Regulatory and Legal Challenges for Developers of Drug Delivery Devices

1. Regulatory and Legal Challenges for Developers of Drug Delivery Devices Public Workshop: Innovative Systems for Delivery of Drugs and Biologics – Scientific, Clinical, and Regulatory Challenges July 8, 2003 Bethesda, Maryland Jonathan S. Kahan Partner Hogan & Hartson L.L.P. 555 Thirteenth Street, NW Washington, DC 20004-1109 Phone: (202) 637-5794 Fax: (202) 637-5910 E-Mail: JSKAHAN@HHLAW.COM

2. Presentation Overview • Legal Framework for Regulation of Combination Products • FDA’s Historical Approach to the Regulation of Combination Products and Drug Delivery Devices • The Obstacles and Challenges to Efficient Regulation of Drug Delivery Devices • Consideration of New Policies and Procedures to Regulate Drug Delivery Devices

3. Legal Framework for Regulation of Combination Products and Drug Delivery Devices • Drugs • Articles Intended to Prevent, Cure, or Treat Disease • Articles Intended to Affect Structure or Function of the Body (Section 201(h) of FDCA) • Devices • Same Definition As Drugs, but Devices Cannot Achieve Their Primary Purposes Through Chemical or Metabolic Action in or on the Body • Devices Usually Accomplish Their Primary Purpose by “Mechanical” Means

4. Legal Framework • Biologics (Section 351, PHS Act) • A Virus, Serum, Toxin, Antitoxin, Vaccine, Blood, Blood Component or Derivative, Allergenic Product, or Analogous Product • Intended for the Prevention, Treatment or Cure of Diseases or Injuries of Man

5. Legal Framework • Prior to 1990, Combination Products Regulated on a Case-by-Case Basis • Condoms With Nonoxynol-9 • Biliary Lithotripters Used With Ursodeoxycholic Acid • Transdermal Patches for Drug Delivery • Antimicrobial Coated Catheters

6. Legal Framework • The SMDA of 1990 Sought to Add Structure to Combination Product Regulation, Including Drug Delivery Devices • FDA Promulgated Procedures to Effect SMDA • Under SMDA, a Lead Center Within FDA To Be Designated for Review Authority Based On “Primary Mode of Action” • Primary Mode of Action Never Defined by Congress or FDA

7. Legal Framework • Definition of Combination Products (21 C.F.R. § 3.2) • Comprised of Two or More Regulated Components That Are Physically, Chemically, or Otherwise Combined or Mixed and Produced As a Single Entity (e.g., Prefilled Syringes) • Two or More Separate Products Packaged Together in a Single Package or As a Unit (e.g., Lumbar Puncture Kits)

8. Legal Framework • Definition of Combination Products (21 C.F.R. § 3.2) • A Product Packaged Separately but Intended for Use With a Particular Approved Product Where Both Products Are Required to Achieve the Intended Use, Indication, or Effect, and the Approved Product’s Labeling Would Need to Be Changed Upon Approval • Any Investigational Product Packaged Separately, but Intended for Use Only With Another Individually Specified Investigational Product Where Both Products Are Necessary to Achieve the Intended Use

9. Legal Framework • FDA’s Regulatory Structure for Dealing With Drug Delivery Devices • Office of Combination Products • The Center Product Jurisdiction Officers • The Request for Designation • The Pre-IDE/Pre-IND Meetings • Coordination Between CDRH, CBER, CDER

10. FDA’s Historical Regulation of Drug Delivery Devices • Syringes (Prefilled and Non-Prefilled) • Infusion Pumps • Metered Dose Inhalers • Transdermal Patches • Iontopheresis Devices • The Interface Between the 510(k) Notice, PMA, ANDA, and NDA Processes

11. Historical Regulation • The Second Generation of Drug Delivery Devices • Tobacco Products • Laser Activated Drugs • Drug Coated Catheters and Stents • Catheters to Locally Deliver Specific Drugs • Porators and New Patches • The Drug Lollipop or Chewing Gum

12. Historical Regulation • The Evolving Technologies • Drug Delivery Via Chip Technologies • The Closed Loop Physiological Monitor Triggering Drug Delivery • Inhalation for Drug Delivery • Needle-free Drug Delivery • Implantable Encapsulation Technologies • Nanotechnology Drug Delivery Devices

