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 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 
 
 
1 
  Contains Nonbinding Recommendations 
Requesting FDA Feedback on Combination 
Products  
Guidance for Industry and FDA Staff 
 
This guidance represents the Food and Drug Administrations (FDAs) 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 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 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 Staff which, when final, will represent FDAs 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 FDAs 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, 
 
2 
  Contains Nonbinding Recommendations 
We are issuing this guidance consistent with the Agencys 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 pre-
submission  interactions with sponsors developing  combination  products; (2) best practices to 
ensure FDA feedback in such pre-submission  interactions represents the Agencys 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  products 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). 
 
3 
  Contains Nonbinding Recommendations 
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 products 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 CBERProductJurisdiction@fda.hhs.gov, 
CDERProductJurisdiction@fda.hhs.gov or CDRHProductJurisdiction@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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  Contains Nonbinding Recommendations 
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  (face-
to-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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  Contains Nonbinding Recommendations 
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 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. 
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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 application-
based 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 application-
based 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, 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 (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: 
  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 
o
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: 
 
  Information identifying  and describing  the drug and/or biological  product 
o
constituent part(s), including,  as applicable,  chemical name, established or proper 
name, and structure,  
  The route of administration  and/or dosing information  for the drug and/or 
o
biological  product constituent part(s), and  
  If the combination  product, contains an active ingredient  that is included in an 
o
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.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. 
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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:  
  Should include the product name, description of the overall combination  product 
o
and constituent parts, indications  for use statement, and, as applicable,  route of 
administration  and dosing information.   
  Should include,  as relevant, the same information  referenced in Section IV.A.1 
o
above for the constituent parts of the combination  product.  
  Must identify their product as a combination  product (see footnote 12). 
o
  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 FDAs 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 sponsors 
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 sponsors 
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  CPAM Request Process 
CBER  IND, NDA, BLA,  Submit the CPAM request: 
ANDA    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,  Submit a valid eCopy25 to the CBER Document Control Center. 
510(k), De Novo,  Specify the application  number, if applicable,  in the cover 
HDE, PDP   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 cross-
labeled 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 FDAs website at https://www.fda.gov/drugs/electronic-regulatory-submission-and-
review/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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  Contains Nonbinding Recommendations 
Combination 
Lead  Product   
Center  Application Type  CPAM Request Process 
CDRH  IDE, PMA,  Submit a valid eCopy25 to the CDRH Document Control 
510(k), De Novo,  Center. Specify the application  number, if applicable,  in the 
HDE, PDP   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 centers 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 sponsors 
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 CDERs 
Office of Generic Drugs which, when final, will represent FDAs 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/contact-
ombudsman-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 OCPs mailbox at combination@fda.gov. 
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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 face-
to-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), FDAs preliminary 
response will represent the Agencys 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.  
 
FDAs 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:  
  FDA agrees with the proposal or item thereof; 
o
  FDA does not agree with the sponsors proposal or item thereof and why FDA 
o
does not consider the sponsors proposal or item thereof acceptable; or  
  FDA cannot agree to the proposal or item(s) thereof at the time of the response 
o
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 sponsors 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 FDAs 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 
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  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 centers dispute resolution  or appeals process (see below).  
Because the goal of CPAMs is agreement on a sponsors 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 Centers Dispute 
Resolution  or Appeals Process. Dispute resolution/appeals  using the lead centers 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.  
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  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    Application-based 
Type(s)  Examples of Types of Issues  Mechanism17 
Premarket  General questions and requests for feedback on  Pre-submission - 
Approval  product development,  application  preparation,  Meeting & Written 
Application  (PMA)  or postmarket issues  Feedback or Written 
  Feedback Only27  
Premarket  Discuss proposed approach to address specific  Submission  Issue 
Notification  deficiencies identified  during review of certain  Request - Meeting or 
(510(k))  types of device applications  where the  Written Feedback27 
  application  is either currently on hold (e.g., a 
De Novo Request  510(k) request for additional  information),  or 
  where there are questions related to a clinical 
Humanitarian  study design 
Device Exemption  Requests for designation  of device-led  Designation Request 
(HDE)   combination  products as Breakthrough Devices  for Breakthrough 
  based on the eligibility  criteria in section 515B  Device Q-
Investigational  of the FD&C Act  Submission28 
Device Exemption 
(IDE) 
   
