Michael A. Swit, Esq. Vice President

1. Michael A. Swit, Esq. Vice President

2. FDA Regulatory Considerations for Life Sciences CompaniesSwedish-American Chamber of CommerceE-DaysLife Sciences ProgramApril 9, 2008San Diego, California

3. Standard Disclaimers • Views expressed here are solely my own and do not necessarily reflect those of my firm or any of our clients. • These slides support an oral briefing and may not be relied upon solely on their own to support any conclusion of law or fact.

4. Establish FDA Strategy Early!! • Some considerations follow . . .

5. 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

6. Regulatory Status – Drug, Device or Biologic? … • Drug: • described in USP or • intended (via labeling) • to affect the body of man or other animals • to be used in the diagnosis, cure, mitigation, treatment or prevention of disease in man or other animals

7. Regulatory Status – Drug, Device or Biologic? … • Device:defined as involving: "instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or "similar or related article including any component, part or accessory." • in USP/NF or • intended to be used in diagnosis … cure, mitigation, treatment or prevention of disease or other conditions • intended to affect the body of man

8. Regulatory Status – Drug, Device or Biologic? … • Devicedefinition can capture products that resemble drugs if they do not achieve their result via being metabolized in the body or via chemical action within or on the body -- regulated by FDA Center for Devices & Radiological Health (CDRH) • Examples of "drug-like" devices: • Ultrasound contrast media • Contact lens solutions • Oral rinse used as barrier to plaque formation

9. Regulatory Status – Drug, Device or Biologic? … • Devices … • Risk of device determines how regulated • Class I – simplest – “General Controls” • Class II – more risky – “Special Controls” • Class III – most risky – Premarket Approval required • Problem – totally new technology is automatically placed in Class III • Can petition to take out of Class III if you don’t think the new technology is “risky”

10. Regulatory Status – Drug, Device or Biologic? … • Biologics -- • Generally, if derived from human or animal tissue • Not, technically, approved under Federal Food, Drug & Cosmetic Act; but under Public Health Service Act • Therapeutic biologics -- were regulated by FDA Center for Biologics (CBER) using approval standards similar to CDER • therapeutic biotech products now at CDER • vaccines – remain behind • NOTE: "true" biotech products usually are biologics

11. Regulatory Status – Drug, Device or Biologic? … • Is it a “drug,” “device” or “biologic” … or both -- "Combination" or "hybrid" products -- • are regulated per their "primary mode of action" (“PMOA”) • but this may be difficult to discern -- get clarification very early as will impact FDA Center you deal with • can request in writing -- under FDAMA § 416, FDA can't later change its mind w/o your consent or public health reasons exist • FDA -- final rule on “PMOA” – Sept. 2005

12. Type of Submission Required for FDA Approval or Clearance • Drugs: • Full New Drug Application (NDA) • 505(b)(2) NDA or "Paper NDA“ – can be avenue for “innovative” products based on already-approved ingredients • Abbreviated New Drug Application • The OTC Drug route -- • Rx/OTC Switch • OTC Review monograph change • NDA – direct to OTC -- very rare – Abreva® (Avanir/SKB)

13. Type of Submission Required for FDA Approval or Clearance • Devices: • Premarket Approval Application (PMA) – Class III devices • clinical studies will be needed – efficacy and safety • detailed safety data • Premarket Notification under § 510k – Class II (most) and some Class I devices • Standard – “substantial equivalence” to a lawfully marketed product – thus, technically, you are not proofing either safety or effectiveness. • clinical studies MAY be needed (or wanted)

14. Type of Submission Required for FDA Approval or Clearance • Biologics • Biologic License Application (BLA) – covers both • Product • Facility • Generic versions not possible – may change … • Omnitrope approved in EU & U.S. • Legislation pending in U.S. • Still likely to be approached on a case-by-case basis

15. 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

16. What Data – Quantity & Quality – Will FDA Require? … • FDAMA § 119(a) -- • FDAmust 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 • FDAMA § 115(a) -- data from one adequate and well-controlled study and confirmatory evidence can be used to show substantial evidence of effectiveness

17. 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 • But – under strict scrutiny from Congress – many safety issues linked to “fast” approvals

18. 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

19. The FDA Review -- Priority and Speed • General NDA classification system • 1 -- New molecular entity • 2 -- New Salt of Previously Approved Drug (not a new molecular entity) • 3 -- New Formulation of Previously Approved Drug (not a new salt OR a new molecular entity) • 4 -- New Combination of Two or More Drugs • 5 -- Already Marketed Drug Product - Duplication (i.e., new manufacturer)

20. The FDA Review -- Priority and Speed • General NDA classification system … • 6 -- New Indication (claim) for Already Marketed Drug (includes switch in marketing status from prescription to OTC) • 7 -- Already Marketed Drug Product - No Previously Approved NDA (e.g., Unithroid) • NDA Review Priority: • S - Standard -- drugs similar to currently available drugs • P - Priority -- significant advances over existing treatments.

21. The FDA Review -- Priority and Speed • Vioxx Backlash – • FDA – • Now Very Risk adverse • Slower • Leadership fragmented – Crawford resignation • “New” or “Renewed” “Regulators” • Congress • Products Liability Lawyers • U.S. Attorneys • States Attorney General • “Qui Tam” relators

22. FDA-Enforced Barriers to Entry • Orphan Drug Exclusivity-- 7 years for orphan drug for orphan indication • can't “remake the wheel” – blocks brand & generics • Does not block non-orphan indications • Waxman-Hatch Exclusivity – blocks generics • 5 years -- New Chemical Entities • 3 years -- New uses, dosage forms, etc. of previously-approved products • New indications – less useful to prevent generic competition

23. 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

24. 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

25. 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

26. 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

27. The Approval Gate • Hopefully, will open for you!! • But the odds are long, the cost is high, and the time is lengthy • Good luck!!

28. Questions? Call, e-mail, fax or write: Michael A. Swit, Esq. Vice President 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

29. About your speaker… Michael A. Swit, Esq., is a Vice President at The Weinberg Group, Inc., a premier international scientific and regulatory consulting firm, where he develops and ensures the execution of a broad array of regulatory and other services to clients, both directly and through outside counsel. His expertise includes product development strategies, compliance and enforcement initiatives, recalls and crisis management, submissions and related traditional FDA regulatory activities, labeling and advertising, and clinical research efforts for drug, biologic, device, IVD, and other life sciences companies, as well as those in the food and dietary supplement industries. Mr. Swit has been addressing critical FDA legal and regulatory issues since 1984. His vast and 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 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. He received his A.B. degree, magna cum laude, with high honors in history, from Bowdoin College and his law degree from Emory University; he belongs to the California, Virginia and District of Columbia bars.

30. 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.