Guidance for Industry  
How to Write a Request for 
Designation (RFD) 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Office of the Commissioner 
Office of Combination Products 
April 2011 
 
  Guidance for Industry 
How to Write a Request for 
Designation (RFD)
 
 
 
 
 
 
 
 
For questions regarding this document, contact: 
Office of Combination Products (OCP) at 301-796-8930 or combination@fda.gov  
Public Comment 
Written comments and suggestions may be submitted at any time for Agency consideration to the 
Division of Dockets Management, Food and Drug Administration, 5630 Fishers Lane, Room 
1061, (HFA-305), Rockville, MD, 20852.  When submitting comments, please refer to the exact 
title of this guidance document.  Comments may not be acted upon by the Agency until the 
document is next revised or updated. 
 
Additional copies are available from:  
Office of Combination Products 
Office of the Commissioner 
Food and Drug Administration  
WO32 Hub/Mail Room #5129 
10903 New Hampshire Avenue 
Silver Spring, MD 20993-0002 
(Tel) 301-796-8930, (Fax) 301-847-8619 
combination@fda.gov  
http://www.fda.gov/combinationproducts/   
i i TABLE OF CONTENTS 
  
I. PURPOSE .............................................................................................................1 
II. GENERAL INFORMATION REGARDING THE REQUEST FOR 
DESIGNATION PROCESS FOR NON-COMBINATION AND 
COMBINATION PRODUCTS...............................................................................2 
A. What is a non-combination product?............................................................................................2 
B. What is a combination product?....................................................................................................3 
C. What is a Request for Designation?...............................................................................................3 
D. When should an RFD be submitted?.............................................................................................4 
E. Can I request a meeting with OCP to explain my product?........................................................4 
F. How do I submit an RFD for a combination or non-combination product?..............................5 
G. How promptly will FDA review my RFD?....................................................................................5 
H. May I withdraw my RFD after submission?.................................................................................5 
I. What if I disagree with OCPs jurisdictional determination?......................................................5 
J. How can I contact OCP?..................................................................................................................6 
K. Where can I find more information?.............................................................................................6 
III. WHAT INFORMATION MUST I INCLUDE IN AN RFD?.......................6 
A. What information must I include in my RFD?.............................................................................6 
B. What format should I follow for my RFD?...................................................................................7 
C. How should my RFD be addressed?..............................................................................................7 
D. Does FDA accept electronic submissions for RFDs?....................................................................7 
E. What information does FDA recommend that sponsors provide in RFD submissions?...........7 
1. Contact Information. Section 3.7(c)(1)........................................................................................8 
2. Product Name. Sections 3.7(c)(2)(i), 3.7(c)(2)(ii), and 3.7(c)(2)(iii)..........................................8 
3. Description of the Product. Section 3.7(c)(2)..............................................................................8 
ii i 4. Prior Approvals and Agreements. Section 3.7(c)(2)(iv)..............................................................8 
5. Chemical, Physical or Biological Composition. Section 3.7(c)(2)(v).........................................9 
6. Developmental Work and Testing. Section 3.7(c)(2)(vi).............................................................9 
7. Manufacturing Information. Section 3.7(c)(2)(vii)......................................................................9 
8. Proposed Use or Indications. Section 3.7(c)(2)(viii)...................................................................9 
9. Modes of Action and Primary Mode of Action. Section 3.7(c)(2)(ix).........................................9 
10. Schedule and Duration of Use.  Section 3.7(c)(2)(x)...............................................................13 
11. Dose and Route of Administration. Section 3.7(c)(2)(xi)........................................................13 
12. Related Products.  Section 3.7(c)(2)(xii).................................................................................13 
13. Other Relevant Information.  Section 3.7(c)(2)(xiii)...............................................................14 
14.  Sponsors Recommendation.  Section 3.7(c)(3).....................................................................14 
F. How can I limit my submission to 15 pages including attachments as required by the 
regulation, and still provide all the information FDA needs to make its decision?......................14 
IV. CONCLUSION................................................................................................15 
APPENDIX: RFD SCREENING CHECKLIST.................................................16 
 
  
iv  Guidance for Industry 
How to Write a Request for Designation 
(RFD) 
  
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. PURPOSE  
This guidance is intended to clarify the type of information the Office of Combination Products 
(OCP) recommends that a sponsor include in a Request for Designation (RFD).  The goal of this 
guidance is to help a sponsor understand the type of information FDA needs to determine the 
regulatory identity or classification of a product as a drug, device, biological product, or 
combination product,1 and to assign the product to the appropriate Agency component for review 
and regulation.2  This guidance addresses 21 CFR Part 3, as amended by the final rule defining 
the primary mode of action (PMOA) of a combination product (PMOA Final Rule).3  FDA's 
guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited. The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required. 
  
