Requesting FDA Feedback on 

Combination Products 

Guidance for Industry and FDA Staff

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)

December 2020
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TABLE OF CONTENTS 

I. Introduction .................................................................................................................... 2

II. Background .................................................................................................................... 3

A. What are combination products and how does FDA regulate them? ................................. 3

B. Whom should I contact for preliminary or general questions?.......................................... 3

III. Best Practices Regarding Interactions Between FDA and Sponsors of Combination 

Products ................................................................................................................................. 4

A. Sponsor Best Practices.................................................................................................. 5

B. FDA Best Practices....................................................................................................... 6

IV. Feedback Mechanisms Available for Combination Products ....................................... 7

A. Application-based Mechanisms...................................................................................... 7

B. Combination Product Agreement Meetings (CPAMs)...................................................... 9

C. Use of Application-based Mechanisms, CPAMs, and Dispute Resolution..........................15

Appendix 1. Examples of Application-based Mechanisms Available for Device-led 

Combination Products ..........................................................................................................16

Appendix 2. Examples of Application-based Mechanisms Available for Drug or Biological 

Product-led Combination Products .......................................................................................17
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Requesting FDA Feedback on Combination 

Products 

Guidance for Industry and FDA Staff

This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It 

does not create or confer any rights for or on any person and does not operate to bind FDA or the public.

You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 

and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for 

implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number 

listed on the title page of this guidance. 

I. Introduction

The purpose of this guidance is to discuss ways in which combination product sponsors1 can 

obtain feedback from FDA on scientific and regulatory questions and to describe best practices 

for FDA and sponsors when interacting on these topics.2 These interactions can occur through

application-based mechanisms, such as the pre-submission process used in the Center for 

Devices and Radiological Health (CDRH) and the Center for Biologics Evaluation and Research 

(CBER)3 and the formal meetings used in the Center for Drug Evaluation and Research (CDER) 

and CBER,4 or through Combination Product Agreement Meetings (CPAMs),5 as appropriate. 

 

1 As defined in 21 CFR 3.2, a “sponsor” is any person who submits or plans to submit an application to FDA for 

premarket review (e.g., an entity that is developing a combination product for a future application and wishesto 

interact with FDA on scientific or regulatory questionsspecifically related to its combination product). The term 

“application,” for purposes of this guidance,includes an investigational new drug application (IND), new drug 

application (NDA), abbreviated new drug application (ANDA), investigational device exemption (IDE) application, 

premarket approval application (PMA), premarket notification (510(k)), humanitarian device exemption (HDE) 

application, product development plan (PDP), request for classification submitted under section 513(f)(2) of the 

Federal Food, Drug, and Cosmetic Act (FD&C Act) (De Novo request), and biologics license application (BLA).

Note that an HDE may not be the appropriate pathway to market for a combination product. For questions about the 

availability of the HDE pathway for combination products, please contact the Office of Combination Products by 

email at combination@fda.gov. 2 For additional information on principles of premarket review for combination products, including how to 

determine which type of application is appropriate, see Principles of Premarket Pathways for Combination 

Products, Draft Guidance for Industry and FDA Staffwhich, when final, will represent FDA’s current thinking on 

this topic.

3 See Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission Program, Guidance 

for Industry and Food and Drug Administration Staff. 4 See Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products, Draft Guidance for 

Industry, Formal Meetings Between the FDA and Sponsors or Applicants of BsUFA Products, Draft Guidance for 

Industry and Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA, Guidance 

for Industry. When final, these guidances will represent FDA’s current thinking on these topics. 5 The 21st Century Cures Act (Public Law No. 114-255) (Cures Act) amended section 503(g) of the FD&C Act (21 

USC 353(g)) to include a new section 503(g)(2)(A) establishing an additionalmeeting type for combination product 

sponsors – CPAMs – to address the standards and requirements for marketing authorization (e.g., approval, 
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We are issuing this guidance consistent with the Agency’s ongoing commitment to enhancing 

clarity and transparency regarding regulatory considerations for combination products, and in 

accordance with the mandate under section 503(g)(8)(C)(vi) of the FD&C Act (21 USC 

353(g)(8)(C)(vi)), which was added by section 3038 of the Cures Act. Section 503(g)(8)(C)(vi) 

requires FDA to issue a final guidance addressing: (1) the structured process for managing presubmission interactions with sponsors developing combination products; (2) best practices to 

ensure FDA feedback in such pre-submission interactions represents the Agency’s best advice

based on the information provided during these pre-submission interactions; and (3) how 

CPAMs relate to other FDA meeting types, what information should be submitted with a request 

for a CPAM, and the form and content of agreements reached through a CPAM.

II. Background 

This section discusses what combination products are, how they are assigned to a “lead center,” 

intercenter coordination for their premarket review, and whom to contact in FDA regarding 

combination product questions. 

A. What are combination products and how does FDA regulate them? 

A combination product is a product comprised of any combination of a drug, device, and/or

biological product (see 21 CFR 3.2(e)). 6 The drugs, devices, and biological products included in 

combination products are referred to as “constituent parts” of the combination product (see 21 

CFR 3.2(k)). 

A combination product is assigned to an Agency center that will have primary jurisdiction (i.e., 

the “lead center”) for that combination product’s premarket review and regulation. Under section 

503(g)(1) of the FD&C Act (21 USC 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.7 The lead center for premarket review of the combination 

product also has the lead for postmarket regulation. Regardless of the PMOA, Agency 

components coordinate as appropriate to ensure efficient, effective regulation of combination 

products. 

