Practical Issues in Combination Products
Primary Mode of Action & Request for Designation
AdvaMed MTL Conference
May 25, 2006
Suzanne O'Shea
Product Classification Officer
Office of Combination Products
Food and Drug Administration
In the beginning…
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Combination products statutorily recognized in Safe Medical Device Act of 1990
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Required assignment to lead center based on primary mode of action
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Implemented by Chief Mediator and Ombudsman
Office of Combination Products
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Created by Medical Device User Fee and Modernization Act (MDUFMA)
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Office established on December 24, 2002
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OCP given broad oversight responsibilities covering the regulatory life cycle of combination products.
OCP's Roles:
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Make jurisdictional determinations
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Oversee / help coordinate premarket review
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Ensure consistent / appropriate postmarket regulation
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Develop policy, guidance, and regulations
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Serve as a resource for industry and review staff
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Resolve timeliness disputes
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Report to Congress
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Special initiatives
OCP Objectives
Ensure that regulation of every combination product is:
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Clear
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Consistent
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Appropriate
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Predictable
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Transparent
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In a nutshell
OCP answers four questions products might ask -- if they could talk:
1. What am I?
2. Where do I go?
3. What do I do when I get there?
4. How can I get out of there as quickly as possible?
Where is OCP?
Commissioners Office
Office of Combination Products
Center for Biologic Evaluation and Research
Center for Devices and Radiological Health
Center for Drug Evaluation and Research
I am a combination product
Where do I go?
Drugs - CDER
Devices - CDRH
Biologics - CBER
Primary Mode of Action
Primary mode of action is the statutory criterion FDA must use to determine the agency component with primary jurisdiction for the review and regulation of a combination product.
21 U.S.C. § 503(g)
PMOA continued
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PMOA not defined in statute, now defined in regulations:
21 CFR 3.2(k) and (m).
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Final Rule issued on August 25, 2005 and can be accessed at:
Mode of Action
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Mode of Action: the means by which a product achieves an intended therapeutic effect or action.
21 CFR 3.2(k) -
Three types of modes of action: biological product, device, drug
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Combination products typically have more than one identifiable mode of action
Primary Mode of Action
Primary mode of action is 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.
21 CFR 3.2(m)
PMOA algorithm
If unable to determine most important therapeutic action with reasonable certainty, consider:
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Consistency: is there an agency component that regulates other combination products presenting similar questions of S & E with regard to combination product as a whole?
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Safety and Effectiveness: which agency component has the most expertise related to most significant S&E questions presented by combination product?
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PMOA
CDER or CDRH?
Drug Eluting Stent
Primary Mode of Action: Stent opens artery
Secondard Action: Drug prevents inflamation and restenosis of artery.
Regulated by CDRH under device provisions.
Drug Eluting Disk
Primary Mode of Action: Cancer chemotherapy of brain tumor
Secondary Actions: Local drug delivery of drug by device.
Regulated by CDER under drug provision.
More PMOA examples
Spinal fusion device coated with therapeutic protein intended to treat degenerative disc disease
Two modes of action:
- mechanically maintain intervertebral spacing;
- encourage formation of bone within fusion cage.
PMOA attributable here to device component's action to mechanically maintain spacing and stabilize spine
- Protein cannot maintain space and stabilize alone
- Spinal fusion can be obtained without protein
More PMOA examples
Contact Lens Combined with Drug to Treat Glaucoma
Two modes of action: to correct vision
to administer glaucoma drug
Not possible to determine which MOA provides greatest contribution to overall therapeutic effect
Assignment Algorithm:
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Other combination products presenting similar S & E questions
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Agency component with most expertise pertaining to presenting S & E questions
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?? What about second contact lens combined with ??
?? glaucoma drug product ??
The last PMOA example
Interferon Ribavirin Combination Therapy
to treat chronic hepatitis C
Interferon: biologic to treat chronic hepatitis C by causing decline in hepatitis C virus RNA titer
Ribavirin: drug improves liver function in hepatitis C patients, but they relapse
Products used together more effective than interferon alone.
Two modes of action: interferon treats disease; ribavirin enhances efficacy of interferon
PMOA: Interferon
Request for Designation (RFD)
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Voluntary Formal Process
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21 CFR Part 3
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Classification (what am I?)
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Assignment (where do I go?)
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Clarification of Regulatory Pathway
(what do I do when I get there?)
Who should file an RFD?
An RFD should be filed when the
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Classification or
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Assignment
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is unclear or in dispute.
What happens if
I don't file an RFD?
FDA may stay the review clock while a determination is being made.
21 CFR 3.10
When should I file an RFD?
