Performance Report to Congress

Office of Combination 

Products

FY 2021

(as required by the Medical Device User Fee and 

Modernization Act of 2002)
Commissioner’s Report

I am pleased to submit the fiscal year 2021 annual performance report to Congress for the Office 

of Combination Products (OCP), an office in the U.S. Food and Drug Administration (FDA). 

This report includes data from the 18th full year since OCP was established, which was mandated 

by the Medical Device User Fee and Modernization Act of 2002 (P.L. 107-250) that was enacted 

on October 26, 2002. Despite the challenges presented by the COVID-19 pandemic, including a 

reprioritization of FDA’s activities and an increased workload, OCP has continued to fulfill its 

responsibilities relating to its jurisdiction of, premarket review of, and postmarket oversight of 

combination products.

Combination products are therapeutic and diagnostic products that combine a drug, device, 

and/or biological product. Technological advances continue to merge product types and blur the 

historical lines of separation among FDA’s human medical product Centers (that is, the Center 

for Biologics Evaluation and Research, the Center for Drug Evaluation and Research, and the 

Center for Devices and Radiological Health). Combination products involve constituent parts 

that would usually be regulated under different types of regulatory authorities and frequently be 

handled by different FDA Centers. Therefore, these products can raise complex regulatory, 

policy, and review management challenges. For instance, differences relating to the regulatory 

pathways and the considerations for each type of constituent part (i.e., drug, device, and/or 

biological product) can impact the regulatory processes for all aspects of combination product 

development and management. These aspects include preclinical testing, clinical investigation, 

marketing application review, manufacturing and quality control, adverse event reporting, 

promotion and advertising, user fees, and post approval modifications.

OCP continues to enhance the efficiency, consistency, transparency, and predictability of its 

processes for assigning combination products to the appropriate lead Center. OCP facilitates 

interactions between industry and FDA to clearly delineate regulatory pathways; monitor and 

adjust processes to ensure a timely and effective, aligned premarket review; and help ensure 

consistent and appropriate postmarket regulation of combination products.

Combination products are likely to become more complex as new technologies emerge and 

existing technologies mature. OCP will continue to focus on the most pressing and important 

issues relating to the regulation of combination products. OCP is committed to actively assisting 

industry and FDA’s reviewers in understanding the complexities of this regulatory area. 

FDA looks forward to ensuring success in meeting the unique challenges presented in the review 

and regulation of combination products.

Robert M. Califf, M.D.

Commissioner of Food and Drugs
Executive Summary

The U.S. Food and Drug Administration (FDA or Agency) established the Office of 

Combination Products (OCP) on December 24, 2002, as required by the Medical Device User 

Fee and Modernization Act of 2002 (P.L. 107-250). The statutory mission of OCP includes 

ensuring (1) the prompt assignment of combination products (drug-device, biologic-device, drugbiologic, or drug-device-biologic products)

1

to FDA’s Centers; (2) the timely, effective, and 

aligned premarket review of applications for these products; and (3) the consistent and 

appropriate postmarket regulation of combination products.

This annual performance report to Congress covers OCP’s activities and accomplishments 

during fiscal year (FY) 2021 (i.e., October 1, 2020, to September 30, 2021). This report 

highlights the following OCP activities for FY 2021: 

A. Prompt Assignment of Combination Products

Companies may submit Request for Designation (RFD) submissions to obtain formal Agency 

determinations for the classification of a human medical product (e.g., biological product, 

device, drug, or combination product) and/or for the Center assignment (i.e., the lead Center in 

the case of a combination product) for the product’s premarket review and regulation. In FY

2021, OCP issued one combination product and two non-combination product RFD decisions, 

with every classification and/or assignment decision meeting FDA’s 60-day statutory 

requirement for decisions. Alternatively, companies may submit a Pre-Request for Designation 

(Pre-RFD) to obtain informal feedback from OCP on a product’s classification and/or Center 

assignment. In FY 2021, OCP provided classification and Center assignment feedback for 46 

Pre-RFDs. (For more information, see the “Policy and Procedural Activities and 

Accomplishments” section below.)

B. Timely and Effective Combination Product Premarket Review

In FY 2021, OCP conducted several activities related to the premarket review of combination 

products. For instance, OCP received 124 requests for product-specific premarket assistance, the 

responses to which contributed to ensuring FDA’s timely, effective, and aligned review of 

combination products. FDA’s efforts enabled sponsors to expeditiously address FDA’s concerns 

and bring products to market more efficiently, thereby expediting patient access to new treatment 

options. In addition, OCP chaired and/or participated in a number of inter-Center working 

groups to examine complex regulatory issues, clarify regulatory standards, address challenging 

categories of products, update the premarket review process, and address developmental 

considerations for combination products. Further, in FY 2021, FDA received 596 original 

premarket applications for combination products. There were 1,202 inter-Center consulting 

1 Examples of combination product types can be found on the Combination Products website, which is available at 

http://www.fda.gov/CombinationProducts/default.htm.
reviews for combination products in FY 2021. (For more information, see the Policy and 

Procedural Activities and Accomplishments section below.)

C. Consistent and Appropriate Postmarket Regulation

In FY 2021, OCP provided clarification and support for 84 separate postmarket matters. OCP 

continued to chair FDA working groups to address current good manufacturing practices 

(CGMP) and postmarketing safety reporting (PMSR) requirements for combination products. 

OCP also continued to work with the human medical product Centers on registration and listing 

issues, postmarket manufacturing compliance, and other postmarket regulatory issues pertaining 

to specific combination products. These various efforts furthered FDA’s capabilities to identify 

and help mitigate potential risks to patients associated with products currently on the market. 

(For more information, see the “Policy and Procedural Activities and Accomplishments” section 

below.)

D. Policy and Procedural Activities and Accomplishments

In FY 2021, OCP continued to implement section 3038 of the 21st Century Cures Act and to 

develop policy regarding complex regulatory and procedural questions for combination products. 

OCP also continued to develop policy related to both (1) separately distributed medical products 

intended for combined use that are not combination products and (2) the classification and 

assignment of challenging medical products. The Combination Products Policy Council, chaired 

by OCP and consisting of senior leaders from all three human medical product Centers and the 

Office of Clinical Policy and Programs, continued in FY 2021 to support OCP’s related 

activities, some of which are detailed below. 

For example, FDA issued a Federal Register notice2regarding a decision by the U.S. Court of 

Appeals for the District of Columbia Circuit in Genus Med. Techs., LLC v. FDA, 994 F.3d 631 

(D.C. Cir. 2021), which held that FDA cannot classify as a drug any product that meets the 

device definition in section 201(h) of the Federal Food, Drug, and Cosmetic Act. The notice 

(1) announced FDA’s intent to establish a process for making an orderly and efficient 

determination of which products currently regulated by FDA as drugs must now be regulated as 

devices under Genus and (2) solicited public comment on this process. In addition, FDA issued a 

Federal Register notice regarding consolidating its regulatory oversight responsibilities in the 

Center for Biologics Evaluation and Research for certain devices that process autologous human 

cells, tissues, and cellular and tissue-based products (HCT/Ps) at the point of care where the 

device output is intended to mediate the intended therapeutic effect.

3

 Further, OCP continued to 

develop policies related to the following topics: human factors, essential performance 

requirements, principles of premarket pathways for combination products, regulatory 

2 86 FR 43553 (Aug. 9, 2021), available at https://www.federalregister.gov/public-inspection/2021-16944/requestfor-information-genus-medical-technologies-llc-versus-food-and-drug-administration. 

3 86 FR 50887 (Sept. 13, 2021), available at https://www.federalregister.gov/documents/2021/09/13/2021-

18912/consolidation-of-devices-that-process-autologous-human-cells-tissues-and-cellular-and-tissue-based
considerations for cross-labeled combination products and other separately distributed medical 

products intended for combined use, alternative mechanisms to address current good 

manufacturing practice expectations, and unique identifiers for combination products. Also, 

OCP issued system updates and training to enhance not only the efficiency of the inter-Center 

consult process but also access to relevant postmarket information via an online “dashboard.” 