                                                 
1 Section 563 of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) and 21 CFR Part 3. 
2 Section 503(g) of the FD&C Act. 
3 70 FR 49848 (Aug. 25, 2005); also available at http://edocket.access.gpo.gov/2005/pdf/05-16527.pdf. The PMOA 
Final Rule has been in effect since November 23, 2005. 
1  II. GENERAL INFORMATION REGARDING THE 
REQUEST FOR DESIGNATION PROCESS FOR NON-
COMBINATION AND COMBINATION PRODUCTS 
A. What is a non-combination product? 
A non-combination product is a product that is only either a drug, a device, or a biological 
product as each is defined in the FD&C Act.  The term does not include combination products as 
defined in 21 CFR 3.2(e).  In part, Section 201(g) of the FD&C Act (21 U.S.C. 321(g)) provides 
that the term drug means:  
(A) articles recognized in the official United States Pharmacopeia, official 
Homeopathic Pharmacopeia of the United States, or official National Formulary, 
or any supplement to any of them; and (B) articles intended for use in the 
diagnosis, cure, mitigation, treatment, or prevention of disease in man or other 
animals; and (C) articles (other than food) intended to affect the structure or any 
function of the body of man or other animals; and (D) articles intended for use as 
a component of any articles specified in clause (A), (B), or (C). 
Section 201(h) of the FD&C Act (21 U.S.C. 321(h)) provides that the term device means:  
an instrument, apparatus, implement, machine, contrivance, implant, in vitro 
reagent, or other similar or related article, including any component, part, or 
accessory, which is-- 
(1) recognized in the official National Formulary, or the United States 
Pharmacopeia, or any supplement to them, 
(2) intended for use in the diagnosis of disease or other conditions, or in the cure, 
mitigation, treatment, or prevention of disease, in man or other animals, or 
(3) intended to affect the structure or any function of the body of man or other 
animals, and  
which does not achieve its primary intended purposes through chemical action 
within or on the body of man or other animals and which is not dependent upon 
being metabolized for the achievement of its primary intended purposes. 
Section 351(i) (as modified by the Patient Protection and Affordable Care Act) of the Public 
Health Service Act (PHS Act) (42 U.S.C. 262(i)) provides that the term biological product 
means: 
a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or 
derivative, allergenic product, protein (except any chemically synthesized 
2  polypeptide), or analogous product, or arsphenamine or derivative of 
arsphenamine (or any other trivalent organic arsenic compound), applicable to the 
prevention, treatment, or cure of a disease or condition of human beings.  
B. What is a combination product? 
A combination product is comprised of a combination of a drug and a device; a biological 
product and a device; a drug and a biological product; or a drug, a device, and a biological 
product.  Under 21 CFR 3.2(e), a combination product is defined to include: 
1. A product comprised of two or more regulated components (i.e., drug/device, biologic/device, 
drug/biologic, or drug/device/biologic) that are physically, chemically, or otherwise combined or 
mixed and produced as a single entity; 
2. Two or more separate products packaged together in a single package or as a unit and 
comprised of drug and device products, device and biological products, or biological and drug 
products; 
3. A drug, device, or biological product packaged separately that according to its investigational 
plan or proposed labeling is intended for use only with an approved individually specified drug, 
device, or biological product where both are required to achieve the intended use, indication, or 
effect and where, upon approval of the proposed product, the labeling of the approved product 
would need to be changed (e.g., to reflect a change in intended use, dosage form, strength, route 
of administration, or significant change in dose); or 
4. Any investigational drug, device, or biological product packaged separately that according to 
its proposed labeling is for use only with another individually specified investigational drug, 
device, or biological product where both are required to achieve the intended use, indication, or 
effect. 
Examples of combination products are available at 
http://www.fda.gov/CombinationProducts/AboutCombinationProducts/ucm101496.htm.  
C. What is a Request for Designation? 
An RFD is also referred to as an applicants letter of request (see 21 CFR 3.2(j)).   It is a written 
submission to OCP.  RFDs generally request a determination of (1) the regulatory identity or 
classification of a product as a drug, device, biological product, or combination product, and/or 
(2) either the component of FDA that will regulate the product if it is a non-combination product, 
or which Agency Center4 will have primary jurisdiction for premarket review and regulation if it 
is a combination product.  A letter of designation, see 21 CFR 3.2(i), (alternatively referred to as 
a designation letter) is FDAs formal response to an RFD and is a binding determination with 
                                                 
