommended adjustments to specific aspects of the proposed rule.
Several commenters, while supporting rulemaking to address PMSR for
combination products, recommended alternative approaches as discussed
in Comment 27.
To make it easier to identify comments and our responses, the word
``Comment'' appears before the descriptions of the comments, and the
word ``Response'' appears before our response. We have also numbered
comments to help distinguish among them. The number assigned to each
comment is purely for organizational purposes and does not signify
relative value or importance of comments or the order in which they
were received. Certain comments are grouped together under a single
number because the subject matter of the comments was similar.
A. Section 4.100--What is the scope of this subpart?
(Comment 1) Some commenters sought clarification of safety
reporting requirements for investigational combination products through
guidance or expansion of the scope of the rule, including for
investigational combination products that contain a legally marketed
article as a constituent part. One commenter asked if the Agency is
planning to publish guidance on this issue. One commenter asked that
the Agency clearly lay out the responsibilities of the manufacturer of
an approved product in the investigational setting.
(Response 1) Safety reporting for investigational products is an
important issue for combination products, just as it is for drugs,
devices, and biological products. However, this rule only discusses the
PMSR requirements for combination products that have received marketing
authorization. As stated in Sec. 4.100(b), this rule does not apply to
investigational combination products. The safety reporting requirements
for investigational new drugs are in 21 CFR 312.32, and the safety
reporting requirements for investigational devices are in 21 CFR
812.150. The Agency intends to continue developing guidance relating to
this topic for combination products. If you have questions regarding
how to comply with the reporting requirements for your investigational
combination product, please raise them with the review division in
CDER, CBER, or the Center for Devices and Radiological Health (CDRH)
that is responsible for reviewing your application, or with the Office
of Combination Products (OCP) as needed.
(Comment 2) Some commenters requested that the Agency clarify which
entities and products are subject to this rule. Some commenters
proposed clarifying that this rule applies only to application holders.
Other commenters sought clarification of the rule's applicability to
devices marketed under a 510(k) clearance and to non-applicants,
including contract manufacturers. One commenter asked for clarification
of whether the rule
[[Page 92611]]
would apply to component suppliers. One commenter sought clarification
of which entities have reporting requirements under this rule for
combination products composed of constituent parts marketed under
separate applications. One commenter proposed that the Agency prepare a
comprehensive list of products by class, product code or other
designations that are subject to this rule.
(Response 2) As also discussed in section II (discussions of
Sec. Sec. 4.100 and 4.101), in light of comments received, we have
amended this rule to clarify which entities it addresses and what PMSR
requirements apply to them. We have clarified that this rule applies
only to ``combination product applicants'' and ``constituent part
applicants,'' as those terms are defined in Sec. 4.101. We also have
clarified the final rule to state which requirements apply to
combination product applicants and which apply to constituent part
applicants.
Under Sec. 4.101 of this rule, the term ``applicant'' is defined
to mean a person holding an application (BLA, NDA, ANDA, PMA, HDE, PDP,
de novo classification request or premarket notification (510(k))
submission) under which a combination product or constituent part has
received marketing authorization (see also definitions for
``application'' and ``device application''); ``combination product'' is
defined to mean a product meeting the definition for this term under
Sec. 3.2(e); and the term ``constituent part'' is defined as in Sec.
4.2 to mean a drug, device, or biological product that is part of a
combination product. The term ``combination product applicant'' is
defined to mean an applicant holding the application(s) for a
combination product (i.e., either holding the application for the
entire combination product or the applications for each constituent
part--in some cases the constituent parts of a combination product are
marketed under their own marketing authorizations, as might be the case
for a cross-labeled combination product for example), and ``constituent
part applicant'' is defined to mean an applicant for a constituent part
of a combination product the constituent parts of which are marketed
under applications held by different applicants. In other words, if a
single entity holds the application(s) under which a combination
product is marketed, that entity is the combination product applicant;
there are no constituent part applicants for that combination product.
If instead, one applicant receives marketing authorization to market a
constituent part of a combination product and another applicant
receives marketing authorization to market another constituent part of
that combination product, each of those entities is a constituent part
applicant for their constituent part of that combination product.
Importers, component manufacturers and suppliers, and any other
entities that do not meet the definition of combination product
applicant or constituent part applicant, are not subject to this
rule.\5\
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\5\ We note that all entities that are not subject to this rule
but that have reporting requirements under other regulations must
comply with those requirements, including, as appropriate, with
respect to events relating to a combination product. For example,
although they are not applicants under this rule, entities marketing
unapproved combination products must comply with all applicable PMSR
requirements, for instance under 21 CFR part 310, for their
products. Similarly, all entities subject to PMSR requirements under
parts 314, 600, 606, 803, and 806 must comply with those
requirements including for events relating to a combination product.
We note that non-applicants subject to reporting requirements
under 314.80 and 600.80 may provide their reports to the applicant
rather than the Agency. Similarly, non-applicants subject to
reporting requirements under part 803 may request a reporting
exemption from CDRH under Sec. 803.19. Accordingly, entities that
are not combination product applicants or constituent part
applicants, as those terms are defined under this rule (importers,
for example), who have reporting duties under part 803 in relation
to a combination product may request a reporting exemption, subject
to Sec. 803.19. We intend to provide further information on these
topics for combination products in guidance.
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To illustrate how these definitions are used to determine who is
subject to this rule, take the example of a prefilled syringe that
received marketing authorization under an NDA or ANDA held by entity A,
which purchases the syringe components for this product from entity B,
which manufactures the syringe components. Entity A is the only
applicant for the combination product, and, therefore, is the
combination product applicant and must comply with the provisions of
this rule applicable to combination product applicants. There are no
constituent part applicants for the combination product. Entity B has
no reporting duties under this rule (nor does it have any under part
803 or 806 for the syringe components \6\). (It bears noting that
entity A is responsible not only for reporting but also for conducting
any necessary quality investigations for the combination product as a
whole and may need to coordinate with entity B for such investigations
and to address safety issues relating to the device constituent part
for the combination product.) If entity B were also to manufacture and
separately market under a 510(k) complete, finished, empty syringes,
not as part of a combination product, entity B would be subject to
reporting requirements under parts 803 and 806, but would not be
subject to this rule for this device. Entity A would remain the sole
applicant for the combination product, i.e., the combination product
applicant. Similarly, if entity B manufactured syringes to supply to
entity A for inclusion in kits for which entity A received marketing
authorization under an NDA or ANDA, entity A would still be the sole
applicant for the combination product, i.e., the combination product
applicant, since it holds the NDA or ANDA under which the kits received
marketing authorization, and, therefore, only entity A would be subject
to this rule.
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\6\ Parts 803 and 806 apply to, among others, device
``manufacturers,'' and under Sec. Sec. 803.3 and 806.2, device
``manufacturers'' include entities that manufacture components which
are devices that are ready to be used and are intended to be
commercially distributed and intended to be used as is, or are
processed by a licensed practitioner or other qualified person to
meet the needs of a particular patient.
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To take another example, if entity C receives marketing
authorization under a PMA or 510(k) to market an imaging device as a
constituent part of a cross-labeled combination product, and entity D
receives marketing authorization under an NDA or ANDA to market a
contrast agent drug as a constituent part of that same cross-labeled
combination product, then entities C and D are both constituent part
applicants, and both are subject to the provisions of this rule
applicable to constituent part applicants. There is no combination
product applicant for this product.
Regarding one commenter's request for the Agency to develop a
comprehensive list of products subject to this rule, we note that
combination products are marketed for diverse medical purposes and
include a wide variety of constituent parts, making a comprehensive
listing impractical to compile. The definition of combination product
is provided at Sec. 3.2(e), and additional information regarding
product classification is available on the Web page for OCP. In
addition, regulated entities may seek feedback from OCP regarding the
classification of their products, including by submitting a request for
designation (RFD) in accordance with part 3 to obtain a formal decision
from the Agency of whether their product is a drug, device, biological
product, or combination product. Guidance for how to prepare an RFD is
available on OCP's Web page (https://www.fda.gov/CombinationProducts/default.htm).
[[Page 92612]]
B. Section 4.101--How does FDA define key terms and phrases in this
subpart?
(Comment 3) One commenter thought we should clarify what we mean by
``combination product,'' and in particular whether we mean to include
products that combine only two or more of the same type of article,
such as a drug and a drug.
(Response 3) This rule defines combination products as those
products falling within the scope of Sec. 3.2(e). Under Sec. 3.2(e),
a combination product must include: A drug and either a device or
biological product; a device and either a drug or biological product; a
biological product and either a drug or device; or a drug, device, and
a biological product. A product that includes only multiple drugs,
multiple devices, or multiple biological products is not a combination
product as defined in Sec. 3.2(e).
(Comment 4) Some commenters proposed that we clarify what products
fall within the scope of ``cross-labeled'' combination products as
described in Sec. 3.2(e)(3), with some noting that the preamble to the
part 3 regulation (56 FR 58754, November 21, 1991) states that most
drugs, devices, and biological products intended for concomitant use
are not combination products. One commenter stated that the Agency must
issue ``guidance on cross-labeled combination products'' before the
effective date of this rule ``for meaningful implementation of this
rule.''
(Response 4) While we disagree that we must issue guidance on
cross-labeled combination products prior to the effective date for this
final rule, we agree that clarifying when separately distributed
articles constitute a combination product would be helpful. This issue
may be relevant not only for purposes of postmarketing safety
reporting, but to all aspects of the regulation of such combination
products. Whether a drug, device, and/or biological product together
constitute a cross-labeled combination product generally would be
determined during the premarket review process, but sponsors may, for
example, wish to clarify the matter earlier in product development. If
sponsors have questions regarding whether a drug, device, and/or
biological product that are intended to be separately distributed, but
intended to be used with one another constitute a cross-labeled
combination product, we encourage them to contact OCP. If sponsors wish
to obtain a formal classification determination from the Agency, they
may submit an RFD to OCP (see Comment 2).
FDA intends to publish a guidance that provides recommendations on
how to comply with the requirements under this rule for combination
products, including cross-labeled combination products.
(Comment 5) Two commenters noted that the definition of
``constituent part'' incorrectly cited Sec. 3.1(e), a non-existent
provision, rather than Sec. 3.2(e), which is the citation for the
``combination product'' definition.
(Response 5) We have corrected this error by revising the
definition to cite to Sec. 4.2 as ``constituent part'' is defined in
that section.
(Comment 6) Some commenters expressed concerns regarding the
definition of ``constituent part'' for this rule and asked how
constituent parts of combination products compare to components of
devices. Some commenters specifically raised concerns that the
definition of constituent part would result in certain entities, which
are currently not subject to reporting requirements, becoming subject
to PMSR requirements under this rule. Some commenters proposed revising
the definition for ``constituent part'' and adding a definition for
``component'' in this rule to clarify that components of drugs,
devices, and biological products are not constituent parts.