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Before filing any application for premarket review
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As soon as there is sufficient information for FDA to make a determination
RFD Content
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Sponsor information
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Product description
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Proposed use and indications
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Description of primary mode of action
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Recommendation on product classification and Center with primary jurisdiction
21 CFR §3.7 (c)
Also, see Guidance Document on How to Write a Request for Designation at
Guidance Document
How to Write a Request for Designation
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Provides recommendations for information to include in each section of RFD
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Incorporates concepts of PMOA rule
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Goal: to help sponsors provide FDA with information to make appropriate jurisdictional determination
Guidance Document
How to Write a Request for Designation
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Key sections to focus on:
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What is your product?
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Why would your product be used?
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How does your product work?
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What is your product's most important therapeutic action?
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What is the basis for your PMOA analysis?
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How do you think your product should be assigned?
Why? Use assignment algorithm if appropriate.
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RFD Processing
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OCP reviews RFD's for completeness
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If complete, OCP sends acknowledgement letter to sponsor, and copy of RFD's to three Center Liasons
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Center recommendations due to OCP in 21 days
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Consultation among OCP, Centers and Office of Chief Counsel
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Decision reached, response letter prepared, necessary clearances obtained
RFD processing
RFD decision letter must issue within
60 days.
Otherwise,
Sponsor's recommendation takes effect.
21 CFR 3.8(b)
What if I disagree with RFD decision?
Request for Reconsideration
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Submit within 15 days
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Less than 5 page submission, no new information
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FDA response within 15 days
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FDA has been known to change a decision upon reconsideration
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21 CFR 3.8(c)
What's the effect of an
RFD letter?
Designated agency component may be changed without the consent of sponsor only to protect the public health or for another compelling reason.
21 CFR § 3.9(b)
RFD Statistics
October 1, 2005 March 31, 2006
Total Decisions Issued: 16
9 combination product
7 non-combination products
Mean Total Review Time: 34 days
Median Total Review Time: 31.5 days
Range of Total Review Time: 16 to 57 days
Requests for Reconsideration: 2
Response to Requests for Reconsideration 15 days
OCP agrees with sponsor's PMOA recommendation
72 per cent of the time.
How to find out…
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Intercenter Agreements
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Jurisdictional Determinations
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Jurisdictional Updates
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RFD letters for approved products
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Examples of recently approved combination products
See our website at:
Intercenter Agreements
ICA's premised on "most important therapeutic action"
For example: assignment to CDRH of "device incorporating a drug component with the combination product having the primary intended purpose of fulfilling a device function."
Underlying assumption: device provides most important therapeutic action.
1991 ICA's continue to provide helpful guidance but do not address many combination products developed since that time.
Intercenter Agreements
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MDUFMA added Section 503(g)(4) to the Act; requires FDA to review each agreement, guidance, or practice specific to the assignment of combination products to agency centers and determine whether the agreement, guidance or practice is consistent with the requirements of Section 503(g) of the Act.
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Jurisdictional Update issued in September 2005.
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FDA plans to issue Federal Register notice seeking stakeholder comment on agency's review of agreements, guidance and practices.
Jurisdictional Determinations
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"one liners"
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Based on RFD decisions when sufficient supporting information has been made public
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Currently more than 200 jurisdictional determinations have been issued
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Updated periodically
Jurisdictional Updates
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Detailed statement of past jurisdictional decisions pertaining to a class of products
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Demineralized bone matrix;
Catheter lock flush solutions;
Drug eluting stents;
Dental prophylaxis paste;
Metered dose inhaler. -
Issued periodically
RFD letters
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Issued once product covered by RFD letter has been approved or cleared.
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Redacted to remove confidential commercial information.
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50 redacted RFD letters included on OCP web page
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More letters issued periodically
Examples of Approved
Combination Products
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Not necessarily covered by RFD decision
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Link to approval / clearance information
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23 products currently listed
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More products listed as approval / clearance occurs
Chemical Action
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Currently under consideration.
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Should help clarify classification of product as a drug or device.
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Reasonable minds can differ.
Perhaps the easiest
way to find out…
CALL US!
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In FY 2005, OCP responded to 195 "informal" requests for jurisdictional determinations.
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Phone calls and e-mail
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Informal decision issued when jurisdiction is clear in absence of RFD. Based on consultations with Center liaisons.
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Not binding
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Sometimes our recommendation is to submit an RFD.
Contact Us!
Office of Combination Products
15800 Crabbs Branch Way
Suite 200, HFG-3
Rockville, Maryland 20855
Contact Us!
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301-427-1934
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combination@fda.gov