B. Whom should I contact for preliminary or general questions? 

If you are uncertain whether your product is a combination product or a constituent part of a 

combination product, or which center has primary jurisdiction, you can contact the Office of 

 

clearance) of a combination product and/or other issues relevant to a combination product, such as requirements 

related to postmarket modification of the product or current good manufacturing practices (CGMP). 6 A combination solely of two or more of the same type of medical product is nota “combination product” for 

purposes of section 503(g) of the FD&C Act and as defined at 21 CFR 3.2(e). For example, two drugs combined 

into a single dosage form or multiple devices in a kit together would not be combination products.

7 The “primary mode of action” of a combination product is “the single mode of action of a combination product 

expected to make the greatest contribution to the overall intendedtherapeutic effects of the combination product.”

Section 503(g)(1)(C) of the FD&C Act (21 USC 353(g)(1)(C)); see also 21 CFR 3.2(k) (defining “mode of action”), 

(m) (defining “primary mode of action”).
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Combination Products (OCP) (combination@fda.gov). If you wish to obtain a binding 

determination from FDA regarding classification8 and/or center assignment, you may submit a 

request for designation (RFD) to OCP, or if you wish to obtain informal feedback, you may 

submit a pre-RFD to OCP. 9

If you know the lead center for your combination product (e.g., there is a pending submission), 

contact the FDA Point of Contact (POC) (see Section III.B below) or, if you do not yet have an 

FDA POC, contact the lead center Product Jurisdiction Officer (PJO).10 In some circumstances, 

combination products may not require premarket authorization (e.g., some kits), and in those 

cases you should contact the lead center PJO. If you are unsure of the lead center, if you have 

general questions regarding intercenter collaboration on combination products, combination 

product regulation, combination product guidance or policy, or if you need help in navigating the 

combination product review process at FDA, contact OCP (combination@fda.gov).11

III. Best Practices Regarding Interactions Between FDA and 

Sponsors of Combination Products 

Combination product sponsors and the FDA share common goals of ensuring that combination 

products are safe and effective and that the regulatory requirements and processes associated 

with their premarket review and postmarket regulation are clear, efficient, effective, and

appropriately implemented. When sponsors request feedback on combination products, timely 

communication and robust information sharing are critical aspects to help ensure efficient and 

productive interactions between FDA and sponsors. The sections below highlight specific 

considerations to help ensure productive combination product interactions: 

• Appropriate Submission and Processing. Submissions made under an application-based 

mechanism and CPAM requests (hereafter referred to as “submissions/requests”) should 

 

8 Please note that “classification” as used in this guidance refers to a product’s designation as a drug,

device, biological product, or combination product. This is distinct from the use of the term “classification” in

reference to the class (Class I, II, or III) of a device as described in section 513(a) of the Federal Food, Drug, and

Cosmetic Act (FD&C Act). 9 See How to Write a Request for Designation (RFD), Guidance for Industry and How to Prepare a Pre-Request for 

Designation (Pre-RFD),Guidance for Industry;see alsoClassification of Products as Drugs and Devices & 

Additional Product Classification Issues, Guidance for Industry and FDA Staff. 10 The lead center PJO can be contacted at CBERProductJurisdiction@fda.hhs.gov,

CDERProductJurisdiction@fda.hhs.gov orCDRHProductJurisdiction@fda.hhs.gov. 11 OCP is required to: coordinate premarket reviews for combination products; oversee the timeliness of premarket 

reviews and the alignment of feedback to the sponsor; ensure there is a primary POC(s) in the lead center; 

coordinate communications between the lead and consulting center(s) if requested; ensure meetings with the sponsor 

are attended by each center involved in the review, as appropriate; and ensure that the consulting center(s) advise as 

appropriate on relevant regulations, guidances, and policies, and follow this guidance. OCP is also required to 

ensure the consistency and appropriateness of postmarket regulation of combination products.See section 503(g)(8) 

of the FD&C Act (21 USC 353(g)(8)).
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be submitted to the appropriate lead center, identifying the product as a combination 

product12 and appropriately routed by FDA to staff within the centers for review. 

• Timely Use of Appropriate Communication Procedures. Communications between the 

Agency and sponsor should be timely and the mechanisms for such communication (faceto-face meetings, teleconferences, written responses, etc.) should be those that are 

specified in FDA guidance. 

• Clear, Robust Information Sharing. Information sharing between sponsors and the 

Agency, including communications regarding information submitted by sponsors and 

questions and information requests from FDA, should be clear and sufficiently robust to

minimize repeat interactions on the same question and enable FDA to provide clear 

feedback in a timely manner. 

The following sections provide best practices for both sponsors and FDA to enable such 

interactions for combination products whether in the application-based mechanism or CPAM 

context. 

A. Sponsor Best Practices 

Below are recommendations to sponsors that we believe will help to ensure that interactions are 

efficient and productive. 

• Submissions for a Combination Product. Submissions/requests should be submitted to the 

appropriate lead center. As noted in Section IV.B below, a CPAM is only available for 

combination products for which the lead center is clear. It is important that combination 

product sponsors identify their product as a combination product in CPAM requests, as 

well as when utilizing application-based mechanisms. 

• Clear and Appropriate Questions. The specific feedback being requested should be clear 

in the questions being posed. Also, the questions should be appropriate to the stage of 

combination product development. For example, it would not be productive to ask 

questions related to full-scale manufacturing process controls if, for instance, the 

composition/design of the combination product is still being developed. 

