[Federal Register Volume 74, Number 189 (Thursday, October 1, 2009)]
[Proposed Rules]
[Pages 50744-50758]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-23519]


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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: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) proposes to amend the 
combination product regulations to set forth postmarketing safety 
reporting requirements for combination products. Specifically, the rule 
will clarify the postmarketing safety reporting requirements that apply 
when regulated articles (drugs, devices, and biological products) are 
combined to create a combination product. The proposed rule is intended 
to promote and protect the public health by clarifying requirements for 
postmarketing safety reporting for combination products, and is part of 
FDA's ongoing effort to ensure the consistency and appropriateness of 
the regulatory requirements for combination products.

DATES: Submit written or electronic comments on the proposed rule by 
December 30, 2009. Submit comments on information collection issues 
under the Paperwork Reduction Act of 1995 by November 2, 2009, (see the 
``Paperwork Reduction Act of 1995'' section of this document).

ADDRESSES: You may submit comments, identified by Docket No. FDA-2008-
N-0424 and/or RIN number 0910-AF82, by any of the following methods, 
except that comments on information collection issues under the 
Paperwork Reduction Act of 1995 must be submitted to the Office of 
Regulatory Affairs, Office of Management and Budget (OMB) (see the 
``Paperwork Reduction Act of 1995'' section of this document).

Electronic Submissions

    Submit electronic comments in the following ways:
    <bullet> Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.

Written Submissions

    Submit written submissions in the following ways:
    <bullet> FAX: 301-827-6870.
    <bullet> Mail/Hand delivery/Courier (for paper, disk, or CD-ROM 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    To ensure more timely processing of comments, FDA is no longer 
accepting comments submitted to the agency by e-mail. FDA encourages 
you to continue to submit electronic comments by using the Federal 
eRulemaking Portal, as described previously, in the ADDRESSES portion 
of this document under Electronic Submissions.
    Instructions: All submissions received must include the agency name 
and docket number and Regulatory Information Number (RIN) for this 
rulemaking. All comments received may be posted without change to 
http://www.regulations.gov, including any personal information 
provided. For

[[Page 50745]]

additional information on submitting comments, see the ``Request for 
Comments'' heading of the SUPPLEMENTARY INFORMATION section of this 
document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://www.regulations.gov and insert the 
docket number, found in brackets in the heading of this document, into 
the ``Search'' box and follow the prompts and/or go to the Division of 
Dockets Management, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Leigh Hayes, Office of Combination 
Products (HFG-3), Food and Drug Administration, 15800 Crabbs Branch 
Way, suite 200, Rockville, MD 20855, 301-427-1934.

SUPPLEMENTARY INFORMATION:
I. Introduction
II. Description of the Proposed Rule
    A. Background
    B. General Principles
    C. Specific Examples
    D. Additional Considerations
    E. Role of Lead Center
    F. Recordkeeping Requirements
    G. Separate Applications and/or Reporters
    H. Applicability of Proposed Rule to User Facilities and Importers 
and Distributors as Defined in 21 CFR Part 803
    I. Stakeholders' Comments on Postmarketing Safety Reporting 
Applicable to Combination Products
III. Legal Authority
IV. Environmental Impact
V. Paperwork Reduction Act Analysis
VI. Federalism
VII. Analysis of Impacts
    A. Introduction
    B. The Rationale Behind This Proposed Rule
    C. Impact of Proposed Rule
VIII. Request for Comments
IX. Proposed Effective Date

I. Introduction

    As set forth in part 3 (21 CFR part 3), a combination product is a 
product comprised of a combination of a drug and a device; a device and 
a biological; a biological and a drug; or a drug, a device, and a 
biological. 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; (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; (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; 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.\1\ This rule does not address postmarketing 
reporting associated with approved products that are used in 
combination with investigational products.
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    \1\ Combinations of two investigational products as defined at 
Sec.  3.2(e)(4) are outside the scope of this proposed rule. Those 
types of combination products are investigational only and have not 
yet been approved for marketing. This proposed rule applies to all 
combination products for which postmarketing safety reports are 
required.
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    In the past decade, significant advances have been made in the 
development of combination products. In recognition of these advances, 
the Medical Device User Fee and Modernization Act of 2002 (MDUFMA) 
modified section 503(g) of the Federal Food, Drug, and Cosmetic Act 
(the FD&C Act) (21 U.S.C. 353(g)) to require the establishment of an 
Office (Office of Combination Products (OCP)) within FDA's Office of 
the Commissioner. The responsibilities of OCP include ensuring the 
prompt assignment of combination products to agency components, the 
timely and effective premarket review of such products, and the 
consistent and appropriate postmarket regulation of like products 
subject to the same statutory requirements to the extent permitted by 
law (21 U.S.C. 353(g)(4)).
    To date, the agency has not issued regulations on postmarketing 
safety reporting specifically for combination products. Instead, the 
agency has applied provisions from the applicable postmarketing safety 
reporting regulations for 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. However, each set of regulations has certain reporting 
standards and timeframes with unique requirements based upon the 
characteristics of the products for which the regulations were designed 
(i.e., for drugs, devices and biological products).
    External stakeholders have expressed concern about the lack of 
concrete information regarding the postmarketing safety reporting 
regulatory requirements for combination products (see section II.I of 
this document for further discussion). Generally, reporters have 
followed the safety reporting regulations associated with the type of 
marketing application used to approve or clear their combination 
product. For example, if a new drug application (NDA) was used to 
approve a drug/device combination product, reporters generally submit 
postmarketing safety reports in accordance with part 314 (21 CFR part 
314). However, if the device component of the combination product 
malfunctions, the reporter currently has no clear regulatory procedure 
to follow under part 314 when reporting this problem. This lack of 
regulatory clarity could lead to reporting that does not sufficiently 
reflect the combination nature of the product or the fact that an 
adverse experience may be related to a particular constituent part of a 
combination product. This lack of regulatory clarity could also lead to 
incomplete or inconsistent reporting and to FDA not receiving important 
safety information. This could compromise the agency's ability to make 
sound regulatory decisions about product safety and could jeopardize 
the public health.
    To address these concerns, to ensure appropriate ongoing 
postmarketing surveillance of risks, to ensure the consistency of the 
agency's postmarketing regulation of combination products, to 
streamline requirements for reporters by avoiding duplicative reporting 
requirements, FDA proposes to create 21 CFR part 4, subpart B to 
clarify postmarketing safety reporting requirements for combination 
products.\2\
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    \2\ As described in the Department of Health and Human Services 
(HHS) Unified Agenda (72 FR 22490, April 30, 2007), FDA also plans 
to propose regulations on current good manufacturing practice for 
combination products. FDA proposes to codify those requirements in 
part 4, subpart A, and to codify the postmarketing safety reporting 
requirements for combination products in part 4, subpart B.

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II. Description of the Proposed Rule

A. Background

    In the development of this proposed rule, FDA considered the fact 
that each constituent part of a combination product is governed by one 
of three differing sets of reporting provisions. The agency reviewed 
each set of regulations governing postmarketing safety reporting for 
drugs (parts 310 (21 CFR part 310) and 314), biological products (parts 
600 and 606 (21 CFR parts 600 and 606)), and devices (part 803 (21 CFR 
part 803)). This review determined that each set of regulations 
contains many substantially similar requirements as well as certain 
important differences.
    In general, each set of regulations requires reports of death and 
serious adverse events; each provides for periodic and followup 
reports; and each provides a method to signal certain types of safety 
events that warrant expedited reporting. Because of these similarities, 
it is possible to consolidate the requirements so that the combination 
product is subject primarily to the reporting requirements associated 
with the type of marketing application under which the product is 
approved or cleared. However, there are certain significant differences 
in the three sets of regulations. These differences are designed to 
facilitate adverse experience reporting that adequately addresses the 
distinct characteristics and potential safety issues related to a 
particular type of product (i.e., drug, device, and biological 
product). 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 type of marketing application. FDA has 
identified five such provisions, unique to drugs, biologics, or 
devices, that need to be preserved to appropriately reflect the 
combination nature of the product and to ensure consistent and 
appropriate postmarketing safety reporting for combination products:
1. 5-Day Report
    The Medical Device Reporting (MDR) regulation has a provision found 
in Sec.  803.53(a), which requires reporting no later than five work 
days after the day the reporter becomes aware that an MDR reportable 
event associated with the device necessitates remedial action to 
prevent an unreasonable risk of substantial harm to the public health. 
This section also allows FDA to make written requests for the 
submission of all subsequent events of the same nature that involve 
substantially similar devices for the time period specified in the 
written request. Reporters must also maintain a record of any report 
they submit under this provision. This provision is unique to devices; 
a similar provision is not found in the drug or biological product 
reporting regulations.
2. 30-Day Device Malfunction Report
    The MDR regulation also includes Sec.  803.20(b)(3)(ii), which 
requires reporting no later than 30 calendar days after the day the 
reporter becomes aware of information that reasonably suggests the 
device has malfunctioned and that this device or a similar device that 
the reporter markets would be likely to cause or contribute to a death 
or serious injury if the malfunction were to recur.\3\ Reporters must 
also maintain a record of any report they submit under this provision. 
Like the 5-day MDR report, this situation is unique to devices, and the 
drug and biological product reporting regulations do not have 
comparable provisions.
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    \3\ Section 227 of the Food and Drug Administration Amendments 
Act of 2007 (FDAAA) amended section 519(a)(1) of the FD&C Act (21 
U.S.C. 360i) to require 30-day malfunction reports under part 803 
for only certain devices, such as class III devices and class II 
devices that are permanently implantable, life supporting, or life 
sustaining. Other devices, such as class I devices, are subject to 
summary reporting on a quarterly basis. See the proposed definition 
of malfunction report in proposed Sec. Sec.  4.101 and 4.103(b)(2).
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3. 15-Day ``Alert Report'' for Drugs and Biological Products
    A reporter must submit to FDA a report of an adverse experience 
associated with the use of a drug or biological product that is both 
serious and unexpected, whether foreign or domestic, as soon as 
possible but in no case later than 15 days of initial receipt of the 
information as set forth in Sec. Sec.  314.80(c)(1) and (e), and 
600.80(c)(1) and (e). Serious events are reportable within 30 days 
under Sec.  803.20(b)(3)(i) for devices, regardless of whether or not 
they are expected. However, there is no requirement in the MDR 
regulation for expedited (15-day) reporting of an event that is both 
serious and unexpected.
4. 3-Day Field Alert Report
    Another unique provision is Sec.  314.81(b)(1), which requires 
applicants to file ``field alert reports'' when there is information 
concerning certain types of problems with a drug in distribution, such 
as any bacteriological contamination, or any significant chemical, 
physical, or other change or deterioration in a distributed drug 
product, or any failure of one or more distributed batches of the drug 
to meet the specification established for it in its marketing 
application, or any incident that causes the drug product or its 
labeling to be mistaken for, or applied to, another article. Reporters 
must submit this information to the FDA district office that is 
responsible for the facility involved within 3 working days of its 
receipt. They must provide the information by telephone or other rapid 
communication means, with prompt written followup. Reporters must also 
maintain a record of any report they submit under this provision. These 
types of situations are specific to drug products, and neither set of 
regulations found in parts 600 (biological products) or 803 (devices) 
has a similar provision requiring expedited submission of these types 
of reports.
5. Expedited Blood Fatality Report
    Section 606.170 requires expedited reporting of a complication of 
blood collection or transfusion confirmed to be fatal, by telephone, 
facsimile, express mail or electronically transmitted mail as soon as 
possible, and a written report within 7 days after the fatality. 
Reporters must also maintain a record of any report they submit under 
this provision. This situation is specific to blood products. Although 
parts 310, 314, 600 and 803 require expedited reporting of deaths, they 
do not provide for the immediate notification of blood-related 
fatalities.

