Combination Products: Jurisdictional Issues

1. Combination Products:  Jurisdictional Issues MassMEDIC Presentation March 28, 2006 Janice Hogan, Esq. Partner Hogan & Hartson, LLP jmhogan@hhlaw.com

2. Determining Jurisdiction over Combination Products • FDA procedure for determining which center within FDA shall have primary jurisdiction for the premarket review of combination products (21 C.F.R. § 3.1) • FDA determines the appropriate center based on the primary mode of action of the combination product (21 C.F.R. § 3.4) • Designation of center does not preclude consultation with another center, or requiring separate applications

3. Two Alternative Approaches • Combination Products covered by an Intercenter Agreement • Request for Designation for combination products not covered by an Intercenter Agreement or for which the center designation is in dispute or otherwise unclear

4. Intercenter Agreements • Set forth the allocation of responsibility for certain categories of products or specific products (21 C.F.R. § 3.5(a)(1)) • Intercenter Agreements provide non-binding determinations as guidance to the public (21 C.F.R. § 3.5(a)(2)) • The sponsor of a premarket application or required investigational filing for a combination product covered by an Intercenter Agreement should contact the designated center before submitting an application to confirm coverage and to discuss the application process (21 C.F.R. § 3.5(a)(3))

5. Intercenter Agreements • Apply to all 3 centers • Use examples, but not all inclusive • Intercenter Agreements now written so long ago that they are not up to date and are undergoing review for possible revision

6. Request for Designation • Formal determination by FDA on assignment of the lead agency center for the product’s premarket review and regulation • Should be filed whenever: • intercenter agreements do not cover a combination product • product jurisdiction is unclear or in dispute • When to File:Before manufacturer files an application for premarket review (either marketing or investigational)

7. Request for Designation • RFD is a 15 page or less summary document that includes: • identity of sponsor • description of the product • sponsor’s recommendation as to which component should have primary jurisdiction and statement of reasons

8. Request for Designation • Primary mode of action - Key elements in an RFD argument for regulation under the device or drug authorities include: • Relevant legal definitions (drug, device, biologic, combination product) • Scientific description/analysis • Relevant precedents (cite or distinguish) • Policy arguments (re: center expertise, FDA convenience)

9. Request for Designation: Timing • Review Timing • Each Request for Designation will be reviewed for completeness within 5 days of receipt • Within 60 days of receiving a complete request, the FDA will issue a letter of designation specifying the FDA component having primary jurisdiction • If a letter of designation is not issued within 60 days, the sponsor’s recommendation becomes binding

10. Request for Designation: Appeal • Sponsor may request reconsideration of FDA’s decision within 15 days of receiving letter of designation • No new information may be submitted • FDA must act on request for reconsideration within 15 days • FDA may change designation: (a) with the written consent of the sponsor; or (b) without such consent to protect the public health or for other compelling purposes (21 C.F.R. §3.9(b))

11. Request for Designation • Decisions are not public • Lack of transparency leads to industry perception that process is unclear and often seemingly inconsistent • FDA may change designated lead Center with or without written consent of the sponsor to protect the public health or “for other compelling reasons” • Sponsor gets 30 days notice and opportunity to object

12. Why does it matter which center within FDA has jurisdiction? • Drugs, Biologics, and Medical Devices are all subject to unique sets of statutes, regulations, and guidance documents • The separate centers within FDA have different organizational structures, sets of nomenclature, and regulatory cultures

13. Submission Type Average Total FDA Approval Review Time IDE 28 days 510(k) 100 days (FY04) PMA 436 days total from submission to decision (FY04) IND < 30 days NDA 301 days (FY04) BLA 19.8 months (CY04) Regulatory Review and Approval Timeframes

14. Office of Combination Products (OCP) • OCP was established on Dec. 24, 2002, as required by the Medical Device User Fee and Modernization Act of 2002 • Responsibilities include: • assigning an FDA Center to have primary jurisdiction for review of a combination product • ensuring timely and effective premarket review of combination products by overseeing reviews involving more than one agency center

15. Office of Combination Products (OCP) • Responsibilities of OCP (continued): • ensuring consistency and appropriateness of postmarket regulation of combination products • resolving disputes regarding the timeliness of premarket review of combination products • updating agreements, guidance documents or practices specific to the assignment of combination products

16. Jurisdictional Determinations To improve the transparency of the jurisdiction process, FDA now posts a summary list of jurisdictional determinations • “Capsular descriptions” of selected jurisdictional decisions • Limited to products that have been publicly disclosed by the sponsor • Describe prior FDA RFD decisions • Not policy statements

17. Jurisdictional Determinations • Combination Products with Drug Primary Mode of Action • Cytotoxic agent and biologic for targeted cancer treatment • Photosynthesizing drug and light source for cancer treatment • Drug and transdermal iontophoretic delivery system • Drug with implantable delivery device • Drug and radiation emitting device for cancer treatment

18. Jurisdictional Determinations • Combination Products with Biologic Primary Mode of Action • Biologic product with implantable delivery device • Interferon and injector for treatment of hepatitis C • Injectable protein with delivery device for orthopedic use • Drug/Biologic embolization agent • Radiolabeled antibody with detector device

19. Jurisdictional Determinations • Combination Products with Device Primary Mode of Action • Laser and photosynthesizing agent for antimicrobial use • Dialysate with drug component • Drug-eluting cardiovascular stent • Vascular graft with antibiotic • Physical/chemical embolization product • Cardiovascular stent and injectable drug • Orthopedic prosthesis coated with growth factor

20. FDA Guidance • Guidance for Industry and FDA Staff: Application User Fees for Combination Products (April 2005), at http://www.fda.gov/oc/combination/userfees.html • Guidance for Industry and FDA Staff: Submission and Resolution of Formal Disputes Regarding the Timeliness of Premarket Review of a Combination Product (March 2005), at http://www.fda.gov/cber/gdlns/comboprod.pdf • Draft Guidance for Industry and FDA: Current Good Manufacturing Practice for Combination Products (Sept. 2004), at http://www.fda.gov/oc/combination/OCLove1dft.html • Intercenter Consultative/Collaborative Review Process (June 2004), at http://www.fda.gov/oc/ombudsman/intercentersop.pdf