• Comprehensive Rationale and Supporting Information. The submission/request should 

include sufficient information to allow FDA to consider the issue(s) and provide feedback 

without the need for significant additional information requests (see also Sections IV.A

and IV.B below and relevant guidances referenced in Appendices 1 and 2). When 

requesting FDA feedback on a particular issue, sponsors should provide sufficient 

information, as applicable, about how the issue relates to the constituent part(s) as well as

 

12 The Cures Act amended section 503(g) of the FD&C Act to require sponsors seeking “agency action” on a 

combination product to identify the product as such. See section 503(g)(8)(C)(v)(I) of the FD&C Act (21 USC 

503(g)(8)(C)(v)(I)). We believe CPAM requests fall within this provision. Therefore, in a CPAM request, sponsors 

must identify their product as a combination product. Additionally, even if not required for all submissions 

requesting feedback through an application-based mechanism, we recommend that sponsors identify their product as 

a combination product in such submissions to help facilitate combination product reviews.
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the overall combination product.

• Communications Through the Identified FDA POC. The sponsor should communicate 

with FDA through the designated POC. Even in situations where the focus of the request 

is an issue for which expertise primarily resides outside the lead center, communications

should be directed to the identified POC within the lead center who will engage 

appropriate expertise (see Section III.B below). Sponsors can contact the POC within the 

lead center to request engagement of appropriate staff to help to ensure availability of 

necessary expertise and address scheduling matters early in meeting planning.

B. FDA Best Practices

Below are FDA best practices we believe will help to ensure that review of submissions/requests 

is efficient and productive. 

• Notifying Sponsor of the FDA POC.13 Once a submission/request has been accepted, 

consistent with center guidance and processes, the lead center should ensure that the 

sponsor is notified of the FDA POC.14 The POC should coordinate communications 

between the sponsor and FDA staff, including ensuring efficient communications 

involving the non-lead center, and be kept informed of the outcomes of any 

communications between FDA staff and the sponsor.

• Engaging Relevant Expertise. The lead center should engage appropriate expertise from 

other medical product centers and the OCP, as needed, to support comprehensive review 

and feedback for the submission/request. Such staff should be engaged early in the 

review process and invited to related meetings or other interactions with the sponsor, as

appropriate.15 If a sponsor has made a request for participants with particular expertise to 

engage on matters concerning the product, FDA generally intends to include such staff in 

meetings and other interactions when appropriate (e.g., they have expertise relevant to the 

issues being discussed). Sponsors may also request that OCP participate in meetings or 

otherwise engage on regulatory matters concerning combination products (see section 

503(g)(8)(C)(v)(II) of the FD&C Act (21 USC 353(g)(8)(C)(v)(II))). In situations where 

a feedback request relates solely to issues reviewed by the non-lead center, the lead 

center will work to ensure that information is transmitted promptly to the other center. 

• Consolidated, Aligned, and Reliable Feedback. FDA should provide comprehensive 

responses, to the extent possible based on the information provided, to the issues posed in 

the submission/request. The feedback provided to the sponsor should represent the 

current thinking of the FDA based on the information provided and include relevant input 

 

13 Under section 503(g)(8)(C)(iii) of the FD&C Act (21 USC 353(g)(8)(C)(iii)), OCP must ensure that a designated 

person or persons in the primary Agency center is the primary POC(s) for the sponsor of the combination product. 

14 In CBER and CDER, the FDA POC is typically a Regulatory Project Manager(RPM), and in CDRH, the FDA 

POC is typically a Lead Reviewer. 15 See Staff Manual Guide (SMG) 4101, Inter-Center Consult Request Processregarding, among other things,

expectations and processes for intercenter consultation on combination products; see also SMG 4103, Expectations 

and Procedures for Engagement Among Medical Product Centers and Office of Combination Products on 

Regulations and Guidance Pertaining to Combination Products. 
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from all Agency centers and groups involved in review of the submission/request. FDA 

should not generally alter its feedback once provided to the sponsor unless new 

information or updated scientific thinking, for example, including as reflected in 

subsequently issued guidance, regulations or laws, impacts the validity of the previously 

provided feedback. 

IV. Feedback Mechanisms Available for Combination Products 

The sections below discuss the various ways sponsors can interact with FDA via applicationbased mechanisms or CPAMs to discuss combination product issues.16 

A. Application-based Mechanisms 

The application-based mechanisms for interacting with FDA that are available to drugs, devices, 

and biological products are also available for combination products. These mechanisms are 

typically the most efficient and effective for communication with FDA and are based on the 

application type that would be submitted for the combination product. 17 This section provides

considerations for application-based mechanisms when used to address combination product 

issues. Sponsors should also review associated guidance relevant to the specific applicationbased mechanism (see Appendices 1 and 2).

All interactions with FDA should be coordinated through the lead center for the combination 

product (see Section III.A above) and using the application-based mechanisms of that center,

regardless of the feedback being requested. For example, if a sponsor has general questions on 

the drug constituent part of a device-led combination product, that interaction would occur 

through CDRH and the appropriate application-based mechanism would be the pre-submission 

meetings process.18 Coordinating interactions through the lead center helps to ensure appropriate 

engagement from all members of the review team (including, as appropriate, review team 

members in other centers(s)) and that interactions, including those that occur by e-mail and 

telephone, are appropriately captured in the administrative record. Application-based 

mechanisms include specialized meeting types and opportunities designed to address specific 

 

16 Although the Agency can discuss product-specific issues only with the product sponsor and those whom the 

sponsor designates, other entities involved in combination product development (e.g., constituent part developers, 

master file holders) and manufacturing may request feedback from FDA relating to their regulated activities. 