OCP also continued, in FY 2021, to conduct external outreach activities through engagement 

with stakeholder organizations and through a variety of educational and informational 

presentations to national and international audiences and standard-setting bodies. These 

activities were intended to foster a greater understanding of the complex regulatory and scientific 

issues in the developmental, premarket, and postmarket settings for combination products; 

clarify how stakeholders can engage with FDA on these issues; enable FDA to understand and 

consider stakeholders’ questions and concerns; and identify potential areas for regulatory 

convergence across jurisdictions for FDA’s oversight of combination products. 
Table of Contents

I. Introduction ................................................................................................. 1

A. Description of Combination Products ................................................................. 1

B. Statutorily Mandated Functions of OCP .............................................................. 2

C. Performance Results Presented in This Report..................................................... 3

II. Prompt Assignment of Combination Products ........................................ 5

A. Requirement Workload Trends: FY 2017 to FY 2021 .......................................... 5

1. Pre-RFD Workload Performance Results ................................................... 8

B. OCP’s Performance on Internal Center- or Office-Requested Product Classification 

and Center-Assignment Consultations............................................................... 10

C. OCP’s FY 2021 Activities and Accomplishments .............................................. 12

III. Combination Product Premarket Review................................................ 13

A. Number and Types of Combination Products Submitted for Premarket Review..... 13

B. Requirement Workload Trends: FY 2016 to FY 2021 ........................................ 14

1. Inter-Center Consult Requests................................................................. 16

C. Timeliness in Days of the Reviews of Combination Products .............................. 20

D. FY 2020 and FY 2021 Review Performance Results .......................................... 21

1. Premarket Review Facilitation/Oversight ................................................. 23

IV. Combination Product Postmarket Activities .......................................... 27

V. Effective Resolutions of Review Disputes.............................................. 29

A. Percentage of Combination Products Reviewed for Which a Formal Dispute 

Resolution Was Requested .............................................................................. 29

VI. Policy Activities and Accomplishments ................................................. 30

A. Supporting and Implementing Legislative Initiatives.......................................... 30

B. Streamlining Regulation.................................................................................. 30

C. Clarifying Regulatory Policy ........................................................................... 30
D. Other Policy-Related Activities........................................................................ 32

VIII. Additional Activities and Accomplishments .......................................... 37

A. Information Technology.................................................................................. 37

B. External Outreach........................................................................................... 37

FY 2020 Updated Performance Detail................................... 40
Acronym List

510(k) Premarket Notification

ANDA Abbreviated New Drug Application

BLA Biologics License Application

BsUFA Biosimilar User Fee Act

CBER Center for Biologics Evaluation and Research

CDER Center for Drug Evaluation and Research

CDRH Center for Devices and Radiological Health

CFR Code of Federal Regulations

CGMP Current Good Manufacturing Practice

FDA Food and Drug Administration

FY Fiscal Year (October 1 to September 30)

GDUFA Generic Drug User Fee Act

HDE Humanitarian device exemption

ICH International Council for Harmonisation

IDE Investigational Device Exemption

IND Investigational New Drug

IT Information Technology

MDUFA Medical Device User Fee Amendments

MDUFMA Medical Device User Fee and Modernization Acct of 2002

NDA New Drug Application

OCC Office of the Chief Counsel

OCP Office of Combination Products

PDUFA Prescription Drug User Fee Act

PMA Premarket Approval Application

PMOA Primary Mode of Action
PMSR Postmarketing Safety Reporting

Pre-RFD Pre-Request for Designation

RFD Request for Designation

SMG Staff Manual Guide
1

I. Introduction

On October 26, 2002, the Medical Device User Fee and Modernization Act of 2002 (MDUFMA) 

(P.L. 107-250) was signed into law. Among other things, MDUFMA required FDA to establish 

an office “to ensure the prompt assignment of combination products to Agency Centers, the 

timely and effective premarket review of such products, and consistent and appropriate 

postmarket regulation of like products to the extent permitted by law.” In response, FDA 

established the Office of Combination Products (OCP) within the Office of the Commissioner. 

In addition, section 3038 of the 21st Century Cures Act (Cures Act) (enacted December 13, 2016) 

clarified and expanded the duties of OCP to include ensuring the alignment of the premarket 

review of combination products. Information about OCP, including the authorizing text of 

MDUFMA as amended by the Cures Act, can be found on the Combination Products website.4

A. Description of Combination Products

Title 21 of the Code of Federal Regulations (CFR) (section 3.2(e)) states that combination 

products include:

(1) A product comprised of two or more regulated components, i.e., drug/device, 

biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, 

or otherwise combined or mixed and produced as a single entity; 

(2) Two or more separate products packaged together in a single package or as a unit and 

comprised of drug and device products, device and biological products, or biological 

and drug products; 

(3) A drug, device, or biological product packaged separately that, according to its

investigational plan or proposed labeling, is intended for use only with an approved 

individually specified drug, device, or biological product where both are required to 

achieve the intended use, indication, or effect and where upon approval of the proposed 

product the labeling of the approved product would need to be changed, e.g., to reflect a 

change in intended use, dosage form, strength, route of administration, or significant 

change in dose; or,

(4) Any investigational drug, device, or biological product packaged separately that 

according to its proposed labeling is for use only with another individually specified 

4 Available at http://www.fda.gov/CombinationProducts/default.htm.
2

investigational drug, device, or biological product where both are required to achieve 

the intended use, indication, or effect.

Some combination products (1) have the potential to provide enhanced therapeutic advantages 

compared to non-combination medical products5(i.e., devices, drugs, and biological products) 

and (2) incorporate cutting-edge, novel technologies that hold great promise for advancing 

patient care. Combination products may incorporate, for example, advanced delivery systems 

and may include personalized medicine drug-device combinations, biological-device 

combinations, applications of nanotechnology, and other innovative technologies and scientific 

advancements.

B. Statutorily Mandated Functions of OCP 

MDUFMA and the Cures Act have established broad responsibilities for OCP that cover the 

regulatory lifecycle from decisions relating to product jurisdiction to oversight and facilitative 

duties relating to the premarket review and postmarket oversight of combination products.6

However, the primary day-to-day responsibilities for the premarket review and the postmarket 

regulation of combination products remain in the three human medical product Centers – the 

Center for Biologics Evaluation and Research (CBER), the Center for Drug Evaluation and 

Research (CDER), and the Center for Devices and Radiological Health (CDRH). 

Specifically, section 503(g)(8) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 353 

(g)(8)) requires OCP to:

(1) Promptly assign a Center with primary jurisdiction for a combination product;

(2) Ensure the timely and effective premarket review of combination products by 

overseeing the timeliness of reviews and the alignment of the Agency’s feedback to the 

sponsor and by coordinating reviews involving more than one Center;

5 Throughout this document, the terms “medical product” and “human medical product” may be used 

interchangeably, and they refer to human medical products regulated by the Center for Biologics Evaluation and 

Research, the Center for Drug Evaluation and Research, or the Center for Devices and Radiological Health.

6 Under the Prescription Drug User Fee Act Reauthorization of 2017 (PDUFA VI) commitments, FDA initiated an 

independent third-party assessment of FDA’s regulatory activities for combination products, including premarket 

reviews. A final report from this assessment, issued in August 2020, is available at 

https://www.fda.gov/industry/prescription-drug-user-fee-amendments/pdufa-vi-assessment-combination-productreview-practices-pdufa-vi. The report found FDA’s jurisdictional, inter-Center consult request and premarket 

review practices for combination products fundamentally sound but offered recommendations to improve FDA’s 

efficiency, to enhance FDA’s practices through “straightforward” and “minor” refinements to processes, and to 

address technological challenges. These recommendations aligned with the Agency’s ongoing efforts to improve 

and enhance these practice areas. OCP continues to implement the recommendations as discussed in this FY 2021 

Performance Report.
3

(3) Ensure the consistency and appropriateness of the postmarket regulation of like 

products subject to the same statutory requirements to the extent permitted by law;

(4) Resolve disputes regarding the timeliness of the premarket review of combination 

products; and

(5) Review and modify/revise/eliminate, as needed, agreements, guidance documents, or 

practices specific to the assignment of combination products.

OCP serves as a focal point for addressing combination product issues raised by FDA’s 

reviewers and stakeholders and works with the relevant Centers not only to develop guidance 

documents, regulations, processes, and procedures but also to enhance the clarity, transparency, 

efficiency, effectiveness, and consistency of the Agency’s regulation of combination products.

In addition, OCP has responsibility for FDA’s actions on all Requests for Designation (RFDs) 

submitted by industry in accordance with 21 U.S.C. 360bbb-2 and 21 CFR part 3, “Product 

Jurisdiction.” RFDs may request (1) a classification of a particular product as a biological 

product, device, drug, or combination product, (2) a determination of the product’s Center 

assignment, or (3) both. FDA’s responses to RFDs, with respect to classifications and/or Center 

assignments, are binding determinations that may only be changed under the conditions specified 

in 21 U.S.C. 360bbb-2 and 21 CFR 3.9.

C. Performance Results Presented in This Report

This report presents OCP’s FY 2021 activities and accomplishments, including its fulfillment of

statutory mandates. This report presents information and data on OCP’s activities related to the 

following:

7

· Prompt assignment of combination products 

o Timeliness of the classification and assignment of combination products

· Timely and effective premarket review 

o Number and types of combination products under review

o Timeliness of the reviews of combination products

o Number of premarket reviews of combination products that involved a consulting 

Center

7 FDA has initiated various activities related to its implementation of the Cures Act’s requirements for combination 

products, and this report has been modified to provide new information to reflect the Cures Act’s requirements and 

expectations. As implementation of the Cures Act proceeds, the Agency will consider what additional information 

or adjustments may be appropriate for subsequent reports. 
4

· Consistent and appropriate postmarket regulation 

o Efficient, effective, and consistent facility inspections

o Efficient and effective product tracking and tracing

o Timely consideration of safety signals

· Effective resolution of review disputes 

o Timeliness of dispute resolutions regarding combination products

Unless otherwise noted, all performance data are as of September 30, 2021.
5

II. Prompt Assignment of Combination Products

Companies may submit RFD submissions to obtain formal Agency determinations for the 

classification of a human medical product (e.g., biological product, device, drug, or combination 

product) and/or for the assignment of the lead Center for the product’s premarket review and 

regulation. 

OCP is required to formally respond to RFDs by classifying a product as a biological product, 

device, drug, or combination product, as well as to assign a particular product to a lead Center 

(i.e., CBER, CDER, or CDRH). For combination products, OCP assigns the Center with 

primary jurisdiction (the lead Center) based on the product’s primary mode of action (PMOA) 

(see 21 U.S.C. 353(g)(1) and 21 CFR 3.4(a)). RFD submissions are subject to a statutory 60-day 

deadline for FDA response. RFD decisions help sponsors understand the regulatory

requirements applicable to their products.

