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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
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.
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