Although such entities cannot use application-based mechanisms or CPAMs, suchentities may contact the lead 

center for the combination product using the existing process for general inquires (CBER Manufacturers Assistance, 

CDER Drug Information, CDRH Division of Industry and Consumer Education). If the lead center is not known, 

these entities can contact OCP for assistance (combination@fda.gov). The center or OCP will coordinate, as 

necessary, to provide feedback or direct the entity to an appropriate mechanism for additional feedback. 17 While application-based mechanisms are available, and generally should be utilized, for all combination products, 

cross-labeled combination products for which separate marketing authorizations are being sought for the constituent 

parts (e.g., a new drug application (NDA) for the drug and a premarket notification (510(k)) for the device) can raise 

distinct considerations. Prior to filing of separate marketing authorization submissions, all interactions with FDA 

should be coordinated through the lead center for these combination products, regardless of the feedback being 

requested. The sponsor(s) may wish to discuss with the centers (and OCP as needed) how best to ensure efficient, 

coordinated engagement during review of marketing authorization submissions (e.g., in light of the differing user fee 

performance goals associated with the submission types for each constituent part). 18 See Requests for Feedback and Meetings on Medical Device Submissions: The Q-Submission Program, Guidance 

for Industry and Food and Drug Administration Staff. 
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requests (e.g., breakthrough designation for a device) and product types (e.g., complex generics). 

Appendices 1 and 2 list examples of common issues and the application-based mechanisms for

combination product sponsors to use to obtain FDA feedback on them. 

For application-based mechanisms, FDA processing and FDA feedback to the combination 

product sponsor should be provided consistent with the existing process outlined for the type of 

interaction (see relevant guidances referenced in Appendices 1 and 2; see also information on 

electronic submissions). 

1. Information to Include When Requesting Feedback on a Combination 

Product Through an Application-Based Mechanism

For application-based mechanisms, sponsors should refer to applicable guidance (see guidances 

referenced in Appendices 1 and 2) as the primary reference regarding what information to submit 

to FDA. The submission should identify the product for which feedback is being requested as a 

combination product (see section 503(g)(8)(C)(v)(I) of the FD&C Act (21 USC 

353(g)(8)(C)(v)(I)) and footnote 12). In addition to information generally provided under an 

application-based mechanism, the following information should also be included for the non-lead 

constituent part to allow FDA to efficiently review the submission for the combination product 

under the application-based mechanism: 

• For a drug or biological product-led combination product that includes a device 

constituent part: 

o A device description, design diagram or other image,

o Identification of components that are part of the device, and

o If the combination product contains a device constituent part that is a cleared or 

approved device that the sponsor seeks to cross reference, identify the application 

or submission number for the previously cleared or approved device.

• For a device-led combination product: 

o Information identifying and describing the drug and/or biological product 

constituent part(s), including, as applicable, chemical name, established or proper 

name, and structure, 

o The route of administration and/or dosing information for the drug and/or 

biological product constituent part(s), and 

o If the combination product, contains an active ingredient that is included in an 

approved drug product that the sponsor seeks to cross reference or rely upon in 

its submission, the application number of the approved product. 
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B. Combination Product Agreement Meetings (CPAMs)

CPAMs are intended as a means (in addition to the application-based mechanisms) for sponsors 

to obtain clarity and certainty and are available for combination products for which the lead 

center assignment is clear.19 The purpose of a CPAM is to address the standards and 

requirements for marketing authorization of a combination product and other issues relevant to a 

combination product, such as requirements related to postmarket modification of the product or 

CGMPs. 

In response to a written CPAM request, FDA must: 

• Meet with the sponsor within 75 calendar days20 of receiving the request; and

• Document any agreements made with the sponsor in writing and make them part of 

the administrative record. 

See section 503(g)(2)(A)(i) and (iii) of the FD&C Act (21 USC 353(g)(2)(A)(i) and (iii)). 

Any agreement under section 503(g)(2)(A) shall remain in effect unless deviation from it is: 

• agreed upon in writing by the FDA and sponsor; or 

• pursuant to a decision by certain individuals specified in the statute (as appropriate) 

that (1) an issue has been identified since the agreement was reached that is essential 

to determining whether the standard for marketing has been met,21 or (2) it is 

otherwise justifiable to deviate from the agreement based on scientific evidence, for 

public health reasons.

See section 503(g)(2)(A)(iv) of the FD&C Act (21 USC 353(g)(2)(A)(iv)). 

As noted in Section IV.A above, the Agency encourages the use of application-based 

mechanisms as they generally offer the most efficient and effective means to obtain feedback. 

 

19 If FDA concludes that a determination of the PMOA is needed, the sponsor cannot make a CPAM request until 

after the Agency determines the PMOA. See section 503(g)(2)(A)(i) of the FD&C Act (21 USC 353(g)(2)(A)(i)); 

see also Section II.Cregarding how to obtain a classification or PMOA determination. 20 Section 503(g)(2)(A)(i) of the FD&C Act (21 USC 353(g)(2)(A)(i) indicates that “[i]f the sponsor submits a 

written meeting request, the Secretary shall, not later than 75 calendar days after receiving such request, meet with 

the sponsor of such combination product.” 21 Section 503(g)(2)(A)(iv) reads:“Any such agreement shall remain in effect, except— 

(I) upon the written agreement of the Secretary and the sponsor or applicant; or

(II) pursuant to a decision by the director of the reviewing division of the primary agency center, or 

a personmore senior than such director, in consultation with consulting centers and the Office, as 

appropriate, that an issue essential to determining whether the standard for market clearance or other 

applicable standard under this Act or the Public Health Service Act applicable to the combination product 

has been identified since the agreement was reached, or that deviating from the agreement is otherwise 

justifiable based on scientific evidence, for public health reasons.”