(Response 6) The purpose of the term ``constituent part'' is to
identify the drug, device, and/or biological products that are part of
a combination product. We believe the questions and concerns raised in
these comments are fully addressed by the revisions we have made to the
rule. As discussed in sections II.A and B (discussions of Sec. Sec.
4.100 and 4.101) and in response to Comment 2, we have included
definitions of ``combination product applicant'' and ``constituent part
applicant,'' and clarified that this rule applies only to these two
categories of entities.
The term ``component'' is defined elsewhere in Title 21 for drugs
and devices (see 21 CFR parts 210, 212, and 820). Because the term
``component'' is not used in this rule, we determined it is not
necessary to define the term as part of this rulemaking.
C. Section 4.102--What reports must you submit to FDA for your
combination product or constituent part?
(Comment 7) Several commenters requested that the Agency clarify
under what circumstances this rule might require the submission of
multiple reports in relation to the same event. In this regard, some
commenters sought clarification of what reports ``supersede'' others
and under what circumstances the submission of one type of report
applicable to a combination product would obviate the need to submit a
second type of report for the same event. Another commenter sought
clarification of reporting requirements for combination products
comprised of constituent parts marketed under separate constituent part
applications.
(Response 7) Under this rule, combination product applicants and
constituent part applicants must submit reports as required by the PMSR
requirements applicable to that applicant under Sec. 4.102.
Constituent part applicants are subject to only one set of PMSR
requirements under this rule (in addition to the duty to share
information with other constituent part applicants for the combination
product, in accordance with Sec. 4.103 as discussed in section II.D).
Specifically, constituent part applicants must comply only with the
PMSR requirements listed under Sec. 4.102(b) based on the application
type for their constituent part (e.g., parts 803 and 806 PMSR
requirements if the constituent part received marketing authorization
under a device application). Combination product applicants also must
comply with the PMSR requirements applicable to their combination
product under Sec. 4.102(b) based on the application type for their
combination product. In addition, combination product applicants must
comply with the PMSR requirements identified in Sec. 4.102(c) as
applicable based on the types of constituent parts (drug, device, and/
or biological product) that the combination product includes.
We have clarified when a single report may suffice to comply with
more than one reporting requirement for combination product
applicants.\7\ If a combination product applicant submits a report that
satisfies multiple applicable reporting requirements, including all
submission deadlines, for reports required to be submitted in the same
manner, then the applicant does not need to submit any additional
reports to satisfy those reporting requirements. As an example, a
combination product applicant who holds an NDA for a drug-device
combination product must submit both
[[Page 92613]]
15-day reports as described in Sec. 314.80 and malfunction reports as
described in Sec. 803.50, for an event that triggers both duties. That
applicant could satisfy both requirements by submitting a single report
within 15 days that includes all of the information that would be
required in both types of reports for the event.
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\7\ Constituent part applicants are subject only to the PMSR
regulations applicable to their type of constituent part (drug,
device, or biological product) (in addition to the duty to share
information with other constituent part applicants for the
combination product, in accordance with Sec. 4.103 of this rule, as
discussed elsewhere in this preamble). Accordingly, any
circumstances under which they may be able to comply with more than
one reporting requirement through a single report are identified in
those PMSR regulations (see, e.g., Sec. 806.10(f)).
---------------------------------------------------------------------------
(Comment 8) Some commenters sought clarification of the standards
for submitting a report under this rule. One commenter requested
clarification of whether limitations established under Sec. Sec.
314.80 and 600.80 for 15-day reporting requirements with respect to
postmarketing studies apply to combination products under this rule.
Other commenters sought clarification of the standard for when to
submit an expedited report under Sec. 314.80 or Sec. 600.80, which
state that events must be reported if ``associated with'' the use of
the product, ``whether or not considered'' drug or biologic related.
Other commenters requested clarification of how to interpret aspects of
the device reporting standards in part 803, such as the meaning of
``reasonably suggests'' in relation to whether the event is reportable,
the meaning of ``unreasonable risk of substantial harm to the public
health'' in relation to 5-day reports, and the meaning of ``caused or
contributed,'' a term defined under Sec. 803.3.
(Response 8) The standards in this rule for when to submit a report
are those established in the underlying PMSR regulations listed in
Sec. 4.102(b) and (c), including any exceptions provided in those
underlying regulations. The standards and definitions for the
underlying PMSR requirements, such as the definition of ``caused or
contributed'' in Sec. 803.3, remain applicable for combination
products and their constituent parts.
For instance, if you are a combination product applicant for a
drug-device combination product, in deciding whether you must submit a
15-day report for a serious, unlabeled adverse event, you must
determine if the event was ``associated with'' the use of the
combination product, and if so, you must submit the report regardless
of whether you believe the combination product caused or contributed to
the event. Similarly, in deciding whether you must submit a malfunction
report, you must assess, among other things, whether the information
``reasonably suggests'' that the product malfunctioned. If the
information does not ``reasonably suggest'' that a malfunction
occurred, then a malfunction report would not be required.
If you are a combination product applicant and your combination
product received marketing authorization under a device application, in
deciding whether you must submit a serious injury or death report, you
must consider whether the information ``reasonably suggests'' that the
combination product may have caused or contributed to the death or
serious injury in which case you must submit a report even if the event
does not trigger submittal of a 15-day report.
In some cases, a report required under Sec. 4.102(c) for a
combination product applicant may address a constituent part; in
others, it may address the combination product as a whole. For example,
correction or removal that triggers a correction or removal report may
involve the entire combination product. Bacteriological contamination
or a significant change or deterioration to the drug constituent part
that triggers a field alert report may relate to an aspect of
manufacturing for the drug alone, or may also relate to an aspect of
the manufacture of the combination product as a whole that is affecting
the drug constituent part. A manufacturing deviation or other event
that may affect the safety, purity, or potency of a biological product
constituent part and trigger a BPDR may involve the biological product
alone, or the combination product as a whole. In all cases, the report
should fully present the issues, including with respect to each
constituent part and the combination product as a whole, as applicable,
to ensure an appropriate response to the event.
(Comment 9) One commenter sought clarification of what adverse
events would be considered ``unexpected,'' for purposes of Sec. Sec.
314.80 and 600.80 with regard to combination products. Another
commenter asked whether a serious adverse event that is expected under
the drug labeling for a combination product and that does not involve a
device malfunction should be reported in an expedited manner. In
relation to these issues, other commenters also raised whether this
rule will ``require labeling specific to the combination product,'' and
whether a distinct understanding of ``expectedness'' would need to be
developed with respect to combination products marketed under a device
application as opposed to an NDA or BLA due to differences in product
review and labeling.
(Response 9) Under this rule, a serious adverse event could trigger
a requirement for submission of a 15-day report as described in Sec.
314.80 or Sec. 600.80 by a combination product applicant or a drug or
biological product constituent part applicant if the event is not
listed in the current FDA-approved labeling for the combination
product.
While this rule does not establish any labeling requirements, we
recognize that there is a question of what labeling is relevant to a
determination of whether an adverse event is unexpected for purposes of
15-day reports described in Sec. Sec. 314.80 and 600.80, if the
constituent parts of the combination product have their own labeling.
Our goal is to ensure timely, complete reporting without creating
unnecessary redundancy of reporting. Combination product labeling must
meet the labeling requirements for each constituent part, including all
required information regarding the risks associated with the use of the
combination product. The term ``expectedness'' for purposes of Sec.
314.80 or Sec. 600.80 should be interpreted in the same manner
regardless of the type of application(s) under which the combination
product received marketing authorization.
Accordingly, in determining whether an adverse experience is
unexpected, it is appropriate to consider all of the FDA-approved
labeling for the combination product. For example, if the constituent
parts of a cross-labeled combination product have their own labeling,
and the event is addressed in the labeling for either constituent part,
the event is expected for the combination product.
(Comment 10) One commenter proposed that the requirements for
submitting postmarketing 15-day reports and MDRs be consolidated for
combination products, arguing that this would eliminate duplicative
reporting as much as possible and improve efficiency. Other commenters
proposed applying only the reporting requirements associated with the
application type if it is unclear which constituent part or parts
contributed to the event.
(Response 10) We agree with the goal of consolidating requirements
and avoiding unnecessary redundancy in reporting for combination
products. To this end, we have not required submission of serious
injury and death reports under part 803 for combination products that
received marketing authorization under a BLA, NDA, or ANDA and that
include a device constituent part, based on the premise that the
requirements of Sec. Sec. 600.80 and 314.80, respectively, ensure
timely reporting of such events for such combination products. In
addition, as discussed in section II.C, discussion of Sec. 4.102(c),
we have revised the requirement for combination product
[[Page 92614]]
applicants to submit 15-day reports to permit these reports to be
submitted within 30 days for combination products that received
marketing authorization under a device application, so that the timing
for these reports corresponds to the timing for related MDRs for such
combination products, specifically serious injury, death, and
malfunction reports. Further, we have clarified that applicants need
not submit multiple types of reports for the same event if they are
able to satisfy the requirements of each in a single report.
As discussed in the preamble to the proposed rule, there are
certain significant differences in the PMSR regulations for drugs,
devices, and biological products, that address distinct characteristics
and potential safety issues associated with the particular type of
product, and the public health benefit of these unique provisions would
be lost if the combination product were subject solely to the reporting
requirements associated with the application type (74 FR 50744 at
50746). For example, malfunction reports can address distinct issues
that are not captured by other reporting requirements and need to be
submitted for all combination products that include a device
constituent part. Specifically, malfunction reports ensure that the
Agency receives notice of malfunctions of combination products and
device constituent parts if that product or a similar one marketed by
that applicant would be likely to cause or contribute to a death or
serious injury if the malfunction were to recur.
(Comment 11) One commenter argued that the proposed rule included
provisions that could result in inconsistent reporting requirements.
This commenter stated that an applicant for a drug-device combination
product marketed under a single application would have a duty to
address adverse events caused by the device under 15-day reporting
requirements while, if a drug-device combination product were marketed
under separate applications for the drug and device, the 15-day
reporting requirements would extend only to the adverse events caused
by the drug.
(Response 11) This final rule clarifies these reporting
requirements, which we do not consider to be inconsistent. As the
commenter indicates, 15-day reports are required for combination
product applicants and for drug and biological product constituent part
applicants. The scope of these reporting requirements depends on the
type of product (drug, biological product, device, combination product)
that is marketed by the applicant. A combination product applicant must
report unexpected serious adverse events associated with its product,
i.e., the combination product. A drug or biological product constituent
part applicant must report unexpected serious adverse events associated
with its product, i.e., the drug or biological product, and also must
share information it receives with the other constituent part
applicant(s) for that combination product in accordance with Sec.