B. General Principles

    Given the broad similarities in the regulations, the agency 
believes that the simplest and most straightforward way to ensure that 
combination products are regulated consistently is by continuing to 
require reporters to comply with the requirements for postmarketing 
safety reporting associated with the application used to approve or 
clear their combination product (proposed Sec.  4.103(a)), as long as 
the five unique specified provisions particular to each different set 
of regulations are, in fact, complied with by the reporter (proposed 
Sec.  4.103(b)). This supplementation reflects the combination nature 
of the product, and recognizes and preserves each constituent part's 
unique characteristics. Specifically, these unique reporting 
requirements, along with any associated followup reports, are as 
follows: (1) submission of a ``5-day report'' related to the device 
constituent part of a combination product as described in Sec.  
803.53(a); (2) submission of a 30-day ``malfunction report'' related to 
the device constituent part of a combination product as described in 
section 227 of FDAAA and Sec.  803.20(b)(3)(ii); (3) submission of a

[[Page 50747]]

``postmarketing 15-day `Alert report''' associated with the use of a 
drug or biological product constituent part of a combination product, 
as described in Sec. Sec.  314.80(c)(1) and (e), and 600.80(c)(1) and 
(e); (4) submission of a 3-day ``field alert report'' as described in 
Sec.  314.81(b)(1); and (5) submission of an expedited ``blood fatality 
report'' as described in Sec.  606.170.
    Given the unique nature of combination products, more than one 
applicant may be involved in the development of a combination product, 
or more than one marketing application may be submitted. For most 
combination products, however, a single marketing application is 
submitted for the combination product's approval, clearance or 
licensure. In these cases, the marketing application covers all 
constituent parts of the combination product (e.g., both the drug and 
device constituent parts of a drug-device combination product). The 
applicable reporting requirements for this type of circumstance are 
described later in this section (section II.B of this document). In 
some cases, however, separate marketing applications are submitted for 
the various constituent parts of a combination product. This can occur 
when one applicant submits separate marketing applications for the 
various constituent parts of a combination product (e.g., an NDA for 
the drug constituent part and a premarket approval application (PMA) 
for the device constituent part), or when a combination product is 
developed by more than one applicant, each of which holds a marketing 
application for its respective constituent part of the combination 
product. For this type of circumstance, the applicable reporting 
requirements are described in section II.G of this document.
    Under the proposed rule, combination products marketed under a 
single application would be subject to the following reporting scheme:
1. General Requirements (Proposed Sec.  4.103(a))
    A reporter would use the requirements for postmarketing safety 
reporting associated with the approved or cleared application under 
which the combination product is marketed. In general, for combination 
products approved or cleared under the device provisions of the FD&C 
Act, a reporter would utilize medical device reporting under part 803; 
for combination products approved under the drug provisions of the FD&C 
Act, a reporter would use Sec. Sec.  314.80 and 314.81; and for 
combination products licensed under the Public Health Service Act (PHS 
Act), a reporter would use Sec. Sec.  600.80 and 606.170. If you are 
the only reporter for a combination product (i.e., another reporter is 
not responsible for reporting for one of the constituent parts of the 
combination product), you would consider the combination product as a 
whole (i.e., all of its constituent parts) and the application under 
which it is approved or cleared when determining whether an event is 
required to be reported.
2. Additional Requirements (Proposed Sec.  4.103(b))
    When applicable, depending on the type of combination product and 
the nature of the reportable event, a reporter would submit additional 
types of reports and any associated followup reports, to appropriately 
reflect the combination nature of the product. These five types of 
reports, described above, would only be necessary if you would not 
otherwise (already) be required to provide them under the reporting 
framework associated with the application under which your product is 
approved, or if they would be required, but at a later timeframe.
3. Multiple Reporters (Proposed Sec.  4.104)
    If you are not the only reporter for a combination product (e.g., 
you hold an application for one constituent part of the combination 
product, while another reporter holds an application for its other 
constituent part), you are subject to applicable requirements for 
postmarketing safety reporting for your constituent part of the 
combination product. In addition, to ensure the other reporter is aware 
of and can investigate and followup on events you may learn about, you 
must submit the information you receive about events to FDA or the 
other reporter within 5 calendar days of your receipt of the 
information. In turn, you must investigate and report information you 
receive about reportable events provided to you by FDA or another 
reporter for your combination product.
4. Submission and FDA Review of Reports (Proposed Sec.  4.105)
    With the exception of ``field alert reports'' that are submitted to 
the appropriate FDA district office, all reports, including the reports 
associated with the regulatory requirements applicable to your product 
or constituent part, and the additional types of reports (described 
previously) reflecting the combination nature of the product, would be 
submitted using the submission methods identified in the appropriate 
underlying regulations. The lead FDA center charged with review and 
regulation of the combination product will review the reports and may 
consult with other Centers as needed.
5. Recordkeeping Requirements (Proposed Sec.  4.106)
    Records would be kept in accordance with the existing underlying 
regulatory requirements applicable to each type of report.

C. Specific Examples

1. Drug/Device (Approved Under Section 505 of the FD&C Act)
    The proposed rule would preserve the unique postmarketing safety 
reporting requirements for drugs, devices, and biological products 
regardless of the type of marketing application for the combination 
product. For example, for a drug/device combination product regulated 
under the drug provisions of the FD&C Act and approved under an NDA, a 
reporter would follow the NDA reporting provisions set forth in 
Sec. Sec.  314.80, 314.81, 314.98, or 314.540, as is the case for all 
products regulated under part 314. Although the language of part 314 
refers specifically to the drug product, under the proposed rule, if 
you are the only reporter for the combination product, you would 
consider the combination product as a whole (i.e., all of its 
constituent parts including its device constituent parts) and the 
application under which it was approved or cleared when determining the 
reportability of an event under Sec.  314.80(c)(1) (15-day alerts 
report). For example, an event that is both serious and unexpected, 
whether associated with the drug or device constituent part of the 
combination product, would be reported within 15 calendar days of 
initial receipt of such information by the reporter.
    A reporter for a drug/device combination product, approved under an 
NDA, would also be required to submit a reportable device malfunction 
or a 5-day report when necessary for an event related to the device 
constituent part of their combination product, and to include such 
reports in the periodic reports submitted under Sec.  314.80(c)(1). For 
example, a 30-day device malfunction report would be necessary when a 
reporter becomes aware of information that reasonably suggests that the 
device constituent part of the combination product malfunctioned and if 
the malfunction were to recur, it would be likely to cause or 
contribute to a death or serious injury. In that case, a reporter would 
submit, as appropriate, a malfunction report as described in section 
227 of FDAAA, as well as any required followup reports. Similarly, a

