[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]


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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.

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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, [email protected].

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.
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    \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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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\
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    \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.
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    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.
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    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\
---------------------------------------------------------------------------

    \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.
---------------------------------------------------------------------------

    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.
---------------------------------------------------------------------------

    \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.
---------------------------------------------------------------------------

    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 (http://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.
---------------------------------------------------------------------------

    \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 http://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) (http://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 http://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 http://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: http://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: http://www.fda.gov/ohrms/dockets/dockets/03n0203/03n0203.htm.
    3. Individual Case Study Reports, accessed at: (http://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