1. Arrowhead Drug Delivery Summit San Francisco May 14, 2009 Michael A. Swit, Esq. Vice President Drug Delivery -- Perspectives on the FDA Regulatory Environment

2. Standard Disclaimers  Views expressed here are solely mine and do not reflect those of my firm or any of its clients.  This presentation supports an oral briefing and should not be relied upon solely on its own to support any conclusion of law or fact.

3. What We Will Cover  The FDA World – how is it changing?  Combination Product Regulation – where drug delivery intersects with agency purview  How FDA approaches combination products  Real time examples  Getting prepared -- How to focus on FDA regulatory issues in drug delivery

4. The FDA World

5. “Global” Environment  Obama Administration – what does it foretell  Universal health care …?  Comparative effectiveness – keep an eye on this  Increased enforcement/compliance activity – get your house in order – beware the “Fear of Wiley”  FDA Issues  New commissioner – Margaret Hamburg nominated  Cleared yesterday by Senate H.E.L.P. Committee; full confirmation not set yet  any biases/predilections?  Reported she is interested in food safety  Deputy Commissioner – Josh Sharfstein – ex-Waxman staffer

6. FDA Environment -- Drugs  Safety – mantra – life changed on September 30, 2004  Result –  FDA is very risk averse  “Show me”  Don’t get called up in front of Congress for not approving a drug  FDAAA -- increased emphasis on risk/benefit analyses and risk management  Can mandate a REMS – Risk Evaluation and Mitigation Strategy  Can mandate post-approval studies  Industry – must improve early detection of drug event signals

7. FDA Environment – Devices  CDRH – under fire by Capitol Hill – coercion of reviewers by upper management – impact???  Changes at the top?  CDRH Director– staying? House in New Mexico  ODE Director – also “implicated”  OIVD – Gutman left – where to?  Prolonged Congressional inquiry -- very disruptive as diverts resources  Pressures FDA to be much more conservative – e.g., device companies may be required to submit IDEs and resultant clinical data to support the 510(k) process  Alpert – agrees -- more data; less risk tolerance.  Sharfstein just ordered CDRH to re-examine clearance of knee surgery device allegedly secured in part due to Congressional pressure

8. Device Approval/Marketing Issues  510k Process – in spotlight  GAO report – required by FDAAA  Includes a focus on FDA’s failure to require PMAs or reclassify a number of pre-’76 devices as required by the 1990 Safe Medical Devices Act  If put in Class III, PMA’s will be needed  None were IVDs  Focuses on “High risk device” should be under PMA  New intended uses – only found in 1% of 510k’s  New tech. characteristics – only found in 15%  Partial result – call for data on pre-76 devices – April 9  Lingering issue – “substantial equivalence drift”

9. Device Approval/Marketing Issues …  Anticipate more demand for clinical data for Class II devices  Clinical studies – already hard; could get harder  Proposed Physicians Sunshine Act would require physicians to post the disclosure on a federally run website and if they do not file the fine is pretty hefty. $10,000/day.  Disincentive to be an investigator?  Inspections – there is legislative language on Capitol Hill that would require an inspection for every 510k

10. Combination Products – Where Drug Delivery Intersects FDA

11. What Is a Combination Product?  As defined in 21 CFR § 3.2(e), the term combination product includes:  (1) A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity;  (2) Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products;  (3) A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose; or  (4) Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect.

12. The Combination Galaxy Devices  PMA/510(k)/IDE  QSR  MDR Drugs  NDA/IND  cGMP  AERS Biologics  BLA/IND  cGMP+  AERS+ Primary Mode of Action Consultation Regulations

13. A Brief History  Office of Combination Products (“OCP”)  Created by Medical Device User Fee and Modernization Act (MDUFMA)  Office established on December 24, 2002  OCP given broad oversight responsibilities covering the regulatory life cycle of combination products.  Coordinate reviews among FDA Centers  Ensure consistency among similar reviews

14. Section 503(g) of the Act  FDA is required to assign a combination product to a lead Center based on its "primary mode of action“ -- PMOA  PMOA was not defined in the statute or regulations  For some products, PMOA is difficult to identify  Early in development (just don't know)  Products that have two (or more) completely different modes of action, neither of which is subordinate to other  Nanotech – additional challenges