In addition to the above activities, OCP provides informal classification and Center assignment 

responses to Pre-Request for Designation (Pre-RFD) submissions.8 Further, OCP leads and/or 

supports other Agency efforts to develop and publish regulations, guidance documents, and 

policies related to the classification and assignment of medical products (which is discussed 

more fully in the “Policy Activities and Accomplishments” section below).

Frequently, sponsors submit RFDs or Pre-RFDs that are not sufficiently complete for FDA to file 

the submissions and conduct its assessment of the submissions. Many RFDs and Pre-RFDs 

require multiple rounds of filing review before they are accepted for review. In these situations, 

OCP continues to assist sponsors to help ensure they understand what information is needed for 

the product’s classification and assignment, thereby helping ensure that RFD and Pre-RFD 

submissions will be complete for FDA’s review. 

A. Requirement Workload Trends: FY 2017 to FY 2021

OCP received 66 RFD submissions in FY 2021. In addition, OCP reviewed four RFD 

submissions that were carried over at the end of FY 2020. Of the 70 total RFD submissions that 

were reviewed in FY 2021, three submissions (4%9) had a decision issued, 61 submissions (87%) 

were found to have insufficient information for filing, and six submissions (9%) were withdrawn 

8 Responses to Pre-RFD submissions for product classification and jurisdictional assignments do not have a required 

time frame. However, OCP attempts to respond to Pre-RFD submissions in the same time frame as RFDs (i.e., 

within 60 days). Information about Pre-RFD submissions (including the timeliness of OCP responses) is provided 

in the section below titled “Pre-RFD Workload Performance.” 

9 All percent values have been rounded to the nearest whole number for this entire report.
6

by the sponsor. Of the three RFD determinations, one was classified as a combination product 

and two were classified as non-combination products.10

In Table 1, the total number of RFD determinations (i.e., classifications and assignments for both 

combination and non-combination products) in FY 2021 is compared to the previous 5 years. 

Table 1. RFD Determinations from FY 2017 to FY 2021.*

RFD Submissions FY 16 FY 17 FY 18 FY 19 FY 20 FY 21

Total RFD Combination 

Product Classifications/ 

Assignments 

2 5 8 7 7 1

Total RFD NonCombination Product 

Classifications/ 

Assignments

2 3 0 6 2 2

* Over the reported 6-year time frame, a decrease in RFD decisions has been accompanied by an increase in the 

number of Pre-RFD assessments provided by OCP. (See the section below titled “Pre-RFD Workload 

Performance” for more information.)

In FY 2021, the three RFD determinations were all issued by the statutorily mandated 60-day 

deadline. The average RFD review time was 59 days, with a median review time of 58.5 days. 

One RFD determination issued determined that the product was a device-biologic combination 

product type. Two RFD determinations issued determined that the products were noncombination product drugs.

10 OCP did not receive any Requests for Reconsideration in FY 2021.
7

As shown in Table 2, the total number

of RFD combination product determinations 

issued in FY 2021 decreased by six compared to 

FY 2020.

As shown in Table 3, the total number of 

RFD non-combination determinations issued 

in FY 2021 remained the same in FY 2020. 

FY

16

FY

17

FY

18

FY

19

FY

20

FY

21

Total 2 5 8 7 7 1

CBER 0 0 1 1 1 0

CDER 1 4 6 4 4 1

CDRH 1 1 1 2 2 0

0

5

10

15

20

Number of Requests

Table 2. Combination 

Product Assignment 

Determinations.

FY

16

FY

17

FY

18

FY

19

FY

20

FY

21

Total 2 3 0 6 2 2

CBER 0 1 0 2 0 0

CDER 2 0 0 2 1 2

CDRH 0 2 0 2 1 0

0

5

10

15

20

Number of Requests

Table 3. Non-Combination 

Product Assignment 

Determinations.
8

1. Pre-RFD Workload Performance Results 

Now in its fifth formalized program year, OCP continues the Pre-RFD program11 to provide 

preliminary feedback for product classifications and Center assignments (i.e., Pre-RFD 

assessments). The Pre-RFD process offers more flexibility than the RFD process, allowing for 

more discussions between FDA and a sponsor if questions arise during the review. Table 6 

shows OCP’s Pre-RFD submission review workloads from FY 2017 to FY 2021. 

Table 6. OCP’s Pre-RFD Workloads from FY 2017 to FY 2021.

Pre-RFD Assessment 

Decisions

FY 

17

FY 

18

FY 

19

FY 

20

FY 

21

Combination Product 

Assessments 44 48 51 47 30

Non-Combination 

Product Assessments 34 28 29 30 15

Unclassified 

Assessments* 0 6 3 2 1

Total Pre-RFD 

Assessments 78 82 83 79 46

* Pre-RFD assessments may not result in the classification of a product as a drug, device, 

biological product, or combination product, and/or a Center assignment. For instance, products 

that fall under the unclassified category may meet the criteria for regulation solely under section 

361 of the Public Health Service Act and 21 CFR part 1271 or the sponsor for these products 

may have pursued a product assignment and not a classification.

A high percentage of Pre-RFDs cannot be filed because they lack sufficient information to 

initiate review. Of the 46 total Pre-RFD assessments completed by OCP in FY 2021, 28 (61%) 

were issued by OCP’s internally established 60-day goal date that begins when OCP receives 

sufficient information to provide the requested feedback. The average review time for Pre-RFD 

submissions was 89.7 days, with a median review time of 60 days. Other filed Pre-RFDs either 

11 Formalization of the Pre-RFD program as a distinct OCP activity occurred during FY 2016. Consistent with past 

practice, Pre-RFD data presented in the FY 2016 report continued to be grouped with Center-requested consultations 

(i.e., product classification and jurisdictional requests that originated with the Centers and not with product 

sponsors). However, responding to Pre-RFDs and Center-requested consultations are two different OCP activities. 

Therefore, these two different data groups have been independently reported since FY 2017. Center-requested 

consultations are discussed in the following section.
9

were withdrawn by their sponsors prior to OCP issuing its assessment recommendation or 

remain under review due to FDA’s pending implementation of the Genus decision.12 

Tables 7 through 10 provide data on FDA’s Pre-RFD assessments for combination products and 

non-combination products based on the products’ classification and the Center assignment.

Table 7. Number and Timing of Combination Product Pre-RFD Assessments by Product 

Classification.

Classification Pre-RFDs

Issued

Percent

Issued in 

60 Days

Drug-Device 22 68%

Drug-Biologic 0 N/A

DeviceBiologic 6 50%

Drug-DeviceBiologic 2 50%

Total 30 63%

Table 8. Number and Timing of Combination Product Pre-RFD Assessments by Center 

Assignment.

Center 

Assignment

Pre-RFDs

Issued

Percent

Issued in 

60 Days

CDER 18 78%

CBER 3 33%

CDRH 9 44%

Total 30 63%

12 On April 16, 2021, the U.S. Court of Appeals for the District of Columbia Circuit issued a decision in Genus Med. 

Techs., LLC v. FDA, 994 F.3d 631 (D.C. Cir. 2021), holding that FDA cannot classify as a drug any product that 

meets the device definition in section 201(h) of the Federal Food, Drug, and Cosmetic Act. A Federal Register

notice about this decision, issued in August 2021, is available at https://www.federalregister.gov/publicinspection/2021-16944/request-for-information-genus-medical-technologies-llc-versus-food-and-drugadministration. 
10

Table 9. Number and Timing of Non-Combination Product Pre-RFD Assessments by 

Product Classification.

Classification Assignments

Issued

Percent

Issued in 60 

Days

Drug 6 16%

Biologic 0 N/A

Device 9 78%

Total 15 53%

Table 10. Number and Timing of Non-Combination Product Pre-RFD Assessments by 

Center Assignment.

Center 

Assignment

Pre-RFDs 

Issued

Percent

Issued in 60 

Days

CDER 6 17%

CBER 0 N/A

CDRH 9 78%

Total 15 53%

B. OCP’s Performance on Internal Center- or Office-Requested 

Product Classification and Center-Assignment Consultations 

In addition to handling RFDs and Pre-RFDs submitted by industry/sponsors, OCP provides 

classification and Center-assignment feedback for combination and non-combination products in 

response to requests from FDA’s Centers/Offices (i.e., Classification and Center-Assignment 

Consultations (CCA Consults)). For instance, Centers may contact OCP for assistance in 

determining whether the combination product submitted to a Center for review is appropriately 

assigned to that Center or whether the sponsor would need to be referred to OCP for a PreRFD/RFD. The number of CCA Consults submitted to OCP is presented in Table 11.
11

Table 11. Number of CCA Consults by Center from FY 2019 to FY 2021.

Center Assignment FY 19 FY 20 FY 21

CDER 51 44 35

CBER 4 4 8

CDRH 14 27 23

Unassigned* 4 4 3313

Total 73 79 99

* The term unassigned indicates that a determination/assessment of Center 

assignment was not made. This may be the case, for example, if the question before 

OCP solely concerns product classification or if the product is not regulated by a 

human medical product Center. 

