1. FDA Regulatory Considerations for the Biomedical Companies Michael A. Swit, Esq. Vice President, Life Sciences LARTA NIH-CAP COMMERCIALIZATION WORKSHOP Marina Del Rey, California October 17, 2007

2. 2 ANCIENT CHINESE CURSE May You Live in Interesting Times …

3. 3 THESE ARE INTERESTING REGULATORY TIMES September 30, 2004 – the beginning of the current era of drug regulation –Vioxx –SSRI’s and suicidal ideation Since then: –Tysabri –Avandia New Lynchpin of Regulatory Process – Drug Safety

4. 4 INTERESTING REGULATORY TIMES … FDA Leadership –Top -- In disarray 2004 -- McClellan left to go to CMS; Crawford interim Commissioner Summer 2005 – Crawford confirmed by Senate Sept. 2005 – Crawford abruptly resigns 2006 – Andrew von Eschenbach becomes acting December 2006 – von Eschenbach confirmed Sept. 2007 – General Counsel resigns –Deputies & Associates – many leave at end of 2006

5. 5 The Perfect Storm? The Current FDA Regulatory Equation -- (Drug Safety Lynchpin) + (Leadership Vacuums) = an approval process mired in uncertainty, fear and decision paralysis PLUS A Democratic Congress PLUS September 30, 2007 – Deadline Day –PDUFA Reauthorization Sunsets –Pediatric Exclusivity and Pediatric “Rule” Sunsets EQUALS Congress in driver’s seat to drive change?? –But, still have 2 more years of Bush

6. 6 The Result – FDAAA FDAAA -- Food and Drug Administration Amendments Act of 2007 -- H.R. 3580 (422 pages) Negotiated compromise – passed House on September 20 and Senate on September 21 Signed by President on Thurs., September 27, 2007 Public Law 110-85

7. 7 Key Provisions for Drug Industry PDUFA Reauthorization Prescription Drug Advertising Review Fees DTC Advertising Penalties Drug Safety Provisions Clinical Trials Registry & Results Data Base Critical Path Initiative – Reagan-Udall Foundation Pediatric Exclusivity and Pediatric “Rule” Reauthorization Citizen Petitions – limits FDA authority to delay approvals Biosimilars – NOT COVERED by FDAAA

8. FDA's Three Key Development Roles: "Gatekeeper" to the marketplace -- the new drug approval process "Cop on the beat" or "Enforcer" -- ensuring quality compliance via inspection and enforcement actions (e.g. criminal charges) "Sentinel" of Safety Concerns - during development and post-approval 8

9. What Data – Quantity & Quality – Will FDA Require? Will vary -- FDA has extensive discretion here Key task -- try to get clarity as soon as possible in the process -- Ways to do so: –Pre-IND or Pre-IDE meeting -- encouraged by FDA prior to start of human clinicals –End of Phase 2 Meeting - also encouraged -- here's where you want to "lock" them in 9

10. What Data – Quantity & Quality – Will FDA Require? FDAMA § 119(a) -- –FDA must meet with you on design of studies; and –Any agreement on study design must be written and can't be changed later w/o your consent unless a new safety or effectiveness issue arises later –“Special Protocol Assessments” – FDA process for implementing – aka “SPA” (see Slide 7) FDAMA § 115(a) -- data from one adequate and well- controlled study and confirmatory evidence can be used to show substantial evidence of effectiveness 10

11. What Data – Quantity & Quality – Will FDA Require? … "Pure" proof of clinical effectiveness may not be needed -- e.g., under “Fast Track,” may be able to use: –Surrogate endpoints –Clinical endpoints –Phase IV study will be needed usually 11

12. 12 The SPA – Panacea or Pablum? Good news – you theoretically have FDA locked in Bad news – FDA is locked in to your plan and, if problems arise in clinicals, are you boxing your firm in to a lack of flexibility?

