[Federal Register Volume 83, Number 55 (Wednesday, March 21, 2018)]
[Proposed Rules]
[Pages 12292-12294]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-05687]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 4

[Docket No. FDA-2008-N-0424]


Postmarketing Safety Reporting for Combination Products; Draft 
Guidance for Industry and Food and Drug Administration Staff; 
Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notification of availability.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
the availability of a draft guidance for industry and FDA staff 
entitled ``Postmarketing Safety Reporting for Combination Products.'' 
This draft guidance addresses certain means by which applicants may 
comply with the final rule on postmarketing safety reporting (PMSR) 
requirements for combination products that FDA issued on December 20, 
2016. Combination products are products composed of two or more 
different types of medical products (drug, device, and/or biological 
product). Although the PMSR regulations for drugs, devices, and 
biological products share many similarities, each set of regulations 
establishes distinct postmarketing reporting requirements, standards, 
and timeframes. The final rule provides clarity on the PMSR 
requirements for combination products to ensure consistent and complete 
reporting while avoiding duplication. This draft guidance is not final 
nor is it in effect at this time.

DATES: Submit either electronic or written comments on the draft 
guidance by June 19, 2018 to ensure that the Agency considers your 
comment on this draft guidance before it begins work on the final 
version of the guidance.

ADDRESSES: You may submit either electronic or written comments on any 
Agency guidances at any time as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2008-N-0424 for ``Postmarket Safety Reporting for Combination 
Products.'' Received comments will be placed in the docket and, except 
for those submitted as ``Confidential Submissions,'' publicly viewable 
at https://www.regulations.gov or at the Dockets Management Staff 
between 9 a.m. and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852.
    You may submit comments on any guidance at any time (see 21 CFR 
10.115(g)(5)).
    Submit written requests for single copies of the draft guidance to 
the Office of Combination Products, Food and Drug Administration, Bldg. 
32, Rm. 5129, 10903 New Hampshire Ave., Silver Spring, MD 20993. Send 
two self-addressed adhesive label to assist that office in processing 
your requests. See the SUPPLEMENTARY INFORMATION section

[[Page 12293]]

for electronic access to the draft guidance document.

FOR FURTHER INFORMATION CONTACT: Melissa Burns, Office of Combination 
Products, Food and Drug Administration, 301-796-5616, 
[email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a draft guidance for industry 
and FDA staff entitled ``Postmarket Safety Reporting for Combination 
Products.'' This guidance addresses how to comply with the final rule 
on postmarketing safety reporting (PMSR) requirements for combination 
products that FDA issued on December 20, 2016 (81 FR 92603, hereafter 
referred to as the ``combination product PMSR final rule''). 
Combination products are products composed of two or more different 
types of medical products (drug, device, and/or biological product). 
Although the PMSR regulations for drugs, devices, and biological 
products share many similarities, each set of regulations establishes 
distinct reporting requirements, standards, and timeframes. The final 
rule provides clarity on the PMSR requirements for combination products 
to ensure consistent and complete reporting while avoiding duplication.
    Elsewhere in this issue of the Federal Register, FDA is also 
publishing a compliance policy guidance for the combination product 
PMSR final rule.
    The combination product PMSR final rule applies to combination 
products that are subject to premarket review by FDA. The entities 
subject to the final rule are ``Combination Product Applicants'' and 
``Constituent Part Applicants.'' A Combination Product Applicant holds 
the only application for a combination product or all the applications 
for the separately marketed constituent parts of a combination product. 
A Constituent Part Applicant holds an application for a constituent 
part of a combination product the constituent parts of which are 
marketed under separate applications held by different applicants. 
Major provisions of the final rule are discussed in the guidance 
including:
     Application Type-Based PMSR. These requirements apply to 
both Combination Product Applicants and Constituent Part Applicants and 
are based on the application type under which the combination product 
or constituent part received marketing authorization.
     Constituent Part-Based PMSR. These requirements apply only 
to Combination Product Applicants and are based on the types of 
constituent parts included in the combination product. The rule 
provides mechanisms for Combination Product Applicants to submit a 
single report to satisfy multiple reporting requirements if all of the 
information to be reported can be submitted in the same manner and the 
report satisfies all applicable reporting requirements, including all 
submission timelines.
     Information Sharing. These requirements apply only to 
Constituent Part Applicants, mandating that these applicants share 
certain adverse event information with one another relating to their 
combination product.
     Submission Process for Combination Product PMSR 
Information. These requirements specify how Combination Product and 
Constituent Part Applicants must submit PMSR information to the Agency.
     Records Retention. These requirements specify what records 
Combination Product and Constituent Part Applicants must maintain and 
how long to maintain them.