4.103. The other constituent part applicant(s) then must comply with
any applicable PMSR requirements for its product with respect to that
event, including preparation and submission of reports as appropriate.
(Comment 12) One commenter sought clarification of when the clock
starts for a 5-day report (as described in Sec. Sec. 803.3 and
803.53).
(Response 12) This rule does not affect or change when the clock
starts for reporting requirements. The clock starts for a 5-day report
for a combination product as it would for a device. As required under
Sec. 803.53(a), the clock begins when you become aware that a
reportable event necessitates remedial action to prevent an
unreasonable risk of substantial harm to the public health. Or, as
required under Sec. 803.53(b), the clock begins when you receive a
written request from FDA for the submission of a 5-day report.
Additional information on the timing requirements associated with 5-day
reports is in the CDRH guidance document ``Medical Device Reporting for
Manufacturers'' available at https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm359566.pdf.
(Comment 13) One commenter proposed BPDRs as an additional type of
required report to include among the specified required reports listed
in proposed Sec. 4.103(b), arguing that BPDRs serve a purpose similar
to field alert reports and, therefore, would be appropriate to include
as well.
(Response 13) We agree with this comment. To ensure the
completeness of postmarketing safety reports for combination products
that include a biological product constituent part, including
combination products that received marketing authorization under an
NDA, ANDA, or device application, we are explicitly including BPDRs
under Sec. 4.102(c). Similar to field alert reports for drugs, BPDRs
address events associated with manufacturing that represent a deviation
from current good manufacturing practice, applicable regulations,
applicable standards or established specifications, or represent an
unexpected or unforeseeable event that may affect the safety, purity,
or potency of the product. Therefore, we are adding BPDRs to the list
of types of reports under Sec. 4.102(c) that a combination product
applicant must submit if the combination product includes a biological
product constituent part.
(Comment 14) One commenter sought clarification of the application
of part 806 device correction and removal reporting requirements within
the proposed PMSR system for combination products. The commenter also
sought confirmation that part 806 reporting requirements can be met for
combination products through part 803 reporting, as they can for
devices that are not constituent parts of combination products.
(Response 14) To address this comment, we have expressly
incorporated under Sec. 4.102(c) correction and removal reporting
described in Sec. 806.10 and associated recordkeeping requirements
described in Sec. 806.20. We have made this change to provide clarity,
promote efficiency, and ensure the completeness of postmarketing safety
reports for combination products that include a device constituent
part.
Part 806 implements, in part, section 519(g) of the FD&C Act (21
U.S.C. 360i), which was enacted due to Congressional concern that
device manufacturers were carrying out product corrections or removals
without notifying FDA or not doing so in a timely fashion (H.R. Rep.
No. 101-808, at 29 (1990); S. Rep. No. 101-513, at 23 (1990)). Congress
explained that industry's failure to report corrections and removals,
particularly those undertaken to reduce risks associated with the use
of a device, ``denies the agency the opportunity to fulfill its public
health responsibilities by evaluating device-related problems and the
adequacy of corrective actions'' (S. Rep. No. 101-513, at 23), and
``has seriously interfered with the FDA's ability to take prompt action
against potentially dangerous devices'' (H. R. Rep. No. 101-808, at
29).
FDA believes that correction and removal reporting and
recordkeeping for combination products containing a device constituent
part is necessary to protect the public health as envisioned by
Congress, by ensuring that the Agency has current and complete
information regarding those actions taken by applicants to reduce risks
to health caused by their products. Reports of such actions will
improve the Agency's ability to evaluate problems and to take prompt
action against potentially dangerous combination products, regardless
of the type of
[[Page 92615]]
application under which the combination product received marketing
authorization.
As for all of the PMSR requirements incorporated into this rule by
reference, the standards for how to report under Sec. 806.10 and for
recordkeeping under Sec. 806.20 are not affected by this rule,
including not having to submit an 806 report if the correction or
removal is addressed in a report submitted under part 803 (Sec.
806.10(f)). To enable efficient reporting and avoid unnecessarily
redundant reports, this rule provides that part 803 reporting
requirements can be satisfied through submission of drug or biological
product reports, as explained in response to comment 7. Similarly, part
806 reporting requirements also can be satisfied through submission of
an MDR or 15-day report, so long as the report includes all of the
information needed to comply with the requirements of part 806 and is
filed within 10 working days of initiating the correction or removal,
as described in Sec. 806.10.
In circumstances in which a 15-day report or MDR is not triggered
but reporting under part 806 is required, reports of corrections or
removals should be sent to the FDA in the same manner as for other such
reports unless otherwise specified by the Agency. Currently, reports
required under part 806 are submitted to the district office for the
district in which the reporting facility is located, on the basis that
the district office can best monitor the firm's removal or corrections
activities in a timely fashion. Combination product applicants for
combination products with a device constituent part who initiate a
correction or removal that is not required to be reported to FDA under
806.10, must maintain a record of the correction or removal as
described in Sec. 806.20.
(Comment 15) Some commenters sought clarification of the
applicability of section 227 of the Food and Drug Administration
Amendments Act of 2007 (FDAAA) concerning the reporting of malfunctions
to FDA, including the use of summary reporting, for Class I devices and
for Class II devices that are not permanently implantable, life
supporting, or life sustaining. Some commentators sought clarification
of how the status of ``life-supporting'' or ``life-sustaining'' would
apply to combination products, and whether the intended use of the
combination product would determine the status of the device
constituent part. One commenter sought clarification of how such a
class-based approach would be applied to combination products approved
under NDA or BLA, for which no express classification may have been
made for the device constituent part.
(Response 15) FDA issued a notice in the Federal Register (76 FR
12743, March 8, 2011) clarifying that Class I and II device
manufacturers and importers must continue to submit malfunction reports
in accordance with part 803, pending future action by FDA to address
the malfunction reporting requirements for Class I and Class II devices
addressed in FDAAA. Accordingly, combination product applicants for
combination products that include a device constituent part, and
constituent part applicants for device constituent parts, must comply
with part 803 requirements as described in this rule pending such
further Agency action. At this time, therefore, malfunction reporting
duties are the same for all combination products that include a device
constituent part, regardless of whether the combination product or
device constituent part would be considered life-supporting or life-
sustaining, and regardless of whether the device constituent part would
be considered a Class I, II, or III device.
(Comment 16) One commenter sought clarification of whether the
periodic reports addressed in proposed Sec. 4.103(c) should be
considered ``expedited'' reports for purposes of this rule.
(Response 16) FDA has retitled this provision to ``Other reporting
requirements for combination product applicants'' for clarity because
it addresses periodic safety reports for drug and biologic-led
combination products and also addresses under what circumstances
additional reports for device-led combination products are required
upon Agency request. This rule does not modify the timing of periodic
safety reports. The purpose of Sec. 4.102(d) is to clarify which
combination product applicants must submit periodic safety reports and
other safety reports, and what information they must include in such
reports. The intent of Sec. 4.102(d), in conjunction with Sec.
4.102(a), (b), and (c) is to ensure that the Agency obtains complete,
timely postmarketing safety information regarding combination products
while avoiding unnecessary burden to applicants.
(Comment 17) One commenter proposed the reorganization of proposed
4.103(b) to parallel the structure of Sec. 4.103(a).
(Response 17) We have not adopted this approach because Sec.
4.102(c) is intended to address a different issue than Sec. 4.102(b).
Section 4.102(b) (like proposed Sec. 4.103(a)) addresses requirements
that constituent part applicants and combination product applicants
must satisfy for their marketed products depending upon the type of
application under which it received marketing authorization, and
structuring the provision based on the type of application that the
applicant holds provides a clear, efficient way to identify such
requirements. In contrast, the purpose of Sec. 4.102(c) (like proposed
Sec. 4.103(b)) is to state which additional requirements a combination
product applicant must satisfy based on the types of constituent parts
included in the combination product, which are most clearly and
efficiently listed by constituent part type (drug, biological product,
or device).
D. Section 4.103--What information must you share with other
constituent part applicants for the combination product?
(Comment 18) Some commenters requested clarification of whether
proposed Sec. 4.104(a) applied if there were a single application
holder for the combination product but the combination product included
an article approved under another application held by another entity
for independent marketing not related to the combination product. Other
commenters asked for clarification of which applicants for constituent
parts of combination products could be subject to proposed Sec.
4.104(a) and (b) if the combination product were not approved under a
single application. Some commenters proposed an approach under which,
if there is a single application for the combination product, the
holder of that application would report to FDA in accordance with
proposed Sec. 4.103, and FDA would then decide whether any other
application holders for articles included in the combination product
should be notified and whether to seek additional reports from them.
(Response 18) As reflected in the preamble to the proposed rule
(see 74 FR 50744 at 50749 to 50750), proposed Sec. 4.104(a) was
intended to apply if the constituent parts of the combination product
were being marketed by different entities, including when the
constituent parts received marketing authorization under separate
applications held by different applicants. As explained in the response
to Comment 2, we have revised the rule to apply to combination product
applicants and constituent part applicants, in part to clarify which
entities are subject to it. Accordingly, we have revised this provision
to clarify that it applies solely to constituent part applicants.
Section 4.103 of this final rule is not intended to establish any
[[Page 92616]]
duties for entities who hold a marketing authorization to market a
product not as part of a combination product, even if the same article
is part of a combination product for which another entity received
marketing authorization (e.g., the second entity might have combined
the article with another product to make a co-packaged or single-entity
combination product, or market the article for a new use with another
product as a cross-labeled combination product).
For example, if entity A holds an approved application to market a
cross-labeled combination product that includes a device and a drug,
and entity B holds an approved application to market the drug for a
different use (i.e., not as part of the combination product), then
entity A would be the combination product applicant for that
combination product, and neither entity A nor B would be a constituent
part applicant for that combination product. Therefore, Sec. 4.103
would not require either entity A or B to share information with the
other.
In contrast, if entity A holds an approved PMA to market a device
as one constituent part of a cross-labeled combination product (i.e.,
entity A is the constituent part applicant for the device constituent
part of the combination product), and entity B holds an approved NDA to
market a drug as the other constituent part of that combination product
(i.e., entity B is the constituent part applicant for the drug
constituent part of the combination product), then Sec. 4.103 would
require both entities A and B to share postmarketing safety information
with each other for the specified types of events relating to that
combination product.
Regarding the issue of which entities would be subject to proposed
Sec. 4.104(b), we have decided to eliminate the provision as
unnecessary. Constituent part applicants that receive information from
another constituent part applicant must comply with the same duties
under Sec. 4.102(b) with respect to this information as they must with
respect to any information they receive regarding a postmarketing
safety issue for their product, including the duty to submit
postmarketing safety reports as required.
(Comment 19) Some commenters argued that the 5-day deadline under
proposed Sec. 4.104(a) for information sharing was too short. Some
commenters recommended instead tying the timeframe to the nature of the
event. Some argued that it is not warranted or useful to share
information automatically within a 5-day timeframe because it leaves
entities little time to evaluate the information before sharing it and
could result in unnecessary redundancy of reporting.