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reporter would submit a 5-day report, as defined in Sec.  803.3 and 
described in Sec.  803.53(a), if there is a reportable event regarding 
a device constituent part of a combination product that necessitates 
remedial action to prevent an unreasonable risk of substantial harm to 
the public health. In either case, since the drug/device combination 
was approved under an NDA, the report would be submitted to the address 
specified in part 314. Any report submitted to FDA would also be 
described in the periodic reports required by Sec.  314.80(c)(2).
2. Biological Product/Device (Approved Under Section 351 of the PHS 
Act)
    The specified device reporting requirements would be similarly 
applied, as described in section II.C.1 of this document, if a 
biological product/device combination product is approved under a 
biologics license application (BLA). A reporter would follow the 
biologics reporting provisions set forth in Sec. Sec.  600.80 and 
606.170 (for products with blood or blood component constituent parts) 
as would be the case for any product licensed under section 351 of the 
PHS Act. In general, reporting under Sec.  600.80 would also cover the 
device constituent part, not including 5-day MDR reports and 30-day MDR 
malfunction reports. As stated in the previous example, if you become 
aware of information that reasonably suggests that the device 
constituent part of the combination product malfunctioned and that if 
the malfunction were to recur it would be likely to cause or contribute 
to a death or serious injury, you would submit a 30-day malfunction 
report as described in section 227 of FDAAA, and any required followup 
reports. Likewise, you would submit a 5-day report for a reportable 
event regarding a device constituent part of a combination product that 
necessitates remedial action to prevent an unreasonable risk of 
substantial harm to the public health. Since the biological product/
device combination was approved under a BLA, the reports would be 
submitted as described in Sec.  600.80 and to the address specified in 
Sec.  600.2. A reporter would also describe any 5-day and malfunction 
reports submitted to FDA in the periodic reports required by Sec.  
600.80(c)(2).
3. Drug or Biological Product/Device (Approved or Cleared Under the 
FD&C Act's Device Authorities)
    The proposed rule would also preserve the unique reporting 
requirements relevant to drugs and biological products that may be 
constituent parts of a combination product, if the combination product 
is regulated under the device provisions of the FD&C Act. For example, 
if a drug/device combination product is approved under a PMA or cleared 
under a premarket notification (510(k)), you would comply with the 
applicable postmarketing safety reporting requirements set forth in 
part 803, as you would for other products regulated under the device 
provisions of the FD&C Act. Although the language of part 803 refers 
specifically to devices, under the proposed rule, if you are the only 
reporter for the combination product, you would, in general, submit 
postmarket safety reports for the combination product, including its 
drug or biological constituent parts, under part 803. You would also 
comply with the 15-day alert report requirements, under Sec. Sec.  
314.81(c)(1) or 600.80(c)(1), for the drug or biological product 
constituent parts, if such requirements applied. In addition, you would 
comply with a 3-day field alert report, for the drug constituent part, 
if Sec.  314.81(b)(1) applied. For example, if a death or serious 
injury occurred, whether associated with the drug or device constituent 
part of the combination product, you would report it in accordance with 
part 803. However, if a serious, unexpected adverse experience occurred 
that is associated with the use of the drug constituent part of the 
combination product, you would investigate and submit a ``postmarketing 
15-day `Alert' report,'' and any required followup reports, as 
described in Sec.  314.80(c)(1).\4\ A 30-day MDR report for this event 
would not be required. Likewise, if you receive a report that there is 
bacteriological contamination of the drug constituent part of your 
distributed combination product, or another type of event described in 
Sec.  314.81(b)(1) related to the drug constituent part of your 
distributed combination product, you would submit a field alert report 
to the appropriate FDA district office within 3 working days of your 
receipt of the information.
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    \4\ Even though, in this example, the combination product is 
approved under the device authorities, you would submit a 15-day 
alert report, if required, for the drug constituent part, regardless 
of whether the drug constituent part ``caused or contributed to'' a 
reportable event.
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    Similarly, the proposed rule would also preserve the unique 
reporting requirements relevant to blood-related fatalities. If a 
device/biological product combination product containing blood or a 
blood component was approved under a PMA, a reporter would follow the 
reporting requirements described in part 803. However, a reporter would 
instead submit a ``postmarketing 15-day `Alert' report'' as described 
in Sec.  600.80(c)(1) for a serious, unexpected adverse experience 
associated with the use of the biological product constituent part of 
the combination product. A 30-day MDR report for this event would not 
be required. Similarly, a reporter would submit a report, as described 
in Sec.  606.170, for a blood-related fatality. Since the device/
biological product combination was approved under a PMA, the reports 
would be submitted to the address specified in part 803.
4. Drug/Biological Product (Approved Under Section 505 of the FD&C Act 
or Section 351 of the PHS Act)
    Drug and biological product reporting requirements are very 
similar, with two exceptions being Sec.  606.170, the provision which 
concerns expedited reporting of blood-related fatalities and Sec.  
314.81(b)(1) the provision which concerns reporting of certain types of 
problems with a drug in distribution, such as bacteriological 
contamination, a significant change in or deterioration of the drug, 
failure of the drug product to meet application specifications, or an 
incident that causes the drug product or its labeling to be mistaken 
for, or applied to, another article. A reporter with a drug/biological 
combination product approved under a BLA would be required to follow 
the postmarketing safety reporting procedures set forth in parts 600 
and 606 (for a combination product with a blood or blood component 
constituent part). Compliance with these provisions would satisfy the 
reporting requirements for an adverse experience that is associated 
with the use of either the drug or biological product constituent parts 
of the combination product, unless you receive information of the type 
described in Sec.  314.81(b)(1) concerning the drug constituent part of 
the product, in which case you would submit a ``field alert report.'' 
Similarly, a reporter with a drug/biological combination product 
approved under an NDA would follow the postmarketing safety reporting 
provisions described in part 314. Compliance with these provisions 
would satisfy the reporting requirements for an adverse experience 
associated with the use of either the drug or the biological product 
constituent part, unless the biological product constituent part 
contained blood or a blood component. In that case, if you have a drug/
biological combination product that contained blood or a blood 
component approved under a NDA, you would comply with part 314, and, if 
applicable, submit an expedited blood fatality report as described in 
Sec.  606.170. Reporting the

[[Page 50749]]

event within the timeframe set forth in Sec.  606.170 would also 
fulfill your requirement to report a serious, unexpected event within 
15 days under Sec.  314.80(c)(1).

D. Additional Considerations

    FDA does not expect or desire that reporters submit duplicate 
reports, and this proposal is intended to ensure that duplicative 
reporting does not occur. Under this proposal, take, for example, a 
reporter who submits a 15-day alert report for a serious, unexpected 
adverse experience associated with the use of a drug constituent part 
of a drug/device combination product approved under a PMA and subject 
to part 803 as discussed previously (the reporter would follow the 
reporting requirements, standards and timeframes specified in part 
803). In this case, submission of the 15-day alert report and any 
associated followup reports would fulfill the requirement for 
submission of a 30-day report under part 803 for a serious event, 
regardless of whether or not it was expected. In other words, reporting 
the serious, unexpected event that is associated with the drug 
constituent part of your combination product within 15 days would also 
fulfill your requirement to report a serious event, regardless of 
expectedness, within 30 days under the MDR regulation. Similarly, if 
the combination product is comprised of a biological product component 
containing blood and a drug component, submission of a ``blood fatality 
report'' and any associated followup reports, as soon as possible and 
with a written report within 7 days, would satisfy the requirement to 
report a death or serious injury within 15 days under part 314.
    We note that this proposed rule applies to mandatory safety reports 
submitted to the agency, i.e., those reports currently submitted on 
Form 3500A or the CIOMS I or Vaccine Adverse Event Reporting System 
(VAERS) form, or their electronic equivalents, periodic safety reports, 
as well as ``field alert reports'' related to the drug constituent part 
of a combination product. This proposed rule does not change any annual 
or periodic reporting timeframes. Furthermore, the regulations proposed 
here do not supersede other reporting requirements found in 21 CFR 
parts 314, 600, 606, 803, or 806. Finally, FDA's authority to require 
additional postmarketing safety reporting for a particular product 
under other regulatory provisions, e.g., conditions of approval or 
postmarketing commitments, is unaffected by this rule.

E. Role of Lead Center

    For a combination product approved or cleared under one marketing 
application, the ``lead'' Center, i.e., the Center with primary 
responsibility for the review and regulation of the combination 
product, will have lead responsibility for review of all postmarketing 
safety reports, regardless of whether a particular constituent part is 
associated with the event. After the lead Center receives the 
postmarketing safety report, it will consult as needed with the other 
Center(s).
    For example, for a drug/device combination product approved under 
an NDA by the Center for Drug Evaluation and Research (CDER), all 
reports required by part 314 under proposed Sec.  4.103(a), as well as 
under the two unique specified provisions for devices (5-day or 30-day 
device malfunction reports) under proposed Sec.  4.103(b)(1) and 
(b)(2), would be submitted to the address required for all other 
postmarketing safety reports the reporter submits (in this case, those 
required by part 314). CDER would have the lead on their review, and 
CDER would consult the Center for Devices and Radiological Health 
(CDRH) as needed.

F. Recordkeeping Requirements

    In considering the recordkeeping requirements that should apply for 
postmarketing safety reporting for combination products, the agency 
chose to use the time periods set forth in the regulations for drugs, 
devices, and biological products because both stakeholders and the 
agency are familiar with those requirements. As a result, under 
proposed Sec.  4.106(a), records pertaining to reportable events under 
parts 310, 314 and 600 would be kept for 10 years, and records for 
reportable events under part 803 would be kept for 2 years or the 
expected life of the combination product, whichever is longer. Under 
proposed Sec.  4.106(b), the recordkeeping requirements for the five 
additional provisions specified in proposed Sec.  4.103(b) would each 
be the same as those currently required by the underlying regulations 
from which these requirements were derived.