13. The Challenges and Obstacles of New Drug Delivery Technologies • Many Drug Delivery Devices Are Developed By Device Companies for Uses With Approved Drugs or Biologics • Creates Challenges if the Device Allows the Drug to Be Used For: • New and Different Indications • Different Mode of Delivery (e.g., I.V. vs. Topical) • Different Drug Dosage/Schedule • The Challenge of Modifying the Drug Formulation to Optimize Delivery With the Device

14. Challenges and Obstacles • Is a New NDA Required for the Drug if You Have a Different Delivery Mechanism Than the Mechanism Described in the NDA Approved Labeling? • Does the PMA Process or the NDA Process Predominate in Drug Delivery Review? • Does the Drug Labeling and the Device Labeling Have to “Mutually Conform?” • What is the definition of mutually conforming labeling? • Does the labeling have to be identical or just similar in spirit? • Who resolves issues of cross-labeling and how? • What is the Regulatory Path if the Device is Designed to Deliver a Family of Drugs?

15. Challenges and Obstacles • The Challenge of Pharma/Device Industry Cooperation • The Regulatory Process Can Be Made Easier If the Pharmaceutical Manufacturer Authorizes Access to Its NDA and Clinical/Preclinical Files to the Device Company or Files an NDA or NDAS to Support the Device Approval • Often the Device Allows Broadened Uses of the Drug – an Incentive for Pharma Cooperation • In Some Cases, the Device May Allow Use of Less Drug Through More Optimal Delivery – a Disincentive for the Pharma Cooperation

16. Challenges and Obstacles • The Regulatory Implications of Pharma/Device Interaction • Without Pharma Cooperation (NDA, DMF Access and Research Cooperation), Device Companies Have a Difficult Time Obtaining NDA Approval • The Applicability of the Section 505(b)(2) Process in Approving New Drug Delivery Devices, Where the Route of Administration Is Outside NDA/ANDA Approvals

17. Challenges and Obstacles • The Regulatory Pathway Conundrum • Should a 510(k) or PMA be required along with an NDA for each new drug delivery device? • The “pullout PMA” or “pullout NDA” paradigm • Can a PMA be approved that includes drug component labeling? • The Cypher Serolimus Eluting Coronary Stent on Raptor™ Over-the-Wire Delivery System • The device industry’s historical difficulty in navigating the NDA/ANDA process

18. Challenges and Obstacles • The Lead Center Conundrum • Drugs Used With New Drug Delivery Devices Are Often Modified in: • Formulation • Dosage administration • Dosing schedule • Should CDER or CBER Always Have Lead Jurisdiction of the Drug or Biologic? • Does FDA Routinely Focus on the Last Thing the Product Does to Define “Primary Mode of Action”? • Drug delivery catheters • Transdermal drug delivery • The photodynamic therapy paradigm

19. New Approaches to Drug Delivery Devices • Is the FDA’s Interpretation of Primary Mode of Action Outdated? • Can the Process Be Streamlined? • If the Drug to be Delivered Is Already Approved for Delivery in Similar Doses, Schedule, and Formulation, Can Jurisdiction be Given to CDRH With Consultation by CDER/CBER?

20. New Approaches • Should There Always be Preference For One Approval Submission? • Is the Idea of the New NDA or NDA Supplement Along with a PMA or 510(k) for the Drug Delivery Device Outmoded and Inefficient? • Does FDA Need New Legislation to Accomplish a “Unitary Approval Mechanism” for Drug Delivery Devices?

21. New Approaches • How Best to Define “Primary Mode of Action”? • Factors to Consider in Defining Primary Mode of Action - What is the Innovative Drive Behind the Product? - What Role Does Safety and Efficacy Play in Defining Primary Mode of Action? - How Will the Product be Used? - Who Will Use the Product? • Should the Primary Mode of Action Standard be Legislatively Replaced?

22. Conclusion • The Present System of Dual Approvals is Not Optimal • The Primary Mode of Action Standard, as Presently Implemented Without Guidance, is Difficult to Apply and Interpret • New FDA Guidance on Classes of Drug Delivery Devices and the Regulatory Pathways Would Be a Significant Help • The Intercenter Agreements are Outdated

23. Conclusion • Move Toward a Unitary Drug Delivery Device Approval Mechanism with Single Center Jurisdiction is Needed • The OCP Should Have the Power to Oversee and Play a Significant Role in Novel Drug Delivery Device Approvals