4 Section 503(g) of the FD&C Act defines the term agency center as a center or alternative organizational 
component of the Food and Drug Administration. 
3  respect to classification and/or center assignment that may be changed under conditions specified 
in Section 563 of the FD&C Act and 21 CFR 3.9 in the regulations.5  
D. When should an RFD be submitted? 
It is not necessary to submit an RFD for every product.  We recommend submitting an RFD 
when the classification of a product or the Agency Center to which it should be assigned is 
unclear or in dispute.  Sponsors are encouraged to submit an RFD as soon as they have sufficient 
information for FDA to make a decision regarding classification or assignment of a product.   
The RFD should be submitted before filing any investigational or marketing application for the 
product.  This will avoid a potential stay of the review clock if the classification or assignment of 
the product under review is determined to be unclear or in dispute during the review process.  
See 21 CFR 3.10.  This will also help you avoid expending unnecessary time and resources, by 
ensuring that whatever submission for investigational use or marketing approval you may 
ultimately make is of the appropriate type and to the appropriate Agency component. 
If you have classification or assignment questions regarding multiple related products or product 
families that have different configurations, ingredients, and/or proposed uses or indications, we 
recommend submitting a separate RFD for each product. 
E. Can I request a meeting with OCP to explain my product? 
We encourage you to contact OCP before submitting your RFD if you have any questions, 
including if you are uncertain about the type of information to include or about the need to 
submit an RFD.  However, it is not necessary to meet with OCP regarding most product 
classification and assignment questions or about an RFD submission.   
In most cases, the Agency will be able to make its determination based on a well-written RFD.  
However, if you believe a meeting with OCP would be helpful in providing the Agency with a 
better understanding of how the product works, you can request a meeting prior to submitting an 
RFD.  Such a request should include an explanation of the issues you would like to be addressed 
in the meeting.  OCP will then decide whether to grant the request.   
Due to a mandatory short timeframe for reviewing RFDs, in general, OCP will not grant a 
request for a meeting after the RFD is submitted.  Meeting requests may be submitted by writing 
to OCP at the address listed in Part III.C of this guidance document or by e-mail to 
combination@fda.gov.  Please label your correspondence as a Meeting Request. 
                                                 
5 Though a designation letter is generally binding as to classification and/or assignment of a particular product, that 
determination pertains only to the product described in the designation letter.  Further, if there is a change in, for 
example, an intended use or component of the product, or if the sponsor or Agency becomes aware of additional 
information that reveals that the mode or modes of action differ from what was originally described in the RFD, a 
new determination may be appropriate. 
4  F. How do I submit an RFD for a combination or non-combination 
product? 
The RFD process is outlined in 21 CFR Part 3.  The regulation addresses (1) who should file; (2) 
when to file; (3) what to file; and (4) where to file an RFD.  Part III of this document addresses 
the recommended format and specific content of an RFD in detail.  The required information to 
include in an RFD is described in 21 CFR 3.7 (available at 
http://www.fda.gov/CombinationProducts/GuidanceRegulatoryInformation/ucm109108.htm). 
G. How promptly will FDA review my RFD? 
Within 5 business days of its receipt of an RFD, OCP will review the submission for 
completeness and determine whether the RFD contains the required information. See 21 CFR 
3.8(a).  OCP will then either send the sponsor an acknowledgement letter confirming the filing 
date of the RFD, or notify the sponsor that the RFD was not filed, and identify the information 
needed to make the RFD complete for filing.  For filed RFDs, the acknowledgement letter will 
also identify the date by which FDA plans to respond to the RFD.   
If FDA does not issue a designation letter within 60 calendar days of the filing of the RFD, as 
required by 21 CFR 3.8(b), the sponsors recommendation for the classification or assignment of 
the product will become the designated  classification or assignment.  See Section 563 of the 
FD&C Act and 21 CFR 3.8(b). 
H. May I withdraw my RFD after submission? 
Yes, you may withdraw your RFD by notifying OCP in writing any time after its submission and 
before FDA issues its letter of designation.  When FDA issues its letter of designation, it 
constitutes an Agency determination that may only be changed in accordance with 21 CFR 
3.9(b).  See also section 563 of the FD&C Act.  Once the date-stamped letter of designation is 
issued by FDA, you may not withdraw your RFD. 
I. What if I disagree with OCPs jurisdictional determination? 
If you disagree with OCPs jurisdictional determination, 21 CFR Part 3 provides a mechanism 
for you to request that OCP reconsider its decision.  Under 21 CFR 3.8(c), you may request 
reconsideration of a decision within 15 calendar days of receipt of the designation letter.  A 
request for reconsideration under 21 CFR 3.8(c) cannot exceed five pages, and cannot include 
any new information that was not contained in your original RFD.  FDA will review and act in 
writing within 15 calendar days of our receipt of the request for reconsideration.6 
If you wish to present additional information or new data that was not presented in the RFD, you 
may submit a new RFD containing this information.  OCP will consider this RFD a new 
submission. 
                                                 
6 As with any agency decision, a review may be requested under 21 CFR 10.75. 
5  J. How can I contact OCP? 
Contact information for OCP, including mailing address, e-mail address, and phone number, are 
listed on the front page of this guidance document and in Parts III.C and D below. 
K. Where can I find more information? 
More information about product classification and assignment and regarding the regulation of 
combination products is available on the OCP website at 
http://www.fda.gov/CombinationProducts/default.htm.    
 
