Postmarketing Safety Reporting for 
Combination Products 
Guidance for Industry and FDA Staff 
 
FINAL GUIDANCE 
 
 
 
 
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 
https://www.fda.gov/combination-products 
 
For questions regarding this document, contact the  
Office of Combination Products at 301-796-8930 or combination@fda.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) 
 
 
July 2019 
 
1  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
I.  Introduction ............................................................................................................................ 3 
II.  Background ............................................................................................................................ 4 
A.  What Is a Combination Product? ................................................................................................. 4 
B.  How Does FDA Review and Regulate Combination Products? ................................................. 5 
III.  General Considerations for Combination Product PMSR Compliance .......................... 5 
A.  Who Is Subject to the Combination Product PMSR Final Rule? ............................................. 6 
B.  What Safety Reporting Requirements Apply to Me if I Am a Combination Product 
Applicant or Constituent Part Applicant? ........................................................................................... 8 
IV.  Specific PMSR Requirements .......................................................................................... 10 
A.  Individual Case Safety Reports for Combination Product Applicants ................................... 11 
B.  Other (Non-ICSR) Combination Product PMSR Report Types for Combination Product 
Applicants .............................................................................................................................................. 21 
C.  Streamlined Reporting for Combination Product Applicants ................................................. 24 
D.  Information Sharing Between Constituent Part Applicants .................................................... 24 
E.  Recordkeeping Requirements for Combination Product and Constituent Part Applicants 25 
V.  Process Considerations for Combination Product Applicants ........................................... 27 
A.  How to Submit Combination Product PMSR Information to FDA ........................................ 27 
B.  What Information to Include in Combination Product PMSR Reports ................................. 31 
VI.  Examples .......................................................................................................................... 36 
A.  Drug Application Combination Product.................................................................................... 36 
B.  Device Application Combination Product ................................................................................. 38 
Appendix 1. Combination Product (CP) PMSR Requirements by Application and Product 
Type............................................................................................................................................... 40 
Appendix 2.  Flowcharts for Combination Product ICSR Requirements ................................. 41 
Appendix 3.  Combination Product Postmarketing Safety Reporting Considerations for 
Entities that are Not Applicants............................................................................................... 43 
 
   
2  Contains Nonbinding Recommendations 
 
Guidance for Industry and FDA Staff: 
Postmarketing Safety Reporting for Combination 
Products 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for or on 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.  To discuss an alternative approach, contact the FDA office responsible for this guidance as 
listed on the title page.    
I.  Introduction 
This guidance addresses certain ways to comply with the final rule on postmarketing safety1, 2 
reporting (PMSR) requirements for combination products that FDA issued on December 20, 
2016 (81 FR 92603) and that is codified in 21 CFR Part 4, Subpart B (hereafter the combination 
product PMSR final rule, final rule, or rule).  Although the PMSR regulations for drugs, 
devices, and biological products share many similarities, each set of regulations establishes 
distinct reporting requirements, including reporting triggers and timeframes.  The rule addresses 
PMSR requirements for combination products that have received FDA marketing authorization, 
to ensure consistent and complete reporting while avoiding duplication.   
 
Section II of the guidance provides general information on combination products and how FDA 
regulates them.  Section III provides a summary of the combination product PMSR final rule and 
an overview of which entities are subject to the final rule and what safety reporting requirements 
apply to them.  Section IV provides more detailed discussion of specific combination product 
PMSR report types.  Section V provides guidance on where, how, and when to submit PMSR 
reports to FDA.  Section VI provides hypothetical scenarios that illustrate certain ways to 
comply with certain combination product PMSR requirements.  While this guidance focuses on 
the combination product PMSR final rule, it also addresses associated topics including 
postmarketing safety reporting requirements applicable to entities not covered by the rule (see 
Appendix 3). 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidance documents describe the agencys current thinking on a topic 
and should be viewed only as recommendations, unless specific regulatory or statutory 
 
1 As described in the federal register notice for the combination product PMSR final rule, the term postmarketing 
safety is used because the rule concerns certain postmarket events, including manufacturing events, malfunctions, 
and events causing injury to users, and the reporting requirements relating to product and patient safety that arise 
from these events.  The final rule supports the underlying purpose of postmarketing safety reporting for all medical 
products, namely to protect the public health by ensuring continued safety and effectiveness of the product after it is 
placed on the market. 
2 Note additional statutory or regulatory requirements may apply in relation to postmarket safety events, such as 
relevant submission and review requirements for postapproval modifications for example.  Neither the PMSR rule 
nor this guidance is intended to alter such requirements or Agency policy concerning them. 
3  Contains Nonbinding Recommendations 
 
requirements are cited.  The use of the word should in agency guidance documents means that 
something is suggested or recommended, but not required.  
II.  Background 
A. What Is a Combination Product? 
A combination product is a product composed of any combination of a drug, a device, and a 
biological product.3  Each drug, device, and biological product included in a combination 
product is referred to as a constituent part of the combination product. 
 
Under 21 CFR 3.2(e), a combination product includes: 
 
  A product composed 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.  
Examples of single-entity combination products include a prefilled syringe, 
transdermal patch, or drug-eluting stent.  
 
  Two or more separate products packaged together in a single package or as a unit and 
comprising drug and device products, device and biological products, or biological 
and drug products.  Examples of co-packaged combination products include 
surgical and first-aid kits. 
 
  A drug, device, or biological product packaged separately that according to its 
investigational plan or proposed labeling is intended for use only with an approved 
individually specified drug, device, or biological product where both are required to 
achieve the intended use, indication, or effect and where upon approval of the 
proposed product the labeling of the approved product would need to be changed, 
e.g., to reflect a change in intended use, dosage form, strength, route of 
administration, or significant change in dose.  A light-emitting device that is intended 
for use with a specific light-activated drug may be an example of such a cross-
labeled combination product. 
 
  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 
 
3 Applicants and FDA generally resolve whether a product is a combination product, or a constituent part of a 
combination product, as defined in 21 CFR Part 3, prior to approval or clearance of the application.  Whether you 
are seeking marketing authorization or your product is already cleared or approved, if you are uncertain of whether it 
is a combination product or a constituent part of a combination product or its Center assignment, we encourage you 
to contact the Office of Combination Products (OCP).  If you wish to obtain a binding  determination from FDA, 
you may submit a request for designation to OCP (see Guidance for Industry, How to Write a Request for 
Designation (RFD), at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/how-write-
request-designation-rfd), or if you wish to obtain informal feedback, you may submit a Pre-RFD (see Guidance 
for Industry, How to Prepare a Pre-Request for Designation (Pre-RFD), at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/how-prepare-pre-request-designation-pre-rfd). 
4  Contains Nonbinding Recommendations 
 
the intended use, indication, or effect (another basis for cross-labeled combination 
product status). 
B. How Does FDA Review and Regulate Combination Products? 
A combination product is assigned to an Agency center that will have primary jurisdiction (i.e., 
the lead Center) for that combination products regulation, including for ensuring compliance 
with postmarketing regulatory requirements.  Under section 503(g)(1) of the Federal Food, Drug, 
and Cosmetic Act (FD&C Act) (21 U.S.C. 353(g)(1)), assignment of a combination product to a 
lead Center is based on a determination of which constituent part provides the primary mode of 
action (PMOA) of the combination product.4  If, for example, the PMOA of a device-biological 
product combination product is attributable to the biological product constituent part, the center 
responsible for premarket review of such a biological product would have primary jurisdiction 
for the regulation of the combination product.   
 
Regardless of the PMOA, Agency components will coordinate as appropriate to ensure efficient, 
effective, and appropriately consistent PMSR policies and review of PMSR information.  For 
combination product PMSR, the lead Center will coordinate with the other center(s) and the 
Office of Combination Products (OCP), as appropriate, in light of the issues raised and expertise 
needed, on review of PMSR information and any responses to the submitter. 
III.  General Considerations for Combination Product PMSR 
Compliance   
The combination product PMSR final rule addresses 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 (See section III.A below for additional 
explanation of these two categories of entities).  Major elements of the final rule are: 
 
  Application Type-Based Reporting Requirements.  These requirements apply to both 
Combination Product Applicants and Constituent Part Applicants, based on the 
application type under which the combination product or constituent part received 
marketing authorization.  (See section III.B.1 for more detailed discussion of application 
type-based reporting requirements.) 
  Constituent Part-Based Reporting Requirements.  Constituent part-based reporting 
requirements apply only to Combination Product Applicants and are based on the types 
of constituent parts included in the combination product. (See sections III.B.2 and IV 
below for detailed discussion of these requirements.)   
 
4 The primary mode of action is the single mode of action (drug, device, or biological product) of a combination 
product expected to make the greatest contribution to the overall intended therapeutic effects of the combination 
product (see 21 USC 353(g)(1)(C) and 21 CFR 3.2(m); see also 21 CFR 3.2(k) (defines mode of action)).  For 
more information on product classification, assignment, and PMOA, see Guidance for Industry, How to Write a 
Request for Designation (RFD), at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/how-write-request-designation-rfd. 
5  Contains Nonbinding Recommendations 
 
  Information Sharing.  The rule requires Constituent Part Applicants to share certain 
postmarketing safety information they receive with one another.  (See section IV.D below 
for detailed discussion.) 
  Submission Process.  The rule specifies how Combination Product and Constituent Part 
Applicants must submit PMSR information to the Agency.  (See section V.A for detailed 
discussion of how to submit information to the Agency.)   
  Streamlined reporting.  The rule offers means to satisfy certain reporting requirements 
together in the same report.  (See sections IV.C and V.A.3 for detailed discussion of 
streamlined reporting opportunities and methods.) 
 
  Records Retention.  The rule specifies what records Combination Product and 
Constituent Part Applicants must maintain and how long to maintain them.  (See section 
IV.E below for detailed discussion.) 
A. Who Is Subject to the Combination Product PMSR Final Rule? 
The combination product PMSR final rule applies to two types of applicants, Combination 
Product Applicants and Constituent Part Applicants (21 CFR 4.100(a)).5  These terms and the 
related terms, applicant and application are defined at 21 CFR 4.101. 
 
  Applicant and Application.  Applicant means a person holding an application under 
which a combination product or constituent part of a combination product has received 
marketing authorization (such as approval, licensure, or clearance).  Applications under 
this rule are:  New Drug Applications (NDAs), Abbreviated New Drug Applications 
(ANDAs), Biologics License Applications (BLAs) and Device Applications6 
(Premarket Approval Applications (PMAs), Product Development Protocols (PDPs), 
Humanitarian Device Exemptions (HDEs), De Novo Classification Requests (De Novos), 
and Premarket Notification Submissions (510(k)s)). 
 
  Combination Product Applicant means the applicant that holds the only application or all 
applications for a combination product.7  (Note that the Combination Product Applicant 
holds the application, but may not be the manufacturer, e.g., if the combination product is 
manufactured by a contract manufacturer.)  Following are examples of Combination 
Product Applicants:   
  A company that holds an approved PMA for a drug-eluting stent (a single-entity 
o
combination product).  
 
5 There are other entities involved with the manufacture and distribution of combination products that are not 
applicants and, therefore, not subject to the combination product PMSR final rule, but who have postmarketing 
safety reporting obligations under FDAs regulations and the FD&C Act.  Postmarketing safety reporting for such 
entities is addressed in Appendix 3.  Entities with questions regarding how to comply with reporting requirements 
applicable to non-applicants should contact the lead Center or OCP, as needed. 
6 21 CFR 4.101. 
7 Id. 
6  Contains Nonbinding Recommendations 
 
  A company that holds an approved NDA for a pre-metered dry powder inhaler co-
o
packaged with a filled drug product cartridge (a co-packaged combination 
product).   
  A company that holds an approved BLA for a vaccine supplied in a pre-filled 
o
syringe configuration (a single-entity combination product). 
  A company that holds both an approved PMA for a laser system that is indicated 
o
for photoactivation of a specific drug and an approved NDA for the specific drug 
that requires photoactivation by that laser system (which, together, compose a 
cross-labeled combination product). 
 
  Constituent Part Applicant means an applicant that holds an application for a constituent 
part of a combination product, the other constituent part(s) of which is marketed under an 
application held by a different applicant.8  Generally, there would be Constituent Part 
Applicants if the combination product is marketed by two different entities in a cross-
labeled configuration.  For example, where a laser system (device) and light-activated 
drug compose a cross-labeled combination product (see 21 CFR 3.2(e)), the following 
would be Constituent Part Applicants: 
  The entity that holds the approved PMA for the laser system for this combined 
o
use.  
  The separate entity that holds the approved NDA for the light-activated drug for 
o
this combined use.   
 
In summary:  
 
  If one company is the applicant for a combination product that is marketed under a single 
application (e.g., a drug-eluting stent), then this entity is the Combination Product 
Applicant, and there are no Constituent Part Applicants for the product. 
   
  If one company holds the applications to market products for use together as constituent 
parts of a combination product (e.g., the company holds both the NDA for a specific 
photoactivated drug and the PMA for a device used to activate that drug where the two 
products compose a cross-labeled combination product), then that company is the 
Combination Product Applicant, and there are no Constituent Part Applicants.   
 