We note that although the provision does not expressly refer to whether marketing clearance or other applicable 

standard “has been met,” that appears to be the meaning of the statutory provision.
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1. Information to Include When Requesting Feedback on a Combination 

Product Through a CPAM

Below are recommendations on what should be included in CPAM requests at the time the 

request is submitted (see also Section IV.B.2 below). 

• Product Information. Sponsors: 

o Should include the product name, description of the overall combination product 

and constituent parts, indications for use statement, and, as applicable, route of 

administration and dosing information. 

o Should include, as relevant, the same information referenced in Section IV.A.1 

above for the constituent parts of the combination product. 

o Must identify their product as a combination product (see footnote 12). 

• Background. Sponsors should describe the status of product development, summarize any 

previous interactions with FDA on the product, including applications, application-based 

mechanisms, other meetings, RFDs or pre-RFDs, and identify the proposed regulatory 

pathway if not already established.

• Meeting Request. Sponsors should include the requested form of communication (i.e., 

face-to-face meeting, teleconference, or written response). If proposing a face-to-face 

meeting or teleconference, provide three proposed meeting dates and times within the 75-

day timeframe and a proposed agenda that includes the allotted time to discuss each 

proposal. 

• Agreement Proposals. Sponsors should identify the specific proposals and/or items of the 

proposal(s) for which the sponsor seeks FDA agreement. These should be grouped by 

discipline (e.g., Pharmacology/Toxicology, Pharmaceutical Quality/Chemistry and 

Manufacturing Controls (CMC), Engineering, Human Factors) where possible. The 

issues should be limited to those for which the sponsor is seeking agreement from FDA.

• Rationale and Data Supporting Proposals. Sponsors should provide rationale(s) and data 

adequate to support FDA’s review of the agreement proposals, and organize the 

rationale(s) and data by topic when appropriate. 

• Attendees. Sponsors should include a list of planned participants from the sponsor’s 

organization, including names and titles. A list of names, titles and affiliations of 

consultants and interpreters should also be included. If this information changes, it should 

be updated no later than 5 business days prior to the meeting. All non-U.S. citizens 

attending a meeting in an FDA facility are subject to additional security screening. You 

should inform the FDA POC of non-U.S. citizens attending no less than two weeks prior 

to the meeting to ensure the appropriate information is available and provided. If the 

sponsor wishes to request that a specific FDA staff member or expertise be included in 
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the meeting, that information should be included in the CPAM request (see also Section 

III above).

2. Submitting a CPAM Request

CPAM requests should: 

• Be submitted to the lead center for the combination product using the processes 

described in Table 1 below; 

• Identify the submission as a “Combination Product Agreement Meeting Request” in the 

cover letter; 

• Identify the type of engagement being requested (face-to-face meeting, teleconference, 

or written response); and

• Provide the complete information described in Section IV.B.1 above, so that FDA can

assess whether a CPAM is the most efficient mechanism for interaction, coordinate 

between centers, and ensure that FDA has sufficient information to evaluate the 

agreement proposal(s) or specific items thereof. 

FDA encourages sponsors, where possible, to consolidate related issues for the combination 

product that are ready for consideration into a single CPAM request, as opposed to submitting 

multiple CPAM requests. FDA discourages submitting multiple CPAM requests for related 

issues because the Agency would likely not be able to reach agreement on the sponsor’s 

proposals independently. FDA also discourages submission of CPAM requests if there is an 

application for the combination product under active FDA review; application-based 

mechanisms should be used, as appropriate, at that stage. 

Sponsors should follow the submission process described in Table 1 to ensure appropriate receipt 

and routing of the CPAM request. 
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Table 1. Submission Process for CPAM Requests22

Lead 

Center

Combination 

Product 

Application Type CPAM Request Process

CBER IND, NDA, BLA, 

ANDA

Submit the CPAM request:

• Electronically or to the CBER Document Control Center;23

• Address CPAM request to the appropriate review division; 

and

• Specify the application number, if applicable, in the cover 

letter.24

NOTE: The CPAM package (including all information 

necessary for review) should be provided with the initial 

request.

IDE, PMA, 

510(k), De Novo, 

HDE, PDP 

Submit a valid eCopy25 to the CBER Document Control Center. 

Specify the application number, if applicable, in the cover 

letter.

CDER IND, NDA, BLA Submit the CPAM request:

• Electronically or to the CDER Document Control Center;23

• Address CPAM request to the appropriate review division; 

and

• Specify the application number, if applicable, in the cover 

letter.24 

NOTE: The CPAM package (including all information 

necessary for review) should be provided with the initial 

request.

ANDA If the ANDA has not yet been submitted to FDA, submit the 

CPAM request: 

• Electronically to CDER NextGen Collaboration Portal. 

• Specify the application number.24

If the ANDA is being submitted at the same time as the CPAM 

request, or the ANDA has already been submitted to FDA, 

submit the CPAM request: 

• Through the FDA Electronic Submission Gateway (ESG).

