regulation of combination products mark a. heller wilmer cutler pickering hale and dorr llp...
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REGULATION OF COMBINATION PRODUCTS
Mark A. Heller
Wilmer Cutler Pickering Hale and Dorr LLP
MassMEDIC Combination Product Program, March 28, 2006
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SAFE MEDICAL DEVICES ACT—1990 What is a Combination Product?
– Examples are (1) monoclonal antibody combined with a therapeutic drug;
(2) drug-eluting stent, pacing lead with steroid-coated tip; (3) prefilled
syringes, insulin injector pens, metered dose inhalers; and (4) surgical tray
with surgical instruments, drapes and antimicrobial swabs
Reason for Combination Product provision Enacted section 503(g) of the Act—“primary mode of
action” basis for assigning lead jurisdiction to CDER,
CDRH, or CBER
(Cont’d)
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Amended definitions of “drug” and “device” =
distinguished between the two based on the manner in
which the “primary intended purpose[]” of the product is
achieved, i.e., primary mode of action FDA’s discretion = use any resources “necessary to
ensure adequate review” Ultimately, purpose of law was to limit FDA’s discretion in
selecting review center and to require the promulgation
implementation regulations
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Agency promulgated 21 CFR Part 3 in 1991
Defined “combination product”
Recognized Intercenter Agreements— Nonbinding guidance
created to clarify jurisdictional issues
Created Requests for Product Designations of combination and
single entity products
Request for Designation content requirements
Defined binding nature of designation
Described reconsideration
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FDAMA 1997
Established authority to classify drugs, devices,
biological products and combination products, and
identify the component of FDA that will regulate the
product 60 days for agency to make determination; 60 day
hammer Binding unless sponsor’s consent to change or public
health reasons based on scientific evidence
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BELIEFS LEADING TO MDUFMA 2002 Designations generally timely but inconsistent No continuing oversight of review Issues with standards to be used when more than one
center involved in a review Postmarket responsibilities not addressed Little transparency: With the exception of two (now
nine) “jurisdictional updates” posted on website,
designation decisions were not publicly available Opportunity for reauthorization of user fees
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MDUFMA—2002
Established Office of Combination Products (“OCP”) within the Office of the Commissioner to promptly assign, oversee, and coordinate reviews of combination products Purpose: Ensure timely and effective premarket review Ensure consistent and appropriate postmarket
regulation
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Duties of OCP Assignment of center with primary jurisdiction (lead center) for
combinations according to section 503(g) (primary mode of action)
within 60 days
Coordination of reviews involving more than one center and
oversight of timeliness
Resolution of disputes regarding the timeliness of premarket
reviews unless dispute is “clearly premature”. However, no direct
substantive dispute resolution role (dispute first considered by
primary center, followed if necessary by Commissioner’s review:
Commissioner must consult with OCP)
Review, update or delete existing assignments, agreements,
guidances, and practices
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THE DESIGNATION PROCESS
Strategically, decide whether to go to Center or OCP If OCP, meet with Office Submit RFD early OCP will assign product to lead center based on a
determination of the “primary mode of action.” KEY: PRIMARY mode of action
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Definition of “primary mode of action”August 25, 2005 Final Federal Register Notice Defines primary mode of action 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.”
Establishes algorithm for cases in which it is not possible to determine which mode
of action provides the most important therapeutic action: Assign product to agency
component that regulates combination products with similar safety and
effectiveness questions, or, if no other products with similar safety and
effectiveness questions, to agency component with the most expertise regarding
the most significant safety and effectiveness questions presented by the
combination product
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POSTMARKET ISSUES
Current Good Manufacturing Practices (cGMPs) - FDA
Guidance for Industry and FDA (Sept. 2004):
– There are no current good manufacturing practices (cGMPs) for
combination products
– FDA believes that products that are manufactured separately and later
combined are subject to the governing cGMP regulations that apply to
each individual product
– FDA believes that combination products that are produced as a single
entity or are co-packaged are subject to the cGMP regulation applicable
to the regulated component (but compliance can generally be achieved
by following one of the cGMPs)
(Cont’d)
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Labeling – March 28, 2005 Federal Register Notice of
Public Meeting
– 21 CFR Part 3 contemplates mutually conforming labeling
– FDA encourages “sponsors” to work together when bringing to
market products that are intended to be used together
– FDA/Drug Information Association cross labeling workshop on May
10, 2005: discuss issues that arise when sponsors develop product
for use with another cleared or approved product and the other
product’s labeling is not changed
(Cont’d)
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Postmarket Safety Reporting
– FDA believes that appropriate reporting may be achieved
by following the regulatory provisions for the type of
application under which the product was approved/cleared
– but may use dual reporting
– In interim, consult with OCP
Postmarket requirements should reflect the regulatory
status of the combination product, i.e., device, drug or
biological product. From a jurisdictional perspective
there is no such thing as a combination product.