  If one entity holds the NDA for the drug constituent part and a separate entity holds the 
PMA for the device constituent part of that cross-labeled combination product, those two 
entities would be the Constituent Part Applicants for that combination product, and there 
would be no Combination Product Applicant for that product.   
 
  A company is a Constituent Part Applicant only if that entity holds an application to 
market that product as a constituent part of a combination product.   
 
For example, SyringeCo holds a 510(k) for a general-use syringe for injection and 
markets empty syringes under this 510(k).  PharmaCo purchases syringes from 
 
8 Id. 
7  Contains Nonbinding Recommendations 
 
SyringeCo and includes them with drug product vials in a co-packaged combination 
product for which PharmaCo holds the approved NDA.  Because SyringeCo does not 
hold an application under which the syringe is marketed as a constituent part of a 
combination product, SyringeCo is not a Constituent Part Applicant for a combination 
product.9  Rather, PharmaCo is the Combination Product Applicant for the co-packaged 
combination product, and there are no Constituent Part Applicants for the combination 
product.10 
B. What Safety Reporting Requirements Apply to Me if I Am a 
Combination Product Applicant or Constituent Part Applicant? 
This section summarizes safety reporting requirements associated with the constituent parts of 
combination products (i.e., 21 CFR Part 314 requirements for drugs, 21 CFR Parts 600 and 606 
requirements for biological products, and 21 CFR Parts 803 and 806 requirements for devices), 
and the information sharing requirements that ply to Constituent Part Applicants under the 
rule.11, 12  (See also Appendix 1, which provides a summary table of the PMSR requirements in 
the final rule applicable to the various types of Combination Product and Constituent Part 
Applicants, and section IV for additional discussion of the PMSR requirements specified in the 
rule for Combination Product Applicants.) 
 
9 SyringeCo would have its own postmarketing safety reporting obligations under 21 CFR Part 803 that apply to its 
device. 
10 Although outside the scope of this guidance, it is worth noting that, under this example, PharmaCo is required to 
establish and maintain procedures to ensure that supplied syringes meet all required specifications (see 21 CFR Part 
4, Subpart A; see also Guidance for Industry and FDA Staff, Current Good Manufacturing Practice Requirements 
for Combination Products (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/current-
good-manufacturing-practice-requirements-combination-products) (providing guidance on requirements imposed by 
regulation)).  Purchasing controls should include, for example, appropriate provisions to allow communications and 
information sharing between SyringeCo and PharmaCo when necessary to investigate adverse events that involve 
the syringe.  
11 Although investigational combination products are not subject to the combination product PMSR final rule, if the 
combination product or constituent part used in the clinical investigation is already legally marketed, entities must 
report adverse events that occur in the investigational setting as required by the PMSR requirements that apply to 
that entity for that marketed combination product or constituent part.  For example, if a Combination Product 
Applicant is legally marketing a drug-device combination product under an NDA and receives a report of a 
malfunction that occurred during investigation of that combination product for a new use, that Combination Product 
Applicant must report the malfunction to FDA under 21 CFR 4.102(c)(1)(ii) (see also section IV.A.3).  See related 
discussion of use of marketed products in clinical investigations in Guidance for Industry and Food and Drug 
Administration Staff, Medical Device Reporting for Manufacturers (https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/medical-device-reporting-manufacturers)  and Guidance for Industry 
and Investigators, Safety Reporting Requirements for INDs and BA/BE Studies (https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/safety-reporting-requirements-inds-investigational-new-drug-
applications-and-babe).  Entities with questions regarding how to comply with reporting requirements applicable to 
investigational combination products should contact the lead Center or OCP, as needed. 
12 There are provisions on exemptions, alternatives, and waivers under some of the PMSR regulations (see, e.g., 21 
CFR 314.90, 600.90, and 803.19).  These provisions apply to combination products.  Questions about requesting 
exemptions, alternatives, or waivers should be directed to the lead Center or OCP, as needed. 
8  Contains Nonbinding Recommendations 
 
1.  Application type-based reporting requirements apply to BOTH Combination 
Product Applicants and Constituent Part Applicants 
Both Combination Product Applicants and Constituent Part Applicants must meet the safety 
reporting requirements associated with the application type under which their combination 
product or constituent part received marketing authorization (21 CFR 4.102(b)).  Under 21 CFR 
4.102(b), Combination Product and Constituent Part Applicants who hold: 
 
  NDAs/ANDAs are subject to the safety reporting requirements described in 21 CFR Part 
314 
 
  BLAs are subject to the safety reporting requirements described in 21 CFR Parts 600 and 
606 
 
  Device Applications are subject to the safety reporting requirements described in 21 CFR 
Parts 803 and 806 
2.  Constituent part-based reporting requirements apply ONLY to Combination 
Product Applicants 
In addition to application type-based reporting requirements, only Combination Product 
Applicants are also subject to certain safety reporting requirements associated with the 
constituent parts of the combination product (see 21 CFR 4.102(c)).  (See section IV below for 
more detailed discussion, including streamlined reporting opportunities.) 
Reporting under a single application.  Listed below are the additional reporting requirements 
Combination Product Applicants must meet based on the types of constituent parts in the 
combination product and the application type for the combination product: 
  NDA/ANDA/BLA for a combination product that contains a device constituent part.  The 
Combination Product Applicant must also comply with (21 CFR 4.102(c)(1)): 
  Five-day reporting requirements (see 21 CFR 803.3, 803.53, and 803.56) 
o
  Malfunction reporting requirements (see 21 CFR 803.50 and 803.56) 
o
  Correction and removal reporting and recordkeeping requirements for events that 
o
do not require a report (see 21 CFR 806.10 and 806.20) 
 
  BLA or Device Application for a combination product that contains a drug constituent 
part.  The Combination Product Applicant must also comply with (21 CFR 4.102(c)(2)): 
  Field alert reporting (FAR) requirements (see 21 CFR 314.81) 
o
  Fifteen-day reporting requirements (see 21 CFR 314.8013) 
o
 
 
13 The reporting requirements under 21 CFR 314.80 and 600.80 are equivalent.  Combination products with both 
drug and biological product constituent parts need not submit separate Fifteen-day reports to comply with each 
requirement.  Submitting a single Fifteen-day report containing the required information is sufficient (see also 
section IV.A.1). 
9  Contains Nonbinding Recommendations 
 
  ANDA/NDA or Device Application for a combination product that contains a biological 
product constituent part.  The Combination Product Applicant must also comply with (21 
CFR 4.102(c)(3)): 
  Biological product deviation reporting (BPDR) requirements (see 21 CFR 600.14 
o
and 606.171) 
  Fifteen-day reporting requirements (see 21 CFR 600.8013) 
o
 
Reporting under separate applications.  If a Combination Product Applicant markets the 
constituent parts of the combination product under separate applications, then under 21 CFR 
4.102(b), the Combination Product Applicant must comply with the PMSR requirements 
associated with each application type.  The Combination Product Applicant would appropriately 
meet the reporting requirements in 21 CFR 4.102(b) by reporting separately for each constituent 
part in accordance with the requirements and processes associated with the application type for 
that constituent part.  Such reports should address how the event is related to the constituent part 
and the combination product as a whole to the extent such information is available.14 
3.  Information sharing requirements apply ONLY to Constituent Part Applicants 
Constituent Part Applicants must share with the other Constituent Part Applicant(s) for the 
combination product, within 5 calendar days from receipt, initial information received on the 
following events associated with the combination product (see section IV.D for more detailed 
discussion): 
 
  Deaths or serious injuries as described in 21 CFR 803.3, and 
 
  Adverse experiences as described in 21 CFR 314.80(a) or 600.80(a). 
 
(See 21 CFR 4.103.) 
IV.  Specific PMSR Requirements  
This section discusses in greater detail certain PMSR requirements under the final rule.  Sections 
IV.A and IV.B describe the constituent part-based reporting requirements applicable to 
Combination Product Applicants (see 21 CFR 4.102).  Section IV.C describes means for 
Combination Product Applicants to streamline reporting (see 21 CFR 4.102).  Section IV.D 
describes information sharing requirements for Constituent Part Applicants (see 21 CFR 4.103), 
and Section IV.E describes recordkeeping requirements for Combination Product Applicants and 
Constituent Part Applicants (see 21 CFR 4.105).  (The process requirements for submitting 
reports under 21 CFR 4.104 are addressed in section V.) 
 
With regard to PMSR for Combination Product Applicants, this discussion is not meant to 
describe every reporting requirement but rather to help these entities understand PMSR 
requirements not associated with the application type for their product, with which they may be 
 
14 In addition to the information required under the applicable regulations, the Combination Product Applicant 
should include the Combination Product Identifier and, in the narrative, the application number for the other 
constituent part(s). 
10  Contains Nonbinding Recommendations 
 
less familiar, and to highlight considerations specific to combination products for complying 
with PMSR requirements.  Because it is expected that Constituent Part Applicants are already 
familiar with the reporting regulations applicable to their product type (drug, device, or 
biological product), reporting considerations specifically for Constituent Part Applicants are not 
a focus of the discussion.15  Rather, this section focuses on information-sharing and record-
keeping requirements for these applicants.   
 
21 CFR 4.102(a) establishes that, for Combination Product Applicants, the safety reporting 
requirements under 4.102(b) based on the application type and under 4.102(c) based on the 
constituent parts of the combination product, apply to the combination product as a whole.  
Accordingly, the entire combination product and each constituent part should be considered in 
determining whether a report is required and what information to include.  For clarity, 
adjustments have been made in the discussion of these requirements in sections IV.A and B 
below, such as using the term product in place of the term drug, biological product, or 
device. 
A. Individual Case Safety Reports for Combination Product Applicants 
Throughout this guidance 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 and 600.80), Five-day 
reports (see 21 CFR 803.3, 803.53, and 803.56), Malfunction reports (see 21 CFR 803.50 and 
803.56), and reports of deaths or serious injuries (see 21 CFR Part 803).16   
 
Please note that each of the sections below discusses circumstances under which the specified 
report type may be required for Combination Product Applicants.  These discussions are not 
intended to identify all reports that may be required for the events described, and different 
reports may be required for similar events to those described depending on the specific 
circumstances.  As indicated below, in some cases, multiple report types may be required, and it 
may be possible to satisfy multiple reporting requirements in the same submission as discussed 
more fully in section IV.C and section V.A.3 below.  
 
(See also Appendix 2, presenting flowcharts illustrating how to determine whether ICSRs must 
be submitted by Combination Product Applicants under the combination product PMSR final 
rule.)   
 
15 However, it is important to note that Constituent Part Applicants should consider events in their entirety, including 
the events implications for the safe and effective use of the combination product as a whole, to ensure they provide 
complete, comprehensive reporting for their constituent part. 
16 Note that death and serious injury reporting requirements (see 21 CFR Part 803) are not explained in this section 
because, under the combination product PMSR final rule, they apply only to Combination Product and Constituent 
Part Applicants who are marketing their product under a Device Application, and these applicants are expected to be 
familiar with these application type-based reporting requirements.  Similarly, we do not explain the reporting of 
non-expedited (non-Fifteen-day) ICSRs under 21 CFR 314.80 and 600.80 in this section because these requirements 
apply only to Combination Product and Constituent Part Applicants who are marketing their product under an 
ANDA, NDA, or BLA, and these entities are expected to be familiar with these application type-based reporting 
requirements. 
11  Contains Nonbinding Recommendations 
 
1.  Fifteen-day Reports (see 21 CFR 314.80 and 600.80)17 
Fifteen-day reporting requirements apply to combination products that contain a drug or 
biological product constituent part (see 21 CFR 4.102(b)(2) and (b)(3) and 4.102(c)(2)(ii) and 
(c)(3)(ii)).18  Combination Product Applicants must submit Fifteen-day reports for:  
 
  adverse experiences that are both serious and unexpected19  
  within fifteen calendar days for combination products marketed under an ANDA, NDA, 
or BLA  
  or within 30 calendar days for combination products marketed under a Device 
Application, as explained below.20 
 
(See 4.102, 314.80(a) and (c), and 600.80(a) and (c).) 
 
Adverse experience.  An adverse experience is any adverse event associated with the use 
of the combination product, whether or not considered related to the product.21 
 
Seriousness.  A serious adverse experience is any adverse experience 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 aforementioned outcomes.  (See 21 CFR 314.80(a) and 600.80(a).) 
 