III.  WHAT INFORMATION MUST I INCLUDE IN AN 
RFD? 
A. What information must I include in my RFD? 
According to 21 CFR 3.7(c), you are required to include the following information in your RFD, 
as applicable.  Section III.E of this guidance further clarifies FDAs recommendations for the 
information that should be provided for each of these sections. 
1.  The identity of the sponsor, including company name and address, establishment 
registration number, company contact person and telephone number (3.7(c)(1)). 
2.  A description of the product, including:  
i.  Classification, name of the product and all component products, if applicable 
(3.7(c)(2)(i));  
ii.  Common, generic, or usual name of the product and all component products 
(3.7(c)(2)(ii));  
iii.  Proprietary name of the product (3.7(c)(2)(iii));  
iv.  Identification of any component of the product that already has received 
premarket approval, is marketed as not being subject to premarket approval, or 
has received an investigational exemption, the identity of the sponsors, and the 
status of any discussions or agreements between the sponsors regarding the use of 
this product as a component of a new combination product (3.7(c)(2)(iv));  
v.  Chemical, physical, or biological composition (3.7(c)(2)(v));  
vi.  Status and brief reports of the results of developmental work, including animal 
testing (3.7(c)(2)(vi));  
vii.  Description of the manufacturing processes, including the sources of all 
components (3.7(c)(2)(vii));  
viii.  Proposed use or indications (3.7 (c)(2)(viii));  
ix.  Description of all known modes of action, the sponsors identification of the 
single mode of action that provides the most important therapeutic action of the 
product, and the basis for that determination (3.7(c)(2)(ix));  
6  x.  Schedule and duration of use (3.7(c)(2)(x));  
xi.  Dose and route of administration of drug or biologic (3.7(c)(2)(xi));  
xii.  Description of related products, including the regulatory status of those related 
products (3.7(c)(2)(xii)); and  
xiii.  Any other relevant information (3.7(c)(2)(xiii)).  
3.  The sponsors recommendation as to which Agency component should have primary 
jurisdiction (3.7(c)(3)). 
B. What format should I follow for my RFD? 
We recommend that you follow the format and organization described in 21 CFR 3.7(c)(1)-(3). 
We recommend that you identify each required section of an RFD, in the order presented in the 
regulation, followed by your response. We recommend you use a standard typeface (e.g., Times 
New Roman), which should be in an easily readable font size (e.g., 12). 
As explained in 21 CFR 3.7(c), RFDs are limited in length to 15 pages, including attachments. 
C. How should my RFD be addressed? 
You should submit your original RFD, and two copies, to:  
 
Office of Combination Products 
Office of the Commissioner 
Food and Drug Administration  
WO32 Hub/Mail Room #5129 
10903 New Hampshire Avenue 
Silver Spring, MD 20993-0002 
 
In order for the RFD to be sent to the correct location, the envelope should be clearly marked as 
a Request for Designation. 
D. Does FDA accept electronic submissions for RFDs? 
Yes. You may submit your original RFD by e-mail to combination@fda.gov7 in a common 
electronic format, such as a Portable Document Format (PDF) in addition to two copies sent to 
the address listed in part C. above.  
E. What information does FDA recommend that sponsors provide in 
RFD submissions? 
Sponsors must provide the information required in 21 CFR 3.7.  FDA recommends including the 
following information to ensure sufficient information is available for FDA to determine the 
regulatory identity and most appropriate assignment of the product: 
                                                 