Table 12 details additional OCP activities related to product classification and Center assignment 

that do not fall within the classification and assignment activities reported above. These 

additional activities include responding to email queries regarding the Pre-RFD and/or RFD 

processes, providing feedback to sponsors regarding the design of their studies to evaluate the 

PMOA of a combination product, and/or holding informational meetings/teleconferences with 

sponsors that plan to submit RFD or Pre-RFD submissions. 

Table 12. Number of OCP’s Additional Product Classification and Center-Assignment 

Activities from FY 2019 to FY 2021.

FY 19 FY 

2014 FY 21

Jurisdiction/Classification 

Activities15 463 950 375

13 Prior to FY 2021, CCA consults that were determined to be unassigned—due to the sponsor being referred to 

OCP to request product classification or Center-assignment feedback via a Pre-RFD or RFD—were captured as an 

additional activity, as can be seen in Table 12. Due to system enhancements in FY 2021, OCP now shows these as 

unassigned CCA consults in Table 11.

14 There was not an obvious cause for the increase in additional product classification and Center-assignment 

activities in FY 2020. 

15 Within FY 2021, OCP enhanced its ability to track inquiries and other activities by launching a technical solution, 

which will likely enable a more granular assessment of the queries received and the ability to identify topics that 

may warrant more guidance.
12

C. OCP’s FY 2021 Activities and Accomplishments 

Table 13 highlights OCP’s Activities for classification and Center-assignment for FY 2021. 

Table 13. Specific FY 2021 Activities by OCP.

Type of Activity FY 2021 Activities

Issuing required RFD assignments 

within 60 days

OCP issued all RFD assignments by the statutory 60-

day determination deadline.

Clarifying standards for product 

classification and preparing 

guidance on this issue

OCP continued to:

· Chair a working group composed of staff from 

CDER, CDRH, CBER, and the Office of the 

Chief Counsel (OCC) to clarify interpretive 

standards and to address the classification and 

assignment for challenging categories of 

products.

· Pursue and support related policy initiatives, 

including (1) clarifying standards for crosslabeled combination product classification and 

assignment, (2) clarifying the regulatory status 

of software used with a drug or biological 

product, (3) determining when 

container/closures are also considered devices, 

and (4) classifying articles that meet both the 

biological product and device definitions.

Enhancing the timeliness, 

consistency, and clarity of 

jurisdictional decisions across 

FDA

OCP continued to facilitate product classification and 

jurisdictional meetings with CBER, CDER, CDRH, 

and OCC staff to exchange information and discuss 

challenging product classification and assignment 

issues before FDA.

Developing part 3 regulations

OCP continued to lead efforts to finalize a rule to 

amend part 3 for clarity and consistency with more 

recent legislative and policy developments.
13

III. Combination Product Premarket Review 

OCP is responsible for ensuring the timely, effective, and aligned premarket review of 

combination products. This responsibility includes overseeing the timeliness of reviews, the 

consistency of FDA’s feedback to sponsors, and the coordination of reviews in which more than 

one Center needs to participate. 

In 2002, FDA established procedures for CBER, CDER, and CDRH staff to follow when 

requesting, receiving, handling, processing, and tracking inter-Center consults (also referred to as 

“inter-Center consult requests” in this document). These procedures were formally incorporated 

into the FDA Staff Manual Guide (SMG) 4101 (titled “Inter-Center Consult Request Process”).

16

 

FDA updated this SMG in June 2018 to improve inter-Center coordination for combination 

products and to enhance the timeliness and consistency of inter-Center reviews.

Consistent with OCP’s mandates under the Cures Act, in FY 2021, FDA continued its efforts to 

improve the inter-Center consult process for combination products, including completing 

significant updates to the information technology (IT) system. In addition, OCP continued to 

(1) enhance its monitoring of quantitative metrics on inter-Center consults and (2) solicit 

qualitative input, including feedback from users via surveys and direct user interactions. These 

efforts have been used to identify opportunities for improvements in the inter-Center consult 

process, FDA’s IT systems, FDA’s staffing utilization, and the resources available to staff, which 

ultimately ensures an efficient review process and promotes alignment of Agency efforts. OCP 

also continued to lead some and support other Agency efforts to develop and publish regulations, 

issue guidance documents, and develop other public-facing documents regarding the premarket 

review of combination products (as discussed more fully in the “Policy Activities and 

Accomplishments” section below).

A. Number and Types of Combination Products Submitted for 

Premarket Review

FDA is required to report the number and types of combination products submitted for review. 

The following items explain FDA’s performance data that will be presented in this subsection.

· Data on the number and types of combination products submitted for review in FY 2021 

by CBER, CDER, and CDRH (including submissions filed or received in FY 2021), as 

well as the timeliness of these reviews. 

· When reporting timeliness in days for the review for CBER-led or CDER-led 

combination products, the Prescription Drug User Fee Act Reauthorization of 2017

(PDUFA VI) goals were referenced for priority and standard new drug applications 

(NDAs) and applicable biologics license applications (BLAs), the Generic Drug User Fee 

16 See https://www.fda.gov/media/81927/download.
14

Amendments (now GDUFA II) goals were referenced for abbreviated new drug 

applications (ANDAs), and the Biosimilar User Fee Amendments (now BsUFA II) goals 

were referenced for the biosimilar BLAs. For CBER-led or CDRH-led combination 

products, Medical Device User Fee Amendments (now MDUFA IV) goals were 

referenced for expedited and original premarket approval applications (PMAs), premarket 

notifications (510(k)s), De Novos, and device BLAs.

· Some product review goals, such as for NDAs, are defined by the number of months 

given to review the product. Due to the differences in the numbers of days in each month 

(28 to 31), 10 months represents a range from 304 days (such as February 1 to December 

1) to 306 days (such as March 15 to January 15), and 6 months represents a range from 

182 days (such as February 15 to August 15) to 184 days (such as July 15 to January 15).

· The median review times were based on FDA’s first-cycle review performance results for 

PDUFA VI goals. For MDUFA IV goals, the median review times were based on the 

total MDUFA IV decision review time. The actual review time was used when only one 

action was measured.

B. Requirement Workload Trends: FY 2016 to FY 2021

As shown in Table 14, 596 original applications were submitted for review in FY 2021.

Table 14. FY 2016 to FY 2021 Submission Review Workloads.

Submission/ Request FY 16 FY 17 FY 18 FY 19 FY 20 FY 21

Total Combination Products 

Submitted for Review 330 566 390 518 557 596

As reflected in Table 15, of all original combination product applications, 78 percent were 

received by CDER, 16 percent were received by CDRH, and 7 percent were received by CBER.
15

Table 16 presents the 596 original applications for combination products received in FY 2021, 

broken down by the identified 10 application types and by the product’s initial classification into 

one of nine categories of combination products.17 The same table reflecting applications 

received in FY 2020 has been updated in Appendix A to reflect corrections and actions as of 

September 30, 2021. The majority of the applications received in FY 2021 were original 

investigational new drug applications (INDs) (53 percent), followed by ANDAs (21 percent). 

Also, the most common combination product category was the pre-filled drug delivery 

device/system (28 percent).

17 The classifications are presented as “initial” because adjustments are made to these numbers for each fiscal year to 

reflect corrections and subsequent actions that may inform the classification status, such as the ultimate status of 

products initially placed in category 8 (for certain possible combination products). 

FY 16 FY 17 FY 18 FY 19 FY 20 FY 21

Total 330 566 390 518 557 596

CDRH 95 138 102 126 75 93

CDER 199 375 246 339 432 464

CBER 36 53 42 53 50 39

0

200

400

600

800

1000

1200

1400

Number of Submissions

Table 15. Combination Product Original 

Applications Submitted, by Center.
16

Table 16. Workload by Combination Product Category Number.

Application Type 1 2 3 4 5 6 7 8 9 Total

Original NDA 13 24 0 1 0 0 0 0 3 41

Original BLA 1 0 11 0 0 0 0 0 2 14

Original PMA 0 0 0 4 0 0 0 0 0 4

Original 510(k) 5 0 1 39 0 0 1 0 0 46

Original IND 14 63 51 4 4 43 9 116 11 315

Original Investigational 

Device Exemption 

(IDE)

1 0 0 24 13 0 5 2 6 51

Original Humanitarian 

Device Exemption 

(HDE)

0 0 0 0 0 0 0 0 0 0

Original ANDA 34 81 0 0 0 0 0 0 8 123

Biosimilar BLA 0 0 0 0 0 0 0 0 0 0

De Novo 0 0 0 2 0 0 0 0 0 2

Total 68 168 63 74 17 43 15 118 30 596

Combination Product Category Key: 

1 = convenience kit or co-package

2 = pre-filled drug delivery device/system

3 = pre-filled biologic delivery device/system

4 = device coated/impregnated/otherwise combined with drug

5 = device coated or otherwise combined with biologic

6 = drug/biologic combination

7 = separate products requiring mutually conforming labeling

8 = possible combination based on mutually conforming labeling of separate products

9 = other type of combination product

1. Inter-Center Consult Requests

This section reports on the number of inter-Center consults for combination products, a related 

but distinct topic from the number of submissions for combination products. Unlike submission 

data, these data reflect consultations relating to original applications and supplements to 

combination product applications, as well as consultations relating to postmarket oversight for 

combination products. Consultations between Centers are expected during FDA’s premarket 

review of most combination products; these consultations help ensure that relevant FDA 

expertise, as well as consistency in FDA’s regulatory practice, is applied to each review.