Unexpectedness.  An unexpected adverse experience is any adverse experience that is not 
listed in the current labeling for the product.  This includes events that may be 
symptomatically and pathophysiologically related to an event listed in the labeling but 
 
17 21 CFR 314.80(c) and 600.80(c) use the term 15-day Alert reports.  In the combination product PMSR final rule 
(see 21 CFR 4.101), these reports are defined as Fifteen-day reports, and this term will be used throughout this 
guidance.  
18 When considering submission of a Fifteen-day report to FDA, at a minimum, applicants should have knowledge 
of the following four data elements: 1) an identifiable patient, 2) an identifiable reporter, 3) a suspect product, and 
4) an adverse experience.  For additional information, see Draft Guidance for Industry, Postmarketing Safety 
Reporting for Human Drug and Biological Products Including Vaccines (https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/postmarketing-safety-reporting-human-drug-and-biological-products-
including-vaccines) which, when final, will represent the FDAs current thinking on this topic. 
19 For additional information on these definitions, refer to the Draft Guidance for Industry, Postmarketing Safety 
Reporting for Human Drug and Biological Products Including Vaccines (https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/postmarketing-safety-reporting-human-drug-and-biological-products-
including-vaccines) which, when final, will represent the Agencys current thinking on this topic. 
20 For additional information on these definitions, refer to the Draft Guidance for Industry, Postmarketing Safety 
Reporting for Human Drug and Biological Products Including Vaccines (https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/postmarketing-safety-reporting-human-drug-and-biological-products-
including-vaccines) which, when final, will represent the Agencys current thinking on this topic. 
21 As described in 21 CFR 314.80(a) and 600.80(a), adverse experiences include any failure of expected 
pharmacological action and adverse events occurring: in the course of the use of the product in professional practice, 
from product overdose whether accidental or intentional, from product abuse, or from product withdrawal.   
12  Contains Nonbinding Recommendations 
 
differ from the event because of greater severity or specificity (see 21 CFR 314.80(a) and 
600.80(a)).  Whether an event is expected for purposes of Fifteen-day reporting is 
based on whether the event is listed in any current labeling accompanying the 
combination product, including any labeling accompanying individual constituent parts.  
For a cross-labeled combination product, if the event is listed in the labeling 
accompanying either of the constituent parts, the event is considered expected.   
  
For example, consider a combination product approved under an NDA that contains a delivery 
device used to insert the drug constituent part into the body.  If the delivery device breaks during 
drug delivery, causing the patient to hemorrhage and be hospitalized to surgically remove the 
device fragments (an unlabeled adverse event), the Combination Product Applicant must submit 
a Fifteen-day report because hemorrhage is both a serious and unexpected adverse experience 
associated with the use of the combination product.   
 
Combination products under Device Applications.  For combination products marketed under a 
Device Application, Fifteen-day reports must be submitted within 30 calendar days, rather than 
fifteen (see 21 CFR 4.102(c)(2)(ii) and (c)(3)(ii)).  If the Combination Product Applicant for 
such a combination product receives a report of an event that qualifies for reporting both as a 
death or serious injury report under 21 CFR Part 803 and as a Fifteen-day report because the 
event is unexpected, the Combination Product Applicant may satisfy both reporting requirements 
by submitting a single report that is identified both as a death or serious injury report and as a 
Fifteen-day report, within the 30-calendar day submission timeline (see sections IV.C and V.B.2 
below for further discussion).22   
 
Combination products that contain both a drug and biological product constituent part(s).  A 
Combination Product Applicant for a combination product that contains both a drug and 
biological product constituent part need not submit two separate Fifteen-day reports for the same 
event.  The Fifteen-day reporting requirements are equivalent in 21 CFR 314.80 and 600.80 and 
submitting a single Fifteen-day report containing the required information is sufficient (see 
sections IV.C and V.A.3 below for further discussion).  
 
Additional information on adverse experience reporting in the drug context can be found at:  
https://www.fda.gov/drugs/surveillance/postmarketing-surveillance-programs.   
2.  Five-day Reports (see 21 CFR 803.3, 803.53, and 803.56)   
Five-day reporting requirements apply to combination products that contain a device constituent 
part (21 CFR 4.102(b)(1) and 4.102(c)(1)(i)).   
 
22 While FDA anticipates such scenarios will be rare, a Combination Product Applicant for a combination product 
marketed under a Device Application may receive a report of an event that triggers a Fifteen-day report but not a 
death or serious injury report, if the event is associated with the use of the combination product but the applicant 
does not believe the information reasonably suggests that the product may have caused or contributed to the event.   
 
13  Contains Nonbinding Recommendations 
 
Combination Product Applicants for such combination products must submit Five-day reports no 
later than five work days after the day the Combination Product Applicant becomes aware23 
either that: 
  A reportable event for the combination product necessitates remedial action to prevent 
an unreasonable risk of substantial harm to the public health or  
  We (FDA) have made a written request for the submission of a [Five-day] report (21 
CFR 803.53).   
Remedial action includes any action other than routine maintenance or servicing . . . 
where such action is necessary to prevent recurrence of a reportable event (21 CFR 
803.3(v)).   
For example, a Five-day report would be required in the following scenario.  The applicant for a 
prefilled rescue inhaler approved under an NDA determines that a reportable adverse event was 
caused by a design flaw that causes the inhaler actuator to fail and the drug to not be delivered.  
The design flaw is known to be present in the product in the field, and the product in the field 
can fail in the same manner, likely resulting in life-threatening injury or death (which would pose 
an unreasonable risk of substantial harm to the public health).  Once the applicant determines 
that it is necessary to remove the product from the market until the design can be corrected (i.e., 
becomes aware that remedial action is necessary to prevent an unreasonable risk of substantial 
harm to the public health), it must file a report within five work days (see 21 CFR 803.53).   
Likewise, a Five-day report would be required under 21 CFR 803.53 if the applicant for a drug-
coated catheter approved under a PMA determines that a serious injury caused by the catheter 
breaking was the result of a manufacturing problem with the bonding process and decides to 
remove affected product lots from the market (to prevent an unreasonable risk of substantial 
harm to the public health).   
For both of these examples, the applicant must also report the removal action (see 21 CFR 
4.102(b)(1), (c)(1)(iii) and 21 CFR Part 806) and can do so as part of the Five-day report (see 
sections IV.B.3 below for additional discussion of correction and removal reports and 
streamlining of these reports with Five-day reports). 
Note, submission of a Five-day report (or correction or removal report) does not alter an 
applicants obligation to submit other postmarketing safety reports for the product.  Applicants 
must continue to assess events, and report them to FDA as required, in accordance with all the 
PMSR requirements applicable to the product. 
 
 
23 Applicants are considered to have become aware when any employee with management or supervisory 
responsibilities over persons with regulatory, scientific, or technical responsibilities, or whose duties relate to the 
collection and reporting of adverse events, becomes aware, from any information, including any trend analysis, that 
a reportable event or events necessitates remedial action to prevent an unreasonable risk of substantial harm to the 
public health (see 21 CFR 803.3(b)).  If FDA has requested Five-day reports for certain events in accordance with 
21 CFR 803.53(b), applicants are also considered to have become aware when any employee becomes aware of such 
an event occurring (see 21 CFR 803.3(b)). 
14  Contains Nonbinding Recommendations 
 
Additional information on Five-day reports can be found at:  https://www.fda.gov/medical-
devices/medical-device-safety/medical-device-reporting-mdr-how-report-medical-device-
problems. 
3.  Malfunction Reports (see 21 CFR 803.50 and 803.56)   
Malfunction reporting requirements apply to combination products that contain a device 
constituent part (see 21 CFR 4.102(b)(1), 4.102(c)(1)(ii), 803.50, and 803.56).   
 
Combination Product Applicants for such combination products must submit Malfunction reports 
no later than 30 calendar days24 after the applicant receives or otherwise becomes aware of 
information that: 
 
  Reasonably suggests25 
  The product has malfunctioned and 
  The product, or a similar product marketed by the applicant, would be likely to cause or 
contribute to a death or serious injury if the malfunction were to recur (21 CFR 
803.3(o)(2)(ii) and 803.50).   
  
Malfunction.  When used in the combination product context, malfunction means the 
failure of a device constituent part or of the product as a whole to meet its performance 
specifications or otherwise perform as intended (see 21 CFR 4.102(a) and 803.3(k)).  
Performance specifications include all claims made in the labeling for the device 
constituent part or for the combination product as a whole (see 21 CFR 4.102(a) and 
803.3(k)). 
 
Serious injury.  As described in 21 CFR 803.3(w), serious injury is an injury or illness 
that: (1) [i]s life-threatening, (2) [r]esults in permanent impairment of a body function or 
permanent damage to a body structure, or (3) [n]ecessitates medical or surgical 
intervention to preclude permanent impairment of a body function or permanent damage 
to a body structure.  Permanent means irreversible impairment or damage to a body 
structure or function, excluding trivial impairment or damage.   
 
Malfunction reports and Fifteen-day reports.  Of particular note for combination products that 
contain a device constituent part and are marketed under an ANDA, NDA, or BLA, a 
Malfunction report is required in addition to a Fifteen-day report if the information reasonably 
suggests that an adverse experience (see footnote 21 and associated text) that was both serious 
and unexpected was caused or contributed to by the malfunction (see 21 CFR 4.102(c)(1)(ii), 
314.80, 600.80, and 803.50).   
 
 
24 Note, an altenative, voluntary program for reporting of malfunctions is available for certain combination products 
see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reporting-
combination-products.   
25 Under 21 CFR 803.20(c), any information, including professional, scientific, or medical facts, observations, or 
opinions, may reasonably suggest that a product has caused or may have caused or contributed to a reportable event. 
15  Contains Nonbinding Recommendations 
 
For example, a Combination Product Applicant determines that a Fifteen-day report is required 
after a serious unexpected adverse event related to over-infusion from an NDA-approved, co-
packaged drug and infusion set.  After submitting the Fifteen-day report, the applicant 
determines that failure of the infusion set to meet its specifications could have caused or 
contributed to the event.  In this case, a Malfunction report must also be submitted (see 21 CFR 
803.3(k) and 803.50) and should be submitted as a follow-up report to the initial Fifteen-day 
report, identified as a Malfunction report.26  FDA does not intend to object if the report is 
submitted within 30 calendar days after the day the applicant becomes aware of the reportable 
malfunction (see also section IV.A.4 below discussing follow-up reports).27   
 
A Malfunction report may also be required when a Fifteen-day report is not.  For example, an 
NDA applicant receives a report that a medical professional noticed before use that the sterile 
barrier for a co-packaged syringe was compromised and discarded the syringe before using it on 
a patient.  No Fifteen-day report is required because there was no adverse event; however, a 
malfunction report would be required if the breach in the sterile barrier would be likely to cause 
or contribute to a death or serious injury (such as an infection requiring hospitalization for 
treatment of the infection) if it were to recur (see 21 CFR 4.102(c)(1)(ii) and 803.50).  Likewise, 
if an NDA applicant receives a report that the needle of an auto-injector deployed early and no 
dose, or a partial dose, was delivered, the NDA applicant must submit a Malfunction report if the 
product would be likely to cause or contribute to a serious injury or death if the malfunction 
recurred, even if there was no patient injury or death associated with the reported malfunction 
event (see 21 CFR 4.102(c)(1)(ii) and 803.50).28    
 
Additional information on Malfunction reports can be found at:  https://www.fda.gov/medical-
devices/medical-device-safety/medical-device-reporting-mdr-how-report-medical-device-
problems. 
4.  Follow-up Reports (see 21 CFR 314.80, 600.80, 803.56)  
As described in 21 CFR 4.101, the requirements for Fifteen-day, Five-day, and Malfunction 
reporting for combination products include requirements for follow-up reports.  Follow-up 
reporting requirements also apply to death and serious injury reports submitted by Combination 
Product Applicants for combination products that receive marketing authorization under a 
Device Application (see 21 CFR 4.102(b)(1) and 803.56).  Follow-up reports are required when 
 
26 Follow-up reports should be submitted consistent with the technical instructions for the applicable FDA adverse 
event reporting system.  See Section V.A.2 for information on FDA Adverse Event Reporting Syste (FAERS), 
Elecronic Medical Device Reporting System (eMDR), and Vaccine Adverse Event Reporting System (VAERS). 
27 Note that had the Combination Product Applicant become aware of the reportable malfunction before submitting 
the Fifteen-day report, it could have submitted a single report within 15 days to meet both requirements (see also 
Section V.A.3 below). 
28 Reportable malfunctions (as well as reportable death and serious injuries) may involve medication errors such as 
in this example of partial or missed dose.  Medication errors are events that are preventable and may cause or lead to 
inappropriate medication use or patient harm while the medication is in the control of the health care professional, 
patient, or consumer, see https://www.fda.gov/drugs/drug-safety-and-availability/medication-errors-related-cder-
regulated-drug-products.  When submitting malfunction reports that involve medication errors, the applicant should 
include related medication error Reaction/Event codes or Device/Patient Problem codes (see Section V.B.2) and a 
discussion of the medication error in the narrative section of the report. 
16  Contains Nonbinding Recommendations 
 
the ICSR submitter becomes aware of reportable new information related to the event that was 
not available at the time of the initial report (see 21 CFR 314.80, 600.80, and 803.56).   
 
Submission timelines.  A follow-up report must be submitted within 15 calendar days of receipt 
of the new information for Fifteen-day reports for combination products marketed under an 
ANDA, NDA, or BLA (see 21 CFR 314.80 and 600.80) (but see Use of follow-up reports to 
satisfy different types of ICSR requirements below).  For example, if a Combination Product 
Applicant for an NDA-approved combination product receives reportable new information 
related to a previously submitted Fifteen-day report, the information must be submitted as a 
follow-up report within 15 calendar days of receipt of the new information (see 21 CFR 314.80).  
For combination products marketed under a Device Application, follow-up reports for Fifteen-
day, Five-day, Malfunction, and death or serious injury reports must be submitted within 30 
calendar days (see 21 CFR 4.102(c)(2)(ii), 4.102(c)(3)(ii), and 803.56), though the Combination 
Product Applicant may choose to submit follow-up reports on or before the due date.    
 