7 RFDs submitted to other e-mail accounts will not be accepted. 
7   1. Contact Information. Section 3.7(c)(1) 
In addition to the required information, such as your name and your companys name, its street 
address, company establishment registration number (if applicable), and telephone number, we 
recommend you also include your fax number, e-mail address, and alternate company contact 
person and contact information. 
 2. Product Name. Sections 3.7(c)(2)(i), 3.7(c)(2)(ii), and 3.7(c)(2)(iii) 
You must identify the classification, common, generic and/or usual names of your product and of 
all components of your product (if applicable).  If you have chosen a proprietary name for your 
product, you must include that in your RFD.  If any of this information is not known, please state 
this. 
3. Description of the Product. Section 3.7(c)(2) 
You must include a description of your product as outlined in 3.7(c)(2).  It may be helpful to 
provide descriptive diagrams for complex products.  For combination products with separate 
constituent parts (i.e., the drug, device, and/or biological product of which your combination 
product is comprised are not combined into a single entity), you should also explain how you 
intend to market your product.  For example, describe whether the constituent parts will be 
provided in a kit or co-package, or, if sold separately, how they will be labeled for use together.  
4. Prior Approvals and Agreements. Section 3.7(c)(2)(iv) 
This provision requires you to identify any component of the product that: 
  has received premarket approval/clearance;  
  is marketed as not being subject to individual premarket approval/clearance (e.g., under 
an over-the-counter drug monograph, as a human cellular/tissue product subject only to 
section 361 of the PHS Act, or as a device exempt from the premarket notification 
requirements in section 510(k) of the FD&C Act); or  
  has received an investigational exemption.  
Furthermore, Section 3.7(c)(2)(iv) requires you to identify the sponsor of any such component.  
You must also include the status of any discussions or agreements that you have had with the 
sponsor(s) regarding the use of the product(s) as a component of a new combination product. 
If you have previously submitted information about your product to  the Agency under a 
provision of the FD&C Act or an FDA regulation (e.g., under a request for device classification 
in accordance with section 513(g) of the FD&C Act, a 510(k) premarket notification, a new drug 
application (NDA) under section 505 of the FD&C Act or an investigational new drug 
application (IND) under 21 CFR 312, etc.), please reference any identifying number that is 
associated with that submission. 
8  If there are no prior approvals, clearances, or agreements, please state so. 
5. Chemical, Physical or Biological Composition. Section 3.7(c)(2)(v) 
A fundamental part of your products description is its chemical, physical and/or biological 
composition.  You must include this information in your submission according to 21 CFR 
3.7(c)(2)(v).  Please identify all of the components or the ingredients, the purpose of each, and 
their concentration or amount.  It may be helpful to provide this information in a tabular format.     
6. Developmental Work and Testing. Section 3.7(c)(2)(vi) 
This section requires that you include the status and brief reports of the results of developmental 
work, including animal testing.  See 21 CFR 3.7(c)(2)(vi).  We recommend that you summarize 
any available preclinical and clinical studies, with particular emphasis on those studies which 
establish the mode(s) of action and (for a combination product) the PMOA of the product.  
Information demonstrating the mode(s) of action of a product (e.g., whether or not a product or a 
component of a product works by chemical action or by being metabolized), and the PMOA of a 
combination product are important for the appropriate classification and jurisdictional 
assignment of your product. 
7. Manufacturing Information. Section 3.7(c)(2)(vii) 
You must include a description of the processes that will be used to manufacture your product, 
including the sources of all components. See 21 CFR 3.7(c)(2)(vii).  A brief description and/or 
flowchart will generally suffice. 
8. Proposed Use or Indications. Section 3.7(c)(2)(viii) 
Like the explanation of the composition of your product, the proposed use or indications section 
is a critical section of your RFD.  You are required to submit this information under 21 CFR 
3.7(c)(2)(viii).  You should state concisely and clearly the proposed use(s) or indication(s) for 
your product.  This information can be relevant both to the classification and assignment of your 
product. 
9. Modes of Action and Primary Mode of Action. Section 3.7(c)(2)(ix) 
This is the cornerstone of the RFD submission.  The modes of actions of products are typically 
critical to FDAs determination of whether a product is a drug, device, biological product, or 
combination product, and to the Agencys determination of the PMOA for a combination product 
upon which an assignment depends.  The regulation requires that you provide a description of all 
known modes of action, and, for combination products, identify the PMOA, and the basis for that 
determination.  See 21 CFR 3.7(c)(2)(ix).  Additional information on modes of action and 
PMOA is provided below.  
9  Modes of Action. 21 CFR 3.2(k) defines mode of action as:  the means by which a product 
achieves an intended therapeutic effect or action.  For purposes of this definition, therapeutic 
action or effect includes any effect or action of a combination product intended to diagnose, cure, 
mitigate, treat, or prevent disease, or affect the structure or any function of the body. 
Because combination products are comprised of more than one type of regulated article 
(biological product, device, or drug), and each constituent part contributes a mode of action, 
combination products will have more than one mode of action. 
Under 21 CFR 3.7(c)(2)(ix), your RFD must include a description of each mode of action of your 
product and should explain how each mode of action is achieved and which components or 
ingredients are responsible for each mode of action.  You should also state whether each mode of 
action contributes a drug, device, or biological product mode of action, and explain the basis for 
your conclusion.  It may be helpful to cite published literature8 or the developmental work and 
testing you provided under Section 3.7(c)(2)(vi) to support your explanation. 
Primary Mode of Action.9  21 CFR 3.2(m) defines primary mode of action (PMOA) as the 
single mode of action of a combination product that provides the most important therapeutic 
action of the combination product.  The most important therapeutic action is the mode of action 
expected to make the greatest contribution to the overall intended therapeutic effects of the 
combination product.  As with mode of action, for purposes of PMOA, therapeutic effect or 
action includes any effect or action of the combination product intended to diagnose, cure, 
mitigate, treat, or prevent disease, or affect the structure or any function of the body. 
If your product is a combination product, under 21 CFR 3.7(c)(2)(ix) and 3.7(c)(3), you must 
identify the mode of action that you believe to be the single mode of action that provides the 
most important therapeutic action of the combination product; i.e. the PMOA.  You must also 
include the basis for why you think that action is the most important.  Literature references are 
often helpful in supporting your argument or you may wish to refer to any data you provided in 
your response to Section 3.7(c)(2)(vi).  
Though not an exhaustive list (because each combination product presents different questions 
about its scientific characteristics and use), some factors that we consider when determining 
PMOA are provided below.  We recommend that you consider and address these as appropriate 
when explaining the PMOA of your combination product: 
  The proposed use(s) or indication(s) for the product;  
                                                 