There can be, for example, multiple consults for a single combination product submission or, 

alternatively, a submission may not warrant a consult because (1) the relevant expertise resides 

in the lead Center and (2) a consultation is not otherwise needed to ensure consistent review 

standards. Combination product consults to CDER from other Centers are most often for 

expertise related to chemistry, manufacturing, and controls; pharmacology and toxicology; 

biopharmaceutics; human factors; or clinical review. Combination product consults to CDRH

from other Centers are most often for expertise related to the technical (e.g., biocompatibility) 
17

and engineering/performance review of delivery devices or for assessments of facilities for 

premarket applications; other CDRH consult topics include human factors and software.18 

OCP oversees and facilitates coordination among review Centers under the inter-Center consult 

process to ensure consults are completed in a timely manner. For example, OCP monitors 

ongoing inter-Center consult requests for correctness (e.g., ensuring the information in the 

consult requests are complete and confirming the requests are being directed to the correct 

recipient) and timeliness (e.g., ensuring that consults allow the recipient adequate time to 

complete the request while accounting for the established product review goals); clarifies internal 

operating procedures, roles, and responsibilities related to the inter-Center consult process; helps 

identify consulting divisions and contacts; facilitates consultant access to review documents; and 

manages help desks. OCP periodically reviews inter-Center consult request data and conducts 

additional assessments, as needed, to ensure that the inter-Center consult request process 

supports the timely, consistent, and effective review of combination products. Additionally, 

OCP receives and responds to external requests for OCP assistance (i.e., communications and/or 

clarification of product-specific review findings) in resolving Center timeliness issues. 

OCP works with CBER, CDER, and CDRH in identifying potential areas of improvement and 

implementing changes to improve the consult process. An efficient and effective inter-Center 

consult request process helps Centers meet their user fee performance commitments and 

promotes alignment of Agency efforts, all of which ultimately helps bring new treatment options 

to patients sooner.

In FY 2021, there were 1,202 inter-Center consults for combination products. Table 17 shows 

the number of FY 2021 inter-Center consults requested by each of the three human medical 

product Centers.

18 Of note, there are other inter-Center consults that may not directly involve combination products. For example, 

consults regarding the use of companion diagnostics with drug or biological products that do not comprise a 

combination product, investigational studies of a non-combination product that involve another Center’s products or 

expertise, requests for clinical expertise that may not be available in a particular Center, and communications 

between Centers to determine whether postmarket safety events or signals regarding a noncombination product 

warrant further investigation. Furthermore, cross-Center collaboration occurs through additional pathways (e.g., the 

Medical Oncology Review and Evaluation team of FDA’s Oncology Center of Excellence). These consults are not 

captured in the counts but are often conducted under the same process outlined in SMG 4101 (see 

http://www.fda.gov/media/81927/download).
18

In Table 18, the total number of inter-Center consults in FY 2021 is compared to the previous 5 

years. 

Table 18. FY 2016 to FY 2021 Inter-Center Consult Workloads.

Submission/Request FY 16 FY 17 FY 18 FY 19 FY 20 FY 21

Total Inter-Center 

Consult Requests 1,130 1,419 1,445 1,328 1,146 1,202

In Table 19, the number of inter-Center consult requests during FY 2021 is broken down by the 

lead Center (i.e., the Center requesting the consult) and the consulted Center (i.e., the reviewing 

Center).

FY 15 FY 16 FY 17 FY 18 FY 19 FY 20 FY 21

Total 932 1,130 1,419 1,445 1,328 1,146 1,202

CBER 53 9 105 118 133 124 119

CDER 499 793 881 867 792 656 661

CDRH 380 328 433 460 403 366 422

 -

 200

 400

 600

 800

 1,000

 1,200

 1,400

 1,600

Number of Requests

Table 17. Inter-Center Consult Requests by 

Lead/Reviewing Center.
19

Table 19. Number of Premarket Review Inter-Center Consults for Combination Products 

by Lead and Consulted Center.

Lead 

Center Consulted Center

CBER CDER CDRH CVM* OC Number of 

Consults

CBER -- 22 96 1 -- 119

CDER 11 -- 650 -- -- 661

CDRH 5 415 -- -- 2 422

Total 16 437 746 1 2 1,202

* In addition to consultations to CBER, CDER, and CDRH, the Center for Veterinary Medicine (CVM) may be consulted either (1) when a 

unique aspect of a product’s indication, formulation, design, or performance raises concerns that require review by another Center or (2) when the 

expertise to review a particular aspect of the product resides in another Center. The inclusion of CVM in the inter-Center consult process, when 

appropriate, ensures a comprehensive review of the product.

In Table 20, the number of inter-Center consults is broken down by application type at each 

Center.
20

Table 20. Number of Premarket Review Inter-Center Consults by Application Type and 

Lead Center.*

Application Type

Lead Center

CBER CDER CDRH Number of Consults

ANDA -- 71 -- 71

BLA 6 110 -- 116

IND/Pre-IND 99 348 -- 447

NDA -- 128 -- 128

510(k) -- -- 2 2

De Novo -- -- 17 17

IDE 7 -- 86 93

PMA -- 135 135

Pre-Submission 6 -- 178 184

Other** 1 4 4 9

Total 119 661 422 1,202

* Inter-Center consult counts include consults for supplements, amendments, etc. to a marketing authorization, not just for original 

submissions.

** For example, an inter-Center consult related to an Emergency Use Authorization may fall in this “Other” category.

C. Timeliness in Days of the Reviews of Combination Products

FDA is required to report the timeliness of its reviews of combination products. Table 21 

summarizes the review types and applicable review performance targets for original NDAs, 

ANDAs, Prescription Drug User Fee Act BLAs, BsUFA BLAs, PMAs, De Novos, and 510(k)s. 

PDUFA VI, GDUFA II, BsUFA II, and MDUFA IV established review performance goals for 

many types of drug, device, and biological product premarket applications. These goals reflect 

current expectations about the portion of premarket applications that will have an action within a 

specified time frame. Performance goals apply only to a portion of all applications of a certain 

type, and they do not require that every application be reviewed in accordance with the 

applicable timeframe. Typical goals range from 50 percent to 90 percent and vary by year. 

· For MDUFA IV performance goals, refer to 

https://www.fda.gov/media/102699/download.

· For PDUFA VI performance goals, refer to https://www.fda.gov/media/99140/download.

· For GDUFA II performance goals, refer to 

https://www.fda.gov/media/101052/download. 

· For BsUFA II performance goals, refer to https://www.fda.gov/media/100573/download.
21

Table 21. Performance Goals for Original Applications.

User Fee Program Original 

Application Type Review Type Review Goal Within

PDUFA VI NDAs Priority 6 Months

PDUFA VI NDAs Standard 10 Months

PDUFA VI BLAs Priority 6 Months

PDUFA VI BLAs Standard 10 Months

MDUFA IV Expedited and 

Original PMAs

Standard with No Advisory 

Committee Input 180 Days

MDUFA IV Expedited and 

Original PMAs

Standard with Advisory 

Committee Input 320 Days

MDUFA IV 510(k)s Standard 90 Days

MDUFA IV BLAs Priority 6 Months

MDUFA IV BLAs Standard 10 Months

BsUFA II Biosimilar BLAs Standard 10 Months

GDUFA II ANDAs Standard 10 Months

GDUFA II ANDAs Priority without Pre-Submission 

Facility Correspondence 10 Months

GDUFA II ANDAs Priority with Pre-Submission 

Facility Correspondence 8 Months

MDUFA IV De Novos Standard 150 Days

The timelines for new medical entities and BLAs that fall under PDUFA VI’s “Program” Review Model are 10 months for standard 

applications and 6 months for priority reviews from the 60-day filing date (or 12 months and 8 months respectively, from the date of 

submission of the application).

FDA’s premarket review performance information for CBER, CDER, and CDRH is based on a 

fiscal year receipt cohort. This approach calculates performance information for submissions for 

the fiscal year in which FDA received them, regardless of when FDA acted on or approved the 

submissions. The following subsection, entitled “FY 2020 and FY 2021 Review Performance 

Results,” updates FDA’s final review performance results on the FY 2020 combination product 

submissions and presents FDA’s preliminary19 review performance results on the FY 2021 

combination product submissions through September 30, 2021.

D. FY 2020 and FY 2021 Review Performance Results

Table 22 shows the final FY 2020 review goal performance results. 

19 Preliminary means that the numbers are based on final decisions at the time of the data run and might change.
22

Table 22. Final FY 2020 Review Goal Performance Results.

Original 

Application 

Type

Review

Type

Review 

Goal 

Within

Number of 

Combination 

Products

Median or 

Actual 

Review 

Time 

(Days)

Range of 

Review 

Time

(Days)

NDAs Priority 6 Months 9 238 59 to 456

NDAs Standard 10 

Months 16 304 60 to 388

BLAs Priority 6 Months 1 214 214

BLAs Standard 10 

Months 2 364 285 to 426

Biosimilar 

BLAs Standard 10 Months 1 361 361

Expedited and 

Original 

PMAs

Standard 180 or 

320 Days 3 178 158 to 266

510(k)s Standard 90 Days 61 86 29 to 94

ANDAs Standard 10 

Months 70 300 283 to 466

ANDAs

Priority without 

Pre-Submission 

Facility 

Correspondence

10 

Months 13 302 268 to 430

ANDAs

Priority with 

Pre-Submission 

Facility 

Correspondence

8 Months 5 238 230 to 240

De Novos Standard 150 Days 0 N/A N/A

This includes a review within 180 days for decisions without advisory committee input or a review within 320 days for decisions with advisory 

committee input, respectively. 