Use of follow-up reports to satisfy different types of ICSR requirements.29  If a Combination 
Product Applicant submits an initial Malfunction report and later determines that a Fifteen-day 
report must also be submitted for that event, the Combination Product Applicant should submit 
the Fifteen-day report as a follow-up report to the initial Malfunction report.  The same approach 
should be used if the initially submitted report was a Fifteen-day report or a non-expedited ICSR 
required under 21 CFR 314.80(c)(2)(ii)(B) and 600.80(c)(2)(ii)(B) (for serious and expected, and 
nonserious, adverse experiences), and the Combination Product Applicant later determines that a 
Malfunction report is also required; the applicant should submit the Malfunction report as a 
follow-up to the initial report.   
 
Note that for a drug or biologic-led combination product, the Agency does not intend to object if 
the applicant submits the Malfunction report as a follow-up to the previously submitted Fifteen-
day report within 30, rather than 15, calendar days after the day the applicant becomes aware of 
information that a reportable malfunction also occurred.  A Malfunction report for an event that 
was originally reported in a non-expedited ICSR must be submitted within 30 calendar days after 
the day the applicant becomes aware of information that reasonably suggests that a reportable 
malfunction also occurred, and follow-up reports for the malfunction are required when the 
applicant becomes aware of reportable new information on the malfunction (see 21 CFR 
4.102(c)(1), 803.50, and 803.56).  (See also Section V.B.3 discussing information to include in 
follow-up reports.)  
5.  Combination Product ICSR Information Included in Periodic Safety Reports   
Under the combination product PMSR rule, periodic reporting is required for combination 
products marketed under an NDA, ANDA, or BLA (21 CFR 4.102(d)(1), see 21 CFR 
314.80(c)(2) and 600.80(c)(2)).  If such a combination product includes a device constituent part, 
these periodic reports must include a summary and analysis of the Five-day and Malfunction 
reports submitted during the reporting interval for the periodic safety report(see 21 CFR 
 
29 If a Five-day report is required related to a previously submitted ICSR, due to the public health significance, the 
Five-day report should be submitted as an initial report.  
17  Contains Nonbinding Recommendations 
 
4.102(d)(1)).  (See section V.B.4 below for additional information on how to submit such 
information in a periodic safety report.)   
 
For combination products marketed under a Device Application, periodic reporting is not 
required.  Additional reporting is required only if the FDA notifies the Combination Product 
Applicant in writing that the Agency requires additional information (see 21 CFR 4.102(d)(2)).  
When such reporting is required for a combination product, which the Agency anticipates will be 
rare, FDA will specify what additional safety information is needed (see 21 CFR 4.102(d)(2)). 
6.  Combination Product ICSRs for Foreign Events or Experiences   
The reporting requirements for foreign events for combination products align with the underlying 
regulatory requirements for drugs, devices, and biological products for such events (see 21 CFR 
4.102).  In addition, even to the extent it may not be required to be reported under FDA 
regulations, we recommend the reporting of foreign events for products marketed outside the 
U.S., as discussed further below, to enhance awareness and understanding of safety 
considerations that may be relevant to U.S. combination products, as for other medical products.  
 
General considerations.  Combination Product Applicants are not expected to report on foreign 
events that did not involve their product (for example, if they can confirm that the event was 
instead associated with another applicants product).  When reporting an event for a product 
marketed only outside the U.S., the Combination Product Applicant should include the foreign 
trade name/brand name, and should submit that information in a manner consistent with the 
process for the lead Center.  See also Section V.B.2 regarding information to include in 
combination product ICSRs.   
 
Fifteen-day Reports.  Combination Product Applicants must submit Fifteen-day reports for 
foreign experiences consistent with the requirements for drugs and biological products (see 21 
CFR 4.102(b) and (c), 314.80(c)(1) and 600.80(c)(1)).  Specifically, foreign reports of serious, 
unexpected adverse experiences must be submitted as Fifteen-day reports (see 21 CFR 4.102(b) 
and (c), 314.80(c)(1) and 600.80(c)(1)).  Combination Product Applicants should also submit 
Fifteen-day reports for events associated with foreign products that they market that have the 
same active moiety (or active ingredient for biological product constituent parts) as the U.S.-
marketed product,30 even if the formulation, dosage form, strength, or route of administration of 
the foreign-marketed product is different than that of the U.S.-marketed product.  For example, if 
in the U.S. the applicant markets only a prefilled syringe of a drug containing an active moiety, 
and outside the U.S. the applicant markets an oral dosage form containing the same active 
moiety, the applicant should report adverse events that are both serious and unexpected for that 
oral dosage form to the FDA and reference the U.S. product application number in the report.   
 
Device ICSRs.  Consistent with the approach for devices, Combination Product Applicants for 
combination products containing device constituent parts should submit Malfunction reports to 
 
30 For additional information see Draft Guidance for Industry, Postmarketing Safety Reporting for Human Drug and 
Biological Products Including Vaccines (https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/postmarketing-safety-reporting-human-drug-and-biological-products-including-vaccines) which, when 
final, will represent the FDAs current thinking on this topic. 
18  Contains Nonbinding Recommendations 
 
FDA for otherwise reportable malfunctions, for both devices and device constituent parts of 
combination products marketed outside the U.S. by that applicant that are the same as, or similar 
to, the device constituent part of the applicants U.S.-marketed combination product if the 
malfunction is likely to occur in the U.S.-marketed combination product.31,32  For combination 
products marketed under a Device Application, Combination Product Applicants should also 
submit death and serious injury reports for foreign events for both devices and device constituent 
parts of combination products marketed outside the U.S. by that applicant that are the same or 
similar to the device constituent part of the applicants U.S.-marketed combination product if 
such event is likely to occur in the U.S.-marketed combination product.  For purposes of this 
guidance, FDA considers a device or device constituent part of a combination product marketed 
outside the U.S. by the applicant to be similar to the device constituent part of the applicants 
U.S.-marketed combination product if the device or device constituent part of the combination 
product marketed outside the U.S. by the applicant:33 
 
  Is of the same type (e.g., would have the same product code) as the device constituent 
part of the applicants U.S.-marketed combination product;    
 
  Has the same basic design and performance characteristics related to safety and 
effectiveness as the device constituent part of the applicants U.S.-marketed combination 
product; and 
 
  Is for the same general purpose and function as the device constituent part of the 
applicants U.S.-marketed combination product. 
 
Devices and device constituent parts of combination products marketed outside the U.S. that 
differ only in minor features unrelated to safety or effectiveness (e.g., as may be the case for 
different sizes or other minor design changes to the device constituent part of the U.S.-marketed 
combination product) can be considered similar.  Devices and device constituent parts of 
combination products may be manufactured to slightly modified specifications to meet standards 
in different countries.  If such device or device constituent part is similar to the device 
constituent part of the U.S.-marketed combination product, as described above, then any events 
that would otherwise require an ICSR should be reported if the event is likely to occur in the 
U.S.-marketed combination product.  
 
Examples.  A Combination Product Applicant: 
 
 
31 See Guidance for Industry and FDA Staff, Medical Device Reporting for Manufacturers 
(https://www.fda.gov/regulatory-information/search-fda-guidance-documents/medical-device-reporting-
manufacturers) 
32 If a  malfunction occurs with a U.S.-marketed combination product, and the criteria in 21 CFR 803.50 are met, 
then a Malfunction report must be submitted to the FDA, regardless of whether the event occurs in the U.S. 
33 The considerations described here for a same or similar device or device constituent part are aligned with related 
content in the Guidance for Industry and FDA Staff, Medical Device Reporting for Manufacturers 
(https://www.fda.gov/regulatory-information/search-fda-guidance-documents/medical-device-reporting-manufacturers).  
The language from the guidance has been adapted to facilitate application to combination products that contain a 
device constituent part and is not intended to alter the discussion of foreign reporting for devices in the Medical 
Device Reporting for Manufacturers guidance. 
19  Contains Nonbinding Recommendations 
 
  That markets a coronary drug-eluting stent (DES) in the U.S. should submit Malfunction 
reports for otherwise reportable malfunctions regarding DES deformation for a coronary 
DES coated with a different antiproliferative drug that the applicant markets outside the 
U.S. if that DES differs only in size from, and is otherwise similar to (as described 
above), the DES marketed in the U.S., and the malfunction is likely to occur in the U.S.-
marketed combination product. 
 
  Should submit Malfunction reports for foreign events involving otherwise reportable 
malfunctions of needle-stick prevention features for the applicants prefilled syringe 
marketed outside the U.S., if (i) there are only minor differences in the needle-stick 
prevention features of its pre-filled syringe marketed in the U.S. that do not change the 
basic design and performance characteristics of the syringe as related to safety and 
effectiveness, and (ii) the malfunction is likely to occur in the U.S.-marketed combination 
product.   
 
However, the recommendation to submit Malfunction reports for foreign events would 
not apply with respect to failures of needle-stick prevention features when such features 
of its foreign-marketed syringes are not the same as or similar to that of a syringe that is 
part of its U.S. marketed combination product.  For example, if the foreign-marketed 
prefilled syringe uses a hinged recapping feature whereas the design used in the syringe 
in the U.S.-marketed combination product is a sliding sleeve, malfunction reports 
involving failures of the hinged recapping feature in the foreign-marketed product would 
not be relevant for the U.S.-marketed combination product and therefore the 
recommendation for malfunction reporting would not apply.   
 
  Should submit Malfunction reports for foreign events involving otherwise reportable 
malfunctions of a similar inhaler with a drug cartridge, relating to a users inability to 
deliver a dose.  For example, the Combination Product Applicant should submit a report 
if (i) the inhaler has only minor differences (e.g., minor differences in the shape of the 
external housing) as compared to the inhaler used in the applicants U.S.-marketed 
combination product, and (ii) the malfunction is likely to occur in the U.S.-marketed 
combination product.   
 
However, the recommendation to submit Malfunction reports related to foreign events 
would not apply with respect to clogged inhaler nozzles if the basic design and 
performance characteristics related to safety and effectiveness of the inhaler in the 
foreign-marketed product are different because in such cases, the malfunction is not 
likely to occur in the inhaler of the U.S.-marketed combination product.  For example, the 
recommendation to submit Malfunction reports would not apply if the blockage results 
from the actuator nozzle orifice having a diameter that is significantly smaller, i.e., that 
significantly alters performance in the inhaler of the foreign marketed product, as 
compared to the inhaler in the U.S.-marketed product. 
 
Combination Product Applicants who have questions about reporting requirements or reporting 
recommendations for foreign events should contact the lead Center or OCP, as needed. 
20  Contains Nonbinding Recommendations 
 
B. Other (Non-ICSR) Combination Product PMSR Report Types for 
Combination Product Applicants 
Please note that each of the sections below discusses circumstances under which the specified 
report type may be required.34  These discussions are not intended to identify all reports that may 
be required in relation to the events described, and the reports required in events similar to those 
described may differ, depending on the specific circumstances.  As indicated below, in some 
cases, multiple report types may be required and it may be possible to satisfy multiple reporting 
requirements in the same submission as discussed more fully in section V.A.3 below.  
1.  Field Alert Reports (see 21 CFR 314.81) 
Field alert reporting requirements apply to distributed combination products that contain a drug 
constituent part (see 21 CFR 4.102(b)(2) and 4.102(c)(2)(i)).  See also sections IV.C and V.A.3 
below regarding streamlining of FAR and BDPR reporting.   
 
Combination Product Applicants for such combination products must submit FARs within three 
working days of receipt of information for: 
 
  [A]ny incident that causes the [product] or its labeling to be mistaken for, or applied to, 
another article, or concerning any bacteriological contamination, or any significant 
chemical, physical, or other change or deterioration in the distributed [product] or  
  [A]ny failure of one or more distributed batches of the [product] to meet the 
specification established for it in the application (21 CFR 314.81).   
 
We also recommend that Combination Product Applicants submit additional information, 
including updates, as it becomes available.35 
 
A FAR is required for any of the issues described above that could have resulted from the 
manufacturing process for any of the constituent parts of the combination product or for the 
combination product (see 21 CFR 4.102(a) and 314.81).  A FAR must be submitted even if the 
issue resulted from material supplied to the applicant by another party (21 CFR 314.81 makes no 
distinction on this basis).   
 
For example, bacteriological contamination of a distributed prefilled syringe could be the result 
of contamination during the manufacturing of the drug prior to filling, contamination of the 
syringe before it is filled, or contamination that occurs during the filling process.  In any case, if 
the product is contaminated, a FAR must be submitted (see 21 CFR 4.102 and 314.81).   
 
