E-Mail: JSKAHAN@HHLAW.COM 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

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

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

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

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

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

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)

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

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

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

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

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

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

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?

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

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

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

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

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?

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?

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?

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

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