Table 23 shows preliminary FY 2021 review goal performance results through September 30,

2021. 
23

Table 23. Preliminary FY 2021 Review Goal Performance Results.

Original 

Application Type

Review

Type

Review 

Goal 

Within

Number of 

Combination 

Products

Median or 

Actual 

Review 

Time (Days)

Range of 

Review 

Time

(Days)

NDAs Priority 6 Months 12 182 150 to 245

NDAs Standard 10 

Months 25 302 6 to 393

BLAs Priority 6 Months 3 224 182 to 245

BLAs Standard 10 

Months 5 364 336 to 456

Biosimilar BLAs Standard 10 

Months 0 N/A N/A

Expedited and 

Original PMAs Standard

180 or 

320 

Days

3 180 112 to 180

510(k)s Standard 90 Days 26 86 0 to 230

ANDAs Standard 10 

Months 65 301 275 to 491

ANDAs

Priority without 

Pre-Submission 

Facility 

Correspondence

10 

Months 28 300 219 to 464

ANDAs

Priority with 

Pre-Submission 

Facility 

Correspondence

8 Months 5 239 217 to 337

De Novos Standard 150 Days 0 N/A N/A

This includes a review within 180 days for decisions without advisory committee input or a review within 320 days for decisions with 

advisory committee input, respectively. 

1. Premarket Review Facilitation/Oversight

OCP continues to facilitate the premarket review of combination products that raise complex 

regulatory issues, scientific/technical concerns, or procedural challenges. OCP fosters early 

interactions between sponsors and FDA to help clearly delineate the regulatory pathways for the 

development of combination products and to help ensure the expeditious review of the premarket 

submissions for these products. Responding to requests from both industry and FDA’s review 

staff, OCP provides guidance on regulatory challenges unique to combination products, 

including topics spanning the developmental and review process across all submission types. 

OCP also serves as a resource for FDA staff on the appropriate use and interpretation of 
24

combination product categorization for premarket submissions and in determining the correct 

combination product categories for data reporting purposes. In addition, OCP leads or 

participates in product-specific meetings and discussions (1) to ensure efficient and effective 

communications between sponsors and FDA’s review staff and between FDA’s review staff,

(2) to align data expectations for products raising similar regulatory questions, and (3) to respond 

to regulatory questions related to combination products.

The number of OCP’s product-specific documented premarket review actions from FY 2016 to 

FY 2021 are presented in Table 24. In particular, in FY 2021, OCP received 124 requests for 

product-specific assistance, the responses to which contributed to ensuring the timely, effective, 

and aligned review of combination products.20 

Table 24. Number of OCP’s Documented Premarket Activities from FY 2016 to FY 2021.

FY 

16

FY 

17

FY 

18

FY 

19

FY 

20

FY 

21

Premarket Review 

Activities 266 525 321 144 188 124

Notably, in FY 2021, OCP addressed issues including the following: 

· Clarification of submission pathways and related development considerations for generic 

combination products;

· Novel drug and biological products combined with new technological delivery systems 

that may have unique risk profiles; 

· Alignment of pharmacology/toxicology and biocompatibility data requests to sponsors; 

· Regulatory considerations for the review of combination products for rare disease 

populations; 

· Cross-Center consistency for potential clinical hold or approvability review assessments; 

· Accuracy, consistency, and clarity of the labeling of separately distributed products 

intended for combined use; and

20 Decreases in OCP’s premarket activities have coincided with FDA’s ongoing implementation of the updated interCenter consult request processes, launched in FY 2018 and FY 2019, which include updating IT systems, enhancing 

training, and providing other resources for Centers’ staff.
25

· Development and labeling considerations for combination products that incorporate 

mobile communication technologies or digital health innovations.

In addition to addressing these issues, OCP completed the following premarket activities during 

FY 2021:

· For SARS-CoV-2- or COVID-19-related product development, OCP provided rapid 

support to the Centers in developing responses to sponsors about the classification and 

Center assignment of their applicable product and provided guidance to the sponsors 

relevant to their product. OCP participated in developing a template to facilitate FDA's 

review of its responses to industry for COVID-19 submissions for over-the-counter and 

prescription combination products.

· OCP facilitated the resolution of master file review communication uncertainties and led

an inter-Center working group to align the Agency master file processes. 

· OCP hosted premarket meetings with industry and Agency subject-matter experts to 

provide clarifications on the use of master files for specific combination products.

· OCP assisted the Centers and industry on regulatory and scientific issues relating to 

specific combination products or to specific categories of combination products. 

Examples of these activities are presented in Table 25.
26

Table 25. Other Significant Premarket Review Facilitation or Assistance Provided by OCP 

in FY 2021.

Type of Activity FY 2021 Accomplishments

Providing Significant 

Premarket Review 

Facilitation or 

Assistance

With respect to the following specific products or categories of 

products, and other premarket regulatory issues, OCP provided 

significant assistance with:

· Novel drug-device cancer therapies or treatment selection 

technologies;

· Injector delivery systems (e.g., intrathecal infusion systems);

· Facilitation of premarket current good manufacturing practice 

(CGMP)/21 CFR part 4 compliance assessments;

· Clarification of the IND human factors protocol submission 

process and the review of these study results;

· Implication of packaging changes during product development;

· Alignment of IND and IDE review requirements for combination 

products;

· Consideration of the suitability of a single combination product 

application or separate submissions for each constituent part;

· Facilitation of FDA’s human factors review timeliness 

considerations;

· Facilitation of resolution of issues raised by use of data 

previously in a closed master file;

· Facilitation of consistent reviews of on-body wearable injection 

or infusion systems;

· Review considerations for combination products that include 

software for monitoring, treatment dose adjustment, or product 

ordering;

· Considerations for drug-device interactions in implants;

· Facilitation of interactive dialogue between the review team and 

the application holder to address deficiencies identified by crossCenter consultants;

· Facilitation of FDA’s resolution of informal premarket 

timeliness concerns; 

· Facilitation of FDA’s resolution of review process concerns 

raised by novel bone void filler; and

· Implementation testing of the new electronic common technical 

document database for premarket review of submissions in 

CDER and CBER.
27

IV. Combination Product Postmarket Activities 

The Center to which a combination product is assigned for premarket review has primary 

jurisdiction for the regulation of the combination product, including for ensuring compliance 

with postmarketing regulatory requirements and performing postmarket surveillance. OCP is 

tasked with ensuring the consistency and appropriateness of the postmarket regulation of 

combination products. Hence, FDA is required to describe in this report any improvements in 

the consistency and appropriateness of the postmarket regulation of combination products. 

The right balance of premarket and postmarket oversight activities can facilitate timely patient 

access to safe and effective products. Consistent and appropriate postmarketing regulatory 

requirements help the Agency prevent, detect, and respond quickly to a product safety or product 

quality problem, which minimizes the risk of patients encountering such problems. Postmarket 

inspection and other activities for the appropriate control of manufacturing procedures is one 

important element to ensure marketed products remain safe and effective. Postmarket 

surveillance activities are also critical to protect patients from risks associated with products 

currently on the market. Combination products pose particular challenges due to their 

complexity and the range of scientific, technical, and regulatory issues that can arise.

OCP undertakes a variety of compliance-related and postmarket oversight activities to help 

ensure the safety and quality of combination products. These activities include leading the 

Agency’s efforts to develop and publish regulations, guidance documents, and other publicfacing documents regarding postmarketing safety reporting (PMSR) requirements and CGMPs 

for combination products (as discussed more fully in the “Policy Activities and 

Accomplishments” section below), coordinating and overseeing FDA’s actions relating to novel 

and complex postmarket safety issues and CGMP compliance questions, and facilitating and 

leading meetings between industry and FDA regarding these matters. In addition, OCP may 

provide support for FDA’s CGMP facility inspections and the inspection of products at ports of 

entry, assist in responding to product-specific safety signals and defect issues, or offer guidance 

on compliance and enforcement actions. In addition, OCP works with other Agency components 

to develop and present trainings, procedures, IT updates, and other tools to enhance the 

efficiency and consistency of postmarket regulatory activities.

OCP’s FY 2021 product-specific actions related to the consistency and appropriateness of 

postmarket regulatory activities are reflected in Table 26.
28

Table 26. Documented Product-Specific Postmarket Regulatory Activities from FY 2016 to 

FY 2021.

FY 

16

FY 

17

FY 

18

FY 

19

FY 

20

FY 

21

Postmarket Regulatory 

Activities 50 74 86 62 113 84

OCP engaged in 84 product-specific, postmarket-related matters involving issues such as the 

application of CGMP and quality system regulations for inspections of combination products, the 

appropriate mechanisms and responsibilities for reporting adverse events, and the requirements 

for facility registration and product listing.21 In addition, at the request of the Centers, OCP 

facilitated or led working groups to assess safety signal evaluations to determine the Agency’s 

response to the safety issue.

These efforts have helped improve the consistency of postmarket regulation in a number of 

ways, including the following:

· Clarifying stakeholders’ and FDA’s understanding of combination product CGMP 

requirements and inspectional approaches (see also the discussion of a final compliance 

program under the “Policy Activities and Accomplishments” section below); and

· Continuing to facilitate the implementation of the PMSR final rule22 for combination 

products’ requirements (through analyzing data, training staff, and enhancing a technical 

tool for postmarket staff).

