Compliance Policy for Combination 
Product Postmarketing Safety 
Reporting 
 
Immediately  in Effect Guidance for 
Industry and Food and Drug 
Administration Staff 
 
 
Comments may be submitted at any time for Agency consideration.  Submit written comments to 
the Dockets Management Staff (HFA-305), Food and Drug Administration,  5630 Fishers Lane, 
rm. 1061, Rockville,  MD 20852. Submit  electronic comments to https://www.regulations.gov. 
All comments should be identified  with the docket number listed in the notice of availability  that 
publishes in the Federal Register. 
 
Additional copies are available from: 
Office of Combination Products 
Food and Drug Administration 
WO32, Hub/Mail Room #5129 
10903 New Hampshire Avenue 
Silver Spring, MD 20993 
(Tel) 301-796-8930 
(Fax) 301-847-8619 
http://www.fda.gov/oc/combination 
 
For questions regarding this document, contact Melissa Burns, Office of Combination  Products, 
at 301-796-8930 or melissa.burns@fda.hhs.gov 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Office of Combination Products (OCP) 
Center for Biologics Evaluation and Research (CBER) 
Center for Drug Evaluation and Research (CDER) 
Center for Devices and Radiological Health (CDRH) 
 
April 2019
 
  Contains Nonbinding Recommendations 
Compliance Policy for Combination Product 
Postmarketing Safety Reporting 
Immediately in Effect Guidance for Industry and 
Food and Drug Administration Staff 
 
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic.  It 
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.  
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance.  
I.  Introduction 
This guidance document is intended to assist Combination  Product Applicants who are subject to 
the Combination  Product Postmarketing Safety Reporting Final Rule (hereafter combination 
product PMSR final rule, final rule, or rule), issued on December 20, 2016 (81 FR 92603), 
and codified in 21 CFR Part 4, Subpart B.  This guidance document discusses FDAs compliance 
policy for the rule.  FDA does not intend to enforce certain requirements under the rule, 
specifically  21 CFR 4.102(c) and (d), 4.104(b)(1) and (b)(2), and 4.105(b), for a period of time 
as discussed further in section III below.  FDA intends to delay enforcement of these provisions 
to ensure that Combination  Product Applicants have sufficient time to update reporting and 
recordkeeping systems and procedures, including  their information  technology systems, to 
comply with these requirements, and in doing so, have sufficient time to consider the 
recommendations and technical specifications that FDA intends to provide through guidance to 
support compliance.  For all other provisions  of 21 CFR Part 4, Subpart B, FDA intends to 
enforce (or continue enforcing) the requirements per its usual policies as of the compliance date 
provided in the final rule.   
 
FDAs guidance documents, including  this guidance, do not establish legally  enforceable 
responsibilities.   Instead, guidances describe the Agencys current thinking  on a topic and should 
be viewed only as recommendations,  unless specific regulatory or statutory requirements are 
cited.  The use of the word should in Agency guidance means that something is suggested or 
recommended, but not required. 
II.  Background 
In the Federal Register of December 20, 2016 (81 FR 92603), FDA published  a final rule for 
postmarketing  safety reporting (PMSR) for combination  products as defined at 21 CFR 3.2(e).  
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, which are applicants that hold the only application  for a combination  product or all 
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  the applications  for the constituent parts (drug, device, or biological  product) of a combination 
product, and Constituent Part Applicants, which are applicants for a constituent part of a 
combination  product the constituent parts of which are marketed under applications  held by 
different applicants (see 21 CFR 4.100 and 4.101). 
 
Under the final rule, Combination  Product Applicants must comply with:  application  type-based 
PMSR requirements (PMSR requirements associated with the application  type under which the 
combination  product received marketing authorization) (see 21 CFR 4.102(a) and (b)), 
constituent part-based PMSR requirements (specified in the rule based on the types of 
constituent parts included  in the combination  product) (see 21 CFR 4.102(c) and (d)), and 
associated submission  process and recordkeeping requirements (see 21 CFR 4.104(b) and 
4.105(b)). 
 
In the preamble to the final rule (81 FR at 92619), FDA stated that the compliance date for the 
application  type-based PMSR requirements for Combination  Product Applicants and Constituent 
Part Applicants under 21 CFR 4.102(a) and (b), and for the submission  process and 
recordkeeping requirements for Constituent Part Applicants under 21 CFR 4.104(a) and 
4.105(a)(1), respectively, was the same as the effective date for the final rule (January 19, 2017).  
These requirements are generally the same as for any other entity holding  such an application  for 
its product, and we expected all applicants subject to this rule to already be in compliance with 
these provisions  as such provisions  generally refer to existing regulations that such applicants 
have generally followed.  With respect to the PMSR requirements of 21 CFR 4.102(c) and (d), 
4.103, 4.104(b), and 4.105(a)(2) and (b), the final rule established a compliance date 18 months 
following  the effective date of the rule (i.e., compliance date of July 19, 2018). 
III.  FDA's Compliance  Policy for the Combination  Product 
PMSR Final Rule 
FDA does not intend to enforce the following  provisions  of the combination  product PMSR final 
rule applicable to Combination  Product Applicants prior to the dates provided in the bullets 
below:  21 CFR 4.102(c) and (d) (constituent part-based PMSR requirements), 4.104(b)(1) and 
(b)(2) (submission  process for constituent part-based Individual  Case Safety Reports (ICSRs)1), 
and 4.105(b) (recordkeeping requirements).   
 
  July 31, 2020, for Combination  Product Applicants using the FDA Adverse Event 
Reporting System (FAERS) and Electronic Medical Device Reporting System (eMDR) to 
report ICSRs. 
 
  January 31, 2021, for Combination  Product Applicants using the Vaccine Adverse Event 
Reporting System (VAERS) to report ICSRs. 
 
                                              
1 The term Individual Case Safety Report (ICSR) is used to describe a report of an event experienced by an 
individual user of a combination product, including adverse events and malfunctions.  For purposes of the 
combination product PMSR final rule and this guidance, ICSRs encompass Fifteen-day reports (see 21 CFR 314.80, 
600.80), Five-day reports (see 21 CFR 803.3, 803.53, 803.56), Malfunction reports (see 21 CFR 803.50, 803.56), 
and death or serious injury reports (21 CFR Part 803). 
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  FDA intends to delay enforcement of the above provisions  to ensure that Combination  Product 
Applicants have sufficient time to update reporting and recordkeeping systems and procedures, 
including  their information  technology  systems, to comply with these requirements.  During the 
period of delayed enforcement, FDA intends to focus on educating Combination  Product 
Applicants on the above provisions  with which they may be less familiar, including  providing 
guidance to help them comply with these provisions.   The period of delayed enforcement will 
provide Combination  Product Applicants with additional  time to consider the recommendations 
and technical specifications  that FDA intends to provide through the aforementioned guidance as 
they update their systems and procedures to comply with these provisions. 
 
For all other provisions  of 21 CFR Part 4, Subpart B, FDA intends to enforce the requirements 
per its usual policies2 because FDA does not believe significant  updates to systems and 
procedures are necessary to comply with these provisions.    
                                              
2 FDAs usual enforcement policies would apply in deciding whether to take enforcement action for violations in 
any given case, including the consideration of numerous factors such as whether the Agencys resources would be 
best spent on a particular case.  
3