(Response 19) We disagree with these comments. The provision calls
for sharing information that the constituent part applicant receives
regarding an adverse event relating to the combination product, and
does not require the applicant to prepare a report in accordance with
any of the regulatory reporting requirements established under parts
314, 600, 606, 803, or 806. The duty under Sec. 4.103 does not require
a constituent part applicant to analyze, investigate, or organize the
information or take any other actions beyond forwarding the information
as received to the other constituent part applicant(s) for the
combination product and maintaining certain records. Accordingly, we
believe 5 calendar days is a reasonable deadline that does not impose
undue burden, while enabling timely reporting by the constituent part
applicant(s) with whom the information is shared.
Such an expedited sharing of information is important to ensure
timely, complete reporting with regard to adverse events that may have
been brought to the attention of only one constituent part applicant
for a combination product. Enabling each constituent part applicant to
review in a timely manner the information related to the combination
product enhances efficiency and thoroughness of reporting because each
constituent part applicant evaluates the information with respect to
its own constituent part and with regard to the reporting requirements
applicable to that type of constituent part.
(Comment 20) Some commenters stated that the information sharing
requirements of proposed Sec. 4.104 should be eliminated; some said
these requirements are unnecessary depending on the nature of the
event, and likely to produce unnecessary, duplicative reporting. Some
commenters proposed that the information sharing requirements under
proposed Sec. 4.104 should apply only if the event is potentially
reportable and that proposed Sec. 4.104(a) should not apply if the
applicant determines that the event does not concern the other
constituent part(s) of the combination product. Other commenters
proposed that if it can be determined that the event is attributable to
only one constituent part, then reporting requirements should apply
only to the application holder for that constituent part. Some
commenters proposed that the rule be revised such that, in the event
that constituent parts of a combination product are being marketed
under separate applications, and it is unclear which constituent
part(s) contributed to the event, the rule would require compliance
only with the reporting requirements for the constituent part providing
the primary mode of action for the combination product.\8\ One
commenter argued that requiring separate reporting to the centers
responsible for each constituent part would be overly burdensome. Some
commenters sought clarification for when an applicant should report to
another applicant or to FDA under proposed Sec. 4.104(a). Some
commenters requested clarification regarding when FDA would notify
application holder(s) for the constituent part(s) of a combination
product if FDA receives information from another application holder for
that combination product. One commenter proposed eliminating the option
of sharing the information with FDA arguing that including FDA in the
process would slow communications and not provide any benefit. One
commenter proposed that subsequent information received relating to the
same event be shared only with FDA or with another applicant in the
same time-frame as a report would be required to be submitted to FDA.
---------------------------------------------------------------------------
\8\ The term ``primary mode of action'' is defined at Sec. 3.2
as the mode of action that provides the most important therapeutic
action of the combination product, i.e., that is expected to make
the greatest contribution to the overall therapeutic effects of the
combination product.
---------------------------------------------------------------------------
(Response 20) The best way for the Agency to receive complete
reports for combination products is to ensure that each constituent
part applicant has an opportunity to review the information received
regarding the specified types of events (serious injuries, deaths, and
other adverse events) for the combination product. Accordingly, we
disagree with the proposals to narrow or eliminate the information
sharing requirement. We do not agree this requirement will produce
unnecessarily duplicative reporting. The trigger for a constituent part
applicant to submit a report to the Agency is not the mere act of
receiving information but a determination that the event is reportable
under the PMSR requirements applicable to that applicant. The Agency
may receive multiple reports regarding the same event because of Sec.
4.103 (formerly Sec. 4.104 in the proposed rule), but this approach
ensures that the Agency has the benefit of each constituent part
applicant's expertise and familiarity regarding its own constituent
part in
[[Page 92617]]
assessing the information with respect to that constituent part.
Regarding the issue of sharing information with FDA as opposed to
other constituent part applicants, we have eliminated the option of
sharing information with FDA as unnecessary and inefficient. We agree
that timely, complete reporting by each constituent part applicant is
best assured by having constituent part applicants share information
they receive directly with one another.
We also agree that when any constituent part applicant shares
information relating to an event with the other constituent part
applicant(s), the information sharing duty ends with respect to that
event. When information is shared, each constituent part applicant must
investigate and report to the Agency, under the applicable PMSR
requirements, regarding the event as they would for any event for which
they receive information. The constituent part applicants may find it
helpful to share with one another additional and followup information
they receive or develop relating to the event, but this is not required
by this rule.
(Comment 21) Some commenters stated that disclosure of event
information to another company might involve disclosure of confidential
and proprietary information. One commenter proposed that the
information be shared with the other applicant if practicable and if it
does not raise concerns regarding confidentiality or proprietary
information.
(Response 21) Section 4.103 does not require the sharing of trade
secret or confidential commercial information with other constituent
part applicants. Further, we have revised this section to specify that
the information required to be shared concern events that involve a
death or serious injury as described in Sec. 803.3, or an adverse
experience as described in Sec. 314.80(a) or Sec. 600.80(a). Such
information is likely to be received from health care facilities,
consumers, and other sources, and therefore, unlikely to contain trade
secret or confidential commercial information.
In regard to the Federal Health Insurance Portability and
Accountability Act (HIPAA), we note that HIPAA only applies to covered
entities (i.e., health plans, covered health care providers, and health
care clearinghouses), and their business associates, and thus is
unlikely to apply to constituent part applicants. Moreover, even if a
constituent part applicant is a HIPAA covered entity or business
associate, we note that HIPAA permits the disclosure of protected
health information (PHI), such as information that identifies a
particular patient, if such disclosures are required by other law. The
HIPAA Privacy Rule permits the use or disclosure of PHI ``to the extent
that such use or disclosure is required by law and the use or
disclosure complies with and is limited to the relevant requirements of
such law.'' 45 CFR 164.512(a)(1). Because Sec. 4.103 of this rule
requires constituent part applicants to share with each other
information received, including PHI, regarding certain events related
to the combination product, a constituent part applicant, which is
subject to HIPAA, would be permitted by HIPAA to make such disclosure.
(Comment 22) Some commenters sought clarification of the start time
for meeting the reporting deadlines under proposed Sec. 4.104(b). One
commenter recommended that it be the day the information is received
from the reporter subject to proposed Sec. 4.104(a).
(Response 22) While the content of proposed Sec. 4.104(b) has been
removed from the rule as unnecessary, we note that the start time for
determining the submission deadline for postmarketing safety reports is
the same as for information received from any other source, and depends
on the type of report and the regulation from which the requirement for
the report arises.
(Comment 23) Some commenters asked for the Agency to provide
examples of the application of proposed Sec. 4.104, including guidance
on what information to include in reports under this provision. One
commenter asked for guidance on the process for submitting information
to the Agency under proposed Sec. 4.104.
(Response 23) Section 4.103 requires the transmittal of information
received. Constituent part applicants do not need to modify, organize,
or evaluate the information; they must only forward the information to
the other constituent part applicant(s) for the combination product. As
discussed in Comment 18, we have eliminated the alternative of sharing
the information with FDA as unnecessary and inefficient. We intend to
provide additional information regarding how to comply with Sec. 4.103
in guidance.
E. Section 4.104--How and where must you submit postmarketing safety
reports for your combination product or constituent part?
(Comment 24) Some commenters sought clarification of how to comply
with the submission requirements for different types of reports for a
combination product. One commenter proposed that the rule expressly
state reports be submitted to ``the approved application'' if there is
only one reporter for the combination product. Another proposed that
reports for a combination product marketed under one application be
submitted to the lead center, while those for combination products
marketed under separate applications for different constituent parts in
some, but not all, cases be submitted to the center responsible for the
particular constituent part's application. One commenter noted a need
to clarify how to make electronic submissions for combination products.
(Response 24) As discussed in section II.E (discussion of Sec.
4.104), we have revised the rule to clarify how and where to submit
postmarketing safety reports for constituent part applicants and for
combination product applicants. In keeping with comments received,
Sec. 4.104(a) requires constituent part applicants to submit their
reports in the same manner as any other applicant holding the same kind
of application for a product (e.g., a constituent part applicant
holding a PMA for a device constituent part must submit reports in the
same manner as any other applicant holding a PMA for a device).
We have drawn a distinction between types of postmarketing safety
reports submitted by combination product applicants. With regard to
ICSRs, we have adopted an approach consistent with comments suggesting
that reports be submitted to the lead center and in accordance with the
procedures associated with the application type for the combination
product. Specifically, Sec. 4.104(b) requires such combination product
applicants to submit 5-day, 15-day, and malfunction reports, if
required for their product, in the manner described in the PMSR
regulations associated with the application type for the combination
product. For example, if the combination product received marketing
authorization under an NDA, then 5-day, 15-day, and malfunction
reports, and all followup reports, would be submitted how and where
described in part 314 for 15-day reports and followup reports to them.
This approach promotes efficiency and ensures that all such reports
relating to the same event are pooled together, and that multiple ICSR
reporting requirements for the same event can be satisfied through a
single submission (so long as that submission meets the content and
deadlines for each reporting requirement).
At the same time, it is appropriate for specific components of the
Agency to have the lead for addressing certain distinct types of
reports, in light of such factors as the issues raised in the
[[Page 92618]]
reports, logistical considerations for Agency response, and efficient
engagement of appropriate Agency expertise. Specifically, correction or
removal reports, field alert reports, and BPDRs are currently directed
to specific Agency offices to ensure efficient, effective assessment
and response. Accordingly, under Sec. 4.104(b), all combination
product applicants must direct field alert reports and BPDRs to the
same Agency components that currently receive them, in accordance with
the underlying regulations for these reports. For example, if the
combination product includes a biological product, BPDRs must be
submitted to the appropriate component within CDER or CBER in
accordance with parts 600 and 606, based upon which of these two
Centers would ordinarily have jurisdiction over the biological product
included in the combination product. Part 806 does not specify where to
submit correction or removal reports. Accordingly, neither does this
rule, but applicants currently should submit them to the appropriate
FDA district office, unless the information is included in an ICSR for
the event, as explained in response to Comment 14. See Recalls,
Corrections and Removals (Devices) (https://www.fda.gov/medicaldevices/deviceregulationandguidance/postmarketrequirements/recallscorrectionsandremovals/default.htm).
The Agency intends to provide guidance concerning procedural and
technical details of complying with these requirements, including how
to comply with the Centers' electronic reporting requirements. We seek
to take best advantage of information technology and other resources to
maximize the benefit of PMSR while minimizing the burden.
(Comment 25) Several commenters sought guidance regarding the
content, format, and completeness of applicable forms, and appropriate
terminology to use with respect to different types of events and
constituent parts for combination products.