                                              
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    Application-based 
Type(s)  Examples of Types of Issues  Mechanism17 
Investigational  New  Meetings necessary for an otherwise stalled  Type A Meeting31 
Drug Application  product development program to proceed or 
(IND) for PDUFA29  to address an important safety issue  
Products  Pre-IND, Pre-BLA, Pre-NDA Meetings to  Type B Meeting31 
  discuss content and format of a proposed 
New Drug  marketing or investigational  application 
Application  (NDA)  General questions and requests for feedback  Type C Meeting31  
  on product development  or postmarket 
351(a) Biologic  issues, or use of a biomarker as a new 
License Application  surrogate endpoint 
(BLA)30   Design and size of certain clinical trials,  Special Protocol 
  clinical  studies, or animal studies  Assessment32  
Fast Track Designation,  Breakthrough  Designation 
Therapy Designation,  or Priority Review  Submission33 
Designation 
[Applications with CBER] Designation as a  RMAT Designation34 
Regenerative Medicine Advanced Therapy 
(RMAT)  
INDs for BsUFA35  Initial  assessment limited  to general  Biosimilar  Initial 
Products  discussion regarding feasibility  of licensure  Advisory37 
  under 351(k) of the PHS Act 
                                              
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 FDAs 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 FDAs current thinking on this topic. 
 
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Application    Application-based 
Type(s)  Examples of Types of Issues  Mechanism17 
351(k) BLA36   Meetings necessary for an otherwise stalled  Biological  Product 
development program to proceed or to  Development (BPD) 
address an important safety issue.  Type 1 Meeting37  
Discuss specific issues related to, e.g.,  BPD Type 2 Meeting37 
chemistry, manufacturing,  CMC, study 
design, etc.  
In-depth data review and advice regarding  BPD Type 3 Meeting37 
an ongoing  biosimilar  development  program. 
Format and content of a complete  BPD Type 4 Meeting37 
application  or supplement. 
Design and size of certain clinical trials,  Special Protocol 
clinical  studies, or animal studies  Assessment32  
Abbreviated New  Information on a specific element of generic  Controlled 
Drug Application  drug product development and certain  Correspondence38 
(ANDA)  postapproval submission  requirements 
  Specific scientific issues or questions prior  Product Development 
to submitting  an ANDA   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  Pre-Submission 
submitted  Meeting39 (intended for 
complex products under 
GDUFA II40) 
Specific issues/deficiencies identified  during  Mid-Review Cycle 
review of an application  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-interchangeable-
products.  
38 See Controlled Correspondence Related to Generic Drug Development, Draft Guidance for Industry which, when 
final, will represent FDAs 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. 
 
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Application    Application-based 
Type(s)  Examples of Types of Issues  Mechanism17 
Prior to a pre-IND  [Applications with CBER] Preliminary  INTERACT meeting41 
(for INTERACT) or  consultation  on innovative  investigational 
planned but not yet  products at early stages of development 
submitted NDA,  (prior to a pre-IND) 
BLA, ANDA, or  [Applications with CDER] Potential  Emerging Technology 
IND (for Emerging  concerns regarding the development  and  Program meetings42  
Technologies  implementation  of a novel product or 
Program)  manufacturing technology  prior to filing  a 
regulatory submission 
 
                                              
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-engagement-
regulatory-advice-cber-products.  
42 See Emerging Technology Program for CDER products at https://www.fda.gov/about-fda/center-drug-evaluation-
and-research/emerging-technology-program. 
19