• Specify the application number.24

 

22 Submitting a CPAM request to the lead center would be appropriate for any combination product including crosslabeled combination products for which a sponsor may anticipate submitting or has submitted separate applications 

for each constituent part.

23 See Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product 

Applications and Related Submissions Using the eCTD Specifications, Guidance for Industry. 24 If an application number has not been assigned, see information regarding requesting a pre-assigned application 

number available on FDA’s website at https://www.fda.gov/drugs/electronic-regulatory-submission-andreview/requesting-pre-assigned-application-number. 25 See eCopy Program for Medical Device Submissions, Guidance for Industry and Food and Drug Administration 

Staff.
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Lead 

Center

Combination 

Product 

Application Type CPAM Request Process

CDRH IDE, PMA, 

510(k), De Novo, 

HDE, PDP 

Submit a valid eCopy25 to the CDRH Document Control 

Center. Specify the application number, if applicable, in the 

cover letter.

3. FDA Response to a CPAM 

The following outlines steps for the CPAM process:

• Acceptance of CPAM Request. Requests for CPAMs will generally be granted unless the 

request is not for a combination product or the PMOA for the combination product has 

not been determined (see section 503(g)(2)(A)(i) of the FD&C Act (21 USC 

353(g)(2)(A)(i))). We note that it is not appropriate, however, to use CPAMs to resolve 

disputes that would otherwise be reviewed under the lead center’s dispute resolution 

and/or appeals processes (see also Section IV.C below). 26 We also note that if a sponsor 

does not include sufficient information in its request to allow for meaningful discussion 

or feedback, the Agency would likely not be able to reach agreement on the sponsor’s 

proposal. 

FDA intends to contact the sponsor within 21 calendar days of receiving a CPAM request 

confirming receipt and providing a meeting time (if requested) or providing a substantive 

basis for not granting the CPAM. If FDA believes that an application-based mechanism

may be more efficient and/or provide additional clarity, FDA may contact the sponsor 

and offer to convert to that application-based mechanism. If the sponsor agrees to the 

application-based mechanism, FDA will work with the sponsor so that the sponsor can 

efficiently pursue that mechanism.

• CPAM Interaction. Sponsors may choose to submit a request for a face-to-face meeting, a 

teleconference, or written feedback. If the sponsor submits a request for a face-to-face 

meeting or teleconference, and FDA accepts the request, FDA will schedule the meeting

to occur within 75 calendar days of receiving the CPAM request. Meetings are typically 

one hour in duration. FDA may contact the sponsor if we believe written feedback only 

would be appropriate. FDA intends to provide a preliminary response to the sponsor prior 

to a face-to-face meeting or teleconference (see below). After receiving such a response, 

the sponsor should notify the FDA no later than 3 calendar days following receipt that a 

 

26 See Requests for Reconsideration at the Division Level Under GDUFA, Draft Guidance for Industry (for CDER’s 

Office of Generic Drugs which, when final, will represent FDA’s current thinking on this topic), Formal Dispute 

Resolution: Sponsor Appeals Above the Division Level, Guidance for Industry and Review Staff(for CBER and 

CDER) and Center for Devices and Radiological Health Appeals Processes, Guidance for Industry and Food and 

Drug Administration Staff. Combination product sponsors may obtain information on informal dispute resolution 

options from the lead center Ombudsman staff (see https://www.fda.gov/about-fda/office-chief-scientist/contactombudsman-fda). OCP is also available to assist FDA-regulated entities in resolving issues that may arise between 

them and centers or other FDA components, relating to premarket review or other regulatory issues for combination 

products. Requests for assistance may be submitted to OCP’s mailbox at combination@fda.gov. 
Contains Nonbinding Recommendations

14

face-to-face meeting or teleconference is not needed or identifying the issues which the 

sponsor wants to further discuss at the meeting/teleconference.

• Preliminary Responses, Written Feedback, and CPAM Agreements. If the sponsor 

requests written feedback only, FDA intends to provide final written feedback to the 

sponsor within 75 calendar days of receipt of the request. If the sponsor requests a faceto-face meeting or teleconference, FDA intends to provide the sponsor preliminary 

responses to the CPAM request no later than 5 calendar days before the 

meeting/teleconference. If the sponsor then determines that a meeting/teleconference is 

not needed or is needed to discuss only certain issues (see above), FDA’s preliminary 

response will represent the Agency’s final written feedback (on all or the resolved issues) 

on a CPAM. If the meeting/teleconference is held, FDA intends to provide final written 

feedback to the sponsor within 30 calendar days following the meeting. 

FDA’s final written feedback should include the agreed upon proposals and indicate, for 

each proposal, or item thereof, for which the sponsor sought FDA agreement that: 

o FDA agrees with the proposal or item thereof;

o FDA does not agree with the sponsor’s proposal or item thereof and why FDA 

does not consider the sponsor’s proposal or item thereof acceptable; or 

o FDA cannot agree to the proposal or item(s) thereof at the time of the response 

due to inadequate or insufficient information. Such a response should include a 

summary of the additional scientific data or other information needed to support 

further review of the sponsor’s proposal or item(s) thereof. If a sponsor wants to 

submit information to respond to identified inadequacies/insufficiencies, the 

sponsor can do so by using an application-based mechanism or submitting a new 

CPAM request.

If sponsors would like clarification regarding FDA’s response to a CPAM request, including 

whether a CPAM or another mechanism would be appropriate for future interactions, they should 

promptly contact the FDA POC.

