1. Hogan & Hartson L.L.P. \\\71717/0300 1545901.v1 Slide 1 FDA Public Meeting David M. Fox Hogan & Hartson LLP (202) 637-5678 dmfox@hhlaw.com Regulation of Combination Products November 25, 2002

2. Hogan & Hartson L.L.P. \\\71717/0300 1545901.v1 Slide 2 Overview l Classification l Jurisdiction/Assignment l Regulation l Process

3. Hogan & Hartson L.L.P. \\\71717/0300 1545901.v1 Slide 3 Classification l Single entity F Drug F Device or F Biologic Product l Combination l Sections 563 and 503(g), as amended, clearly recognize “combinations” as a stand-along category

4. Hogan & Hartson L.L.P. \\\71717/0300 1545901.v1 Slide 4 Classification l The new Office of Combination Products, by statute, has responsibility for F timely and effective reviews F ensuring consistent standards, pre- and post- market, for like products F dispute resolution F periodic reporting l The Office must consult with another office on whether a product is a combination

5. Hogan & Hartson L.L.P. \\\71717/0300 1545901.v1 Slide 5 Classification: What is a Combination Product? l Statute (503(g)(1)) F Products that constitute a combination of a drug, a device, or a biologic l Regulation (21 CFR 3.2) F A combination exists when two or more articles are l physically or chemically combined l packaged together or l intended to be used together l Guidance

6. Hogan & Hartson L.L.P. \\\71717/0300 1545901.v1 Slide 6 Combinations l Pre-filled syringes l Albuterol MDIs l Transdermal Patches l Novel delivery (Viadur, Procardia XL) l Laser activated drugs (Visudyne) l Drug coated catheters and stents l Dental polish with drug l Dental barrier with antibiotic l Tobacco products

7. Hogan & Hartson L.L.P. \\\71717/0300 1545901.v1 Slide 7 Single Entity Products l Gas-filled albumin microspheres l Porcine cells in an implantable membrane l Certain tissue-containing bone pastes l Absorbable collagen/thrombin products l Catheter/filtration system to locally deliver specific drug l Electrotransport systems for use with specific drugs

8. Hogan & Hartson L.L.P. \\\71717/0300 1545901.v1 Slide 8 Classification l At least 300 RFD precedents (28/yr) l About 1/3 found to be a combination l Retrospective analysis is needed F Identify factors FDA has relied upon F Need to understand agency’s thinking on how it decides whether a product is a “combination product”

9. Hogan & Hartson L.L.P. \\\71717/0300 1545901.v1 Slide 9 Issues l When does labeling create a combination? l Dosage forms versus delivery systems l Problem of the whole versus the parts F If the whole depends on chemical or metabolic action to achieve its primary intended purposes, is it still a combination? F Or, is it enough to be able to identify separately regulated parts within the whole? l Unitary or single function products

10. Hogan & Hartson L.L.P. \\\71717/0300 1545901.v1 Slide 10 Assignment l Which Center has “primary jurisdiction”? l Section 503(g) F What is the primary mode of action of the product? F Which article within the combination is responsible for the primary mode of action? l FDA is forced to pick one “mode of action”

11. Hogan & Hartson L.L.P. \\\71717/0300 1545901.v1 Slide 11 Assignment: The Gordian Knot l Is it the whole or the relative contribution of each part? l For delivery systems, focus has been on the therapeutic; what is the final, decisive action of the product? l But, “improved drug delivery” can just as easily be primary l Circular, relativistic analysis

12. Hogan & Hartson L.L.P. \\\71717/0300 1545901.v1 Slide 12 Assignment: Untying the Knot l Cannot be resolved through a flow chart l Start with the 100 plus precedents l Develop factors to be weighed F where are like products regulated F what is the innovation, the driver F at point of use, what feature will predominate F what raises the most significant S/E issue F what is likely to be changed post-market

13. Hogan & Hartson L.L.P. \\\71717/0300 1545901.v1 Slide 13 Assignment: A Thought Experiment l In close cases, let sponsor decide l Statutory support in section 563 l Assignment is only where, not how l Less significant in light of MDUFMA l Could provide better APA defense

14. Hogan & Hartson L.L.P. \\\71717/0300 1545901.v1 Slide 14 Regulation: Pre-Market Approval l Single application F pre-loaded syringes F transdermal patches F MDIs l Two or more applications F laser activated drugs F iontophoresis l Hybrid regulation F drug eluting stents

15. Hogan & Hartson L.L.P. \\\71717/0300 1545901.v1 Slide 15 Regulation l Multiple applications may be less of a concern if reviews are coordinated l In most instances, all necessary data can be obtained under a PMA, NDA, or BLA l For drug delivery technologies, consider using PMA as the lead application F same as using BLA/NDA to answer device issues F stent precedent and tobacco suggest an NDA is not needed for the drug component

16. Hogan & Hartson L.L.P. \\\71717/0300 1545901.v1 Slide 16 Process l “Lack of transparency” F include decisional documents in summary approval materials, subject to redactions F include “Annex” to next generation ICAs l Make all precedents available to staff l All classification and assignment decisions need a written record of decision. See section 563 of the FDCA. l Standards for mixed or hybrid regulation should be set forth in a rule

17. Hogan & Hartson L.L.P. \\\71717/0300 1545901.v1 Slide 17 Conclusion l “The [products] all likely meet both the definition of a drug and the definition of a device... and the FDA therefore has discretion in determining how to treat them.... What the FDA is not free to do, however, is to treat them dissimilarly and to permit two sets of similar products to run down two separate tracks, one more treacherous than the other, for no apparent reason.” Bracco Diagnostics v. Shalala (1997).