Likewise, if the coating on a distributed drug-eluting stent does not meet specifications because 
of impurities introduced during formulation of the coating or the stent coating process, or 
 
34 Although not specifically discussed in this section, submittal of additional information may be required after 
submission of a non-ICSR report (see, e.g., 21 CFR 806.10(c)(13) and (d)). 
35 For additional information on follow-up reports to FARs, see Field Alert Report Submission Questions and 
Answers Draft Guidance for Industry (https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/field-alert-report-submission-questions-and-answers-guidance-industry). 
21  Contains Nonbinding Recommendations 
 
because of impurities on the metal stent, a FAR must be submitted (see 21 CFR 4.102 and 
314.81). In addition, if the impurities were due to a drug product received from a supplier, the 
Combination Product Applicant should also communicate with the drug product supplier to 
enable any additional actions and reporting by the drug product supplier as appropriate.  
 
Additional information on FARs can be found in the guidance for industry Field Alert Report 
Submission: Questions and Answers (July, 2021) at: 
https://www.fda.gov/drugs/surveillance/field-alert-report-form-questions-and-answers and 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-
biologics/submitting-field-alert-reports-fars-cber.  
2.  Biological Product Deviation Reports (see 21 CFR 600.14 and 606.171)  
Biological product deviation reporting requirements apply to distributed combination products 
that contain a biological product constituent part (see 21 CFR 4.102(b)(3) and 4.102(c)(3)(i)).  
See also sections IV.C and V.A.3 below regarding streamlining of FAR and BDPR reporting.  
 
Combination Product Applicants for such combination products must submit BPDRs for any 
event, and information relevant to the event, associated with the manufacturing, to include 
testing, processing, packing, labeling, or storage, or with the holding or distribution, of a 
product, if that event:36, 37 
  Represents either  
  a deviation from current good manufacturing practice, applicable regulations, 
o
applicable standards, or established specifications that may affect the safety, 
purity, or potency of that product; or  
  an unexpected or unforeseeable event that may affect the safety, purity, or 
o
potency of that product;  
  Occurs in the applicants facility or another facility under contract with the applicant; and 
  Involves a distributed product.  
 
(21 CFR 600.14 and 606.171).   
 
BPDRs should be submitted as soon as possible and must be submitted no later than 45 calendar 
days from the day of acquiring information reasonably suggesting that a reportable event has 
occurred (21 CFR 600.14 and 606.171). 
 
BPDRs may be required when there are manufacturing process deviations for the combination 
product.  For example, a BPRD is required if there is a manufacturing deviation that could 
impact the purity of a recombinant bone morphogenetic protein in a distributed PMA-approved 
bone graft combination product (see 21 CFR 4.102(c)(3)(i) and 600.14). 
 
36 See also Guidance for Industry, Biological Product Deviation Reporting for Licensed Manufacturers of Biological 
Products Other than Blood and Blood Components  
(https://www.fda.gov/regulatory-information/search-fda-guidance-documents/biological-product-deviation-
reporting-licensed-manufacturers-biological-products-other-blood-and). 
37 See also Guidance for Industry, Biological Product Deviation Reporting for Blood and Plasma  
Establishments (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/biological-product-
deviation-reporting-blood-and-plasma-establishments). 
22  Contains Nonbinding Recommendations 
 
 
An event that triggers a BPDR can be related to any of the constituent parts.  For example, a 
BPDR would be required if a distributed BLA-approved prefilled syringe of a vaccine 
incorporates a syringe component that does not meet required materials specifications and that 
deviation may affect the safety, purity, or potency of the vaccine (see 21 CFR 4.102(a) and 
600.14).         
3.  Correction and Removal Reports (see 21 CFR 806.10) 
Correction and removal reporting requirements apply to combination products that contain a 
device constituent part (21 CFR 4.102(b)(1), (c)(1)(iii), and 806.10).  
 
Combination Product Applicant for such combination products must submit reports of 
corrections and removals: 
 
  Within 10 working days of initiating a correction or removal, to  
  [R]educe a risk to health posed by the [product] or  
  [R]emedy a violation of the [FD&C Act] caused by the [product] which may present a 
risk to health (21 CFR 806.10).   
 
Correction means any repair, modification, adjustment, relabeling, destruction, or 
inspection (including patient monitoring) of a [product] without its physical removal 
from its point of use to some other location (21 CFR 806.2(d)).   
 
Removal means the physical removal of a [product] from its point of use to some other 
location for repair, modification, adjustment, relabeling, destruction, or inspection (21 
CFR 806.2(j)).   
 
For example, a report would be required when removing a combination product from the market 
to address a design issue that poses a risk of injury to the user or removing a product from the 
market due to contaminants that could result in infection or adverse reactions in patients (see 21 
CFR 4.102 and 806.10). 
 
The Combination Product Applicant must submit a written report to FDA of any reportable 
correction or removal of the combination product (see 21 CFR 4.102(b) and (c)), unless the 
information about the correction or removal has already been provided through an ICSR required 
for the combination product, in which case a separate correction or removal report is not required 
(see 21 CFR 806.10).   
 
See note at section IV.A.2 regarding continuing obligation to comply with all PMSR 
requirements even after submission of a correction or removal report. 
 
 
23  Contains Nonbinding Recommendations 
 
C. Streamlined Reporting for Combination Product Applicants 
Under 21 CFR 4.102(b) and (c), a Combination Product Applicant may submit a single report to 
comply with more than one reporting requirement if: 
 
  The reports can be submitted in the same manner, and 
 
  The combined report satisfies all applicable reporting requirements, including all 
submission timelines. 
 
In the same manner means that a report is submitted in the same way (e.g., electronic, paper 
submission) and to the same recipient group within FDA (e.g., via a common electronic 
gateway). 
 
As explained more fully in section V.A.3 below, such streamlined reporting is available for 
submitting multiple types of ICSR, ICSRs and correction and removal reports, and FARs and 
BPDRs. 
D. Information Sharing Between Constituent Part Applicants 
Information sharing requirements apply to Constituent Part Applicants (21 CFR 4.103). Under 
21 CFR 4.103, Constituent Part Applicants must share information: 
 
  No later than 5 days from receipt; 
  With the other Constituent Part Applicant(s) for the same combination product 
regarding;  
  An event associated with the combination product that involves  
  A death or serious injury as described in 21 CFR 803.3, or 
o
  An adverse experience as described in 21 CFR 314.80(a) and 600.80(a).   
o
 
This information must be shared regardless of whether the event is expected or unexpected and 
regardless of whether the Constituent Part Applicant believes it involves only its constituent part 
(see 21 CFR 4.103).  The definition of adverse experience includes death and serious injuries 
(see 21 CFR 314.80(a) and 600.80(a)).  However, other events may constitute adverse 
experiences (see footnote 21 and associated text). 
 
21 CFR 4.103 requires sharing of only initial information received.  To comply with section 
4.103, the Constituent Part Applicant need only share the initial information it receives regarding 
the event and may do so by merely forwarding the information to the other Constituent Part 
Applicant.  There is no requirement to develop a report or analysis of the event for the other 
Constituent Part Applicant, nor to share additional information received regarding the event, 
though FDA recommends such continued coordination to help ensure informed, effective 
reporting to the Agency.   
 
No information on other events is required to be shared.  If a Constituent Part Applicant receives 
information regarding an event that does not involve a death, serious injury or other adverse 
24  Contains Nonbinding Recommendations 
 
experience, the Constituent Part Applicant has no duty under the rule to share the information 
with the other Constituent Part Applicant(s) for the combination product. 
 
Other PMSR duties apply.  In addition to sharing information with each other, Constituent Part 
Applicants must report events to FDA as required by the PMSR regulations applicable to their 
respective constituent part (see 21 CFR 4.102(b)).  Such reports to FDA should address how the 
event is related to the constituent part and the combination product as a whole. 
 
Examples: 
 
  A cross-labeled combination product is composed of a drug constituent part being 
marketed under an NDA held by one Constituent Part Applicant, and a device constituent 
part being marketed under a Device Application held by the other Constituent Part 
Applicant.  The drug Constituent Part Applicant receives information that during use of 
the combination product, a patient received a severe skin burn.  The drug Constituent Part 
Applicant must forward the initial information it receives on the event to the device 
Constituent Part Applicant (see 21 CFR 4.103).  Each applicant must report the event to 
FDA if required under the reporting requirements applicable to its constituent part.       
 
  A cross-labeled combination product is composed of a drug delivery device constituent 
part marketed under a Device Application held by one Constituent Part Applicant and of 
a drug constituent part marketed under an NDA held by the other Constituent Part 
Applicant.  The device Constituent Part Applicant receives information on a device 
constituent part malfunction that did not result in a death, serious injury, or other adverse 
experience.  The device Constituent Part Applicant is not required to share the 
information with the drug Constituent Part Applicant because no serious injury, death or 
other adverse experience occurred, but must report the event to FDA as appropriate under 
21 CFR Part 803. 
 
Constituent part status and information sharing.  As reflected in footnote 3 above, applicants 
that are uncertain of whether their products are constituent parts of combination products may 
contact OCP.  However, we note that the purpose of 21 CFR 4.103 is to ensure sharing of 
adverse event information between entities who are collaborating to market products intended for 
use with one another, to help ensure timely, complete reporting to FDA.  Accordingly, we 
encourage such entities to share such information with one another regardless of whether such 
sharing is required or the products necessarily compose a combination product. 
E. Recordkeeping Requirements for Combination Product and 
Constituent Part Applicants 
21 CFR 4.105 addresses PMSR recordkeeping requirements for Constituent Part Applicants and 
Combination Product Applicants as follows.   
25  Contains Nonbinding Recommendations 
 
1.  Constituent Part Applicants   
Constituent Part Applicants are subject to separate recordkeeping requirements with regard to 
their reporting and their information sharing requirements.  These recordkeeping requirements 
are as follows: 
 
  Retain reporting-related records for the time periods stipulated in the regulations 
applicable to the type of constituent part (see 21 CFR 4.102(b) and 4.105(a)(1)), and  
  Retain information-sharing records in accordance with 21 CFR 4.103, for the longest 
period required for any records under the PMSR requirements applicable to the 
Constituent Part Applicant who shared the information (21 CFR 4.105(a)(2)).   
  Information sharing records must include:   
  A copy of the information provided to the other Constituent Part Applicant(s); 
o
  The date the information was received by the Constituent Part Applicant who 
o
shared the information; 
  The date the information was shared; and  
o
  The name and address of the other Constituent Part Applicant(s) with whom the 
o
information was shared (see 21 CFR 4.103(b)). 
 
Examples.  Consider the following scenarios relating to PharmaCo, which holds an NDA for a 
drug constituent part of a combination product, and MedCo, which holds a PMA for the device 
constituent part:  
 
PharmaCo receives a report of an adverse experience and shares the information with MedCo:  
 
  PharmaCo must retain the required records of sharing the information with MedCo for 10 
years from the date PharmaCo received the information because the only PMSR 
recordkeeping period applicable to PharmaCo is 10 years for adverse drug experiences 
(see 21 CFR 4.105(a)(2) and 314.80(j)).   
 
  MedCo must retain records relating to the event for the time period required under the 
device PMSR regulations applicable to MedCo with regard to the event.  For instance, for 
malfunction, serious injury, or death reporting, MedCo would be required to keep records 
for the longer of 2 years from the date of the event or a period equivalent to the expected 
life of the device,38 whichever is greater, in accordance with the recordkeeping 
requirements under 21 CFR Part 803.   
 
MedCo receives and shares with PharmaCo information about another adverse experience 
associated with administration of the combination product:  
 
  MedCo must retain the required records of sharing the information for the longest of the 
record retention periods applicable to MedCo for the device constituent part, which 
 
38 Under 21 CFR 803.3(f), the expected life of the device means the time that a device is expected to remain 
functional after it is placed into use. Certain implanted devices have specified end of life (EOL) dates.  Other 
devices are not labeled as to their respective EOL, but are expected to remain operational through activities such as 
maintenance, repairs, or upgrades, for an estimated period of time.  
26  Contains Nonbinding Recommendations 
 
would be the longer of 2 years from the date of the event (see 21 CFR 803.18(c)) or 2 
years beyond the expected life of the device (see 21 CFR 806.20 requirements for 
corrections and removals), because Part 806 recordkeeping requirements apply to MedCo 
in addition to the Part 803 requirements (see 21 CFR 4.105(a)(2)).  
 
  PharmaCo would again have to retain this information for the 10-year record-keeping 
period applicable to it for all adverse experiences for its drug constituent part (see 21 
CFR 314.80(j)). 
2.  Combination Product Applicants   
Combination Product Applicants must retain PMSR records for the longest time period required 
for records under all PMSR requirements applicable to the combination product (see 21 CFR 
4.105(b)).  Therefore: 
 
  For drug-biologic combination products, this period is 10 years (see 21 CFR 314.80(j) 
and 600.80(k)).  
 
  For combination products that include a device constituent part, this period would be the 
longer of either 10 years or 2 years beyond the expected life of the product (see 21 CFR 
314.80(j), 600.80(k), 803.18, 806.20). 
 