II. Other Issues for Consideration

    The combination product PMSR final rule allows FDA to receive 
complete, timely postmarketing safety information regarding combination 
products, which is necessary to assure the continued safety and 
effectiveness of such products, while minimizing unnecessary 
duplication and burdens on Combination Product Applicants and 
Constituent Part Applicants. In developing this guidance document to 
accompany the final rule, FDA has clarified ways in which Combination 
Product Applicants can streamline PMSR (see section V.A.3 of the 
guidance). The guidance clarifies under what circumstances the criteria 
for being able to submit a single report to FDA are met, i.e., that: 
(1) The reports can be submitted in the same manner and (2) the 
combined report satisfies all applicable reporting requirements, 
including submission timelines (see section IV.C of the guidance). FDA 
encourages comments on guidance content and mechanisms to improve 
reporting efficiency while still ensuring complete and timely reporting 
or topics where additional detailed discussion may be helpful in the 
guidance. In particular, FDA requests feedback on the following issues 
for consideration to assist the Agency in determining whether 
additional streamlining of reports may be appropriate:
    1. There may be events that would be reportable for a Combination 
Product Applicant as a malfunction and/or a Field Alert Report (FAR) 
and/or a Biological Product Deviation Report (BPDR), e.g., a drug-
device combination product that failed to meet specifications may 
trigger both a malfunction report and FAR. FDA requests feedback on 
circumstances under which such reporting may be redundant or otherwise 
unnecessary and, if so, alternative reporting approaches that will 
assure timely and complete reporting of information to FDA. FDA 
encourages the use of example scenarios to illustrate circumstances 
under which submitting one or a subset of such reports may be 
sufficient to ensure timely and complete reporting.
    2. Although outside the scope of the combination product PMSR final 
rule, in response to comments to the combination product PMSR proposed 
rule, FDA has addressed certain reporting considerations for entities 
involved with the manufacture and distribution of combination products 
but that are not ``applicants'' subject to this rule (see Appendix 3 of 
the guidance). FDA requests feedback on what, if any, additional 
guidance would be helpful to such entities.
    3. FDA is considering updating the Vaccine Adverse Event Reporting 
System (VAERS) with data elements similar to those described in section 
V.B.2 and Appendix 4 of the guidance for the FDA Adverse Events 
Reporting System (FAERS) and the Electronic Medical Device Reporting 
(eMDR) system. FDA is also evaluating what additional data elements to 
include in VAERS with respect to combination products and welcomes 
comments from combination product vaccine reporters on this topic.
    4. FDA also received comments to the combination product PMSR 
proposed rule related to the safety reporting requirements for 
investigational combination products. Although investigational 
combination products are outside the scope of the combination product 
PMSR final rule and this guidance, we will consider comments from 
sponsors on the challenges and the need for additional transparency 
related to safety reporting for investigational combination products. 
FDA will consider these comments in determining the need for additional 
policy and guidance on this topic.

III. Significance of Guidance

    This draft guidance is being issued consistent with FDA's good 
guidance practices regulation (21 CFR 10.115). The draft guidance, when 
finalized, will represent the current thinking of FDA

[[Page 12294]]

on ``Postmarket Safety Reporting for Combination Products.'' It does 
not establish any rights for any person and is not binding on FDA or 
the public. You can use an alternative approach if it satisfies the 
requirements of the applicable statutes and regulations. This guidance 
is not subject to Executive Order 12866.

IV. Paperwork Reduction Act of 1995

    This guidance refers to previously approved collections of 
information found in FDA regulations. These collections of information 
are subject to review by the Office of Management and Budget (OMB) 
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The 
collections of information in 21 CFR 314.80(c) and (e), as well as for 
21 CFR 314.81(b) are approved under OMB control numbers 0910-0001, 
0910-0230, and 0910-0291. The information collection provisions for 21 
CFR 600.80 and 600.81 are approved under OMB control number 0910-0308. 
Those for 21 CFR 606.170 are approved under OMB control number 0910-
0116. Those for 21 CFR 606.171 are approved under OMB control number 
0910-0458. The information collection provisions for 21 CFR 803.50, 
803.53, and 803.56 are approved under OMB control numbers 0910-0291 and 
0910-0437. The information collection provisions for 21 CFR 806.10 and 
806.20 are approved under OMB control number 0910-0359. The information 
collection provisions for 21 CFR 4.102, 4.103, and 4.105 are approved 
under OMB control number 0910-0834.

V. Electronic Access

    Persons with access to the internet may obtain the draft guidance 
at either https://www.fda.gov/CombinationProducts/GuidanceRegulatoryInformation/ucm109110.htm or https://www.regulations.gov.

    Dated: March 15, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-05687 Filed 3-20-18; 8:45 am]
BILLING CODE 4164-01-P