21 The increase in FY 2020’s postmarket regulatory activities largely reflects an unusually high volume of technical 

inquiries relating to coming into full compliance with the 2016 final rule on PMSR for combination products by July 

31, 2020, in accordance with the Compliance Policy for the rule 

(http://www.fda.gov/files/about%20fda/published/compliance-policy-combination-product-postmarketing-safetyreporting.pdf). The Compliance Policy delayed full enforcement of the rule in light of substantive stakeholder input 

supporting the need for such delay to ensure applicants sufficient time to update reporting and recordkeeping 

systems and procedures, including their IT systems.

22 See 81 FR 92603 (Dec. 20, 2016), available at https://www.federalregister.gov/documents/2016/12/20/2016-

30485/postmarketing-safety-reporting-for-combination-products
29

V. Effective Resolutions of Review Disputes

When OCP receives a formal request by a sponsor to resolve a dispute regarding the timeliness 

of the premarket review of a combination product, OCP must resolve the dispute. OCP also 

facilitates communications between sponsors and FDA review staff to identify, clarify, and 

resolve specific concerns associated with review timeliness. This facilitation helps prevent the 

need for formal dispute resolutions.

In addition to sponsor requests for addressing premarket review timeliness issues, OCP may 

receive requests for dispute resolution and/or mediation for other regulatory issues (e.g., interCenter review dispute resolution or requests by product sponsors for assistance either in 

understanding the intent of a review division’s decision or in resolving differences of view 

regarding regulatory requirements).

A. Percentage of Combination Products Reviewed for Which a 

Formal Dispute Resolution Was Requested 

FDA is required to identify the percentage of combination products for which dispute resolution 

with respect to premarket review was requested by the combination product’s sponsor. FDA 

received no formal requests for dispute resolution for combination products in FY 2021. 

Therefore, the percentage is zero of the total combination product submissions (i.e., based on the 

total number of combination product submissions reported in the “Combination Product 

Premarket Review” section of this report). Data provided in the “Premarket Review 

Facilitation/Oversight” section of this report provide examples of OCP’s informal facilitation 

and resolution of issues related to premarket review.
30

VI. Policy Activities and Accomplishments

OCP’s policy activities include leading and contributing to policy initiatives important to the 

regulation of combination products. Key examples of such activities pursued in FY 2021 are 

discussed below and included in the tables to follow.

A. Supporting and Implementing Legislative Initiatives

OCP participated in the development of FDA’s positions in response to congressional inquiries 

and in the development of legislative proposals. Furthermore, OCP continued its efforts, in 

coordination with the human medical product Centers, to implement section 3038 of the Cures 

Act regarding combination products. Activities in this regard included the following: issuing 

regulations and guidance documents, enhancing standard operating procedures, developing 

improvements to IT systems, training staff, and conducting outreach to stakeholders. In addition, 

OCP was involved in implementing PDUFA VI activities related to combination products (e.g., 

developing bridging and human factors guidance documents).

B. Streamlining Regulation

OCP continued its work on amending FDA’s jurisdictional regulations in 21 CFR part 3, 

including considering comments received on the proposed rule,23 to update and clarify the 

regulations in light of legislative and other policy developments. OCP also supported 

rulemakings relating to combination products led by the human medical product Centers, 

including rulemakings on the use of the De Novo classification process for devices and 

combination products and an amendment of device quality system regulations and associated 

adjustments to CGMP requirements for combination products under 21 CFR part 4.

C. Clarifying Regulatory Policy

OCP collaborated with the human medical product Centers to develop and publish regulations, 

guidance documents, notices, safety communications, and internal procedures. 

OCP led the development and publication of the following documents:

· Final guidance document on requesting FDA’s feedback on combination products 

(December 2020)24

23 See 83 FR 22428 (May 15, 2018), available at http://www.federalregister.gov/documents/2018/05/15/2018-

10321/product-jurisdiction.

24 Available at http://www.fda.gov/regulatory-information/search-fda-guidance-documents/requesting-fda-feedbackcombination-products. 
31

· Federal Register notice announcing the Agency’s consolidation of devices that process 

autologous human cells, tissues, and cellular and tissue-based products at the point of 

care to produce a therapeutic article (September 2021)25

OCP contributed to the development and publication of the following documents: 

· Final guidance document on requests for feedback and meetings for medical device 

submissions in the Q-Submission Program (January 2021)26

· Final guidance document on manufacturing considerations for licensed and 

investigational cellular and gene therapy products during the COVID-19 public health 

emergency (January 2021)27

· Draft guidance document on considerations for the implementation of the International 

Council for Harmonisation’s (ICH’s) Q12 guiding principles with respect to FDAregulated products (May 2021)28

· Final guidance document providing a harmonized approach regarding Q12 technical and 

regulatory considerations for pharmaceutical product lifecycle management (May 2021)29

· Final guidance document providing questions and answers on field alert report 

submissions (July 2021)30

· Federal Register notice regarding Genus Med. Techs., LLC v. FDA, 994 F.3d 631 

(D.C. Cir. 2021) (August 2021)31

· Final rule on importation of prescription drugs (October 2020)32

25 86 FR 50887 (Sept. 13, 2021), available at http://www.federalregister.gov/documents/2021/09/13/2021-

18912/consolidation-of-devices-that-process-autologous-human-cells-tissues-and-cellular-and-tissue-based.

26Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-andmeetings-medical-device-submissions-q-submission-program

27 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/manufacturingconsiderations-licensed-and-investigational-cellular-and-gene-therapy-products-during. 

28 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/ich-q12-

implementation-considerations-fda-regulated-products. 

29 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q12-technical-andregulatory-considerations-pharmaceutical-product-lifecycle-management-guidance.

30 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/field-alert-reportsubmission-questions-and-answers-guidance-industry.

31 86 FR 43553 (Aug. 9, 2021), available at https://www.federalregister.gov/documents/2021/08/09/2021-

16944/genus-medical-technologies-llc-versus-food-and-drug-administration-request-for-information-and.

32 Available at https://www.federalregister.gov/documents/2020/10/01/2020-21522/importation-of-prescriptiondrugs.
32

· Final guidance document on importation of certain FDA-approved human 

prescription drugs, including biological products and combination products, under 

section 801(d)(1)(B) of the Federal Food, Drug, and Cosmetic Act (October 2020)33

D. Other Policy-Related Activities

Additional policy-related activities included the following:

· Enhanced procedures and mechanisms for monitoring and enhancing combination 

products’ premarket and postmarket regulatory activities, consistent with section 3038 of 

the 21st Century Cures Act;

· Continued performance evaluations and updates of procedural and IT systems to enable 

the implementation of the final PMSR rule for combination products; 

· Continued developing and training on the PMSR requirements to FDA’s human medical 

product Centers’ product safety offices and other staff involved with addressing safety 

signals; and

· Providing training and reference information on the compliance program for combination 

product CGMPs to inspectors in the Office of Regulatory Affairs’ medical product 

programs and to human medical product Center staff involved with manufacturing and 

compliance activities.

Tables 27 through 29 identify FDA’s policy development work that continued in FY 2022; this 

work is categorized by topic area (i.e., jurisdiction, premarket review, postmarket regulation) and 

activity type.

33 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/importation-certain-fdaapproved-human-prescription-drugs-including-biological-products-and.
33

Table 27. Additional Jurisdictional Regulatory Initiatives.

Type of Activity FY 2021 Activities 

Developing regulations and 

guidance documents

OCP’s jurisdiction-related activities included 

participating in the following Agency rulemaking and 

guidance initiatives:

· Led a cross-Center working group on the scope 

and significance of the status of cross-labeled 

combination products

· Led updates to the guidance on preparation of 

RFDs and Pre-RFDs

Participating in other inter-Center 

and Agency-wide working groups 

to clarify issues related to product 

jurisdiction

OCP’s jurisdiction-related activities included the 

following:

· Continued to enhance the efficiency and 

transparency of the RFD and Pre-RFD 

programs

· Developed standard operating procedures to 

facilitate product classification

Table 28. Additional Premarket Review Regulatory Initiatives.

Type of Activity FY 2021 Activities

Developing regulations, guidance 

documents, and other policy 

documents

OCP’s premarket review-related activities included 

leading the following Agency guidance and other 

policy initiatives:

· Continued to lead the development of a 

guidance document on human factors studies 

for combination products.

· Continued to chair a cross-Center working 

group and lead the development of a draft 

guidance document for the technical aspects of 

intravaginal system combination products.

· Led the development of a final guidance 

document on the technical considerations for 

demonstrating the reliability of combination 

product emergency-use injectors.

· Continued to lead a cross-Center working 

group to develop a guidance document on 

essential performance requirements.
34

Type of Activity FY 2021 Activities

· Continued to work with Centers to assess 

approaches for insulin pump labeling 

considerations.

· Led efforts to:

o Finalize a guidance document on premarket 

principles and pathways for combination 

products. 

o Update a guidance document on the 

application of user fees for combination 

products.

o Revise the published draft guidance 

document on postmarket changes for 

combination products.

o Revise inter-Center agreements on medical 

product Center assignment/regulatory 

coordination.