For example, if an implantable drug-device combination product has an expected life of 3 
years, the longest applicable recordkeeping requirement would be 10 years.  Conversely, 
if that combination product has an expected life of 9 years, the longest applicable 
recordkeeping requirement would be the expected life plus two years (equaling 11 years 
in this case). 
V.  Process Considerations for Combination Product Applicants  
The sections below discuss regulatory requirements under the final rule, and provide guidance to 
Combination Product Applicants,39 on where, how, and when to submit PMSR reports to FDA.  
Because it is expected that Constituent Part Applicants are already familiar with the reporting 
processes applicable to their constituent part, the processes for submitting PMSR reports for 
Constituent Part Applicants are not specifically discussed in these sections (but see 21 CFR 
4.104(a) and footnote 42).   
A.   How to Submit Combination Product PMSR Information to FDA 
1.  What timelines do I follow for submitting the reports? 
Combination Product Applicants follow the timelines associated with the report type with the 
exception that for combination products that receive marketing authorization under a Device 
Application, Fifteen-day reports under 21 CFR 314.80 or 600.80 can be submitted within 30 
 
39 For Combination Product Applicants marketing constituent parts under separate applications, see also Section 
III.B.2.   
27  Contains Nonbinding Recommendations 
 
calendar days, rather than within 15 calendar days (see 21 CFR 4.102(c)(2)(ii) and (c)(3)(ii)).  
The reporting timelines are summarized below. 
  
Table 1.  Timelines for Various Combination Product PMSR Requirements 
Report Type  Timeline for Reporting 
Fifteen-day Reports   ANDA, NDA, and BLA combination products:  No later than 15 
  calendar days from initial receipt of the information by the applicant (see 
21 CFR 314.80(c) and 600.80(c)).  
 
Device Application combination products:  No later than 30 calendar 
days from initial receipt of information by the applicant (see 21 CFR 
4.102(c)). 
Follow-ups to  ANDA, NDA, and BLA combination products: Within 15 calendar days 
Fifteen-day Reports*  of receipt of new information (see 21 CFR 314.80(c) and 600.80(c)).**   
 
Device Application combination products:  No later than 30 calendar 
days from initial receipt of new information by the applicant (see 21 
CFR 4.102(c)). 
Five-day Reports  No later than 5 work days after the day that the applicant becomes 
aware (see footnote 23) that a reportable event(s) necessitates remedial 
action to prevent an unreasonable risk of substantial harm to the public 
health (see 21 CFR 803.53). 
Death/Serious  No later than 30 calendar days after the day that the applicant receives 
Injury/Malfunction  information or otherwise becomes aware of the event (see 21 CFR 
Reports  803.50) 
Supplemental/  Within 30 calendar days of the day that the applicant receives 
Follow-up reports to  information (see 21 CFR 803.56) 
Five-day/ Death/ 
Serious Injury/ 
Malfunction Report*  
Field Alert Reports   Within 3 working days of receipt of the information by the applicant (see 
21 CFR 314.81(b)(1)) 
Biological Product  As soon as possible but not to exceed 45 calendar days from the date of 
Deviation Reports   acquiring information reasonably suggesting that a reportable event has 
occurred (see 21 CFR 600.14(c) and 606.171(c)) 
Correction and  Within 10 working days of initiating correction or removal (see 21 CFR 
Removal Reports  806.10(b)) 
 
*    Note that follow-up reports may be used to submit a different type of ICSR for the same 
event  
**  See section IV.A.4 above, which discusses the submission of follow-up reports to Fifteen-
day reports for malfunctions related to the same event in 30 rather than 15 days. 
28  Contains Nonbinding Recommendations 
 
2.  Where/how do I submit reports? 
ICSRs (including Follow-up Reports).  Combination Product Applicants must submit ICSRs in 
accordance with the procedural requirements in the regulations associated with the application 
type (see 21 CFR 4.104(b)) and should follow relevant policies and procedures of the lead 
Center.    
 
Accordingly, for: 
 
  A Device Application combination product, submit all ICSRs (including Fifteen-
day reports) in accordance with 21 CFR 803.12(a) and associated guidance; 
 
  An NDA or ANDA combination product, submit all ICSRs (including Five-day 
reports and Malfunction reports, if the combination product includes a device 
constituent part) in accordance with 21 CFR 314.80(g) and associated guidance; 
and 
 
  A BLA combination product, submit all ICSRs (including Five-day reports and 
Malfunction reports, if the combination product includes a device constituent 
part) in accordance with 21 CFR 600.80(h) and associated guidance. 
 
For example, if the combination product received marketing authorization under a Device 
Application, submit Fifteen-day reports and follow-up reports to Fifteen-day reports in 
accordance with 21 CFR 803.12(a) and implementation specifications for CDRH eMDR 
(https://www.fda.gov/medical-devices/mandatory-reporting-requirements-manufacturers-
importers-and-device-user-facilities/health-level-seven-hl7-individual-case-safety-reporting-icsr-
files). 
 
Other (Non-ICSR) Report Types.  For report types other than ICSRs (i.e., FARs, BPDRs, and 
correction or removal reports), submit reports in accordance with the procedural requirements 
and policies associated with the report type.   
 
For additional information on reporting, see: 
 
  ICSRs: 
  FDA Adverse Event Reporting System (FAERS) Electronic Submissions 
o
(https://www.fda.gov/drugs/fda-adverse-event-reporting-system-faers/fda-
adverse-event-reporting-system-faers-electronic-submissions). 
  Electronic Medical Device Reporting (eMDR) (https://www.fda.gov/industry/fda-
o
esubmitter/electronic-medical-device-reporting-emdr) 
  Implementation specifications for CDRH eMDR  (https://www.fda.gov/medical-
o
devices/mandatory-reporting-requirements-manufacturers-importers-and-device-
user-facilities/health-level-seven-hl7-individual-case-safety-reporting-icsr-files)   
  Technical specifications for CBER/CDER electronic ICSRs, contained in 
o
Specifications for Preparing and Submitting Electronic ICSRs and ICSR 
Attachments (https://www.fda.gov/media/111763/download) 
29  Contains Nonbinding Recommendations 
 
  CBER Vaccine ICSR Implementation (includes information on the Vaccine 
o
Adverse Event Reporting System or VAERS) 
(https://www.fda.gov/industry/about-esg/cber-vaccine-icsr-implementation) 
 
  Non-ICSRs: 
  Field Alert Reports:  https://www.fda.gov/drugs/surveillance/field-alert-reports 
o
and https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-
regulatory-information-biologics/submitting-field-alert-reports-fars-cber 
  Recalls, Corrections and Removals:  https://www.fda.gov/medical-
o
devices/postmarket-requirements-devices/recalls-corrections-and-removals-
devices 
  Biological Product Deviation Reports:  https://www.fda.gov/vaccines-blood-
o
biologics/report-problem-center-biologics-evaluation-research/general-
instructions-completing-biological-product-deviation-report-bpdr-form-fda-3486 
3.  How can I streamline reporting for the same event? 
ICSRs.  Combination Product Applicants may submit a single ICSR rather than separate reports 
to comply with multiple reporting requirements that are appropriately met through an ICSR for 
the same event (see section IV.C above).  For example: 
 
  Assume a Combination Product Applicant who holds an approved NDA for a drug-
device combination product must submit both a Fifteen-day (see 21 CFR 314.80) and 
Malfunction (see 21 CFR 803.50) report for an event.  That applicant could satisfy both 
requirements by submitting a single report within 15 days that includes all of the 
information required in both types of reports for the event (see 21 CFR 4.102(b) and 
(c)).40    
 
Correction/Removal in ICSR.  Combination Product Applicants may report a correction or 
removal through a serious injury or death report (for Device Application combination products), 
Fifteen-day report, Malfunction report, or Five-day report (see 21 CFR 4.102 and 806.10(f); see 
also 81 FR at 92612-13 and 92615).  For example: 
 
  Assume a Combination Product Applicant who holds an approved PMA for a device-
biological product combination product must submit a Five-day (see 21 CFR 803.3 and 
803.53) and correction or removal (see 21 CFR 806.10) report.  The applicant can satisfy 
both of these requirements by submitting a single report that contains all required 
information and is submitted no more than 5 work days after determining that remedial 
action was needed (see 21 CFR 4.102(b), 803.53, and 806.10(f)).    
  
 
40 Combination Product Applicants for drug and biologic-led combination products are also required to submit non-
expedited ICSRs (ICSRs for adverse experiences that are either serious and expected or nonserious) (see 21 CFR 
4.102(b), 314.80, and 600.80).  If a Combination Product Applicant for a drug or biologic-led combination product 
is required to submit a Malfunction report and a non-expedited ICSR for an event, the applicant could submit a 
single report within 30 days that includes all of the information required in both types of reports for the event (see 21 
CFR 4.102(b) and (c), 314.80, 600.80, and 803.50). 
30  Contains Nonbinding Recommendations 
 
Non-ICSRsFARs and BPDRs.  If an event for a distributed combination product that includes a 
drug and a biological product constituent part requires submission of both a FAR and BPDR, 
FDA does not intend to object if the Combination Product Applicant submits a single report for 
both the FAR and BPDR provided that the report: 
 
  Is designated either as a FAR for an NDA/ANDA combination product or as a BPDR for 
a BLA combination product,  
  Contains sufficient information about the event and the combination product, including 
relevant information about both the drug and biological product constituent parts (e.g., 
trade name, active ingredient(s), dosage form, strength) and the issues triggering both a 
FAR and BPDR,  
  Is submitted in accordance with the procedures of the lead Center, and 
  Is submitted within the shorter time-frame (i.e., within the 3-working day time-frame for 
a FAR, as opposed to the 45-calendar day time-frame for a BPDR).   
 
We encourage Combination Product Applicants interested in establishing procedures for 
submitting such combined FAR/BPDR reports to discuss the approach with the lead Center or 
OCP. 
B. What Information to Include in Combination Product PMSR 
Reports41 
1.  General Content when Submitting Combination Product PMSR Reports 
PMSR reports for combination products: 
 
  Must contain all information required for the report type under the applicable 
regulations, including relevant information on the entire product (including each 
constituent part) (21 CFR 4.102), and   
  In situations where the Combination Product Applicant submits multiple types of reports 
for the same event or product problem, the reports should include references to related 
PMSR reports, including previously filed PMSR reports, consistent with the reporting 
policies and practices of the lead Center. 
2.  Additional Information to Include in Combination Product ICSRs 
This section identifies the types of information that Combination Product Applicants should 
include in ICSRs if not already required under the applicable regulations for the report type, to 
enable efficient, effective evaluation.42  Please see technical specifications and instructions for 
 
41 See also footnote 24.  
42 For ICSRs submitted by Constituent Part Applicants, in addition to the information required under the applicable 
regulations for their product type, include the Combination Product Identifier and, in the narrative, the application 
number for the other constituent part(s). 
31  Contains Nonbinding Recommendations 
 
the various ICSR reporting mechanisms for specific details on how to complete and submit 
reports.43     
The following information should be provided, including the information regarding constituent 
parts of the combination product, regardless of which constituent part(s) may have been 
implicated in the event.  For example, even if an event requiring a Fifteen-day report appears to 
have no relationship to the device constituent part(s), you should include the information on the 
device constituent part(s) of the combination product.   
 
See also https://www.fda.gov/combination-products/guidance-regulatory-
information/postmarketing-safety-reporting-combination-products for examples illustrating the 
reporting of the information below to FDA reporting systems (FAERS, etc).  
 
  Combination Product Identifier.  Indicate that the report is for a combination product.  If 
an applicant markets a product in both a non-combination and combination product 
configuration (e.g., the same drug packaged with and without a syringe), the combination 
product identifier should only be included for events that occurred with the combination 
product configuration.44   
 
  Report Type(s).  Identify the type of report(s).  If one submission is being made to cover 
multiple reporting requirements, each report type should be identified (e.g., if the report 
covers both Fifteen-day and Malfunction reporting requirements, the appropriate 
identifier should be included for each of these report types). 
 
  Patient Identifier.  Provide a patient identifier.  If there was no patient involved in the 
event (e.g., if a malfunction occurred and no patient was involved), enter None. 
 
  Reporter Identifier.  Identifier for the individual that provided the report to the 
Combination Product Applicant. 
 
