Requests for Designations: Combination Products reporting and records

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 301-7968930 or [email protected].

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

Contains Nonbinding Recommendations
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 sponsors 1 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.

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 wishes to
interact with FDA on scientific or regulatory questions specifically 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 [email protected].
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 Staff which, 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 additional meeting type for combination product
sponsors – CPAMs – to address the standards and requirements for marketing authorization (e.g., approval,
1

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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 not a “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 intended therapeutic 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) ([email protected]). If you wish to obtain a binding
determination from FDA regarding classification 8 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 ([email protected]). 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

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 also Classification 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 [email protected],
[email protected] or [email protected].
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)).
8

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be submitted to the appropriate lead center, identifying the product as a combination
product 12 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.
•

B.

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.

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

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 Process regarding, 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.
13

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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
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, such entities 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 ([email protected]). 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.
16

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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 days 20 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.

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.C regarding 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 person more 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.
19

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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 75day 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
Combination
Lead
Product
Center Application Type
CBER IND, NDA, BLA,
ANDA

CDER

IDE, PMA,
510(k), De Novo,
HDE, PDP
IND, NDA, BLA

ANDA

CPAM Request Process
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.
Submit a valid eCopy 25 to the CBER Document Control Center.
Specify the application number, if applicable, in the cover
letter.
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.
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

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.
22

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Combination
Lead
Product
Center Application Type
CDRH IDE, PMA,
510(k), De Novo,
HDE, PDP
3.

CPAM Request Process
Submit a valid eCopy25 to the CDRH Document Control
Center. Specify the application number, if applicable, in the
cover letter.

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

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 [email protected].
26

13

Contains Nonbinding Recommendations
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
14

Contains Nonbinding Recommendations
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.).26 For 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.
15

Contains Nonbinding Recommendations

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)
Premarket
Approval
Application (PMA)
Premarket
Notification
(510(k))
De Novo Request
Humanitarian
Device Exemption
(HDE)
Investigational
Device Exemption
(IDE)

Examples of Types of Issues
General questions and requests for feedback on
product development, application preparation,
or postmarket issues
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
Requests for designation of device-led
combination products as Breakthrough Devices
based on the eligibility criteria in section 515B
of the FD&C Act

Application-based
Mechanism17
Pre-submission Meeting & Written
Feedback or Written
Feedback Only 27
Submission Issue
Request - Meeting or
Written Feedback27

Designation Request
for Breakthrough
Device QSubmission 28

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.
27

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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)
Investigational New
Drug Application
(IND) for PDUFA 29
Products
New Drug
Application (NDA)
351(a) Biologic
License Application
(BLA) 30

INDs for BsUFA 35
Products

Examples of Types of Issues
Meetings necessary for an otherwise stalled
product development program to proceed or
to address an important safety issue
Pre-IND, Pre-BLA, Pre-NDA Meetings to
discuss content and format of a proposed
marketing or investigational application
General questions and requests for feedback
on product development or postmarket
issues, or use of a biomarker as a new
surrogate endpoint
Design and size of certain clinical trials,
clinical studies, or animal studies
Fast Track Designation, Breakthrough
Therapy Designation, or Priority Review
Designation
[Applications with CBER] Designation as a
Regenerative Medicine Advanced Therapy
(RMAT)
Initial assessment limited to general
discussion regarding feasibility of licensure
under 351(k) of the PHS Act

Application-based
Mechanism17
Type A Meeting 31
Type B Meeting31
Type C Meeting31

Special Protocol
Assessment 32
Designation
Submission 33
RMAT Designation 34
Biosimilar Initial
Advisory 37

Prescription Drug User Fee Act (PDUFA)
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.
29
30

17

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Application
Type(s)
351(k) BLA 36

Abbreviated New
Drug Application
(ANDA)

Examples of Types of Issues
Meetings necessary for an otherwise stalled
development program to proceed or to
address an important safety issue.
Discuss specific issues related to, e.g.,
chemistry, manufacturing, CMC, study
design, etc.
In-depth data review and advice regarding
an ongoing biosimilar development program.
Format and content of a complete
application or supplement.
Design and size of certain clinical trials,
clinical studies, or animal studies
Information on a specific element of generic
drug product development and certain
postapproval submission requirements
Specific scientific issues or questions prior
to submitting an ANDA

Format and content of the ANDA to be
submitted
Specific issues/deficiencies identified during
review of an application

Application-based
Mechanism17
Biological Product
Development (BPD)
Type 1 Meeting37
BPD Type 2 Meeting37
BPD Type 3 Meeting37
BPD Type 4 Meeting37
Special Protocol
Assessment32
Controlled
Correspondence 38
Product Development
Meeting 39 (intended for
complex products under
the Generic Drug User
Fee Amendments of 2017
(GDUFA II) 40)
Pre-Submission
Meeting39 (intended for
complex products under
GDUFA II40)
Mid-Review Cycle
Meetings39 (intended for
complex products under
GDUFA II40)

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.
36

18

Contains Nonbinding Recommendations
Application
Type(s)
Prior to a pre-IND
(for INTERACT) or
planned but not yet
submitted NDA,
BLA, ANDA, or
IND (for Emerging
Technologies
Program)

Examples of Types of Issues
[Applications with CBER] Preliminary
consultation on innovative investigational
products at early stages of development
(prior to a pre-IND)
[Applications with CDER] Potential
concerns regarding the development and
implementation of a novel product or
manufacturing technology prior to filing a
regulatory submission

Application-based
Mechanism17
INTERACT meeting 41

Emerging Technology
Program meetings 42

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.
41

19