8 When possible, you should cite published literature that is readily available.  If you choose to cite in press 
literature or other published literature that you believe would be difficult for the Agency to obtain, you should 
provide copies of the referenced material with your RFD.  We do not intend to count this type of supporting material 
toward the 15 page limit of your RFD.  However, information or data which is only available in your companys 
internal research report(s) should be included in the 15 page RFD.  
9 If your product is a non-combination product, then you would not need to identify a PMOA for the product.  
However, if there is reason to believe that your product might be a combination product (i.e., it may have two or 
more ingredients or components whose modes of action may be different), you should identify which mode of action 
makes the greatest contribution to the overall intended therapeutic effect of the product, and explain the basis for 
your conclusion.  
1 0   How it achieves its overall intended therapeutic effect(s);  
  The relative contribution of each constituent part to the proposed use(s) or indication(s), 
and to the overall intended therapeutic effect(s) of the product; 
  The duration of the contribution of each constituent part toward the intended therapeutic 
effect(s) of the product; and 
  Any data or information provided by you or that is available in scientific literature that 
describes and supports the mode of action expected to make the greatest contribution to 
the overall intended therapeutic effects of the product.  
If OCP does not have enough information to determine the PMOA of your product directly or 
cannot determine the PMOA with reasonable certainty, OCP will assign the combination product 
in accordance with the assignment algorithm at 21 CFR 3.4(b). 
Assignment Algorithm.  For some combination products, it may not be possible for you or us to 
determine with reasonable certainty which mode of action of the product provides the most 
important therapeutic action.  Determining the PMOA of a combination product is also 
complicated for products where the product has two completely distinct therapeutic effects 
achieved by completely different modes of action, neither of which is subordinate to the other 
(e.g., vision-correcting contact lenses impregnated with a drug for treating glaucoma).  In such 
an instance, 21 CFR 3.7(c)(3) requires the sponsor to recommend which Agency component 
should have primary jurisdiction based on the assignment algorithm at 21 CFR 3.4(b). 
The algorithm has two steps.  Under the first step, if there are other combination products that 
present similar questions of safety and effectiveness with regard to the combination product as a 
whole, the Agency will assign the combination product to the Agency component that regulates 
those other combination products.  See 21 CFR 3.4(b).   
However, there may be no other combination products that present such similar questions of 
safety and effectiveness.  For example, the RFD might present the first such combination 
product, or the combination product presented might differ in its intended use, design, 
formulation, etc., such that it presents different safety and effectiveness questions than existing 
combination products.  In such cases, we would turn to the second step, under which we would 
assign the combination product to the Agency component with the most expertise related to the 
most significant safety and effectiveness questions presented by the combination product.  Id.   
Factors relevant to application of the algorithm.  The factors listed below are intended to further 
illustrate the kinds of issues that may be relevant when determining whether a new combination 
product presents safety and effectiveness issues similar to those presented by a previous 
combination product, or which are the most significant safety and effectiveness questions 
presented by a combination product. We note that the list of factors below is not all-inclusive.  
Also, FDA may consider individual characteristics of the specific product.  Such case-by-case 
analysis allows the Agency to take into account, for example, technological developments, 
evolving scientific understanding, and specific factual information concerning the particular 
product, such as its composition, or mechanism of action for achieving an intended use.   
1 1 The following questions are not listed in order of importance; indeed some factors may be 
weighted more than others depending on various issues presented by each individual 
combination product.  If you believe FDA may need to consider the algorithm in the assignment 
of your product (i.e., if your products most important therapeutic action cannot be determined 
with reasonable certainty), then we recommend you consider and address these and/or other 
safety and effectiveness issues, as applicable, for your product: 
  What is the intended use(s)/indication(s) for use of the product?  
  What is the overall therapeutic effect(s) of the product as a whole?  
  Does a device constituent part incorporate a novel or complex design or have the 
potential for clinically significant failure modes?  
  Is a drug constituent part a new molecular entity or new formulation?  
  Has a generic version of the drug been approved under section 505(j) of the FD&C Act?  
  Does the drug have a narrow therapeutic index?  
  Is the biological product constituent part a particularly fragile molecule?  
  How well understood are the products constituent parts?  Is one constituent part 
relatively common, while another presents more significant safety and effectiveness 
issues relating to the risks it poses, its effectiveness, or its novelty?  
  Which constituent part raises greater risks?  
  Have any of the constituent parts been previously approved or cleared for the same or a 
similar use?  
  Is there a new indication, route of administration or a significant change in dose or use of 
one of the constituent parts?  
Addressing the assignment algorithm in your RFD.  If you cannot determine with reasonable 
certainty the most important therapeutic action of your combination product, you must 
recommend an assignment for your product based on the assignment algorithm at 21 CFR 3.4(b).  
See 21 CFR 3.7(c)(3).  Under the first step, you should consider whether FDA regulates other 
combination products that present similar questions of safety and effectiveness with regard to the 
combination product as a whole.  In other words, you should consider whether an FDA Center 
has direct experience with a combination product similar to yours.  You should identify any such 
other combination products that you are aware of that you believe FDA should consider in 
determining the assignment of your product, and explain how your product is similar.  For 
