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.