4. Validity of Agreements Made Through CPAM

Any agreement made through the CPAM process shall remain in effect except in the limited 

circumstances set forth in section 503(g)(2)(A)(iv) of the FD&C Act (21 USC 353(g)(2)(A)(iv)) 

as discussed in Section IV.B above. New information or updated scientific thinking, for example,

including as reflected in subsequently issued guidance, may result in FDA identifying an issue 

that is essential to determining whether the standard for marketing authorization has been met. In 

addition, the formal agreement is product specific and is predicated on the sponsor not changing 

the basis of the agreement, such as failing to follow an agreed upon pre-clinical or clinical 

protocol, making substantive changes to an endpoint, altering the proposed intended use or 

indications or product design/contents, changing the manufacturing process or controls, or 

changing the investigational plan. CPAM agreements that are not subsequently followed by the 

sponsor are no longer valid, though FDA may consider data or information generated as it deems 
Contains Nonbinding Recommendations

15

appropriate for premarket review or postmarket regulation, as applicable. When FDA 

determines, for example, during review of a subsequent related submission, that a CPAM 

agreement is no longer in effect – entirely or in part – under section 503(g)(2)(A)(iv), FDA 

intends to notify the sponsor in writing of which portions of the agreement are no longer in effect 

and the basis for the decision. 

C. Use of Application-based Mechanisms, CPAMs, and Dispute 

Resolution 

Consistent with our past practices, FDA intends to continue to provide as reliable and definitive 

feedback as possible based on the information provided. The Agency encourages combination 

product sponsors to interact through application-based mechanisms to provide FDA an 

opportunity to evaluate technical data or engage in scientific discussion before considering a 

CPAM.

Issues Appropriate for Application-Based Mechanisms. Application-based mechanisms are 

generally appropriate for requesting feedback on scientific issues, study design, testing

approaches, or application preparation considerations for combination products or clarifying

topics for which FDA has already published technical guidance (see Appendices 1 and 2 for 

examples of the types of issues appropriate for application-based mechanisms). If sponsors have 

questions on which application-based mechanism is appropriate, they should contact the lead 

center POC (if known) or the lead center PJO10 if the sponsor has not previously interacted with 

FDA on the combination product.

Issues Appropriate for CPAMs. CPAMs may be appropriate for seeking agreement from FDA on 

an approach if previous feedback under an application-based mechanism has not provided 

sufficient certainty. CPAM should not be used to resolve disputes that would otherwise be 

addressed under the lead center’s dispute resolution or appeals process (see below). 

Because the goal of CPAMs is agreement on a sponsor’s proposal(s) or items thereof, more 

information and data may be needed in a CPAM request, as compared to an application-based 

mechanism submission, to increase the likelihood of reaching an agreement. Relatedly, sponsors 

should submit a CPAM request only when they believe they have identified the indication for 

use and design of the combination product and the sponsor should be able to provide sufficiently 

robust information on the merits of the proposal(s) being made to ensure an effective review by 

all relevant disciplines and centers (see also Section IV.B.1 above). For issues where scientific 

evidence is limited and/or scientific thinking is evolving, a CPAM is unlikely to be productive 

(see also Section IV.B.4 above). 

Issues Appropriate for Dispute Resolution/Appeal Through the Lead Center’s Dispute 

Resolution or Appeals Process. Dispute resolution/appeals using the lead center’s process are 

appropriate to address disagreement or disputes over constituent part or combination product 

issues identified as part of an FDA action (e.g., determinations that a product cannot be 

marketed, complete response actions, clinical holds, refuse to receive, etc.).26For example, if a 

combination product sponsor received a complete response (CR) letter related to a constituent 

part issue that it believes had been adequately addressed in the application, the sponsor could 

appeal the CR action following the appropriate process for doing so. 
Contains Nonbinding Recommendations

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Appendix 1. Examples of Application-based Mechanisms Available 

for Device-led Combination Products

The table below provides examples of the application-based mechanisms available for device-led 

combination products. All interactions with FDA should be through the lead center for the 

combination product regardless of the feedback being requested (e.g., the application-based 

mechanisms below should be used for device-led combination product interactions regardless of 

whether the issues involve the device, drug and/or biological product constituent part, or the 

combination product as a whole). 

Application 

Type(s) Examples of Types of Issues

Application-based 

Mechanism17

Premarket 

Approval 

Application (PMA)

Premarket 

Notification 

(510(k))

De Novo Request

Humanitarian 

Device Exemption 

(HDE) 

Investigational 

Device Exemption 

(IDE)

General questions and requests for feedback on 

product development, application preparation, 

or postmarket issues

Pre-submission -

Meeting & Written 

Feedback or Written 

Feedback Only27

Discuss proposed approach to address specific 

deficiencies identified during review of certain 

types of device applications where the 

application is either currently on hold (e.g., a 

510(k) request for additional information), or 

where there are questions related to a clinical 

study design

Submission Issue 

Request - Meeting or 

Written Feedback27

Requests for designation of device-led 

combination products as Breakthrough Devices 

based on the eligibility criteria in section 515B 

of the FD&C Act

Designation Request 

for Breakthrough 

Device QSubmission28

 

27 See Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission Program, Guidance 

for Industry and Food and Drug Administration Staff. 28 See Breakthrough Devices Program, Guidance for Industry and Food and Drug Administration Staff.
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Appendix 2. Examples of Application-based Mechanisms Available 

for Drug or Biological Product-led Combination Products

The table below provides examples of the application-based mechanisms available for drug and 

biological product-led combination products. All interactions with FDA should be through the 

application-based mechanism of the lead center for the combination product, regardless of the 

feedback being requested (e.g., the application-based mechanisms below should be used for drug 

and biological product-led combination product interactions regardless of whether the issues 

involve the device, drug and/or biological-product constituent part or the combination product as 

a whole). 

