# Presentation: 753048

## 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 RaptorTM 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