  Suspect45 Medical Device.  Include the procode that most closely aligns with the device 
constituent part(s), as well as the device common name and/or brand name as 
applicable.46   
 
43 While FDA has identified in this section information that Combination Product Applicants should include in 
ICSRs to help ensure that FDA has complete information on the product and the event, the reporting systems also 
allow Combination Product Applicants to address additional data elements.  Combination Product Applicants are 
encouraged to submit content on these additional data elements as well, when available (see section V.A.2 for 
information on FAERS, eMDR, and VAERS). 
44 If an event is not initially identified as involving a combination product, but additional information received after 
the report is submitted indicates that the event involved the combination product, the combination product identifier 
should be submitted in a follow-up report.  
45 For purposes of combination product ICSRs, the term Suspect Medical Device and Suspect Drug or Biological 
Product do not mean that the identified constituent part is necessarily implicated in the event.  These fields are used 
to identify the constituent parts of the overall Suspect combination product involved in the event.  The 
contribution of any constituent part to the event should be described in the narrative. 
46 Please note, while this information is helpful for efficient review of ICSRs for all combination products with a 
device constituent part, selection of a procode for device constituent parts of ANDA/NDA/BLA combination 
 
32  Contains Nonbinding Recommendations 
 
 
FDA maintains a searchable online procode database that includes both procodes and 
device common names 
(https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPCD/classification.cfm).  Some 
common procodes for device constituent parts of ANDA/NDA/BLA combination 
products are provided at https://www.fda.gov/combination-products/guidance-regulatory-
information/postmarketing-safety-reporting-combination-products.  The Combination 
Product Applicant may contact CDRHs Division of Industry and Consumer Education 
(DICE) (DICE@fda.hhs.gov), as well as OCP, as needed for assistance in determining 
the product code that most closely aligns with their device constituent part.  If there is not 
a procode that closely aligns with the device constituent part, enter the device common 
name and/or the brand name.  Include this device constituent part information regardless 
of whether you believe the device constituent part was implicated in the event.47  
 
  Suspect Drug or Biological Product(s).  Enter the known product attributes for the drug 
or biological product constituent part(s) (e.g., trade name, active ingredient(s), dosage 
form, strength).  Include these drug or biological product attributes regardless of whether 
you believe the drug or biological product constituent part was implicated in the event.  
For NDA/ANDA/BLA approved combination products, include the combination 
products application number in this field.    
 
  Adverse Event Coding. 
  For Device Application combination products, enter at least one Patient Problem 
o
Code, or a descriptive term if there is no code.  FDA maintains a list of patient 
problem codes (https://www.fda.gov/medical-devices/mdr-adverse-event-
codes/coding-resources).    
  For NDA/ANDA/BLA combination products, enter Reaction/Event Coding. FDA 
o
encourages the use of MedDRA (Medical Dictionary for Regulatory Activities) 
terms.  For a malfunction-only report, enter a MedDRA code associated with a 
relevant product quality issue48 or No adverse event.   
 
  Device Problem Code.  Identify at least one device problem code.  FDA maintains a list 
of device problem codes (https://www.fda.gov/medical-devices/mdr-adverse-event-
codes/coding-resources).49  If there is no device problem associated with the ICSR, enter 
the device code for No Known Device Problem for this field.    
 
products does not indicate the device constituent part is classified within that generic type of device nor whether the 
device constituent part would be classified within that generic type if marketed independently. 
47 For combination products that include multiple device constituent parts (e.g., kits of devices co-packaged with a 
drug), each of the device constituent parts should be identified.  If all device constituent parts are contained within 
the same procode (e.g., a needlestick prevention device attached to a prefilled syringe, both of which are covered by 
procode MEG), then only that single procode should be included.  Information regarding any contribution of 
individual device constituent parts to the event should be addressed in the narrative.   
48 For additional information on use of MedDRA coding, see Specifications for Preparing and Submitting Electronic 
ICSRs and ICSR Attachments (https://www.fda.gov/media/76569/download). 
49 CDRH also maintains a list of evaluation codes that provides information if the applicant evaluated the device 
constituent part or combination product. 
 
33  Contains Nonbinding Recommendations 
 
3.  Information to Include in Follow-up ICSRs 
In determining what information to include in follow-up ICSRs, you must follow applicable 
regulations.  We also recommend that you follow applicable policies and procedures associated 
with the application type for the combination product.50  For example, for Device Application 
combination products, include only new, changed or corrected information (see 21 CFR 
803.56(c)).  For NDA/ANDA/BLA combination products, the follow-up ICSR should include 
relevant information from the initial report combined with the new information.51  Note if using 
a follow-up report to submit a different type of ICSR (e.g., to submit a Malfunction report related 
to a previously submitted Fifteen-day report), include all additional information for that report 
type.  See Section IV.A.4 for additional discussion on use of follow-up reports to submit a 
different type of ICSR related to an initial ICSR. 
4.  Information to Include in Periodic Safety Reports for ANDA/NDA/BLA 
Combination Products that Include a Device Constituent Part 
Addressing Five-day and Malfunction reports.  Periodic adverse drug experience reports 
(PADERs) and periodic adverse experience reports (PAERs) for ANDA/NDA/BLA combination 
products must address information from any initial and follow-up Five-day and Malfunction 
reports, in addition to any from Fifteen-day reports, submitted during the reporting interval, and 
should provide this information in the section that contains summary and analysis of reports 
submitted during the interval (see 21 CFR 4.102(d)(1), 314.80(c)(2)(ii) and 600.80(c)(2)(ii)).   
 
Similarly, when a Combination Product Applicant is granted a waiver to substitute the 
International Council for Harmonisation (ICH) E2C format (e.g., ICH E2C(R2) Periodic 
Benefit-Risk Evaluation Report (PBRER)52) instead of the PADER or PAER, the applicant must 
include information about Five-day and Malfunction reports as well as Fifteen-day reports (see 
21 CFR 4.102(d)(1), 314.80(c)(2)(ii) and 600.80(c)(2)(ii)) and should provide this information in 
the body of the report or as an appendix.   
 
 
(https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/PostmarketRequirements/ReportingAdverseE
vents/MDRAdverseEventCodes/ucm584205.htm).  When such evaluation is performed for combination products, 
the evaluation codes, as well as a summary of the evaluation, is required to be included in a serious injury or death 
report, Malfunction report, or Five-day report, and if that information becomes available after such initial report, 
then that information must be included in a follow-up report to such initial report (see 21 CFR 803.52(f)(3) and 
(f)(6)).  However, for NDA/ANDA/BLA combination products, FDA does not intend to object if the applicant does 
not provide the evaluation codes, but instead provides evaluation information in the narrative. 
50 Submitting follow-up ICSRs consistent with the applicable regulations, policies, and procedures associated with 
the application type comports with 21 CFR 4.104(b).  For example, for drug-led combination products, the Center 
for Drug Evaluation and Researchs (CDER) electronic reporting system accepts follow-up reports to ICSRs based 
on the requirements in 21 CFR Part 314 and relevant CDER policies and procedures. 
51 For additional information, see Draft Guidance for Industry, Postmarketing Safety Reporting for Human Drug and 
Biological Products Including Vaccines (https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/postmarketing-safety-reporting-human-drug-and-biological-products-including-vaccines) which, when 
final, will represent the FDAs current thinking on this topic. 
52
 For more information about PBRER, see Guidance for Industry, E2C(R2) Periodic Benefit-Risk Evaluation 
Report (PBRER)  (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e2cr2-periodic-
benefit-risk-evaluation-report-pbrer). 
34  Contains Nonbinding Recommendations 
 
Analysis of Five-day and Malfunction reports versus Fifteen-day reports.  The summary and 
analysis of Five-day and Malfunction reports should be presented separately from the summary 
and analysis of Fifteen-day reports.  Applicants should provide separate summary tabulations for 
Malfunction and for Five-day reports, respectively, that were reported during the reporting 
interval, regardless of whether the malfunction or Five-day reportable action related to an 
adverse event.  These tabulations should include device problem codes and any adverse event 
terms that were included in Malfunction or Five-day reports, with counts of occurrences for each.  
If a Malfunction or Five-day report related to an adverse event (e.g., the event required both a 
Fifteen-day and Malfunction report), the adverse event should also be accounted for in the 
summary tabulations for adverse events.  
 
Any questions on periodic safety reporting for a combination product should be directed to the 
lead Center for the combination product or OCP, as needed. 
5.  Additional Information to Include in non-ICSR Combination Product Reports 
(Correction and Removal Report, FAR, or BPDR) 
In addition to the information required to be included in the type of report, we recommend that 
the following information also be included. 
 
When submitting a correction or removal report, the report should: 
 
  Identify the product as a combination product and provide a description of the 
combination product, including its constituent parts, and how these constituent parts are 
or may be involved in the correction or removal.  With respect to the device constituent 
part(s), the report should include the device product code. 
  Include the Combination Product Applicant name, address, telephone number, and 
contact person (if not otherwise required to be included in the correction or removal 
report). 
 
When submitting a FAR, the report should: 
 
  Identify the product as a combination product and provide a description of the 
combination product, including its constituent parts, and how these constituent parts are 
or may be involved with the issue.  If the product includes a device constituent part(s), 
the report should include at least one of the following:  the device product code, the 
device common name and/or the brand name.   
 
When submitting a BPDR, the report should: 
 
  Identify the product as a combination product and provide a description of the 
combination product, including its constituent parts, and how these constituent parts are 
or may be involved with the issue.  If the product includes a device constituent part(s), 
the report should include at least one of the following:  the device product code, the 
device common name and/or the brand name.  
35  Contains Nonbinding Recommendations 
 
VI.  Examples 
The hypothetical examples in this section illustrate PMSR considerations for Combination 
Product Applicants under 21 CFR Part 4.  This section is not intended to reflect a complete 
analysis of the reporting obligations that may apply, and specific products and events may raise 
distinct issues that are not taken into account in the hypothetical scenarios presented below.  If 
manufacturers have specific questions, FDA recommends that they contact the lead Center for 
the product or OCP, as needed, for assistance. 
A. Drug Application Combination Product 
1.  Product Description and Scenario 
A Combination Product Applicant holds an NDA for a combination product consisting of a 
sterile syringe pre-filled with an injectable drug.  The applicant receives a report that a user had 
difficulty pulling back the syringe plunger rod and when he managed to pull the plunger back, 
the entire plunger came out, and the product sprayed into his eyes, causing temporary blindness 
and requiring medical intervention to prevent serious damage to his eyes.  The Combination 
Product Applicant reviews the combination product labeling and notes that potential blindness is 
not an expected adverse event discussed in the labeling.   
2.  Initial ICSR Reporting 
The Combination Product Applicant assesses its ICSR reporting obligations for the event (see 
Chart 2.1 in Appendix 2): 
 
  Was the event an adverse experience that was both serious and unexpected? 
 
YES.  The event was both serious and unexpected (was not included in the product 
labeling).  A Fifteen-day report is required (see 21 CFR 4.102 and 314.80). 
 
  Does the product contain a device constituent part?  YES. 
 
  Did the report reasonably suggest that the product malfunctioned and that the product or a 
similar product marketed by the applicant would be likely to cause or contribute to a 
death or serious injury if the malfunction were to recur?   
 
YES.  The report indicated that the device did not perform as intended, which resulted in 
temporary blindness.  A Malfunction report is required (see 21 CFR 4.102 and 803.50). 
 
  Did the event necessitate remedial action to prevent an unreasonable risk of substantial 
harm to the public health?   
 
NO.  At the time of the initial report, insufficient information is available to the 
Combination Product Applicant to determine whether remedial action is necessary to 
36  Contains Nonbinding Recommendations 
 
prevent an unreasonable risk of substantial harm.  A Five-day report is not required at this 
time.   
 
The reporting timeline for the Fifteen-day report is 15 calendar days and for the Malfunction 
report, it is 30 calendar days (see 21 CFR 314.80 and 803.50, respectively).  The Combination 
Product Applicant provides a report that includes the required information for a Fifteen-day and 
Malfunction report (see 21 CFR 314.80 and 803.52, respectively), as well as the information 
recommended in section V.B.2 above, and submits the report within 15 calendar days and 
thereby complies with both of these combination product PMSR requirements. 
3.  Reporting Based on Additional Information Received 
The Combination Product Applicant continues to investigate the event and determines that the 
supplier of the syringe made changes to the material of the plunger without notifying the 
Combination Product Applicant and that the new material alters the force needed to pull the 
plunger during use. 
 
ICSR Considerations.  Based on this new information, the Combination Product Applicant 
reassesses the event and determines that a remedial action, specifically the removal of lots of the 
combination product that include the syringes with the new material, is necessary to prevent an 
unreasonable risk of substantial harm.  Within five working days of making this determination 
(and prior to initiating the removal), the Combination Product Applicant submits a Five-day 
report to comply with this reporting requirement (see 21 CFR 4.102 and 803.53).   
 
Non-ICSR PMSR Considerations.  The Combination Product Applicant determines that the 
change in material is inconsistent with a specification established in the application for the 
combination product and submits a FAR as required within three working days of receiving the 
information that the lots of the combination product were not meeting the specification 
established in its application (see 21 CFR 4.102 and 314.81). 
 
Because the Combination Product Applicant did not initiate the removal until after submitting 
the Five-day report, it submits a separate correction and removal report via the established 
process (see https://www.fda.gov/medical-devices/postmarket-requirements-devices/recalls-
corrections-and-removals-devices#5) that includes the required information (see 21 CFR 
806.10), as well as the information recommended in sections V.B.1 and V.B.5 above, within 10 
working days of initiating the product removal (see 21 CFR 4.102 and 806.10). 
4.  Additional Considerations for this Scenario 
ICSRs.  If the effects on the users eyes had been expected, a Malfunction report still would have 
been required but not a Fifteen-day report (see 21 CFR 4.102 and 803.50). 
 