(Response 25) Applicants should provide relevant information in as
complete and clear a manner as possible, consistent with the parameters
of the FDA form. Also, we intend to update relevant FDA forms, if
appropriate, including the instructions for how to complete them, and
to develop guidance that provides recommendations for meeting PMSR
requirements under this rule.
F. Section 4.105--What are the postmarketing safety reporting
recordkeeping requirements for your combination product or constituent
part?
(Comment 26) A commenter proposed that the same recordkeeping
requirements apply to all types of reports for a combination product.
(Response 26) We agree with the premise that a uniform set of
record retention requirements apply to all reports relating to a
combination product marketed by a single applicant, i.e., a combination
product applicant. Accordingly, Sec. 4.105(b) requires that
combination product applicants maintain all PMSR records for the
longest time period established in the recordkeeping requirements
associated with the PMSR provisions applicable to the combination
product. This approach allows combination product applicants to
maintain all these PMSR records for a product under one record
retention scheme, and helps ensure that potentially interrelated
records all remain available for events and for the combination
product. Because both parts 314 and 600 currently require record
retention for 10 years, at this time, all combination product
applicants must retain PMSR records for at least 10 years.
In contrast to combination product applicants, constituent part
applicants market only a drug, device, or biological product rather
than a complete combination product. This distinction is acknowledged
and reflected in the approach taken throughout the rule in establishing
PMSR requirements for constituent part applicants. The requirements for
record retention by constituent part applicants align with the overall
approach of the rule. Specifically, Sec. 4.105(a)(1) requires that
constituent part applicants comply with the underlying recordkeeping
requirements, including timeframes, established in the PMSR
requirements identified in Sec. 4.102(b) as applicable based on their
product's application type. This ensures that constituent part
applicants comply with the same requirements as any other applicant
marketing a drug, device, or biological product.
The essential difference between constituent part applicants and
other applicants for drugs, devices, and biological products is the
distinct relationship of constituent part applicants' products to one
another as parts of a combination product. The information sharing
requirements of Sec. 4.103 reflect this distinct relationship and the
overarching need for coordination between constituent part applicants
to ensure the safety and effectiveness of the combination product. As
explained in section II (discussion of Sec. 4.103), Sec. 4.103(b)
includes an explicit recordkeeping requirement in relation to the
information constituent part applicants are required to share with one
another under Sec. 4.103(a). Section 4.103 is intended to ensure
complete, timely reporting for the combination product as a whole. To
support this goal, while at the same time aligning the record retention
requirement for the records required under Sec. 4.103(b) with the
overall approach of this rule for constituent part applicants, Sec.
4.105(a)(2) requires constituent part applicants to maintain the
specified records of information shared for the retention period
established in the PMSR recordkeeping requirements for that constituent
part applicant's constituent part if there is only one period
established, and the longest recordkeeping requirement established in
those requirements if those requirements establish more than one record
retention period. We believe that this retention period will ensure
that the information remains available to the applicants and the Agency
for a sufficiently long period to inform investigation of events and
responses to them for the combination product, and enable the Agency to
assess compliance with Sec. 4.103, without imposing undue burden on
constituent part applicants. This approach also avoids the complexities
of tying the retention period for records relating to the information
sharing provision to the record retention requirements applicable to
the other constituent part applicant(s).
G. Alternate Approaches
(Comment 27) Several commenters proposed that the Agency adopt a
wholly different PMSR approach for combination products, with some
supporting the Agency's proposed approach as an interim measure until a
unified framework is developed either for combination products in
particular or for all FDA-regulated medical products. Some commenters
proposed adopting the most stringent set of PMSR requirements
applicable to the combination product. Others called for developing a
harmonized approach for combination products, with one commenter
calling for a public meeting to address the issue and another for such
a system to be put in place after a single reporting porthole is
established for all regulated products. One commenter called for FDA to
develop a
[[Page 92619]]
PMSR system for combination products consistent with Global
Harmonization Task Force guidelines, International Organization for
Standardization standards, and European Commission guidelines. This
comment emphasized that such other approaches rely on the ``primary
intended action'' of the combination product to determine what PMSR
requirements should apply. Some commenters recommended applying only
the reporting requirements applicable to the application type. One
commenter emphasized challenges of complying with multiple reporting
systems.
(Response 27) The Agency has considered alternate approaches to
PMSR for combination products, including in relation to the public
hearing held on November 25, 2002, and the workshop held on July 8,
2003. We have considered such options and presented in the preamble (74
FR 50744 at 50745 to 50747) the Agency's reasons for pursuing the
approach described in the proposed rule. In finalizing this rule, FDA
again determined that the approach described in this rule allows FDA to
receive complete, timely postmarketing safety information regarding
combination products, which is necessary to assure the continued safety
and effectiveness of such products, using established standards and
systems, while minimizing unnecessary duplication and burdens on
combination product and constituent part applicants.
H. Guidance and Agency Internal Coordination and Training
(Comment 28) Various commenters requested that the Agency address
implementation of this rule through guidance. Commenters noted the
importance of ensuring that this rule is as clear as possible. Most
commenters requested that the guidance present how the rule would apply
to different types of combination products and different types of
events. Several commenters requested that this guidance include a
decision tree, flow charts, tables, algorithm, or other organizational
and explanatory tools to clarify how to comply with the reporting
requirements applicable to a combination product. One commenter asked
for guidance on whether to cross-reference reports submitted to
different locations, such as field alert reports and 15-day reports.
Some commenters proposed that the Agency issue guidance prior to
publication of this rule. One commenter called for the guidance to
address how Agency personnel will coordinate to ensure compliance and
how the Agency will monitor implementation of this rule's requirements.
One commenter called for the Agency to ensure that the lead center has
appropriate expertise to address adverse event reports for a
combination product and that training, guidance, and cross-assignment
of staff might be helpful in this regard. Another commenter proposed
that the Agency take appropriate measures to ensure timely, effective
communication between Agency components with respect to postmarketing
safety reports for combination products. Some commenters also noted the
importance of appropriate training and other Agency personnel
considerations.
(Response 28) We intend to publish guidance that provides
recommendations on how to comply with the requirements under this rule
for combination product applicants and constituent part applicants,
including such matters as cross-referencing of reports. We appreciate
the comments received on this issue and look forward to further
feedback in response to the publication of this final rule and of the
draft guidance we may issue. With regard to the requests that we issue
guidance prior to issuance of this final rule, we clarified and revised
the rule in certain respects, and we did not believe it would be
appropriate to anticipate the content of this final rule by publishing
guidance concerning its content prior to its finalization.
We agree that appropriate training of Agency staff and timely,
effective coordination among Agency components to address postmarketing
safety reports for combination products are important efforts that the
Agency continues to address.
I. Effective Date and Compliance Dates
(Comment 29) Some commenters proposed that the Agency delay the
effective date for this rule, arguing that 180 days would not provide
sufficient time to take steps to come into compliance, including to
develop, validate, and implement new systems, alter procedures and
commercial arrangements, and train staff as needed to comply with this
rule's requirements. Some proposed making the effective date 1 year
after issuance. One commenter proposed 2 years.
(Response 29) We do not agree that it would be appropriate to delay
the effective date of this rule. However, in light of these comments,
and in consideration of the costs of this rule as discussed in section
VIII, we have decided to extend the compliance date with respect to
certain provisions of the rule for combination product applicants and
constituent part applicants, for a period of 18 months following the
effective date of this rule.
The duties for both combination product and constituent part
applicants under Sec. 4.102(a) and (b), and for constituent part
applicants under Sec. Sec. 4.104(a) and 4.105(a)(1) are generally the
same as for any other entity holding such an application for its
product, and we expect all applicants subject to this rule already to
be in compliance with these provisions for their products as these
provisions generally refer to existing regulations that such applicants
have generally followed (see 74 FR 50744 at 50745). Accordingly, the
effective date for the rule is 30 days after the date of its
publication and the compliance date for these provisions is the same as
the effective date for this rule. However, with respect to the
requirements of Sec. 4.102(c) and (d) for combination product
applicants, the requirements of Sec. Sec. 4.103 and 4.105(a)(2) for
constituent part applicants, and the requirements of Sec. Sec.
4.104(b) and 4.105(b) for combination product applicants, the
compliance date will be 18 months following the effective date of this
rule.
J. Miscellaneous
(Comment 30) Some comments concerned coordination of various Agency
activities related to adverse events including then pending Agency
rulemakings concerning electronic reporting, adverse event report
database management and searchability, forms referenced in this and
other rulemakings, and harmonization efforts with foreign regulatory
agencies.
(Response 30) The Agency has taken into account such coordination
considerations. Pending FDA rulemakings were one consideration in
deciding to streamline this rule by using cross-references to
requirements of the underlying regulations listed in Sec. 4.102,
without repeating the substance of those requirements. As noted in
section II (see discussion of Sec. 4.101), this approach will minimize
the need to revise this regulation should the underlying regulations be
amended. Similar considerations have informed our determination to
reference in Sec. 4.104 the reporting procedures required in the
underlying regulations. As discussed in Response 25, we intend to
update relevant FDA forms, if appropriate, including the instructions
for how to complete them, and to develop guidance that provides
recommendations for meeting PMSR requirements under this rule.
With respect to international harmonization, we remain committed to
such efforts, including with respect to PMSR requirements for
combination
[[Page 92620]]
products. A practical challenge for combination products in particular
is that international collaboration and harmonization efforts are at an
early stage for these products. At the same time, there is a current
need to clarify FDA's PMSR requirements for this class of products. We
have taken an approach that integrates underlying PMSR approaches for
drugs, devices, and biological products, which have benefited in
various respects from international harmonization efforts. We are
committed to continuing to work with our foreign counterparts on PMSR
and other issues for combination products.
IV. Legal Authority
The Agency derives its authority to issue the regulations in
proposed part 4 subpart B from 21 U.S.C. 321, 331, 351, 352, 353, 355,
360, 360b-360f, 360h-360j, 360l, 360hh-360ss, 360aaa-360bbb, 371(a),
372-374, 379e, 381, 383, and 394, and 42 U.S.C. 216, 262, 263a, 264,
and 271. For a drug approved under an NDA or an ANDA, section 505(k) of
the FD&C Act (21 U.S.C. 355) requires the applicant to submit reports
concerning clinical experience and other data or information with
respect to the drug to FDA and to establish and maintain related
records. Section 505(k) provides the Agency with authority to specify
by regulation which data or information must be submitted in such
reports. FDA used this statutory authority, among others, in issuing
the Agency's regulation concerning postmarketing reporting of adverse
drug experiences and other postmarketing reports including field alert
reports. The regulations for postmarketing reporting of adverse drug
experiences and for field alert reports are set forth in Sec. 314.80
and Sec. 314.81, respectively.