G. Separate Applications and/or Reporters

    For some combination products, separate marketing applications are 
submitted for the individual constituent parts of a combination 
product. In some cases, one reporter holds all the applications used to 
approve or clear the combination product; in other cases, the reporter 
holds only one application that governs one constituent part of the 
combination product, while a different reporter holds the application 
for the other constituent part.
    Under proposed Sec.  4.103(a), if you are the only reporter for a 
combination product, you would consider each of the reporting 
requirements specified in proposed Sec.  4.103(a) and comply with each 
that is applicable to your combination product or constituent part. For 
example, if you hold a single marketing application covering the entire 
combination product, under proposed Sec.  4.103(a), you would be 
subject primarily to the set of reporting requirements associated with 
that type of marketing application (e.g., part 803 if your product is 
approved under a PMA). However, if you hold two marketing applications 
for your combination product (e.g., an NDA for the drug constituent 
part and a PMA for the device constituent part), under proposed Sec.  
4.103(a), you would be subject to the reporting requirements under part 
803 for your device constituent part, and to the reporting requirements 
under part 314 for your drug constituent part. In the special 
circumstance of holding two marketing applications for your combination 
product, and you can reasonably determine the constituent part that 
caused the adverse event, you only consider that particular constituent 
part when determining your reporting requirements. For example, if you 
hold multiple marketing applications for a combination product and you 
reasonably conclude that the adverse event was related to the drug 
constituent part, you would only follow the reporting requirements 
under part 314. Similarly, if the adverse event was related to the 
device constituent part, you would only follow the reporting 
requirements under part 803; if the adverse event was related to the 
biological product constituent part, you would only follow the 
reporting requirements under parts 600 and 606. If it is unclear which 
constituent part led to the adverse event, you would satisfy reporting 
requirements for each constituent part of the combination product.
    If you do not hold all of the applications used to approve or clear 
the constituent parts of your combination product, you would comply 
with the requirements for postmarketing safety reporting associated 
with the application used to approve or clear your constituent part of 
the combination product. Additionally, under proposed Sec.  4.104(a), 
you would submit the information you receive about an adverse event to 
FDA or the reporter for the other constituent part of

[[Page 50750]]

the combination product within 5 calendar days of your receipt of the 
information. Under proposed Sec.  4.104(b), if the other reporter 
receives such information from you, that reporter would then 
investigate and report the event in accordance with the statutory 
provisions and regulatory requirements for postmarketing safety 
reporting for their constituent part of the combination product. For 
example, if you hold the application for a drug constituent part of a 
drug/device combination product approved under an NDA, and you receive 
information regarding an event, you would comply with part 314, i.e., 
the reporting provisions associated with your application, in 
determining reportability of the event. You would also send the 
information about the event to FDA or the reporter for the device 
constituent part of the combination product within 5 calendar days of 
receiving the information. If you choose to notify the device reporter 
within 5 calendar days, the device reporter would investigate and 
report the event in accordance with part 803, i.e., the reporting 
provisions associated with that reporter's application. In some cases, 
the regulations will not require the other reporter to submit the 
report; in other circumstances, depending on the nature of the 
reportable event, the regulations will require the other reporter to 
submit a report. FDA recognizes that in these relatively rare 
circumstances, the agency may receive duplicate reports regarding one 
incident. However, FDA believes these requirements are necessary in 
order to promote and protect the public health by ensuring consistent 
and appropriate ongoing postmarketing surveillance of risks, and ensure 
both manufacturers are aware of and appropriately investigate and 
follow up on events involving their constituent part(s) of a 
combination product.

H. Applicability of Proposed Rule to User Facilities and Importers and 
Distributors as Defined in Part 803

    The proposed rule does not apply to user facilities required to 
report to FDA under part 803. Section 803.30 requires user facilities 
to report deaths to FDA and serious injuries to the device manufacturer 
within 10 days. Since user facility reporting already includes early, 
expedited reporting of deaths and serious injuries, it encompasses the 
types of additional reports described in proposed Sec.  4.103(b) 
related to drug and biological product constituent parts, i.e., serious 
and unexpected adverse experiences and blood-related fatalities. 
Therefore, no further supplementation is necessary in order for user 
facility reporting to reflect the combination nature of a product.
    The proposed rule also does not apply to distributors as defined in 
part 803, i.e., those who further the marketing but do not repackage or 
otherwise change the container, wrapper, or labeling. Under Sec.  
803.18(d), device distributors are required to maintain records of 
incidents but not to report to FDA.
    Importers of combination products subject to part 803 would be 
subject to the proposed rule. Under part 803, importers are required to 
report deaths and serious injuries to FDA, and device malfunctions to 
the manufacturer.\5\ Importers of combination products regulated under 
the device provisions of the FD&C Act would continue to be subject to 
part 803. Such importers would submit to FDA reports described in 
proposed Sec.  4.103(b) to provide for earlier, expedited reporting of 
serious, unexpected adverse experiences associated with the drug or 
biological product constituent parts of a combination product they are 
importing. Importers would also submit expedited reporting of 
fatalities related to a blood constituent part of the imported 
combination product.
---------------------------------------------------------------------------

    \5\ Under section 227 of FDAAA, if an importer is required, 
under part 803, to submit a report concerning a device malfunction 
to the manufacturer, the importer must submit the report to the 
manufacturer in accordance with part 803.
---------------------------------------------------------------------------

I. Stakeholders' Comments on Postmarketing Safety Reporting Applicable 
to Combination Products

    FDA held a public hearing on November 25, 2002, and a public 
workshop on July 8, 2003, to discuss various issues pertaining to 
combination products, including postmarketing safety reporting for 
combination products. Stakeholders provided a number of thoughtful 
written comments, regarding postmarketing safety reporting, to a 
docket, which FDA opened to further facilitate the discussion of 
combination product issues. The agency has carefully reviewed all the 
comments we received, and we have considered them in the development of 
this proposed rule. Two common themes that emerged from the comments 
were: (1) The need for consistency in reporting requirements and (2) 
avoidance of duplicative reporting. We believe that the provisions set 
forth in this proposal provide a framework that adequately addresses 
these concerns.
    Some stakeholders have suggested that FDA consider developing an 
entirely new postmarketing safety reporting scheme for combination 
products. Such a scheme might, for example, harmonize the varying 
definitions, reporting standards, timeframes, and other differences 
between the postmarketing safety reporting regulations for drugs, 
devices, and biological products. However, as described previously, 
given the broad similarities in the regulations, the agency determined 
that the simplest and most straightforward approach is to continue to 
require reporters to comply with the requirements for postmarketing 
safety reporting associated with the application used to approve or 
clear the combination product, as long as there is compliance, as 
appropriate, with the five unique provisions. This approach recognizes 
and preserves each constituent part's unique characteristics, while 
allowing reporters and FDA to continue to use mechanisms for reporting 
that are currently in practice.
    Finally, some stakeholders have recommended that the agency develop 
a comprehensive information technology (IT) system for postmarketing 
safety reporting of combination products. The agency acknowledges the 
need to make IT accommodations to have its postmarketing safety 
reporting procedures work efficiently. The agency is developing an 
internal electronic infrastructure for combination product safety 
reports. We anticipate that we will be able to implement this 
infrastructure prior to the effective date of any final rule based on 
this proposed rule. In parallel with that project, we are currently 
enhancing mechanisms for FDA to receive combination product 
postmarketing safety reports electronically and for intercenter 
consultation of these reports upon their receipt. Additionally, we 
recognize that it may be necessary to make minor changes to the Form 
FDA 3500A, the VAERS form, the periodic safety report, the Form FDA 
3331, and Form FDA 3486, or their electronic equivalents and/or 
instructions to accommodate the postmarketing safety information 
required by this rule. We invite comment on what changes might be 
necessary and will provide further instructions for practical 
implementation in conjunction with any final rule that may issue after 
this proposed rule.
    FDA believes these proposed postmarketing safety reporting 
requirements will ensure the consistency and appropriateness of 
postmarketing safety reporting for combination products. The rule 
provides that, regardless of the type of marketing application used to 
approve or clear the product or the Center with primary responsibility 
for its review, each combination product will be

[[Page 50751]]

subject to similar postmarketing safety reporting requirements. The 
rule recognizes and incorporates the similarities of the reporting 
requirements in the different sets of regulations, while also ensuring 
appropriate reporting by recognizing and preserving the unique 
provisions which embody necessary safety signals, given the combination 
nature of the product. These safety reporting requirements will help 
ensure the submission of necessary and appropriate information to 
expedite FDA's safety review and evaluation, and thereby will enhance 
the agency's ability to promote and protect the public health. The 
proposed rule when finalized will affect postmarketing safety reports 
submitted on or after the effective date of any final rule issued as a 
result of this proposed rule.

III. Legal Authority

    The agency derives its authority to issue the regulations in 
proposed 21 CFR part 4 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, Federal Food, Drug, and Cosmetic Act, 
and 42 U.S.C. 216, 262, 263a, 264, and 271, Public Health Service Act. 
Of these, certain authorities are particularly significant. For a drug 
approved under an NDA or an abbreviated new drug application, section 
505(k) requires the applicant to submit reports, concerning clinical 
experience, 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. This regulation is set forth in Sec.  314.80.
    For a device, section 519 of the FD&C Act (21 U.S.C. 360i) 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, found in part 803.
    For a biological product, section 351 of the 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) also prohibits falsely labeling a biological 
product. FDA used section 351 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).
    There is considerable overlap in the postmarket safety reporting 
requirements for drug, 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 postmarket safety 
reporting regulations. Overall, the regulatory framework governing 
postmarket safety reporting 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 adverse events, which are not found in 
the other sets of regulations. These are as follows: MDR 5-day Reports, 
MDR 30-day malfunction reports, Drugs/Biologics 15-day alert reports, 
Drugs 3-day field alert reports, and Expedited Blood Fatality Reports. 
As set forth in this proposal, it is crucial that these 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 
discreet regulatory identities when they become constituent parts of a 
combination product. In general, the postmarket safety reporting 
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 postmarketing 
safety reporting requirements. For example, in the case of a device and 
biological product combination product, the MDR regulation in part 803 
and the biological product postmarket reporting of adverse experiences 
regulation in Sec.  600.80 would apply to the combination product. 
However, this proposed rule is intended to clarify that a reporter must 
only comply with the postmarketing safety requirements associated with 
the application used to approve or clear the combination product. In 
the example above of a device-biologic combination product, if the 
combination product has an approved BLA, the reporter would use Sec.  
600.80 to report postmarketing adverse experiences for the combination 
product. In addition, as explained in this proposal, the reporter must 
comply with whichever of five specific requirements apply. In the case 
of a device-biologic combination product with an approved BLA, the 
reporter would also have to file MDR 5-day Reports and MDR 30-day 
malfunction reports if the criteria for such reports were met. Under 
this legal framework, if you demonstrate compliance with the applicable 
requirements of the set of regulations (e.g., biological product 
postmarket safety reporting) associated with the approved application 
(e.g., BLA), and comply with any applicable specified unique provisions 
(e.g., MDR 30-day malfunction reporting), you will be considered to 
have satisfied all applicable requirements from the other set of 
reporting regulations (e.g., MDR regulation).
    The legal authority for this 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, requires the Office of Combination 
Products (OCP) to ``designate'' a product as a combination product as 
well as to ensure ``consistent and appropriate postmarket regulation of 
like products subject to the same statutory requirements.'' Further, 
section 563 of the FD&C Act, 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, 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 the proposed rule is founded on the 
postmarket safety reporting regulatory