15. PMOA -- Determining Which Center Leads  PMOA = Primary Mode of Action; not defined in statute, but in regulations  Final Rule – 8/25/2005; 70 Fed. Reg. 49848  http://www.fda.gov/OHRMS/DOCKETS/98fr/05-16527.pdf  Mode of Action: the means by which a product achieves an intended therapeutic effect or action. 21 CFR 3.2(k)  Three types of modes of action: biological product, device, drug  Combination products typically have more than one identifiable mode of action

16. PMOA … Primary mode of action is the single mode of action of a combination product that provides the most important therapeutic action of the combination product. The most important therapeutic action is the mode of action expected to make the greatest contribution to the overall intended therapeutic effects of the combination product. Source: 21 CFR 3.2(m)

17. The PMOA Decision Tree If unable to determine most important therapeutic action with reasonable certainty, consider:  Consistency: is there an agency component that regulates other combination products presenting similar questions of S & E with regard to the combination product as a whole?  Safety and Effectiveness: which agency component has the most expertise related to most significant S&E questions presented by combination product?

18. Not Sure – Requests for Designations (RFDs)  Voluntary Formal Process under 21 CFR Part 3  Seeks to determine:  Classification  Assignment  Clarification of Regulatory Pathway  If don’t file, FDA may stay review clock while a determination is made  When:  Before any application for premarket review  As soon as enough info exists for FDA to make a decision

19. RFD’s …  Key sections to focus on:  What is your product?  Why would your product be used?  How does your product work?  What is your product’s most important therapeutic action?  What is the basis for your PMOA analysis?  How do you think your product should be assigned? Why? Use assignment algorithm if appropriate.

20. RFD’s …  OCP reviews RFD’s for completeness  If complete, OCP sends acknowledgement letter to sponsor, and copy of RFD’s to three Center Liaisons  Center recommendations due to OCP in 21 days  Consultation among OCP, Centers and Office of Chief Counsel  Decision reached, response letter prepared, necessary clearances obtained  Decision must issue within 60 days; if not YOUR recommendation wins!!

21. RFD’s …  Request for Reconsideration  Submit within 15 days  Less than 5 page submission, no new information  FDA response within 15 days  FDA has been known to change a decision upon reconsideration  Effect of RFD Letter – designated FDA Center can only be changed without your consent to protect the public health or another compelling reason.  Source: 21 CFR 3.9(b)

22. How Many Applications?  Concept Paper on Marketing Applications for Combination Products  http://www.fda.gov/oc/combination/singlesepconpaper.pdf  Basics:  PMOA does not ensure application status; but lead Center  Single application usually is sufficient  Exceptions  One component is already approved, but labeling will need to be changed  Biologics – legally can have separate apps. for components  When the components are “separate and complex” – e.g., a device in combination with a new molecular entity drug/biologic  Where needed to “apply mechanisms to ensure appropriate regulation or unique regulatory requirements” not available under one app.  Example: gene therapy

23. How Many Applications?...  You Might Want Two – perhaps:  To qualify for Waxman-Hatch Exclusivity  Orphan Drug Status  To protect proprietary data if 2 firms are involved  Complex decision tree suggested in concept paper on how these are handled  Examples  Single application – pre-loaded syringes, transdermal patches  Two or more – laser activated drugs, iontophoresis

24. Drug Delivery Successes at FDA  Neupro Patch – Early Parkinson’s Disease – rotigotine transdermal  InFuse Bone Graft – for filling in missing tooth bone  Methlyphenidate Patch – ADHD in children  Emsam Patch – Selegiline for depression  Exubera – inhaled insulin –  Not a market success  Integrated glucose monitor and insulin delivery system

25. Getting Prepared -- Focusing on FDA Regulatory Issues in Drug Delivery

26. Be Prepared  “Validate” plans early  Take advantage of FDA meeting opportunities  Pre-IND, EOP2, Pre-NDA/BLA filing  Pre-IDE  VC’s – will expect you to know what you are doing  But, don’t roll over and accept what FDA says without questions  Don’t Assume Europe and U.S. Think Alike  BioSimilars – EU is ahead of U.S.  Scientific Advice process

27. Be Prepared …  When does drug delivery become the PMOA?  Historically, with delivery systems, the focus on the therapeutic moiety  But, could the improved delivery be the PMOA?  Try to be a PMA – stent precedent allows you where the drug component does not need an NDA  Know Your Partners  Audit them  Their problems are yours – e.g., Cialis and Lilly

28. Ancient Chinese Curse May You Live In Interesting Times … (possibly an ancient Chinese Curse)

29. 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 Questions?

30. About your speaker… Michael A. Swit, Esq., is a Vice President 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 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.