For a device, section 519 of the FD&C Act requires manufacturers
and importers to establish and maintain records, make reports, and
provide information, as FDA may reasonably require to assure that such
device is not adulterated or misbranded and to otherwise assure its
safety and effectiveness. FDA utilized this statutory authority, in
addition to other authorities, in issuing the MDR regulation and the
correction and removal regulation, found in parts 803 and 806,
respectively.
For a biological product, section 351 of the Public Health Service
Act (PHS Act) (42 U.S.C. 262) requires FDA to approve a BLA on the
basis of a demonstration that the product is safe, pure, and potent
(section 351(a)(2)(C) of the PHS Act). Section 351(a)(2)(A) of the PHS
Act requires FDA to establish by regulation requirements for the
approval, suspension, and revocation of BLAs. Section 351(b) of the PHS
Act also prohibits falsely labeling a biological product. FDA used
section 351of the PHS Act as statutory authority, along with other
sources of statutory authority, in issuing the postmarketing reporting
of adverse experiences regulation for biological products. This
regulation is found in Sec. 600.80. In proposing Sec. 600.80, FDA
indicated that information made available to the Agency through the
adverse experience reports contemplated under Sec. 600.80 could
establish that a biological product is not safe or properly labeled and
that the license should be revoked (55 FR 11611 at 11613, March 29,
1990). FDA used section 351 of the PHS Act as statutory authority,
along with other sources of statutory authority, in issuing the BPDR
regulations for biological products. These regulations are found in
Sec. Sec. 600.14 and 606.171. In issuing these regulations, FDA stated
that these reports would enable FDA to respond when public health may
be at risk, provide FDA with uniform data to track trends that may
indicate broader threats to the public health, and help ensure
facilities are taking appropriate actions to investigate and correct
biological product deviations. (65 FR 66621 at 66623, November 7,
2000).
There is considerable overlap in the PMSR requirements for drugs,
devices, and biological products. The regulatory schemes for adverse
event reporting for drugs and biological products are identical in most
respects. The MDR regulation has many similarities to the drug and
biological product PMSR regulations. Overall, the regulatory framework
governing PMSR for each type of product is intended to achieve the same
general goals.
Nevertheless, these three sets of regulations differ somewhat
because each is tailored to the characteristics of the types of
products for which it was designed. For instance, each set of
regulations contains certain specific requirements pertaining to
particular products or types of postmarketing safety events that are
not found in the other sets of regulations. The additional requirements
for combination product applicants that FDA considers necessary are as
follows: 5-day reports, 15-day reports, malfunction reports, correction
or removal reports, field alert reports, and BPDRs. As set forth in
this rule, it is crucial that these additional requirements be met if
they apply.
The legal framework underlying this proposed rule is twofold. The
first is that drugs, devices, and biological products do not lose their
discrete regulatory identities when they become constituent parts of a
combination product. In general, the PMSR requirements specific to each
constituent part of a combination product also apply to the combination
product itself. Therefore, all combination products are subject to at
least two sets of PMSR requirements. For example, in the case of a
device and biological product combination product, the PMSR
requirements applicable to devices and to biological products would
apply to the combination product. However, this rule is intended to
clarify that a combination product applicant may comply only with the
PMSR requirements associated with the application under which the
combination product received marketing authorization and certain,
specified PMSR requirements associated with the other constituent
part(s). Taking the example of a device-biologic combination product,
if the combination product has an approved BLA, the combination product
applicant (holder of the BLA) would use parts 600 and 606 to make
postmarketing safety reports for the combination product. In addition,
as explained in this rule, the combination product applicant must also
comply with all of the specified requirements that apply to the
product. Thus, in this case, the combination product applicant must
also comply with the reporting requirements for 5-day reports,
correction or removal reports, and malfunction reports if the criteria
for such reports are met. Under this legal framework, if you
demonstrate compliance with the applicable requirements of the set of
regulations (e.g., biological product PMSR) associated with the
approved application (e.g., BLA), and comply with any applicable
specified additional provisions (e.g., 5-day reports, correction or
removal reports, and malfunction reports), you will be considered to
have satisfied all applicable PMSR requirements associated with the
combination product, including its constituent parts.
The legal authority for this streamlining approach is based on the
following. Although combination products retain the regulatory
identities of their constituent parts, the FD&C Act also recognizes
combination products as a category of products that are distinct from
products that are solely drugs, devices, or biological products. For
example, section 503(g)(4)(A) of the FD&C Act (21 U.S.C. 353b(g)(4)(A))
requires OCP to ``designate'' a product as a combination product as
well as to
[[Page 92621]]
ensure ``consistent and appropriate postmarket regulation of like
products subject to the same statutory requirements.'' Further, section
563 of the FD&C Act (21 U.S.C. 360bbb-2) governs the ``classification''
of products as ``drug, biological product, device, or a combination
product subject to section 503(g)'' (emphasis added). In this respect,
the FD&C Act identifies a combination product as a distinct type of
product that could be subject to specialized regulatory controls. In
addition, for the efficient enforcement of the FD&C Act under section
701 (21 U.S.C. 371), FDA has the authority to develop regulations to
ensure sufficient and appropriate ongoing assessment of the risks
associated with combination products.
The second legal framework for this rule is founded on the
postmarket safety reporting regulatory scheme associated with the
application under which the combination product is approved, plus any
applicable requirements associated with the additional six specified
report types listed in this rule. Although similar in effect to the
previously discussed framework, this approach is based on the legal
authority FDA used to issue each of its three existing regulations for
postmarketing safety reporting for drugs, devices, and biological
products. In the context of this rule, such authority would include,
but not be limited to, sections 505(k) and 519 of the FD&C Act, and
section 351 of the PHS Act. Under this authority FDA is now issuing
additional requirements based on the six additional specified report
types. This means that in the case, for example, of a device-biologic
combination product, approved under a BLA, section 351 of the PHS Act
(in addition to other applicable authorities) would provide the
authority for FDA to require postmarketing safety reporting in
accordance with parts 600 and 606. Furthermore, section 351 of the PHS
Act also would provide the authority for the Agency to require
additional reporting for the device-biologic combination product (5-day
reports, malfunction reports, and correction or removal reports) if the
criteria for such reports are met.
V. Analysis of Environmental Impact
FDA has determined under 21 CFR 25.30(a), 25.30(h), and 25.31(a)
through (c) that this action is of a type that does not individually or
cumulatively have a significant effect on the human environment.
Therefore, neither an environmental assessment nor an environmental
impact statement is required.
VI. Paperwork Reduction Act of 1995
This final rule contains information collection provisions that are
subject to review by the Office of Management and Budget (OMB) under
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The title,
description and respondent description of the information collection
provisions are shown in the following paragraphs with an estimate of
the annual reporting and recordkeeping burdens. Included in the
estimate is the time for reviewing instructions, searching existing
data sources, gathering and maintaining the data needed, and completing
and reviewing each collection of information.
Title: Postmarketing Safety Reporting for Combination Products.
Description: This final rule describes the PMSR requirements for
combination products. In the development of this final rule, the Agency
considered the fact that a combination product is subject to the PMSR
provisions applicable to its constituent parts (drug, device, and/or
biological product). The Agency reviewed each set of regulations
governing PMSR for new drugs (part 314), biological products (parts 600
and 606), and devices (parts 803 and 806). The review determined that
each set of regulations contains many substantially similar
requirements.
Given the broad similarities in the PMSR regulations, the Agency
determined that, to ensure consistent, appropriate PMSR for combination
products that received marketing authorization under a single
application, we need only require that combination product applicants
comply with the regulatory requirements for PMSR associated with the
application, and with additional, specified provisions from the other
set(s) of PMSR requirements applicable to the other constituent part(s)
of the combination product. This approach recognizes and addresses PMSR
considerations relevant to each type of constituent part of a
combination product while avoiding unnecessary redundancy and burden.
Specifically, the additional reporting requirements specified in
this rule, along with any associated followup reports, are: (1)
Submission of a ``5-day report'' as described in Sec. 803.53 if the
combination product contains a device constituent part; (2) submission
of a ``malfunction report'' as described in Sec. 803.50 if the
combination product contains a device constituent part; (3) submission
of a ``correction or removal report'' as described in Sec. 806.10 if
the combination product contains a device constituent part; (4)
submission of a ``field alert report'' as described in Sec. 314.81 if
the combination product contains a drug constituent part; (5)
submission of a 15-day report as described in Sec. 314.80 or Sec.
600.80 if the combination product contains a drug or biological product
constituent part, respectively; and (6) submission of a ``BPDR'' as
described in Sec. Sec. 600.14 and 606.171 if the combination product
contains a biological product constituent part.
For combination products for which the constituent parts received
marketing authorization under separate applications held by different
entities, the Agency has determined that compliance with the PMSR
requirements associated with the application type for the constituent
part is sufficient. In addition, constituent part applicants must share
safety information they receive related to certain events with the
other constituent part applicant(s).
We note that the PMSR information collections for drugs, biological
products, and devices found in Sec. Sec. 314.80, 314.81, 600.80,
600.81, 606.170, 606.171, 803.50, 803.53, 803.56, 806.10, and 806.20
have already been approved and are in effect. The pertinent PMSR
information collection provisions for Sec. 314.80(c) and (e), as well
as for Sec. 314.81(b) are approved under OMB control numbers 0910-
0001, 0910-0230, and 0910-0291. The information collection provisions
for Sec. Sec. 600.80 and 600.81 are approved under OMB control number
0910-0308. Those for Sec. 606.170 are approved under OMB control
number 0910-0116. Those for Sec. 606.171 are approved under OMB
control number 0910-0458. The information collection provisions for
Sec. Sec. 803.50, 803.53, and 803.56 are approved under OMB control
numbers 0910-0291 and 0910-0437. The information collection provisions
for Sec. Sec. 806.10 and 806.20 are approved under OMB control number
0910-0359.
While this rule serves to permit combination product applicants to
comply with a streamlined subset of the PMSR requirements applicable to
all of their constituent parts, we recognize that some combination
product applicants have been complying with only the reporting
requirements associated with their application type. As a result, the
information collection described here refers to the reporting and
recordkeeping requirements for the six additional report types
specified in this rule. It also refers to the new information sharing
and related recordkeeping requirement applicable to constituent parts
marketed under separate applications.
[[Page 92622]]
These requirements are necessary to ensure: (1) Consistent PMSR for
combination products and constituent parts, (2) that the Agency
receives necessary information to promote and protect the public
health, (3) appropriate ongoing assessment of risks, and (4) consistent
and appropriate postmarketing regulation of combination products. This
rule enables applicants to comply with these requirements while
avoiding unnecessary duplicative reporting, for example, by limiting
the number of PMSR requirements with which combination product
applicants must comply and by authorizing applicants to submit only a
single, complete report for an event even if multiple reporting duties
apply to the same event.