[[Page 50752]]

scheme associated with the application, under which the product is 
approved, plus any applicable requirements of the five unique reporting 
provisions listed in this proposal. Although similar in effect to the 
first framework described previously, this approach is based on the 
legal authority FDA used to issue each of its three existing 
regulations for postmarket safety reporting for drugs, devices, and 
biological products. In the context of this proposal, 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 five unique reporting 
provisions. 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 postmarket safety reporting under 
Sec.  600.80. Furthermore, section 351 would provide the authority for 
the agency to require additional reporting for devices (MDR 5-Day 
Reports and MDR 30-Day Malfunction Reports if the criteria for such 
reports are met).
    This legal theory applies to all combination products subject to 
this proposal. It is particularly relevant, however, for those 
combination products involving a drug constituent part and approved 
under a BLA or approved or cleared under the device authorities. This 
is because section 505(k) of the FD&C Act requires the submission of 
reports ``in the case of any drug for which an approval of an 
application filed under subsection (b) or (j) [of section 505] is in 
effect * * *''.

IV. Environmental Impact

    FDA has determined under 21 CFR 25.30(a), 25.30(h), 25.30(j), 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.

V. Paperwork Reduction Act Analysis

    This proposed rule contains information collections that are 
subject to review by OMB under the Paperwork Reduction Act of 1995 (44 
U.S.C. 3501-3520). A description of these provisions is given below 
with an estimate of the annual reporting and recordkeeping burden. 
Included in the estimate is the time for reviewing instructions, 
searching existing data sources, gathering and maintaining the data 
needed, and completing and reviewing each collection of information.
    FDA invites comments on the following topics: (1) Whether the 
proposed collection of information is necessary for the proper 
performance of FDA's functions, including whether the information will 
have practical utility; (2) the accuracy of FDA's estimate of the 
burden of the proposed collection of information, including the 
validity of the methodology and assumptions used; (3) ways to enhance 
the quality, utility, and clarity of the information to be collected; 
and (4) ways to minimize the burden of the collection of information on 
respondents, including through the use of automated collection 
techniques, when appropriate, and other forms of information 
technology.
    Title: Postmarketing Safety Reporting for Combination Products
    Description: This proposed rule clarifies postmarketing safety 
reporting requirements for combination products. In the development of 
this proposed rule, the agency considered the fact that each 
constituent part of a combination product is governed by one of three 
differing sets of reporting provisions for drugs, devices, and 
biological products. The agency reviewed each set of regulations 
governing postmarketing safety reporting for drugs (parts 310 and 314), 
biological products (parts 600 and 606), and devices (part 803). The 
review determined that each set of regulations contains many 
substantially similar requirements. Given the broad similarities in the 
regulations, the agency determined that the simplest and most 
straightforward way to ensure that combination products are regulated 
consistently is by continuing to require reporters to comply with the 
regulatory requirements for postmarketing safety reporting associated 
with the application used to approve or clear the combination product, 
as long as the five unique provisions particular to each different set 
are also applied. This supplementation reflects the combination nature 
of the product, and recognizes, preserves, and distinguishes each 
constituent part's unique characteristics. Specifically, these unique 
reporting requirements, along with any associated followup reports, 
are: (1) submission of a ``5-day report'' related to the device 
constituent part of a combination product as described in Sec.  
803.53(a); (2) submission of a 30-day ``malfunction report'' related to 
the device constituent part of a combination product as described in 
section 27 of FDAAA and Sec.  803.20(b)(3)(ii); (3) submission of a 
``postmarketing 15-day `Alert report''' for a serious, unexpected 
adverse experience associated with the use of a drug or biological 
product constituent part of a combination product, as described in 
Sec. Sec.  310.305(c), 314.80(c)(1) and (e), and 600.80(c)(1) and (e); 
(4) submission of a 3-day ``field alert report'' related to the drug 
constituent part of a combination product as described in Sec.  
314.81(b)(1); and (5) submission of an expedited ``blood fatality 
report'' concerning a fatality related to the blood or blood component 
constituent part of a combination product as described in Sec.  
606.170.
    We note that the postmarketing safety reporting information 
collections for drugs, biological products, and devices found in 
Sec. Sec.  314.80, 314.81, and 600.80, 600.81, 606.170, 803.20, and 
803.53 have already been approved and are in effect. The pertinent 
postmarketing safety reporting information collection provisions for 
Sec.  314.80(c) and (e), as well as for Sec.  314.81(b) are approved 
under OMB Control No. 0910-0001, which expires May 31, 2011, OMB 
Control No. 0910-0230, which expires July 31, 2012, and OMB Control No. 
0910-0291, which expires December 31, 2011. The information collection 
provisions for Sec. Sec.  600.80 and 600.81 are approved under OMB 
Control No. 0910-0308, which expires on September 30, 2011. Those for 
Sec.  606.170 are approved under OMB Control No. 0910-0116, which 
expires February 29, 2012. Finally, the information collection 
provisions for Sec. Sec.  803.20 and 803.53 are approved under OMB 
Control No. 0910-0437, which expires on July 31, 2012. As a result, the 
information collection described here refers only to the reporting and 
recordkeeping requirements for the five unique reporting requirements 
that are being applied because the product is a combination product. 
FDA does not expect or desire that reporters submit duplicate reports, 
and this proposal is intended to ensure that duplicative reporting does 
not occur.
    These proposed requirements are necessary to: (1) Ensure consistent 
postmarketing safety reporting, (2) ensure that the agency receives 
necessary information to promote and protect the public health, (3) 
avoid duplicative reporting, (4) ensure appropriate ongoing assessment 
of risks, and (5) ensure consistent and appropriate postmarketing 
regulation of combination products.
    Description of Respondents: Any person required to submit or record 
a reportable event under Sec. Sec.  310.305, 314, 600, 606, or 803, 
except for user facilities and device distributors as defined in part 
803.

[[Page 50753]]

    Proposed Sec.  4.103(b)(1) requires reporters for combination 
products comprised of a device constituent part to report no later than 
5 work days after the day the reporter becomes aware that an MDR 
reportable event associated with the device constituent part of the 
combination product necessitates remedial action to prevent an 
unreasonable risk of substantial harm to the public health. This 
section also allows FDA to make written requests for the submission of 
all subsequent events of the same nature that involve substantially 
similar devices or device constituent parts of a combination product 
for the time period specified in the written request. This section only 
applies to reporters who would not otherwise submit a ``5-day report'' 
under the requirements associated with the application used to approve/
clear the combination product with the device constituent part. 
Reporters must also maintain a record of any report they submit under 
this provision.
    Proposed Sec.  4.103(b)(2) requires reporters for combination 
products comprised of a device constituent part to report no later than 
30 calendar days after the day the reporter becomes aware of 
information that reasonably suggests the device constituent part of the 
combination product has malfunctioned and that this device constituent 
part or a similar device constituent part that the reporter markets 
would be likely to cause or contribute to a death or serious injury if 
the malfunction were to recur. This section only applies to reporters 
who would not otherwise submit a 30-day ``malfunction report'' under 
the requirements associated with the application used to approve/clear 
the combination product with the device constituent part. Reporters 
must also maintain a record of any report they submit under this 
provision.
    Proposed Sec.  4.103(b)(3) requires reporters for combination 
products comprised of a drug or a biological product constituent part 
to report each adverse experience associated with the use of the drug 
or biological product constituent part of the combination product that 
is both serious and unexpected, whether foreign and domestic, as soon 
as possible but in no case later than 15 calendar days of initial 
receipt of the information by the sponsor. This section only applies to 
reporters who would not otherwise submit a ``postmarketing 15-day 
`Alert report''' under the requirements associated with the application 
used to approve/clear the combination product with the drug or 
biological product constituent part(s). Reporters must also maintain a 
record of any report they submit under this provision.
    Proposed Sec.  4.103(b)(4) requires reporters for combination 
products comprised of a drug constituent part to report information 
concerning any bacteriological contamination, or any significant 
chemical, physical, or other change or deterioration in the drug 
constituent part of a distributed contribution product, or any failure 
of one or more distributed batches of the drug constituent part of a 
combination product to meet the specification established for it in its 
marketing application. Reporters must submit this information to the 
FDA district office that is responsible for the facility involved 
within 3 working days of its receipt. They must provide the information 
by telephone or other rapid communication means, with prompt written 
followup. This section only applies to reporters who would not 
otherwise submit a 3-day ``field alert report'' under the requirements 
associated with the application used to approve/clear the combination 
product with the drug product constituent part. Reporters must also 
maintain a record of any report they submit under this provision.
    Proposed Sec.  4.103(b)(5) requires reporters for combination 
products comprised of a biological product constituent part containing 
blood or a blood component, if a complication of blood collection or 
transfusion is confirmed to be fatal as described in Sec.  606.170(b), 
to report by telephone, facsimile, express mail or electronically 
transmitted mail as soon as possible, and a written report within 7 
days after the fatality. This section only applies to reporters who 
would not otherwise report such an event within this timeframe under 
the statutory provisions and regulatory requirements associated with 
the application used to approve/clear the combination product with the 
biological product constituent part containing blood or a blood 
component. Reporters must also maintain a record of any report they 
submit under this provision.