example, if you have developed a new drug for treating glaucoma that will be combined with a 
contact lens, and you are aware of other products reviewed by FDA that consist of a contact lens 
and another drug for this intended use, you should identify those products.   
If you do not believe that your product as a whole is similar to other combination products that a 
Center has already reviewed or that you are aware a Center is currently reviewing, you should 
address the second step of the algorithm.  Even if you believe your product is similar to another, 
we recommend that you explain how you think we should assign your product should we find it 
necessary to move to this second step in the algorithm.  For this part of the algorithm, you should 
identify the most significant safety and effectiveness questions presented by your combination 
product, and explain, in your opinion, which Center has the most expertise related to those 
questions.  For example, if this is the first time the Agency is presented with a vision-correcting 
contact lens containing a glaucoma drug, then, using the factors described above, you should 
1 2 explain, in your opinion, which Center has more expertise to answer these questions.  In this 
case, you might explain that the most significant safety and effectiveness questions are related to 
the characterization, manufacturing, and clinical performance of the drug component, while the 
safety and effectiveness questions raised by the vision-correcting contact lens are considered 
more routine.  Based on these criteria, you might recommend that CDER has the most expertise 
related to these issues. 
10. Schedule and Duration of Use.  Section 3.7(c)(2)(x) 
You must briefly explain how often and for how long your product is intended to be used.  For 
example, if your product is a non-combination device that would be implanted in the body during 
one surgical procedure, you should state the duration for which it is implanted or if it will be 
implanted with the expectation that, as long as the device functions, it will remain in the body 
indefinitely.  In other cases, such as with a wound dressing, for instance, an RFD might explain 
that the dressing should be used over a four-hour period, after which a change of dressing would 
occur if needed, with a maximum of six dressings to be used over a 24-hour time period.  
Another example would be that your product is a drug to be delivered by a device every twelve 
hours over a period of time not to exceed 10 days. 
11. Dose and Route of Administration. Section 3.7(c)(2)(xi) 
As applicable, you should briefly explain the dose (amount) of the drug or biological product (or 
constituent part) to be used, and how it will be used in or on the body.  For example, for a 
combination product wound dressing consisting of a drug and device delivery system, you would 
identify the specific amount of the drug contained in the device, and that it would be applied 
topically to the specific type of wound your product is intended to treat.  If your product is an 
injectable drug, you would explain that the delivery device would be used to inject a specific 
dose of the drug intramuscularly, intravenously, etc. 
Even if you believe your product is a device (containing no drug or biological products), it may 
be helpful to provide information about the dose or route of administration for the product.  For 
example, if your product is an injectable product, such as a wrinkle filler, you should describe 
the amount of product being injected and the site of the injection. 
12. Related Products.  Section 3.7(c)(2)(xii) 
If you think there are other products like yours, or other products with related components, you 
must briefly explain what they are, how they are regulated, and their regulatory status (e.g., 
approved, investigational, etc.) so that we can consider them when classifying and/or making the 
assignment for your product. Please include the product application numbers when available 
(e.g., 510(k) or NDA number).  You should explain any similarities or differences between these 
products and your product and state how these are relevant to the classification and/or 
assignment of your product. 
If you are not aware of other products like yours or other products with related components, 
please state this. 
1 3 13. Other Relevant Information.  Section 3.7(c)(2)(xiii) 
If you think there is anything else we should consider when determining the appropriate 
classification and/or assignment of your product, you should explain that in this portion of your 
RFD.  For example, literature references describing the product, its components, and its modes of 
action are often helpful. 
14.  Sponsors Recommendation.  Section 3.7(c)(3) 
The final section of an RFD must include your recommendation for the classification (drug, 
device, biological product, or combination product) and assignment (CBER, CDER, or CDRH) 
of your product. 
If you believe your product is a non-combination product, you should state whether you believe 
it meets the statutory definition of a drug, device, or biological product and your rationale for this 
recommendation.  Your classification recommendation should be based on the composition, 
mode(s) of action, and intended use(s) of your product.  Based on this recommended 
classification, you should then state your recommendation as to which Center (CBER, CDER, or 
CDRH) should regulate your product.   
If you believe your product is a combination product, you should state what type of combination 
product it may be (e.g., drug/device) and your rationale for this recommendation.  Next, you 
should explain which Center (CBER, CDER, or CDRH) should have primary jurisdiction (the 
lead) for regulation of your product.  This explanation should be based on the composition, 
intended use(s), modes of action, and PMOA of the product.  If you cannot determine which 
single mode of action provides the most important therapeutic action of the product, you must 
use the algorithm set forth in 21 CFR 3.4(b) to make your recommendation of lead Center (see 
Section 9 above). 
If you are unclear whether your product is a combination product or a non-combination product, 
we recommend you provide an analysis for the product being a combination product and for 
being a non-combination product.  
F. How can I limit my submission to 15 pages including attachments 
as required by the regulation, and still provide all the information 
FDA needs to make its decision? 
In FDAs experience, a comprehensive RFD submission, addressing all the information required 
by the regulation and needed by FDA to make its jurisdictional determination, can be 
accomplished within the 15-page requirement.  The most important sections of an RFD are 
summarized in Section IV below.  
 
