1. 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
Phone: (202)
Fax: (202)

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