Application 

Type(s) Examples of Types of Issues

Application-based 

Mechanism17

Investigational New 

Drug Application 

(IND) for PDUFA29

Products

New Drug 

Application (NDA)

351(a) Biologic 

License Application 

(BLA)30 

Meetings necessary for an otherwise stalled 

product development program to proceed or 

to address an important safety issue 

Type A Meeting31

Pre-IND, Pre-BLA, Pre-NDA Meetings to 

discuss content and format of a proposed 

marketing or investigational application

Type B Meeting31

General questions and requests for feedback 

on product development or postmarket 

issues, or use of a biomarker as a new 

surrogate endpoint

Type C Meeting31

Design and size of certain clinical 

clinical studies, or animal studies

trials, Special Protocol 

Assessment32

Fast Track Designation, Breakthrough 

Therapy Designation, or Priority Review 

Designation

Designation 

Submission33

[Applications with CBER] Designation as a 

Regenerative Medicine Advanced Therapy 

(RMAT) 

RMAT Designation34

INDs for 

Products

BsUFA35 Initial assessment limited to general 

discussion regarding feasibility of licensure 

under 351(k) of the PHS Act

Biosimilar

Advisory37

 Initial 

 

29 Prescription Drug User Fee Act (PDUFA) 30 A “351(a) BLA” is an application for licensure of a proposed biological product, submitted under section 351(a) 

of the Public Health Service (PHS) Act, also referred to as a “stand-alone BLA.” 31 See Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products, Draft Guidance for 

Industry which, when final, will represent FDA’s current thinking on this topic. 32 See Special Protocol Assessment, Guidance for Industry. 33 See Expedited Programs for Serious Conditions – Drugs and Biologics, Guidance for Industry. 34 See Expedited Programs for Regenerative Medicine Therapies for Serious Conditions, Guidance for Industry. 35 Biosimilar User Fee Act (BsUFA) 37 See Formal Meetings Between the FDA and Sponsors or Applicants of BsUFA Products, Draft Guidance for 

Industry which, when final, will represent FDA’s current thinking on this topic.
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Application 

Type(s) Examples of Types of Issues

Application-based 

Mechanism17

351(k) BLA36 Meetings necessary for an otherwise stalled 

development program to proceed or to 

address an important safety issue.

Biological Product 

Development (BPD) 

Type 1 Meeting37

Discuss specific issues related to, e.g., 

chemistry, manufacturing, CMC, study 

design, etc. 

BPD Type 2 Meeting37

In-depth data review and advice regarding 

an ongoing biosimilar development program.

BPD Type 3 Meeting37

Format and content of a complete 

application or supplement.

BPD Type 4 Meeting37

Design and size of certain clinical trials, 

clinical studies, or animal studies

Special Protocol 

Assessment32

Abbreviated New 

Drug Application 

(ANDA)

Information on a specific element of generic 

drug product development and certain 

postapproval submission requirements

Controlled 

Correspondence 38

Specific scientific issues or questions prior 

to submitting an ANDA 

Product Development 

Meeting39 (intended for 

complex products under 

the Generic Drug User 

Fee Amendments of 2017 

(GDUFA II)40)

Format and content of the ANDA to be 

submitted

Pre-Submission 

Meeting39 (intended for 

complex products under 

GDUFA II40)

Specific issues/deficiencies identified during 

review of an application

Mid-Review Cycle 

Meetings39 (intended for 

complex products under 

GDUFA II40)

 

36 For additional information on submissions under section 351(k) of the PHS Act, including applications for 

biosimilar and interchangeable products, see https://www.fda.gov/drugs/biosimilars/biosimilar-and-interchangeableproducts. 38 See Controlled Correspondence Related to Generic Drug Development, Draft Guidance for Industry which, when 

final, will represent FDA’s current thinking on this topic.

39 See Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA, Guidance for 

Industry. 40 The GDUFA II Commitment Letter defines “complex products,” which include complex drug-device combination 

products (e.g., prefilled auto-injectors, metered dose inhalers, extended-release injectables). Not all combination 

products are considered complex.
Contains Nonbinding Recommendations

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Application 

Type(s) Examples of Types of Issues

Application-based 

Mechanism17

Prior to a pre-IND 

(for INTERACT) or 

planned but not yet 

submitted NDA, 

BLA, ANDA, or 

IND (for Emerging 

Technologies 

Program)

[Applications with CBER] Preliminary 

consultation on innovative investigational 

products at early stages of development 

(prior to a pre-IND)

INTERACT meeting41

[Applications with CDER] Potential 

concerns regarding the development and 

implementation of a novel product or 

manufacturing technology prior to filing a 

regulatory submission

Emerging Technology 

Program meetings42 

 

41 See INitial Targeted Engagement for Regulatory Advice on CBER producTs (INTERACT) program at 

https://www.fda.gov/vaccines-blood-biologics/industry-biologics/interact-meetings-initial-targeted-engagementregulatory-advice-cber-products. 42 See Emerging Technology Program for CDER products at https://www.fda.gov/about-fda/center-drug-evaluationand-research/emerging-technology-program.