Information Collection Burden Estimate

    FDA estimates the burden for this information collection as 
follows:

                         Table 1.--Estimated Annual Reporting Burden for Human Drugs\1\
----------------------------------------------------------------------------------------------------------------
                      No. of         Annual Frequency       Total Annual        Hours per
21 CFR Section     Respondents         per Response          Responses           Response         Total Hours
----------------------------------------------------------------------------------------------------------------
4.103(b)(1)                     5                     1                  5                  1                  5
----------------------------------------------------------------------------------------------------------------
4.103(b)(2)                    20                    15                300                  1                300
----------------------------------------------------------------------------------------------------------------
4.103(b)(3)                    20                    15                300                  1                300
----------------------------------------------------------------------------------------------------------------
4.103(b)(4)                     5                     1                  5                  1                  5
----------------------------------------------------------------------------------------------------------------
4.103(b)(5)                     5                     1                  5                  1                  5
----------------------------------------------------------------------------------------------------------------
Totals                         55  ....................                615  .................                615
----------------------------------------------------------------------------------------------------------------


        Table 2.--Estimated Annual Postmarketing Safety Recordkeeping Burden for Combination Products\1\
----------------------------------------------------------------------------------------------------------------
                      No. of       Annual Frequency  of     Total Annual
21 CFR Section    Recordkeepers        Recordkeeping          Records       Hours per  Record     Total Hours
----------------------------------------------------------------------------------------------------------------
4.103(b)(1)                     5                     1                  5                 .5                2.5
----------------------------------------------------------------------------------------------------------------
4.103(b)(2)                    20                    15                300                 .5                150
----------------------------------------------------------------------------------------------------------------

[[Page 50754]]

 
4.103(b)(3)                    20                    15                300                 .5                150
----------------------------------------------------------------------------------------------------------------
4.103(b)(4)                     5                     1                  5                 .5                2.5
----------------------------------------------------------------------------------------------------------------
4.103(b)(5)                     5                     1                  5                 .5                2.5
----------------------------------------------------------------------------------------------------------------
Totals                         55  ....................                615  .................              307.5
----------------------------------------------------------------------------------------------------------------

Burden

    Based on FDA's experience regarding receipt of postmarketing safety 
reports for combination products, the agency estimates that there will 
be 55 reporters (who will keep corresponding records) submitting a 
total of 615 reports under proposed 4.103(b) annually (and maintaining 
the records of those reports). In other words, the agency estimates 
that there will be 55 reporters who will avail themselves of these new 
streamlined reporting requirements and benefit from the associated 
burden reductions. For example, manufacturers of drug-device 
combination products marketed under an NDA will now be able to submit 
postmarket safety reports following the requirements for drug products 
and no longer have to submit additional postmarket safety reports 
following the requirements for devices so long as they comply with the 
reporting and recordkeeping requirements of sections 4.103(b)(1) and 
4.103(b)(2).
    Further, FDA estimates, based on its experience with information 
collection regarding postmarketing safety reporting provisions for 
drugs, biological products, and devices, that each report will take 
approximately 1 hour to prepare and submit, and half an hour to fulfill 
the corresponding recordkeeping requirements.
    FDA believes that there are no significant operating and 
maintenance costs associated with this collection of information 
because, in order to legally market their products, reporters are 
required to develop and maintain systems for reporting and maintaining 
records of postmarketing safety events. Therefore, appropriate 
mechanisms for postmarketing safety reporting should already be in 
place, and reporters will accrue no significant additional costs to 
fulfill the requirements set forth here.
    We welcome comments on our estimates of the number of respondents 
who will avail themselves of the new streamlined reporting requirements 
and our burden estimates. Based on these comments, we will revise our 
estimates accordingly of the burden reductions associated with the 
reporting and recordkeeping requirements of Sec. Sec.  314.80, 314.81, 
and 600.80, 600.81, 606.170, 803.20, and 803.53.
    In compliance with the Paperwork Reduction Act of 1995 (44 U.S.C. 
3507(d)), the agency has submitted the information collection 
provisions of this proposed rule to OMB for review.
    The information collection provisions of the proposed rule have 
been submitted to OMB for review. Interested persons are requested to 
fax comments regarding information collection by November 2, 2009, to 
the Office of Information and Regulatory Affairs, OMB. To ensure that 
comments on information collection are received, OMB recommends that 
written comments be faxed to the Office of Information and Regulatory 
Affairs, OMB, Attn: Desk Officer, FAX: 202-395-6974.

VI. Federalism

    FDA has analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. Section 4(a) of the 
Executive Order requires agencies to ``construe * * * a Federal statute 
to preempt State law only where the statute contains an express 
preemption provision or there is some other clear evidence that the 
Congress intended preemption of State law, or where the exercise of 
State authority conflicts with the exercise of Federal authority under 
Federal statutes.'' The sole statutory provision giving preemptive 
effect to the proposed rule is section 751 of the act (21 U.S.C. 379r), 
which would apply only with respect to OTC drug components of 
combinations.\6\
---------------------------------------------------------------------------

    \6\ The proposed rule seeks to clarify which adverse event 
reporting 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 act 
applicable to prescription drugs or biological products. Section 521 
of the act (51 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.
---------------------------------------------------------------------------

VII. Analysis of Impacts

A. Introduction

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and 
the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). In accordance with 
Executive Order 12866, FDA has carefully analyzed the economic effects 
of this proposal and has determined that the final rule, if issued, 
will not be a significant regulatory action as defined by the Executive 
order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because this rule clarifies existing requirements 
and will have no recurring impact on the majority of small firms, the 
agency proposes to certify that the final rule will not have a 
significant economic impact on a substantial number of small entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $133 million, using the most current (2008)

[[Page 50755]]

Implicit Price Deflator for the Gross Domestic Product. FDA does not 
expect this proposed rule to result in any 1-year expenditure that 
would meet or exceed this amount.

B. The Rationale Behind This Proposed Rule

    The purpose of the proposed rule is to codify the postmarketing 
safety reporting requirements for combination products to ensure their 
consistent and appropriate regulation. The current regulations and 
reporting standards for drugs, devices, and biological products are 
similar but each has certain unique requirements. A separate rule 
specific to combination products will clarify how to apply these 
provisions to combination products and avoid applying duplicative or 
unnecessary requirements. The proposed rule will benefit public health 
by helping to ensure that the necessary reports are submitted and 
directed to the appropriate center and that records are maintained for 
the appropriate length of time.

C. Impact of Proposed Rule

    The proposed rule will affect all of the approximately 300 
manufacturers of combination products. Industry should benefit from 
reduced uncertainty regarding how to apply the separate regulations to 
combination products and from more consistent enforcement across the 
agency. This is especially true for developing standard operating 
procedures (SOPs) for new combination products. All firms would incur 
one-time costs to assess their current compliance level to the proposed 
requirements. In addition, some firms may need to alter or add SOPs and 
recordkeeping practices. Estimating the one-time costs is problematic 
because the costs would vary depending on the size of the firm, their 
current business practice, and the number and nature of their products. 
Currently we cannot identify how many combination products there are or 
the extent of the changes that would be needed. Some firms could spend 
as little as 30 minutes while other firms with a variety of combination 
product types, may have to alter or add a number of SOPs. This could 
take 10 to 20 hours per SOP.
    The reporting requirements under proposed Sec.  4.103(b) will also 
generate some annually recurring costs. Because all of the firms have 
reporting systems in place and the reports are submitted on the same 
form as the other types of postmarket safety reports (with the 
exception of field alert reports (proposed Sec.  4.103(b)(4)), we 
estimate that the incremental time to comply with this requirement is 
about 1.5 hours and that we would receive about 615 reports from 55 
firms annually. Assuming an hourly wage plus benefit rate of $42,\7\ 
the annually recurring cost for these requirements would be $38,745 
(1.5 hours x $42/hr x 615 reports). These costs could be at least 
partly offset because some of the proposed reports would be submitted 
in lieu of an existing reporting requirement.
---------------------------------------------------------------------------

    \7\ Wage is based on the 2007 Bureau of Labor Statistic's 
survey, National Industry Specific Occupational Employment and Wage 
Estimate, for standard occupational code 13-1041, compliance officer 
in pharmaceutical and medicine manufacturing (NAICS 325400). The 
mean wage of $30.08 was increased by 40 percent to account for 
fringe benefits for a loaded wage of $42 per hour. http://www.bls.gov/oes/current/naics4_325400.htm#b23-0000.
---------------------------------------------------------------------------

    About 80 to 85 percent of the firms affected by this proposed rule 
are considered small, based on the Small Business Administration's 
definition of a small entity (500 employees for medical device and 
biological product firms and 750 employees for drug firms). Most of 
these small entities are medical device firms and produce combination 
products where the primary modes of action are attributable to medical 
devices. The impact on individual firms will depend on the nature of 
the changes to SOPs needed, the number and type of combination products 
produced, and the number of reports filed annually. Most products will 
not have any postmarket safety reports in a given year and thus there 
would be no annually recurring costs for them. The largest potential 
cost would be a one-time cost to modify existing SOPs. The cost to make 
such modifications is generally lower for small firms than for large 
firms.