Description of Respondents: This rule applies to combination
product applicants and constituent part applicants. Any person holding
the application(s) under which a combination product received marketing
authorization is a combination product applicant. Any person holding an
application under which a constituent part (drug, device, or biological
product) of a combination product received marketing authorization is a
constituent part applicant if the other constituent part received
marketing authorization under an application held by a different
person.
FDA estimates the burden for this information collection as
follows:
Table 3--Estimated Annual Reporting Burden
----------------------------------------------------------------------------------------------------------------
Number of
21 CFR section Number of responses per Total annual Average burden Total hours
respondents respondent responses per response
----------------------------------------------------------------------------------------------------------------
4.102(c)(1)(i) Submitting 5-day 15 98 1,470 1.21 1,779
reports........................
4.102(c)(1)(ii) Submitting 15 98 1,470 1.21 1,779
malfunction reports............
4.102(c)(1)(iii) Submitting 20 1 20 10 200
correction or removal reports..
4.102(c)(2)(i) Submitting field 92 10.8 994 8 7,949
alerts.........................
4.102(c)(2)(ii) and (3)((ii) 1 1 1 1 1
Submitting 15-day reports......
4.102(c)(3) Submitting BPDRs.... 24 6 144 2 288
4.102(d)........................ 1 1 1 1 1
-------------------------------------------------------------------------------
Totals *.................... .............. .............. .............. .............. 11,709
----------------------------------------------------------------------------------------------------------------
Table 4--Estimated Annual Recordkeeping Burden
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number of
21 CFR section Number of records per Total annual Average burden per recordkeeping Total hours
recordkeepers recordkeeper records
--------------------------------------------------------------------------------------------------------------------------------------------------------
4.103(b)/4.105(a)(2) Records of information 33 18 594 .1 (6 minutes)........................... 59
shared by constituent part applicants.
4.105(b) additional record-keeping by device- 279 .45 126 .5 (30 minutes).......................... 63
led combination products.
4.105(b) additional recordkeeping by drug and 186 6 1,116 .5 (30 minutes).......................... 558
biologic-led combination products.
----------------------------------------------------------------------------------------------------------
Totals................................... .............. .............. .............. ......................................... 680
--------------------------------------------------------------------------------------------------------------------------------------------------------
Table 5--Estimated Annual Third Party Disclosure Burden
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number of
21 CFR section Number of disclosures Total annual Average burden per disclosure Total hours
respondents per respondent disclosures
--------------------------------------------------------------------------------------------------------------------------------------------------------
4.103 Sharing information with other 33 18 594 .35 (21 minutes)......................... 208
constituent part applicants.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Based on FDA's experience regarding receipt of postmarketing safety
reports for combination products, the Agency estimates that there will
be 401 reporters (who will keep corresponding records) submitting a
total of 11,709 reports annually under Sec. 4.102(c) and (d) and 33
reporters (who will keep corresponding records) sharing information
eighteen times annually under Sec. 4.103. Further, FDA estimates,
based on its experience with information collection regarding
postmarketing safety reporting provisions for drugs, biological
products, and devices, that each report (or information sharing event
under Sec. 4.103) may take from approximately 20 minutes to 10 hours,
depending on report type, to prepare and submit, and from approximately
6 to 30 minutes to fulfill the corresponding recordkeeping
requirements. FDA believes that there are no significant new operating
and maintenance costs associated with this collection of information
because, in order to legally market their products, all applicants are
required to develop and maintain systems for reporting and maintaining
records of postmarketing safety events. Therefore, appropriate
mechanisms for PMSR should already be in place, and combination product
applicants and constituent part applicants will accrue no significant
additional costs to fulfill the requirements set forth here.
In addition, we estimate that there will no significant new costs
for 15-day reporting (Sec. 4.102(c)(2)(ii) and (3)(ii)) and periodic
reporting (Sec. 4.102(d)(1)) under the rule because there is
significant overlap between the types of events that trigger a 15-day
report for drugs and biological products and the
[[Page 92623]]
events that trigger expedited reporting for devices. We also estimate
there will be no significant new costs for other non-expedited
reporting (Sec. 4.102(d)(2)) because of the expected rarity of the
agency seeking such additional information.
Before the effective date of this final rule, FDA will publish a
notice in the Federal Register announcing OMB's decision to approve,
modify, or disapprove the information collection provisions in this
final rule. An Agency may not conduct or sponsor, and a person is not
required to respond to, a collection of information unless the Agency
displays a currently valid OMB control number.
VII. Federalism
FDA has analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. FDA has determined that the rule
does not contain policies that have substantial direct effects on the
States, on the relationship between the National Government and the
States, or on the distribution of power and responsibilities among the
various levels of government. Accordingly, the Agency has concluded
that the final rule does not contain policies that have federalism
implications as defined in the Executive order and, consequently, a
federalism summary impact statement is not required.\9\
---------------------------------------------------------------------------
\9\ The rule clarifies which PMSR requirements apply when drugs,
devices, and biological products are used to create combination
products. The Agency notes that there are no express preemption
provisions of the FD&C act applicable to prescription drugs or
biological products. Section 521 of the FD&C Act (21 U.S.C. 360k)
contains an express preemption provision that applies to devices;
nonetheless, the Supreme Court concluded in Medtronic, Inc. v. Lohr,
581 U.S. 470, 500-01 (1996), that requirements not applicable to a
particular device do not preempt State law under section 521. Device
adverse event reporting requirements, like the good manufacturing
practice requirements at issue in the Medtronic case, are general
requirements that do not preempt under section 521 of the FD&C Act.
---------------------------------------------------------------------------
VIII. Economic Analysis of Impacts
A. Introduction
We have examined the impacts of the final rule under Executive
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L.
104-4). Executive Orders 12866 and 13563 direct us to assess all costs
and benefits of available regulatory alternatives and, when regulation
is necessary, to select regulatory approaches that maximize net
benefits (including potential economic, environmental, public health
and safety, and other advantages; distributive impacts; and equity). We
have developed a comprehensive Economic Analysis of Impacts that
assesses the impacts of the final rule. We believe that this final rule
is not a significant regulatory action as defined by Executive Order
12866.
The Regulatory Flexibility Act requires us to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. Because the final rule essentially describes the application
of existing postmarketing safety reporting regulations to certain
combination products, we certify that the final rule will not have a
significant economic impact on a substantial number of small entities.
The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires
us to prepare a written statement, which includes an assessment of
anticipated costs and benefits, before issuing ``any rule that includes
any Federal mandate that may result in the expenditure by State, local,
and tribal governments, in the aggregate, or by the private sector, of
$100,000,000 or more (adjusted annually for inflation) in any one
year.'' The current threshold after adjustment for inflation is $146
million, using the most current (2015) Implicit Price Deflator for the
Gross Domestic Product. This final rule would not result in an
expenditure in any year that meets or exceeds this amount.
The full analysis of economic impacts is available in the docket
for this final rule at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.
B. Summary of Costs and Benefits
The final rule will generate one-time administrative costs from
reading and understanding the rule, assessing current compliance,
modifying existing standards of practice, changing storage and
reporting software, and training personnel on the requirements under
this rule. Firms that do not currently comply with the reporting
requirements specified by the final rule will also incur annual
reporting costs from the submission of field alert reports, 5-day
reports, malfunction reports, correction or removal reports, and
biological product deviation reports, as applicable. The annualized
total costs of the rule are between $1.36 and $2.68 million at a 7
percent discount rate and between $1.35 and $2.65 million at a 3
percent discount rate.
The final rule will benefit firms through reduced uncertainty about
the reporting requirements for their specific combination product and
through decreased potentially duplicative reporting. The final rule
will also benefit public health by helping to ensure that important
safety information is submitted and directed to the appropriate
components within the Agency, so that we may receive and review this
important information in a timely manner for the protection of public
health.
Table 6--Summary of Benefits, Costs, and Distributional Effects of Final Rule
--------------------------------------------------------------------------------------------------------------------------------------------------------
Units
Primary ------------------------------------------------
Category estimate Low estimate High estimate Discount rate Period covered Notes
Year dollars (%) (years)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
Annualized.......................... .............. .............. .............. 2016 7 10
Monetized ($millions/year).......... .............. .............. .............. 2016 3 10
Annualized.......................... .............. .............. .............. 2016 7 10
Quantified.......................... .............. .............. .............. 2016 3 10
------------------------------------------------
[[Page 92624]]
Qualitative......................... Firms will benefit from reduced uncertainty
about reporting requirements. The rule will
benefit public health by helping to ensure
Agency components' timely receipt of
postmarketing safety reports.
------------------------------------------------
Costs:
Annualized.......................... .............. $1.36 $2.68 2016 7 10
Monetized ($millions/year).......... .............. $1.35 $2.65 2016 3 10
Annualized.......................... .............. .............. .............. 2016 7 10
Quantified.......................... .............. .............. .............. 2016 3 10
------------------------------------------------
Qualitative.........................
------------------------------------------------
Transfers:
Federal............................. .............. .............. .............. 2016 7 10
Annualized.......................... .............. .............. .............. 2016 3 10
------------------------------------------------------------------------------------------------
Monetized ($millions/year).......... From:
To:
------------------------------------------------------------------------------------------------
Other............................... .............. .............. .............. 2016 7 10
Annualized.......................... .............. .............. .............. 2016 3 10
------------------------------------------------------------------------------------------------
Monetized ($millions/year).......... From:
To:
------------------------------------------------------------------------------------------------
Effects:
State, Local or Tribal Government:
Small Business:
Wages:
Growth:
--------------------------------------------------------------------------------------------------------------------------------------------------------
IX. References
The following references are on display in the Division of Dockets
Management, Food and Drug Administration, 5630 Fishers Lane, Rm. 1061,
Rockville, MD 20852, and are available for viewing by interested
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also
available electronically at https://www.regulations.gov. FDA has
verified the Web site addresses, as of the date this document publishes
in the Federal Register, but Web sites are subject to change over time.
1. FDA Regulation of Combination Products, November 25, 2002,
accessed at: https://www.fda.gov/downloads/CombinationProducts/MeetingsConferencesWorkshops/UCM117123.pdf.
2. Innovative Systems for Delivery of Drugs and Biologics:
Scientific, Clinical and Regulatory Challenges, July 8, 2003,
accessed at: https://www.fda.gov/ohrms/dockets/dockets/03n0203/03n0203.htm.
3. Individual Case Study Reports, accessed at: (https://www.fda.gov/ForIndustry/DataStandards/IndividualCaseSafetyReports/default.htm).
List of Subjects in 21 CFR Part 4
Biological products, Combination products, Drugs, Medical devices,
Regulation of combination products, Reporting and recordkeeping
requirements, Safety.