Correction/Removal in ICSR.  If the Combination Product Applicant had initiated the removal 
within five working days of making the determination that a removal was necessary to prevent 
an unreasonable risk of substantial harm to the public health, it could have submitted a single 
report to satisfy both the Five-day and the correction and removal reporting requirements (see 21 
CFR 4.102 and 806.10(f)).  
37  Contains Nonbinding Recommendations 
 
 
General.  Regardless of what reports an applicant has submitted to FDA for the combination 
product, the applicant must continue to comply with all PMSR requirements for the product.  For 
example, in this scenario, after a Five-day report is submitted, the Applicants requirements 
would include continuing to assess, and submit Fifteen-day reports as required, for adverse 
events (see 21 CFR 4.102(b) and 314.80).  
B. Device Application Combination Product 
1.  Product Description and Scenario 
A Combination Product Applicant holds a PMA for a drug-eluting stent (DES).  The applicant 
receives a report that a patient experienced a life-threatening infection after the DES was 
inserted.  Treatment and extended hospitalization of the patient was required.  The severity of the 
event exceeds any of the warnings on the product labeling.   
 
The Combination Product Applicant is not able to recover the product that was involved in the 
adverse event but is able to identify the product lot and reviews the production records and finds 
no anomalies related to any of the in-process or finished testing performed on that lot.   
2.  Initial ICSR Reporting 
The Combination Product Applicant assesses its ICSR reporting obligations for the event (see 
Chart 2.2 in Appendix 2): 
 
  Was the event an adverse experience that was both serious and unexpected? 
 
YES.  The infection was both serious (life-threatening) and unexpected (was not included 
in the product labeling).  A Fifteen-day report (made within 30 calendar days) is required 
(see 21 CFR 4.102 and 314.80). 
 
  Is the event a reportable death or serious injury? 
 
YES.  The information reasonably suggests that DES may have caused or contributed to a 
life-threatening infection that required medical intervention.  A serious injury report is 
required (see 21 CFR 4.102 and 803.50). 
 
  Did the event necessitate remedial action to prevent an unreasonable risk of substantial 
harm to the public health? 
 
NO.  Review of the production records showed no anomalies in the manufacturing 
process or lot for the product.  No other information available to the applicant indicates 
that a remedial action is necessary at this time.  No Five-day report is required. 
 
The reporting timeline for both the Fifteen-day and serious injury reports is 30 calendar days (see 
21 CFR 4.102 and 803.50).  The Combination Product Applicant submits a report within 30 
calendar days that includes the required information (see 21 CFR 314.80 and 803.52, 
38  Contains Nonbinding Recommendations 
 
respectively), as well as the information recommended in section V.B.2 above, and thereby 
complies with these combination product PMSR requirements. 
3.  Reporting Based on Additional Information Received 
The Combination Product Applicant receives multiple, similar serious infection event reports for 
other patients for the same model of DES.  The Combination Product Applicant performs 
additional investigations and determines that the drug coating had contaminants.  These 
contaminants are traced to production equipment used to apply the drug coating.   
 
ICSR Considerations.  The applicant determines that the contaminants necessitate removal of the 
affected lots to prevent an unreasonable risk of substantial harm to the public health and initiates 
the removal two days later.  Accordingly, the Combination Product Applicant submits a Five-day 
report for the product removal that includes the information required (see 21 CFR 803.52 and 
806.10) and the information recommended in section V.B above.  The applicant submits the 
report within 5 work days of determining that the remedial action is necessary, which is also 
within 10 work days of initiating the removal.  The Combination Product Applicant, thereby, 
satisfies the Five-day and correction and removal reporting requirements (see 21 CFR 4.102, 
803.53, and 806.10). 
 
Non-ICSR Considerations.  Because the applicant included all information required under 21 
CFR 806.10 in its Five-day report, a separate correction and removal report is not required (see 
21 CFR 4.102 and 806.10(f)).   
 
The Combination Product Applicant determines that a FAR is required because of the 
contamination of the drug coating, which occurred during the manufacturing process.  The 
applicant submits a FAR that includes the information required under 21 CFR 314.81, as well as 
the information recommended in sections V.B.1 and V.B.5 above, within 3 working days of 
discovering the contamination issue, satisfying this additional PMSR requirement (see 21 CFR 
4.102 and 314.81).  
4.  Additional Considerations 
In this scenario, the contamination issue was discovered as a result of an adverse event 
investigation.  Note that had the contamination issue been detected prior to any adverse event 
reports, the Combination Product Applicant would first have been required to submit a FAR 
within 3 working days of receiving the information (see 21 CFR 4.102 and 314.81) and would 
also have had to comply with other reporting requirements identified in the example, once 
triggered, by their respective timelines.
39  Appendix 1. Combination Product (CP) PMSR Requirements by Application and Product Type 
Application  Additional Constituent Part-Based Reporting Requirements53, 54   
Type-Based   (see 21 CFR Section(s))   
Requirements    
Applicants  See 21 CFR  Biological  Five-day  Correction   
Product Type   Section(s)  Field  Fifteen- Product Dev.  Fifteen- Reports  Malfunction  and   
(CP =  Alert  day  Reports   day  803.3  Reports  Removal   
Application  Combination    600  803  Reports  Reports  600.14  Reports  803.53  803.50  806.10   
Type  Product)  314  606  806  314.81  314.80  606.171  600.80  803.56  803.56  806.20  Other Duties 
NDA  Drug  X                  Share information with other Constituent 
ANDA  Constituent Part    Part Applicant(s) (21 CFR 4.103) 
Drug-Device  X      Covered by      X  X  X  Address Five-day and Malfunction reports 
CP  Application  in periodic safety reports (21 CFR 4.102(d)) 
Type-Based 
Drug-Biologic  X      X  X         
Requirements 
CP 
Drug-Device- X      X  X  X  X  X  Address Five-day and Malfunction reports 
Biologic CP  in periodic safety reports (21 CFR 4.102(d)) 
BLA  Biologic    X                 Share information with other Constituent 
Constituent Part    Part Applicant(s) (21 CFR 4.103) 
Biologic-Device    X        Covered by Application  X  X  X  Address Five-day and Malfunction reports 
CP  Type-Based  in periodic safety reports (21 CFR 4.102(d)) 
Requirements 
Biologic-Drug    X    X  X         
CP 
Biologic-Drug-   X    X  X  X  X  X  Address Five-day and Malfunction reports 
Device CP  in periodic safety reports (21 CFR 4.102(d)) 
Device  Device      X            Share information with other Constituent 
Application  Constituent Part    Part Applicant(s) (21 CFR 4.103) 
(PMA,  Device-Drug      X  X  X      Covered by Application  Provide additional reports only if specified 
510(k),  CP  Type-Based  in writing by FDA (21 CFR 4.102(d)) 
HDE, PDP,  Device-Biologic      X      X  X  Requirements 
De Novo)  CP 
Device-Drug-     X  X  X  X  X 
Biologic CP 
 
53 Note that there are associated requirements to submit follow-up reports to ICSR reports (see Section IV.A.4 for discussion of the follow-up reporting 
requirements in the regulations). 
54 See Sections IV.C and V.A.3 for discussion of streamlined reporting for for combination products and IV.A.1 regarding Fifteen-day reporting for combination 
products that contain both a drug and biological product constituent part. 
40 
  Appendix 2.  Flowcharts for Combination Product ICSR 
Requirements 
Chart 2.1.  ICSR Reporting Requirements for Combination Products Marketed Under 
NDA/ANDA/BLA*  
   
Event Reported to Combination Product Applicant 
Was the event an adverse  Fifteen-day Report  Required 
Yes 
experience that was both  (Assess Need for Additional 
serious and unexpected?  ICSR Types) 
   
No 
No  Product contains a device 
constituent part? 
 
Yes 
Does the information reasonably 
suggest the product malfunctioned and  Malfunction Report 
that the product or a similar product  Yes  Required  
marketed by the applicant is likely to  (Assess Need for Additional 
cause or contribute to a death or serious  ICSR Types) 
injury if the malfunction were to recur?   
No 
Did the event necessitate 
remedial action to prevent an  Yes  Five-day Report 
unreasonable risk of substantial  Required 
harm to the public health?   
 
No 
No additional ICSRs (other than periodic reports) required unless  Include in Periodic 
new reportable information is received  Reports 
   
* This chart only covers reporting of ICSRs under the combination product PMSR final rule (21 CFR 4.101 and 4.102).  Other report types 
(correction and removal report, FAR, BPDR) may also be required. Note options discussed in Sections IV.C and V.A.3 for streamlining by 
combining ICSRs and/or including correction/removal information.  For ICSRs, there are associated requirements for follow-up reports (see 
Section IV.A.4 for discussion of follow-up reporting requirements in the regulations). 
  
41 
  Contains Nonbinding Recommendations 
 
Chart 2.2.  ICSR Reporting Requirements for Combination Products Marketed Under a 
Device Application* 
Event Reported to Combination Product Applicant 
Fifteen-day Report  
(within 30 days)  Was the event an adverse 
Yes 
Required (Assess  experience that was both 
Need for Additional  serious and unexpected? 
ICSR Types)   
 
No 
Death or Serious 
Injury Report 
Does the information reasonably 
Yes  Required 
suggest product may have caused or 
 (Assess Need for 
contributed to a death or serious injury?  
Additional ICSR 
Types) 
 
No 
Malfunction 
Report  Does the information reasonably suggest 
Required   the product malfunctioned and that the 
Yes 
(Assess  product or a similar product marketed by 
Need for  the applicant is likely to cause or 
Additional  contribute to a death or serious injury if 
ICSR  the malfunction were to recur? 
Types)   
 
No 
Did the event necessitate 
remedial action to prevent an  Yes 
Five-day Report 
unreasonable risk of 
Required 
substantial harm to the 
public health? 
 
No 
No additional ICSRs required unless specified by FDA or new 
reportable information is received 
 
* This chart only covers reporting of ICSRs under the combination product PMSR final rule (21 CFR 4.101 and 4.102).  Other report types 
(correction and removal report, FAR, BPDR) may also be required.  Note options discussed in Sections IV.C and V.A.3 for streamlining by 
combining ICSRs and/or including correction/removal information.  For ICSRs, there are associated requirements for follow-up reports (see 
Section IV.A.4 for discussion of follow-up reporting requirements in the regulations). 
 
 
42  Contains Nonbinding Recommendations 
 
Appendix 3.  Combination Product Postmarketing Safety Reporting 
Considerations for Entities that are Not Applicants 
As discussed in Section III.A, only entities that are Constituent Part Applicants or 
Combination Product Applicants are subject to the combination product PSMR final rule.  
There are other entities, however, involved in the manufacture or marketing of a combination 
product that may have postmarketing safety reporting obligations for the product.  Reporting 
obligations for such entities are indicated below:55  
  Manufacturers, packers, and distributors, whose names appear on the label of over-the-
counter combination products that are not subject to premarket review and include a drug 
constituent part, must comply with the reporting and recordkeeping requirements 
described in section 760 of the FD&C Act (21 U.S.C. 379aa) for the combination 
product. 
 
  Non-applicants listed as a manufacturer, packer, or distributor on the label of a 
combination product that contains a drug or biological product constituent part must 
comply with reporting requirements as described in 21 CFR 314.80 and 600.80 for the 
product, as applicable. 
 
  Manufacturers, packers and distributors of unapproved prescription combination products 
that include a drug constituent part must report and maintain records as described in 21 
CFR 310.305 for the combination product; packers and distributors may meet these 
requirements by reporting to the combination product manufacturer within five days of 
receiving the information and maintaining records of these reports as described in 21 
CFR 310.305(c)(3). 
 
  Manufacturers, importers, and user facilities (see definitions in 21 CFR 803.3) for 
combination products that include a device constituent part, whether or not subject to 
premarket review, must comply with the requirements applicable to them in 21 CFR Part 
803 for the combination product, and may seek exemptions, variances, or alternatives to 
these requirements as described in 21 CFR 803.19(b) (e.g., where there is a Combination 
Product Applicant for the product, other such entities subject to 21 CFR Part 803 may 
seek an exemption from reporting to FDA if they choose instead to report to the 
Combination Product Applicant).  
 
  Manufacturers and importers (see definitions in 21 CFR 806.2) of combination products 
that include a device constituent part must comply with the requirements described in 21 
CFR Part 806 for the combination product. 
 
55 In some cases, the constituent part of a combination product may also be manufactured or marketed separately by 
a different entity as a non-combination product.  PMSR reporting obligations may also apply to such entities.  For 
example, if a Combination Product Applicant purchases syringes to include in its co-packaged combination product 
from a syringe manufacturer who holds a marketing authorization to market the syringes for general use, the syringe 
manufacturer has no PMSR duties for the combination product but has PMSR duties with regard to its syringes 
under 21 CFR Part 803. 
43  Contains Nonbinding Recommendations 
 
If you are such an entity, you should identify the product as a combination product (and you must 
identify the product as a combination product if required under the applicable regulations) and 
provide a complete discussion of the event with respect to the combination product, including 
each constituent part, as appropriate, based on the information available to you.  Entities who 
have questions about these reporting requirements should contact the lead Center or OCP, as 
needed. 
   
44