VIII. Request for Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding this document. 
Submit a single copy of electronic comments or two paper copies of any 
mailed comments, except that individuals may submit one paper copy. 
Comments are to be identified with the docket number found in brackets 
in the heading of this document. Received comments may be seen in the 
Division of Dockets Management between 9 a.m. and 4 p.m., Monday 
through Friday.

IX. Proposed Effective Date

    The agency is proposing that any final rule that may issue based 
upon this proposed rule become effective 180 days after its date of 
publication in the Federal Register.

List of Subjects in 21 CFR Part 4

    Combination products, Biological products, Devices, Drugs, and 
Human cell, tissue, and cellular and tissue-based products, Regulation 
of combination products.
    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, it is proposed that 21 CFR part 4 be 
further amended as proposed to be added at 73 FR 48430, September 23, 
2009 as follows:

PART 4--REGULATION OF COMBINATION PRODUCTS

    1. Add subpart B to part 4 to read as follows:

Subpart B--Postmarketing Safety Reporting for Combination Products

General Provisions
Sec.
4.100 What is the scope of this subpart?
4.101 What are the definitions applicable to this subpart?
4.102 Who reports to FDA?
4.103 What are the reporting requirements?
4.104 How do I report if another reporter is responsible for a 
constituent part of my combination product?
4.105 How, where, and when do I submit postmarketing safety reports 
for combination products?
4.106 What are the postmarketing safety reporting recordkeeping 
requirements?

    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.


Sec.  4.100  What is the scope of this subpart?

    (a) This subpart establishes requirements for postmarketing safety 
reporting for combination products.
    (b) This subpart applies to the configurations of combination 
products described in Sec.  3.2(e)(1), (e)(2), and (e)(3) of this 
chapter. This subpart does not apply to investigational combination 
products as defined in Sec.  3.2(e)(4) of this chapter.
    (c) This subpart applies to all reporters required to report under 
parts 314, 600, 606, and 803 of this chapter, except for user 
facilities and device distributors as defined in part 803 of this 
chapter.
    (d) 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.


Sec.  4.101  What are the definitions applicable to this subpart?

    Act means the Federal Food, Drug, and Cosmetic Act.

[[Page 50756]]

    Adverse experience, as described in Sec. Sec.  310.305(b), 
314.80(a), and 600.80(a) of this chapter and as modified for purposes 
of this subpart, means any adverse event associated with the use of a 
drug or biological product constituent part of a combination product in 
humans, whether or not considered drug or biological product related, 
including the following: An adverse event occurring in the course of 
the use of a drug or biological product in professional practice, an 
adverse event occurring from drug or biological product overdose 
whether accidental or intentional, an adverse event occurring from drug 
or biological product abuse, an adverse event occurring from drug or 
biological product withdrawal, and any failure of expected 
pharmacological action.
    ANDA means abbreviated new drug application as defined at Sec.  
314.3(b) of this chapter.
    Application, for purposes of this subpart, means a new drug 
application, an abbreviated new drug application, a device premarket 
approval application, a device premarket notification submission, a 
humanitarian device exemption application, and/or a biologics license 
application, including all amendments and supplements to them.
    Biological product has the meaning set forth in Sec.  3.2(d) of 
this chapter.
    BLA means biologics license application as described in section 351 
of the Public Health Service Act (42 U.S.C. 262) and Sec.  601.2 of 
this chapter.
    Blood as defined in Sec.  606.3(a) of this chapter means whole 
blood collected from a single donor and processed either for 
transfusion or further manufacturing.
    Blood component as defined in Sec.  606.3(c) of this chapter means 
a blood component or part of a single-donor's blood separated by 
physical or mechanical means.
    Blood fatality report means the report described in Sec.  606.170 
of this chapter of a complication of blood collection or transfusion 
confirmed to be fatal, by telephone, facsimile, express mail, or 
electronically transmitted mail as soon as possible, and a written 
report within 7 days after the fatality.
    Combination product has the meaning set forth in Sec.  3.2(e) of 
this chapter.
    Constituent part is a drug, device, or biological product that is 
part of a combination product as defined in Sec.  3.1(e) of this 
chapter.
    Device has the meaning set forth in section 201(h) of the act (21 
U.S.C. 321(h)).
    Drug has the meaning set forth in Sec.  3.2(g) of this chapter.
    FDA means the Food and Drug Administration.
    Field alert report, as described in Sec.  314.81(b)(1) of this 
chapter and as modified for purposes of this subpart, means a report 
submitted on Form FDA 3331 within 3 working days to the appropriate FDA 
district office when there is information concerning any incident that 
causes the drug constituent part of a distributed combination product 
or its labeling to be mistaken for, or applied to, another article; or 
that contains information concerning any bacteriological contamination, 
or any significant chemical, physical, or other change or deterioration 
in the drug constituent part of a distributed combination product, or 
any failure of one or more distributed batches of a drug constituent 
part of a combination product to meet the specification established for 
it in the application.
    5-day report, as described in Sec. Sec.  803.3 and 803.53 of this 
chapter and as modified for purposes of this subpart, means a medical 
device report (MDR) that must be submitted by a reporter to FDA under 
Sec.  803.53(a) of this chapter no later than 5 work days after the day 
the reporter becomes aware that a MDR reportable event necessitates 
remedial action to prevent an unreasonable risk of substantial harm to 
the public health. FDA can also make a written request for a 5-day 
report for all subsequent events of the same nature that involve 
substantially similar devices or device constituent parts of a 
combination product for the time period specified in the written 
request.
    Followup report as described in Sec. Sec.  314.80(c)(1)(ii), 
600.80(c)(1)(ii), and 803.56 of this chapter and as modified for 
purposes of this subpart, is a report of supplemental, additional or 
followup information related to a reportable event.
    HDE means humanitarian device exemption as discussed in Sec.  
814.100 of this chapter.
    Malfunction, as described in Sec.  803.3 of this chapter and as 
modified for purposes of this subpart, means the failure of a device 
constituent part of a combination product to meet its performance 
specifications or otherwise perform as intended. Performance 
specifications include all claims made in the labeling for the 
combination product. The intended performance of a device constituent 
part refers to the intended use or indication for which the combination 
product is labeled or marketed.
    Malfunction report, as required under section 227 of FDAAA, as 
described in Sec.  803.20(b)(3)(ii) of this chapter, and as modified 
for purposes of this subpart, is a report submitted no later than 30 
calendar days after the day that the reporter becomes aware of 
information that reasonably suggests that one of the marketed device 
constituent parts of a combination product has malfunctioned and that 
the device constituent part or a similar device or device constituent 
part of a combination product marketed by the reporter would be likely 
to cause or contribute to a death or serious injury if the malfunction 
were to recur. A reporter must submit a 30-day malfunction report for 
malfunctions of the following devices: A Class III device; a Class II 
device that is permanently implantable, life supporting, or life 
sustaining; or a type of device that FDA, by notice in the Federal 
Register or letter, indicates should be subject to part 803 of this 
chapter to protect the public health. For Class I and certain Class II 
devices a reporter must submit reportable malfunctions on a quarterly 
basis using a summary format.
    MDR means a medical device report as defined in Sec.  803.3 of this 
chapter.
    MDR reportable event, as described in Sec.  803.3 of this chapter 
and as modified for purposes of this subpart, means an event about 
which the reporter has received or become aware of information that 
reasonably suggests that one of their marketed combination products:
    (1) May have caused or contributed to a death or serious injury; or
    (2) Has malfunctioned and that the device constituent part or a 
similar device or device constituent part of a combination product 
marketed by the reporter would be likely to cause or contribute to a 
death or serious injury if the malfunction were to recur.
    NDA means new drug application as defined in Sec.  314.3(b) of this 
chapter.
    PMA means a device premarket approval application as defined in 
Sec.  814.3 of this chapter.
    Postmarketing 15-day ``alert report,'' as described in Sec. Sec.  
314.80(c)(1) and 600.80(c)(1) of this chapter and as modified for the 
purposes of this subpart, is a report the reporter must make to FDA for 
each adverse experience as defined in this subpart that is both serious 
and unexpected, whether foreign or domestic, as soon as possible but in 
no case later than 15 calendar days of initial receipt of the 
information by the reporter.
    Premarket notification submission means a submission as described 
in Sec.  807.87 of this chapter.
    Reportable event, for purposes of this subpart, is an event that is 
reportable under this subpart or parts 314, 600, 606, or 803 of this 
chapter.

[[Page 50757]]

    Reporter, for purposes of this subpart, is any person or entity 
responsible for evaluating and determining whether an event meets the 
criteria for postmarketing safety reporting or who is required to 
submit or record a reportable event under this subpart or parts 314, 
600, 606, or 803 of this chapter. This term is used interchangeably 
with the term ``you.'' This term does not include user facilities or 
device distributors as defined in part 803 of this chapter.
    Serious adverse experience, as described in Sec. Sec.  314.80(a) 
and 600.80(a) of this chapter and as modified for purposes of this 
subpart, is any adverse experience occurring at any dose associated 
with the use of a drug or biological product constituent part of a 
combination product that results in any of the following outcomes: 
Death, a life-threatening adverse experience, inpatient hospitalization 
or prolongation of existing hospitalization, a persistent or 
significant disability/incapacity, or a congenital anomaly/birth 
defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious 
adverse experience when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.
    Serious injury means the injuries that are defined in Sec.  803.3 
of this chapter. This means an injury or illness that:
    (1) Is life-threatening,
    (2) Results in permanent impairment of a body function or permanent 
damage to a body structure, or
    (3) Necessitates medical or surgical intervention to preclude 
permanent impairment of a body function or permanent damage to a body 
structure.
    Unexpected adverse experience, as described in Sec. Sec.  314.80(a) 
and 600.80(a) of this chapter and as modified for the purposes of this 
subpart, means any adverse experience as defined in this subpart that 
is not listed in the current labeling for the combination product. This 
includes events that may be symptomatically and pathophysiologically 
related to an event listed in the labeling, but differ from the event 
because of greater severity or specificity.
    We means FDA.