Therefore, under the Federal Food, Drug, and Cosmetic Act, the
Public Health Service Act, and under authority delegated to the
Commissioner of Food and Drugs, 21 CFR part 4 is amended as follows:
PART 4--REGULATION OF COMBINATION PRODUCTS
0
1. The authority citation for part 4 continues to read as follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360b-
360f, 360h-360j, 360l, 360hh-360ss, 360aaa-360bbb, 371(a), 372-374,
379e, 381, 383, 394; 42 U.S.C. 216, 262, 263a, 264, 271.
0
2. Add subpart B, consisting of Sec. Sec. 4.100 through 4.105, to read
as follows:
Subpart B--Postmarketing Safety Reporting for Combination Products
Sec.
4.100 What is the scope of this subpart?
4.101 How does FDA define key terms and phrases in this subpart?
4.102 What reports must you submit to FDA for your combination
product or constituent part?
4.103 What information must you share with other constituent part
applicants for the combination product?
4.104 How and where must you submit postmarketing safety reports for
your combination product or constituent part?
4.105 What are the postmarketing safety reporting recordkeeping
requirements for your combination product or constituent part?
Subpart B--Postmarketing Safety Reporting for Combination Products
Sec. 4.100 What is the scope of this subpart?
(a) This subpart identifies postmarketing safety reporting
requirements for combination product applicants and constituent part
applicants.
(b) This subpart does not apply to investigational combination
products, combination products that have not received marketing
authorization, or to persons other than combination product
[[Page 92625]]
applicants and constituent part applicants.
(c) This subpart supplements and does not supersede other
provisions of this chapter, including the provisions in parts 314, 600,
606, 803, and 806 of this chapter, unless a regulation explicitly
provides otherwise.
Sec. 4.101 How does the FDA define key terms and phrases in this
subpart?
Abbreviated new drug application (ANDA) has the same meaning given
the term ``abbreviated application'' in Sec. 314.3(b) of this chapter.
Agency or we means Food and Drug Administration.
Applicant means, for the purposes of this subpart, a person holding
an application under which a combination product or constituent part of
a combination product has received marketing authorization (such as
approval, licensure, or clearance). For the purposes of this subpart,
applicant is used interchangeably with the term ``you.''
Application means, for purposes of this subpart, a BLA, an NDA, an
ANDA, or a device application, including all amendments and supplements
to them.
Biological product has the meaning given the term in section 351 of
the Public Health Service Act (42 U.S.C. 262).
Biological product deviation report (BPDR) is a report as described
in Sec. Sec. 600.14 and 606.171 of this chapter.
Biologics license application (BLA) has the meaning given the term
in section 351 of the Public Health Service Act (42 U.S.C. 262) and
Sec. 601.2 of this chapter.
Combination product has the meaning given the term in Sec. 3.2(e)
of this chapter.
Combination product applicant means an applicant that holds the
application(s) for a combination product.
Constituent part has the meaning given the term in Sec. 4.2.
Constituent part applicant means the applicant for a constituent
part of a combination product the constituent parts of which are
marketed under applications held by different applicants.
Correction or removal report is a report as described in Sec.
806.10 of this chapter.
De novo classification request is a submission requesting de novo
classification under section 513(f)(2) of the Federal Food, Drug, and
Cosmetic Act.
Device has the meaning given the term in section 201(h) of the
Federal Food, Drug, and Cosmetic Act.
Device application means a PMA, PDP, premarket notification
submission, de novo classification request, or HDE.
Drug has the meaning given the term in section 201(g)(1) of the
Federal Food, Drug, and Cosmetic Act.
Field alert report is a report as described in Sec. 314.81 of this
chapter.
Fifteen-day report is a report required to be submitted within 15
days as described in Sec. 314.80 of this chapter or Sec. 600.80 of
this chapter, as well as followup reports to such a report.
Five-day report is a report as described in Sec. Sec. 803.3 and
803.53 of this chapter, as well as supplemental or followup reports to
such a report as described in Sec. 803.56 of this chapter.
Humanitarian device exemption (HDE) has the meaning given the term
in Sec. 814.3 of this chapter.
Malfunction report is a report as described in Sec. 803.50 of this
chapter as well as supplemental or followup reports to such a report as
described in Sec. 803.56 of this chapter.
New drug application (NDA) has the meaning given the term
``application'' in Sec. 314.3(b) of this chapter.
Premarket approval application (PMA) has the meaning given the term
in Sec. 814.3 of this chapter.
Premarket notification submission is a submission as described in
Sec. 807.87 of this chapter.
Product Development Protocol (PDP) is a submission as set forth in
section 515(f) of the Federal Food, Drug, and Cosmetic Act.
Sec. 4.102 What reports must you submit to FDA for your combination
product or constituent part?
(a) In general. If you are a constituent part applicant, the
reporting requirements applicable to you that are identified in this
section apply to your constituent part, and if you are a combination
product applicant, the reporting requirements applicable to you that
are identified in this section apply to your combination product as a
whole.
(b) Reporting requirements applicable to both combination product
applicants and constituent part applicants. If you are a combination
product applicant or constituent part applicant, you must comply with
the reporting requirements identified in paragraphs (b)(1), (b)(2), or
(b)(3) of this section for your product based on its application type.
If you are a combination product applicant, you are required to submit
a report as specified in this paragraph unless you have already
submitted a report in accordance with paragraph (c) of this section for
the same event that: Includes the information required under the
applicable regulations identified in this paragraph, is required to be
submitted in the same manner under Sec. 4.104, and meets the deadlines
under the applicable regulations identified in this paragraph.
(1) If your combination product or device constituent part received
marketing authorization under a device application, you must comply
with the requirements for postmarketing safety reporting described in
parts 803 and 806 of this chapter with respect to your product.
(2) If your combination product or drug constituent part received
marketing authorization under an NDA or ANDA, you must comply with the
requirements for postmarketing safety reporting described in part 314
of this chapter with respect to your product.
(3) If your combination product or biological product constituent
part received marketing authorization under a BLA, you must comply with
the requirements for postmarketing safety reporting described in parts
600 and 606 of this chapter with respect to your product.
(c) Reporting requirements applicable only to combination product
applicants. If you are a combination product applicant, in addition to
compliance with paragraph (a) of this section, you must also comply
with the reporting requirements identified under this paragraph as
applicable to your product based on its constituent parts. If you are a
combination product applicant, you are required to submit a report as
specified in this paragraph unless you have already submitted a report
in accordance with paragraph (b) of this section for the same event
that: Includes the information required under the applicable
regulations for the report identified in this paragraph; is required to
be submitted in the same manner under Sec. 4.104 of this chapter; and,
unless otherwise specified in this paragraph, meets the deadlines under
the applicable regulations for the report identified in this paragraph.
(1) If your combination product contains a device constituent part,
you must submit:
(i) Five-day reports;
(ii) Malfunction reports; and
(iii) Correction or removal reports, and maintain records as
described in Sec. 806.20 of this chapter for corrections and removals
not required to be reported.
(2) If your combination product contains a drug constituent part,
you must submit:
(i) Field alert reports; and
(ii) Fifteen-day reports as described in Sec. 314.80 of this
chapter, which must be
[[Page 92626]]
submitted within 30 calendar days instead of 15 calendar days if your
combination product received marketing authorization under a device
application.
(3) If your combination product contains a biological product
constituent part, you must submit:
(i) Biological product deviation reports; and
(ii) Fifteen-day reports as described in Sec. 600.80 of this
chapter, which must be submitted within 30 calendar days instead of 15
calendar days if your combination product received marketing
authorization under a device application.
(d) Other reporting requirements for combination product
applicants. (1) If you are the combination product applicant for a
combination product that contains a device constituent part and that
received marketing authorization under an NDA, ANDA, or BLA, in
addition to the information otherwise required in the periodic safety
reports you submit under Sec. 314.80 or Sec. 600.80 of this chapter,
your periodic safety reports must also include a summary and analysis
of the reports identified in paragraphs (c)(1)(i) and (ii) of this
section that were submitted during the report interval.
(2) If you are the combination product applicant for a combination
product that received marketing authorization under a device
application, in addition to the reports required under paragraphs (b)
and (c) of this section, you must submit reports regarding
postmarketing safety events if notified by the Agency in writing that
the Agency requires additional information. We will specify what safety
information is needed and will require such information if we determine
that protection of the public health requires additional or clarifying
safety information for the combination product. In any request under
this section, we will state the reason or purpose for the safety
information request, specify the due date for submitting the
information, and clearly identify the reported event(s) related to our
request.
Sec. 4.103 What information must you share with other constituent
part applicants for the combination product?
(a) When you receive information regarding an event that involves a
death or serious injury as described in Sec. 803.3 of this chapter, or
an adverse experience as described in Sec. 314.80(a) of this chapter
or Sec. 600.80(a) of this chapter, associated with the use of the
combination product, you must provide the information to the other
constituent part applicant(s) for the combination product no later than
5 calendar days of your receipt of the information.
(b) With regard to information you must provide to the other
constituent part applicant(s) for the combination product, you must
maintain records that include:
(1) A copy of the information you provided,
(2) The date the information was received by you,
(3) The date the information was provided to the other constituent
part applicant(s), and
(4) The name and address of the other constituent part applicant(s)
to whom you provided the information.
Sec. 4.104 How and where must you submit postmarketing safety reports
for your combination product or constituent part?
(a) If you are a constituent part applicant, you must submit
postmarketing safety reports in accordance with the regulations
identified in Sec. 4.102(b) that are applicable to your product based
on its application type.
(b) If you are a combination product applicant, you must submit
postmarketing safety reports required under Sec. 4.102 in the manner
specified in the regulation applicable to the type of report, with the
following exceptions:
(1) You must submit the postmarketing safety reports identified in
Sec. 4.102(c)(1)(i) and (ii) in accordance with Sec. 314.80(g) of
this chapter if your combination product received marketing
authorization under an NDA or ANDA or in accordance with Sec.
600.80(h) of this chapter if your combination product received
marketing authorization under a BLA.
(2) You must submit the postmarketing safety reports identified in
Sec. 4.102(c)(2)(ii) and (c)(3)(ii) in accordance with Sec. 803.12(a)
of this chapter if your combination product received marketing
authorization under a device application.
Sec. 4.105 What are the postmarketing safety reporting recordkeeping
requirements for your combination product or constituent part?
(a) If you are a constituent part applicant:
(1) You must maintain records in accordance with the recordkeeping
requirements in the applicable regulation(s) described in Sec.
4.102(b).
(2) You must maintain records required under Sec. 4.103(b) for the
longest time period required for records under the postmarketing safety
reporting regulations applicable to your product under Sec. 4.102(b).
(b) If you are a combination product applicant, you must maintain
records in accordance with the longest time period required for records
under the regulations applicable to your product under Sec. 4.102.
Dated: December 14, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-30485 Filed 12-19-16; 8:45 am]
BILLING CODE 4164-01-P
