Our RA Manager Song Seto guides you through the FDAs pathway to get your combination product to the US market. Learn more about the combo products pre-market submission reviews and the other mechanism devised by the FDA and things that you should include in your pre-market submission.

1. www.emmainternational.com
Song Seto, Ph.D.
Regulatory Affairs Manager
Navigating the US
FDA for Combination
Products

2. Leaders in Compliance
Consulting and
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• EMMA International Consulting Group, Inc. is a global leader in
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3. • What is a combination product?
• Jurisdiction of combination
products
• Primary mode of action
• Determining jurisdiction via
Office of Combination Products
• Additional considerations
Outline
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4. • Medical products can be regulated as the
following with the associated Center:
• Drugs – Center for Drug Evaluation and
Research (CDER)
• Devices – Center for Devices and Radiological
Health (CDRH)
• Biologics – Center for Biologics Evaluation and
Research (CBER)
• Office of Combination Products (OCP)
• Within the Office of Special Medical Programs
• Serves as focal point for medical product
classification and assignment issues
FDA Centers

5. 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 biologic 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 whereupon
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.
Combination Product (21CFR3.2(e))

6. 6
Combination Product (21CFR3.2(e))
CombinationProduct
Combination
Product

7. • Device coated or impregnated
with a drug or biologic
• Drug-eluting stent
• Prefilled drug delivery systems
• Prefilled syringes
• Co-packaged combination
products
• Drug or vaccine vial packaged with
a delivery device
Examples

8. • A Center (CDER, CDRH, CBER) has the
“lead” in a combination product
• Example:
• Antibiotic bone void filler
• CDRH is the lead center, CDER is the consulting
center
• Product is filed through CDRH
Some combination products are well-
established, but what do you do if you are
unsure of the jurisdiction of your product?
Jurisdiction

9. • “the single mode of action of a
combination product that provides the
most important therapeutic action of
the combination product.”
• Establishes its regulatory framework
• Example: Drug-eluting stent
• Modes of action:
1. Structural: support lumen of blood
vessel to allow blood flow – device
component
2. Chemical: limit tissue ingrowth – drug
component
• Which mode of action is the most critical?
• PMOA determines lead center
Primary Mode of Action (PMOA)

10. • The algorithm for the jurisdiction
of a product depends on several
factors:
• Is it clear what the PMOA is?
• Does one Center regulate other
combination products presenting
similar questions of safety and
effectiveness?
• Which Center has the most expertise
related to the most significant safety
and effectiveness questions
presented by the combination
product?
Determining Jurisdiction
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11. • Scientific reviewers at OCP will provide initial review
• Reach out to relevant Centers for analysis
• Product Jurisdiction Officer
• Reviewer
• Supervisors
• Inter-center Agreements
Determining Jurisdiction through OCP
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12. • A formal request for regulatory identity or classification, if it is
unclear
Request for Designation (21CFR 3.2(j))
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• Document
• 15 page limit
• Medical product description (e.g.,
components, composition)
• Proposed use or indications
• Brief reports of testing
• Description of all known modes of
action and the firm’s identification
of the primary mode of action with
rationale
• Description of related products,
including the regulatory status of
those related products

13. • Typically for products that are well defined
in the development process
• Within 5 business days, OCP will review
RFD and determine if it contains the
required information
• If RFD is incomplete, it is unfiled
• For filed RFDs, feedback usually provided in
a Letter of Designation within 60 calendar
days
• If feedback is not provided within 60 days,
the firm’s recommendation for the
classification or assignment of the product
will become the designated classification or
assignment
Request for Designation
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14. Reconsideration of Designation
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• If the firm disagrees with the designation set forth by OCP, a
letter of reconsideration is possible
• Written request must be filed
within 15 days of receipt of the
letter of designation
• 5 pages max
• No new information may be
included
• Product jurisdiction officer will respond within 15 days of
receipt

15. Redacted Decision Letters
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• RFD decision letters for
cleared or approved
products are posted on
FDA’s website
• Can provide guidance on
how FDA makes its
jurisdictional determination

16. Capsular Decisions
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https://www.fda.gov/combination-products/classification-and-jurisdictional-information/rfd-jurisdictional-decisions

17. • Informal, non-binding feedback
• Typically feedback provided within 60 days, if sufficient
information is provided
• Can be submitted for products at varying stages of development
• Feedback for specific indication or configuration that can change the
regulatory pathway
Pre-Request for Designation (pre-RFD)
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BY-SA-NC

18. • Document
• No page limit
• Description of product
• Proposed use or indications
• Description of how product achieves its
intended therapeutic/diagnostic effects
• Can include information that would be in
a RFD
• Analysis of PMOA is optional, but
recommended
• Submit to combination@fda.gov
Pre-RFD Recommendations

19. • There is no user fee associated with the pre-RFD or RFD
process
• User fee corresponds to the application that is filed through the
lead center
• CDRH: 510(k), De Novo, PMA…
• CDER: NDA, ANDA,…
• CBER: BLA, …
User Fees
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20. • Clinical studies with combination products typically require one
investigational application
• Investigational New Drug (IND) or Investigational Device
Exemption (IDE)
• Exploratory studies may help define the
components of a combination product
• OCP can assist in determining
jurisdiction
Investigational Combination Products

21. Pre-clinical Studies for Combo Products
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• Considerations:
• Are there interactions between components?
• Does product require additional biocompatibility
testing?
• Does product require new engineering/functional
testing?
• Are there additional leachables/extractables to
characterize?
• Will there be a change in stability of the
drug/biologic?
• Is drug adsorption/adhesion characterized?
• What are the breakdown products?

22. • Pre-Submission
• Feedback on specific questions
• Review staff from applicable
Centers
• Product Jurisdiction Officers
• Adds time, but can be valuable
Additional FDA Interaction
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23. • How to Write a Request for Designation (RFD)
https://www.fda.gov/RegulatoryInformation/Guidances/ucm126
053.htm#IIIB
• How to Prepare a Pre-Request for Designation (Pre-RFD)
https://www.fda.gov/downloads/RegulatoryInformation/Guidan
ces/UCM534898.pdf
• Redacted RFD Decision Letters
https://www.fda.gov/CombinationProducts/JurisdictionalInfor
mation/RFDJurisdictionalDecisions/ucm2007395.htm
Additional Resources

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