REGULATION OF COMBINATION PRODUCTS

1. REGULATION OF COMBINATION PRODUCTS Mark A. Heller Wilmer Cutler Pickering Hale and Dorr LLP MassMEDIC Combination Product Program, March 28, 2006

2. 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) WilmerHale

3. 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 WilmerHale

4. 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 WilmerHale

5. 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 WilmerHale

6. 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 WilmerHale

7. 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 • Ensureconsistent and appropriate postmarket regulation WilmerHale

8. 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 WilmerHale

9. 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 WilmerHale

10. 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 WilmerHale

11. 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) WilmerHale

12. 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) WilmerHale

13. 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. WilmerHale