13. The FDA Review -- Priority and Speed "Fast Track" -- FDAMA § 112 –treats a "serious or life threatening condition" –shows "potential to address unmet medical needs for such condition" –If so, FDA must "facilitate the development and expedite and review" of the drug –Request at time of or after IND filing See 1998 Guidance on Fast Track http://www.fda.gov/cder/guidance/2112fnl.pdf 13

14. 14 The FDA Review – Key Issues Impacting Speed & Criteria Vioxx Backlash – –FDA – Now Very Risk adverse Slower Leadership fragmented – Crawford resignation –“New” or “Renewed” “Regulators” Congress – as now seen via FDAAA Products Liability Lawyers U.S. Attorneys States Attorney General “Qui Tam” relators

15. Tips to avoid problems & speed review Make sure R&D and Sales & Marketing are talking early on -- ensure the indication being studied is one you want to sell Understand, that an approval is not enough – you need to get Medicare &/or private payer reimbursement –Start the reimbursement qualification process early –Design clinical protocols to address payer expectations Private & Government Example -- study your drug in Medicare-age patients 15

16. Tips to avoid problems & speed review… Make sure you are ready to go to “D” from “R” – –Internally – people and systems –Formulation has been rigorously reviewed so as to optimize your chances when going into humans Study and file electronically, if possible Respond to FDA deficiency letters during review promptly, fully, and honestly –Know how the system works – if you don’t agree with a reviewer’s decision, work up the chain of command 16

17. Tips to avoid problems & speed review… If outsourcing, audit aggressively your "vendors:” –CROs, clinical investigators, contract manufacturers, API makers –IRBs – they have been shut down in past –Joint venture partners – e.g., Cialis® – Lilly manufacturing plant problems – delayed about one year –Remember – even when you outsource, you are still ultimately responsible for what happens and you still need to have systems and people in place to ensure your vendors are working correctly Don't bury your head to problems -- investigate and disclose promptly 17

18. 18 Tips to avoid problems & speed review… Don’t fall madly in love with your technology – understand that you have to prove safety and effectiveness – “I just know it works” is not the standard The process is very complex – this is a mere overview – build the right team to tackle –But, be careful with involving lobbyists, Congressmen/women, etc., at any stage

19. 19 Call, e-mail, fax or write: Michael A. Swit, Esq. Vice President, Life Sciences THE WEINBERG GROUP INC. 336 North Coast Hwy. 101 Suite C Encinitas, CA 92024 Phone 760.633.3343 Fax 760.454.2979 Cell 760.815.4762 michael.swit@weinberggroup.com www.weinberggroup.com Questions?

20. 20 About your speaker… Michael A. Swit, Esq., is Vice President, Life Sciences at THE WEINBERG GROUP, where he develops and ensures the execution of a broad array of regulatory and other services to drug and biologics clients seeking to market products in the United States. His expertise includes FDA and CMS development strategies, compliance and enforcement initiatives, recalls and crisis management, submissions and related traditional FDA regulatory activities, labeling and advertising, and clinical research efforts. Mr. Swit has been addressing critical FDA legal and regulatory issues since 1984. His multi-faceted experience includes serving for three and a half years as corporate vice president, general counsel and secretary of Par Pharmaceutical, a prominent, publicly-traded, generic drug company and, thus, he brings an industry and commercial perspective to his work with FDA-regulated companies. Mr. Swit then served for over four years as CEO of FDANews.com, a premier publisher of FDA regulatory newsletters and other specialty information products for the FDA-regulated community. His private FDA regulatory law practice has included service as Special Counsel in the FDA Law Practice Group in the San Diego office of Heller Ehrman White & McAuliffe and with the Food & Drug Law practice at McKenna & Cuneo, both in the firm’s Washington office and later in San Diego. He first practiced FDA regulatory law with the D.C. office of Burditt & Radzius. Mr. Swit has taught and written on a wide variety of subjects relating to FDA law, regulation and related commercial activities, including, since 1989, co-directing a three-day intensive course on the generic drug approval process and editing a guide to the generic drug approval process, Getting Your Generic Drug Approved. A former member of the Food & Drug Law Journal Editorial Board, he also has been a prominent speaker at numerous conferences sponsored by such organizations as RAPS, FDLI, and DIA. A magna cum laude graduate of Bowdoin College, he received his law degree from Emory University Law School and is a member of the California, D.C. and Virginia bars.

21. 21 For more than twenty years, leading companies have depended on THE WEINBERG GROUP when their products are at risk. Our technical, scientific and regulatory experts deliver the crucial results that get products to market and keep them there. Washington, D.C. ♦ San Francisco ♦ Brussels ♦ Edinburgh