Sec.  4.102  Who reports to FDA?

    Any person or entity required to submit to FDA postmarketing safety 
reports for a combination product under parts 314, 600, 606, or 803 of 
this chapter must report under this subpart. This subpart uses the term 
``reporters'' to refer to persons or entities responsible for 
evaluating and determining whether an event meets the criteria for 
postmarketing safety reporting or who are required to submit or record 
a reportable event. Additionally, the term ``you'' as used in this 
subpart refers to reporters. This subpart does not apply to user 
facilities or device distributors subject to medical device reporting 
as defined in part 803 of this chapter.


Sec.  4.103  What are the reporting requirements?

    (a) General requirements. You must consider each of the following 
reporting requirements and comply with each that is applicable to your 
combination product or your constituent part(s), if another reporter is 
responsible for the other constituent part(s) of the combination 
product. If you are the only reporter for the combination product, you 
must consider the combination product as a whole (i.e., all of its 
constituent parts), when determining whether an event is required to be 
reported.
    (1) If your combination product or your device constituent part is 
approved under a PMA or HDE, or is cleared under a premarket 
notification, you must comply with the requirements for postmarketing 
safety reporting described in part 803 of this chapter with respect to 
that combination product or device constituent part.
    (2) If your combination product or your drug constituent part is 
approved under an NDA or an ANDA, you must comply with the requirements 
for postmarketing safety reporting described in part 314 of this 
chapter with respect to that combination product or drug constituent 
part.
    (3) If your combination product or your biological product 
constituent part is approved 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 that combination product or 
biological product constituent part.
    (4) If your combination product or your device constituent part is 
not subject to a marketing application under the device provisions of 
the act because it was legally marketed prior to May 28, 1976, or is 
exempt from premarket notification, you must comply with the 
requirements for postmarketing safety reporting described in part 803 
of this chapter with respect to that combination product or device 
constituent part.
    (b) Additional requirements. If you are the only reporter for the 
combination product, depending on the type of combination product and 
the nature of the reportable event, you must submit, as applicable, the 
following additional reports and any associated followup reports. You 
must submit these additional reports only if the reports are not 
otherwise required to be reported by you under paragraph (a) of this 
section, or would be required, but at a later timeframe than specified 
as follows:
    (1)(i) If your combination product contains a device constituent 
part, you must submit a ``5-day report'' no later than 5 work days 
after the day that you become aware that:
    (A) An MDR reportable event associated with the use of the device 
constituent part of your combination product necessitates remedial 
action to prevent an unreasonable risk of substantial harm to the 
public health. You may become aware of the need for remedial action 
from any information, including any trend analysis; or
    (B) We have made a written request for the submission of a 5-day 
report. If you receive such a written request from us, you must submit, 
without further requests, a 5-day report for all subsequent events of 
the same nature that involve substantially similar devices or device 
constituent parts of a combination product for the time period 
specified in the written request. We may extend the time period stated 
in the original written request if we determine it is in the interest 
of the public health.
    (ii) You must also submit any required followup reports to a ``5-
day report'' required by Sec.  803.56 of this chapter.
    (2) If your combination product contains a device constituent part, 
you must submit a ``malfunction report'' no later than 30 calendar days 
after the day that you become aware of information that reasonably 
suggests the device constituent part, described in this paragraph, of 
your combination product has malfunctioned and that this device 
constituent part or a similar device or device constituent part that 
you market would be likely to cause or contribute to a death or serious 
injury if the malfunction were to recur. You must submit a 30-day 
malfunction report for reportable malfunctions of the following 
devices: A Class III device; a Class II device that is permanently 
implantable, life supporting, or life sustaining; or a type of device 
that FDA, by notice in the Federal Register or letter, indicates

[[Page 50758]]

should be subject to part 803 of this chapter to protect the public 
health. For Class I and certain Class II devices you must submit 
reportable malfunctions on a quarterly basis using a summary format. 
You must also submit any required followup reports to a ``malfunction 
report'' required by Sec.  803.56 of this chapter.
    (3) If your combination product contains a drug or a biological 
product constituent part, you must submit a postmarketing 15-day 
``alert report'', for each adverse experience associated with the use 
of a drug or biological product constituent part of the combination 
product, whether or not considered drug or biological product related, 
that is both serious and unexpected, whether foreign or domestic, as 
soon as possible but in no case later than 15 calendar days of initial 
receipt of the information by the reporter, as required by Sec.  
314.80(c)(1)(i) or Sec.  600(c)(1)(i) of this chapter. You must also 
promptly investigate and submit any required followup reports to a 
postmarketing 15-day ``alert report'' as required by Sec.  
314.80(c)(1)(ii) or Sec.  600(c)(1)(ii) of this chapter.
    (4) If your combination product contains a drug constituent part, 
you must submit a field alert report within 3 working days of your 
receipt to the FDA district office that is responsible for the facility 
involved, by telephone or other rapid communication means and prompt 
written followup, information concerning:
    (i) Any incident that causes the drug constituent part of a 
distributed combination product or its labeling to be mistaken for, or 
applied to, another article; or
    (ii) Any bacteriological contamination or any significant chemical, 
physical, or other change or deterioration in the drug constituent part 
of a distributed combination product, or any failure of one or more 
distributed batches of a drug constituent part of a combination product 
to meet the specification established for it in the application.
    (5) If your combination product contains a biological product 
constituent part containing blood or a blood component, and a 
complication of blood collection or transfusion is confirmed to be 
fatal as described in Sec.  606.170(b) of this chapter, you must submit 
a blood fatality report by telephone, facsimile, express mail, or e-
mail as soon as possible, and a written report within 7 days after the 
fatality.
    (c) Periodic reports. (1) If your combination product is approved 
under an NDA, ANDA, or BLA, you must also include information in 
reports submitted in accordance with paragraphs (b)(1), (b)(2), and 
(b)(5) of this section in the periodic reports you submit under 
Sec. Sec.  314.80(c)(2)(ii)(a) and 600.80(c)(2)(ii)(a) of this chapter. 
Information on these additional reports should be treated as 15-day 
alert reports, i.e., included in narrative summary and analysis of the 
information in the report and an analysis of the 15-day alert reports 
submitted during the reporting interval (all 15-day alert reports being 
appropriately referenced by the applicant's patient identification 
number, adverse reaction term(s), and date of submission to FDA). The 
history of actions taken since the last report because of adverse drug 
experiences (for example, labeling changes or studies initiated) should 
include information on the combination products as a whole (i.e., all 
of its constituent parts).
    (2) If your combination product is approved under a PMA, you must 
also include information in reports submitted in accordance with 
paragraphs (b)(3), (b)(4), and (b)(5) of this section in the periodic 
reports you submit under Sec. 814.82(a)(7) of this chapter.


Sec.  4.104  How do I report if another reporter is responsible for a 
constituent part of my combination product?

    (a) If another person holds an application used to approve or clear 
a constituent part of your combination product, or legally markets a 
constituent part of your combination product without an approved or 
cleared marketing application, in addition to the requirements of Sec.  
4.103(a), you must submit the information you received about the event 
to FDA or the other person within 5 calendar days of your receipt of 
the information.
    (b) If you receive information from the other person that holds an 
application used to approve or clear a constituent part of your 
combination product, or legally markets a constituent part of your 
combination product without an approved or cleared marketing 
application, you must investigate and, if required, report the event in 
accordance with Sec.  4.103(a) and (b).


Sec.  4.105  How, where, and when do I submit postmarketing safety 
reports for combination products?

    (a) You must submit the field alert reports described in Sec.  
4.103(b)(4) to the FDA district office that is responsible for the 
facility involved within 3 working days of receipt of the information.
    (b) You must submit all other postmarketing safety reports required 
under this subpart (i.e., required under Sec.  4.103(a), (b)(1), 
(b)(2), (b)(3), (b)(5), and (c)) using the submission methods and 
timeframes identified in the regulations applicable under Sec.  
4.103(a), (b), and (c) for your combination product or your constituent 
part.


Sec.  4.106  What are the postmarketing safety reporting recordkeeping 
requirements?

    (a) You must maintain records of postmarketing safety reports 
required by Sec.  4.103(a) in accordance with the recordkeeping 
requirements of the underlying regulation(s) identified in Sec.  
4.103(a) that are applicable to your combination product or your 
constituent part.
    (b) You must maintain records of reportable events required by 
Sec.  4.103(b) and (c) for the time period specified as follows:
    (1) 5-day and malfunction reports described in Sec.  4.103(b)(1) 
and (b)(2): for 2 years or the expected life of the combination 
product, whichever is longer;
    (2) Postmarketing 15-day `alert reports' field alert reports, and 
blood fatality reports described in Sec.  4.103(b)(3), (b)(4), and 
(b)(5), and periodic reports as described in Sec.  4.103(c): for 10 
years.

    Dated: September 24, 2009.
David Horowitz,
Assistant Commissioner for Policy.
[FR Doc. E9-23519 Filed 9-30-09; 8:45 am]
BILLING CODE 4160-01-S