OCP participated in the development of the following 

policy documents: 

· Rulemaking on De Novo classification

· Comments for citizen petition responses for 

specific types of generic combination products

· Cross-Center draft guidance document on 

technical considerations for the visual 

inspection of particulates in injectable solutions

· Cross-Center draft guidance document on 

considerations for what constitutes clinical data 

for user fee purposes

· Cross-Center draft guidance document on 

technical considerations for container closures 

that are also device constituent parts

· Final rule on importation of prescription drugs

· Final guidance on importation of prescription 

drugs

· Proposed rule to amend part 820 to align more 

closely with International Organization for 

Standardization 13485 and associated 

amendments to part 4

· ICH’s Q12 implementation guidance document

Assessing regulatory pathways 

for new products intended to be 

OCP continued to work with the Centers and OCC to 

assess approaches for resolving complex legal and 

public health issues associated with the marketing of 
35

Type of Activity FY 2021 Activities

used with another sponsor’s 

already approved product

products intended for use with other legally marketed 

products.

Participating in other inter-Center 

and Agency-wide working groups 

to clarify issues related to the 

combined use of medical 

products

OCP led or participated in working groups with 

Centers and other Agency components regarding the 

following:

· Non-prescription drug availability

· The Agency’s thinking on the regulation of 

certain software output as drug labeling

· Application of artificial intelligence and 

machine learning in investigational, diagnostic 

and treatment settings

· Issues such as importation of prescription 

drugs, good guidance practices, and 

enforcement policies

· Considerations for compounded drugs for use 

with devices

Conducting procedural oversight 

and facilitation

· OCP led a working group regarding the 

monitoring and continuous improvement of the 

inter-Center consult process, including IT 

developments and enhancements. 

· OCP continued to chair a cross-Center working 

group to develop procedures to create 

standardization and efficiency in the 

management of master files that will be used 

by more than one Center.
36

Table 29. Additional Postmarket Review Regulatory Initiatives.

Type of Activity FY 2021 Activities

Leading or participating in 

other Inter-Center and Agencywide working groups to clarify 

issues related to combination 

products 

OCP’s postmarket review-related activities included 

participating in the following initiatives:

· OCP continued to chair working groups relating 

to the PMSR requirements for combination 

products. This work focused on implementation 

of the rule, monitoring engagement between the 

Centers and OCP on postmarket combination 

product issues, and developing and delivering 

internal training. 

· OCP continued leading activities to support 

implementation of CGMP requirements for 

combination products, training inspectional and 

compliance staff, and finalizing a Federal 

Register notice on CGMP 

alternatives/flexibilities.

· OCP continued to work with Centers on track and 

trace programs with respect to combination 

products, including a guidance document on the 

use of unique device identifiers, numeric drug 

codes, and serialized numeric identifiers.

· OCP continued to co-chair a committee on 

combination products of the Association for the 

Advancement of Medical Instrumentation that 

continued to work on best manufacturing 

practices, training of regulated entities’ staff on 

combination product regulation, and best 

practices across the combination products’

lifecycle.

· OCP continued to participate in an ASTM 

International standard setting process to clarify 

terminology related to combination products and 

the combined use of different types of medical 

products. 
37

VIII. Additional Activities and Accomplishments

A. Information Technology

OCP continued to coordinate and participate in IT initiatives to enhance the infrastructure and 

improve the efficiency, consistency, and reliability of information systems and communications 

within and across Agency components and with stakeholders.

· OCP implemented four enhancement releases in FY 2021 to improve the Inter-Center 

Consult Request workflow and data capture system, including changes to better enable 

the requesting Center to know to which group they should send a consult request. 

· OCP implemented 11 enhancement releases in FY 2021 to improve the PMSR dashboard 

functionality and user experience. This tool, to the extent feasible, integrates data on 

combination products from different data sources—such as premarket systems, 

registration and listing systems, and adverse event reporting systems—from all three 

human medical product Centers into a single point of reference to enhance the efficiency 

and consistency of postmarket safety activities. These enhancement releases included 

adding a new data source, automating the connection to several existing data sources, and 

reorganizing and adding content based on user feedback. 

· OCP continued to improve the electronic system that manages the workflow and data 

capture for Pre-RFDs and RFDs. OCP continued the formal pilot with external volunteers 

of a new Pre-RFD and RFD electronic submission process to improve the efficiency and 

completeness of these submissions. 

· OCP provided training, demonstrations, user guides, and other resources to new users 

from all three human medical product Centers for all OCP-led systems. OCP also 

engaged users through surveys, focus groups, direct interactions, and other means to 

solicit feedback and identify potential improvements to the IT systems. 

B. External Outreach

OCP engages trade associations and coalitions (e.g., Combination Products Coalition, Advanced 

Medical Technology Association, the Pharmaceutical Research and Manufacturers of America, 

and the Biotechnology Innovation Organization) that represent the drug, device, biological 

product, and combination product industries; OCP engages them on FDA’s classification, 

assignment, and regulation of combination products and related regulatory topics. These 

engagement efforts enhance two-way communication between the Agency and external 

stakeholders and help address questions or challenges faced by sponsors developing combination 

products. In addition, OCP participated in national and international standards development

organizations, including co-chairing a committee on combination products for the Association 

for Advancement of Medical Instrumentation and supporting the work of the International 
38

Organization for Standardization, ICH, International Medical Device Regulators Forum, and 

ASTM International. OCP also presented at various industry conferences. These conferences 

offered opportunities for Agency officials to engage with stakeholders, to clarify areas of 

stakeholder confusion, and to learn about stakeholder questions and concerns that may warrant 

investigation and, if needed, the development of policy by FDA to address those concerns.

In FY 2021, FDA addressed a wide range of topics about which stakeholders had questions, 

concerns, or proposals for Agency consideration. These topics included emerging issues in 

combination product regulation and the broader area of combined use of separately distributed 

medical products; opportunities for regulatory convergence across jurisdictions; the role of OCP; 

policies and guidance documents under development; rulemakings; regulatory issues for specific 

categories of combination products, particularly cross-cutting regulatory issues for combination 

products and combined use products; and stakeholder priorities for further action. 

Examples of OCP’s FY 2021 outreach activities via industry conferences are included in Table 

30.
39

Table 30. Examples of FY 2021 Outreach Activities.

Type of Activity FY 2021 Accomplishments

Presentations and outreach 

activities

The following are examples of venues/events for which OCP 

provided presentations and/or educational outreach:

· Drug Information Association’s Combination Products 

Conference (October 2020)

· Xavier University Health’s Combination Products Summit 

(October 2020) 

· Drug Information Association’s and FDA’s “Workshop on 

complex generic drug-device combination products” –

Steering Committee to develop the October 2020 

workshop

· Medtech’s Summit: Virtual Medical Device Summit

(October 2020)

· 2020 PDA Combination Products Workshop (October 

2020)

· 3

rd Annual Lifecycle Management for Combination 

Products (November 2020)

· Xavier University Health’s Combination Products Summit 

(September 2021) 

· The Organisation for Professionals in Regulatory Affairs’

Annual Symposium (September 2021)

· Global Bio Conference, South Korean Ministry of Food 

and Drug Safety (September 2021)
40

FY 2020 Updated Performance Detail

The table below reflects the 557 original applications classified into one of nine categories of 

combination products received in FY 2020.

Table 1. Workload by Combination Product Category Number.

Application 

Type 1 2 3 4 5 6 7 8 9 Total

Original NDA 12 11 0 0 0 0 0 0 3 26

Original BLA 2 0 12 0 0 1 0 0 1 16

Original PMA 1 0 0 0 0 0 0 0 0 1

Original 510(k) 4 0 0 29 1 0 2 2 0 38

Original IND 27 38 54 6 8 85 3 96 26 343

Original IDE 0 0 0 16 9 0 7 5 7 44

Original HDE 0 0 0 0 0 0 0 0 0 0

Original ANDA 20 69 0 0 0 0 0 0 0 89

Biosimilar BLA 0 0 0 0 0 0 0 0 0 0

De Novo 0 0 0 0 0 0 0 0 0 0

Total 66 118 66 51 18 86 12 103 37 557

Combination Product Category Key: 

1 = convenience kit or co-package

2 = pre-filled drug delivery device/system

3 = pre-filled biologic delivery device/system

4 = device coated/impregnated/otherwise combined with drug

5 = device coated or otherwise combined with biologic

6 = drug/biologic combination

7 = separate products requiring mutually conforming labeling

8 = possible combination based on mutually conforming labeling of separate products

9 = other type of combination product

Workload by Center Lead

The pie chart to the right shows the number and 

percentage of combination product applications 

in FY 2020 by Center lead, as of September 30, 

2021.

CBER 

50 (9%)

CDER 

432

(78%)

CDRH

75 

(13%)

Combination Product 

Applications (n = 557)
This report was prepared by FDA's Office of Combination Products in 

collaboration with the Office of Planning, Evaluation, and Risk Management 

in the Office of the Commissioner, the Center for Biologics Evaluation and 

Research, the Center for Drug Evaluation and Research, and the Center for 

Devices and Radiological Health. For further information please contact:

Office of Planning and Evaluation

Food and Drug Administration

Centerpark One Building, Room # 72040

4041 Powder Mill Road

Beltsville, Maryland 20705

Phone: 301-796-3843

This report is available on FDA’s home page at https://www.fda.gov/ and on 

OCP’s home page at https://www.fda.gov/combination-products.