1 4 IV. CONCLUSION 
This guidance provides our recommendations for the format and content of an RFD submission. 
We recommend you pay particular attention to these sections of your RFD as applicable: 
  A complete description of the product, including its composition (what is your product?);  
  The intended use/indications of the product (why would your product be used?);  
  The mode(s) of action of the product (how does your product work?);  
  The PMOA of the product (what is your combination products most important 
therapeutic action?);  
  The basis for your PMOA determination (including any literature references and a 
summary of any developmental work or testing that helps describe your products modes 
of action and/or PMOA);  
  The assignment algorithm; and  
  Your classification and assignment recommendations (how do you think your product 
should be classified and assigned, and why?).  
OCP is always available as a resource to you. We strongly encourage you to contact OCP before 
submitting your RFD if you have any questions, or if you are uncertain about the type of 
information to include. 
1 5  
Appendix: RFD Screening Checklist
_____: Original RFD not exceeding 15 pages, including attachments (21 CFR 3.7(c)) 
_____: The identity of the sponsor, including company name and address, establishment 
registration number, company contact person, and telephone number (3.7(c)(1)) 
_____: Description of the product (3.7(c)(2)) 
_____: Classification, name of the product, and all component products, if applicable 
(3.7(c)(2)(i)) 
_____: Common, generic, or usual name of the product and all component products 
(3.7(c)(2)(ii)) 
_____: Proprietary name of the product (3.7(c)(2)(iii)) 
_____: Identification of any component of the product that already has received premarket 
approval, is marketed as not being subject to premarket approval, or has received an 
investigational exemption. The identity of the sponsors, and the status of any discussions or 
agreements between the sponsors regarding the use of this product as a component of a new 
combination product (3.7(c)(2)(iv)) 
_____: Chemical, physical, or biological composition (3.7(c)(2)(v)) 
_____: Status and brief reports of the results of developmental work, including animal testing 
(3.7(c)(2)(vi)) 
_____: Description of the manufacturing processes, including the sources of all components 
(3.7(c)(2)(vii)) 
_____: Proposed use or indications (3.7(c)(2)(viii)) 
_____: Description of all known modes of action, the sponsors identification of the single mode 
of action that provides the most important therapeutic action of the product, and the basis for that 
determination (3.7(c)(2)(ix)) 
_____: Schedule and duration of use (3.7(c)(2)(x)) 
_____: Dose and route of administration of drug or biologic (3.7(c)(2)(xi)) 
_____: Description of related products, including the regulatory status of those related products 
(3.7(c)(2)(xii)) 
1 6 _____: The sponsors recommendation as to which Agency component should have primary 
jurisdiction based on the mode of action that provides the most important therapeutic action of 
the combination product. (3.7(c)(3)) 
_____: For combination products where the mode of action that provides the most important 
therapeutic action cannot be determined with reasonable certainty, the sponsors 
recommendation must be based on the assignment algorithm and an assessment of the 
assignment of other combination products the sponsor wishes FDA to consider during the 
assignment of its combination product. (3.7(c)(3)) 
_____: 1st step of assignment algorithm: assignment of other combination products presenting 
similar safety and effectiveness questions 
_____: 2nd step of assignment algorithm: most expertise related to the most significant safety 
and effectiveness questions 
 
1 7