LIFECYCLE MANAGEMENT STRATEGIES: THE GENERIC PERSPECTIVE Regulatory Affairs Professionals Society Horizons Conference

1. LIFECYCLE MANAGEMENT STRATEGIES: THE GENERIC PERSPECTIVE Regulatory Affairs Professionals Society Horizons Conference March 29, 2007 Michael A.Swit, Esq.Vice President, Life Sciences

2. The Generic View – Defense First; Offense Second? • Defending the Future – ensuring time is not lost to a brand with exclusivity • Understanding Brand Strategies • Patents – not the focus here • Petitions • Reformulations • Formulary Battles • Fighting Back – see Offense? 2

3. The Generic View – Defense First; Offense Second? • Offense • Attacking patents -- not focus of this talk • Attacking a Competitor’s ANDA Exclusivity • Attacking petitions • Carving out unique markets • ANDA Suitability Petition • Morphing Into a Brand Name Company • 505(b)(2) NDAs – 3

4. Brand Attacks – Where They Occur • FDA – • usually in the form of a Citizen Petition linked to a Petition to Stay approvals • Buys 180 days almost immediately • Depending on when filed -- if prior to ANDA approval-- can cause lengthy delays • “Safety” – at heart of brand allegations • Reformulations 4

5. Brand Attacks – Where They Occur • The Courts – primarily in the form of aggressive patent infringement litigation • The Congress– • Special interest legislation – occurred more frequently in Republican Congresses • Less a factor today 5

6. Brand Attacks – Where They Occur • States • Formularies -- safety issues – often similar to those raised at the federal level • Legislatures • substitution restrictions • DAW manipulation 6

7. Brand Attacks – Where They Occur • Pharmacists • 1985 letter to pharmacists regarding substituting propranolol for the patients with the exclusive indication • Coumadin -- Barr counterattacked at this level with a pharmacist education program 7

8. Brand Attacks – Where They Occur • HMOs and Other Private Formularies • Private switch restrictions or incentives to not do so • Qualifying the generic • Doctors • who knows what is being said by the field reps?? 8

9. Citizen Petitions • The “We are only concerned about safety first” Attack -- raising a concern about the generic presenting a higher side effect profile or some other complication that might affect the patient adversely if switched to the generic. • My first encounter -- reformulating out a preservative -- 1986 before the New Jersey formulary • Reply: showed adverse events with old formulation were minor. Generic won. 9

10. Citizen Petitions – “Safety First” • Glaxo/Ventolin -- • longer term clinical studies need to assess full side effect liability; claimed that a key FDAer had expressed concerns about possible paradoxical bronchospasm when small changes made in MDIs. • 24-patient crossover study does not achieve statistical significance in detecting a “true difference” in adverse event rates. • Guidance did not address pediatric use, but the drug is likely to be used in kids even though not so labeled. • FDA: • Assessing side effects is not a direct duty under Waxman-Hatch if bioequivalence can be proven; here there was a good protocol for showing it and FDA has discretion on how to prove bioequivalence. • Did not show any data to prove that there might not be bioequivalence in kids; implication: if bioequivalent in adults, is in kids 10

11. Citizen Petitions – “Safety First” … • Sandoz/Clozapine --not safe to use healthy subjects for the bioequivalence study • FDA: we see no differences in adverse reactions with healthy v. patients if you use 12.5 mg. dose; consulted outside medical expert. 11

12. Citizen Petitions – “Safety First” … • Marion Merrill Dow/Seldane -- requested FDA require multiple dose pharmacokinetic/pharmacodynamic crossover study comparing plasma concentrations of terfenadine, the active metabolite, and QtC changes. • Allegation: the single-dose study design in FDA bioequivalence guide did not consider the safety concerns of low levels of parent terfenadine and their relationship to Qtc prolongation which can cause tachycardia. • FDA: refused to change the study design, saying that: • Pharmacokinetic testing is preferred; pharmacodynamic testing “tend to be so imprecise that statistical criteria can be met only with an unreasonably large number of subjects.” • You failed to show us that the pharmacokinetic studies are inadequate or that what you propose is better. 12

13. Citizen Petitions -- The ”Your bioequivalence study does not really show equivalence”Attack: • Boehringer/Persantine -- (90P-0326)alleged there were deficiencies in bio study done by BioDecision for Purepac -- primarily that the AUC and CMAX were significantly higher than other generics that had already shown bioequivalence • FDA: • Not appropriate to make cross-study comparisons of absolute values. • Values observed were derived from study where the assay methodology was validated, the assay procedure well-controlled, and where the values achieved were not dissimilar to those achieved by other labs. • Also rejected assertion that the lab here was too deficient to be used. 13

14. Citizen Petitions -- The “Comparative clinical trials required to show bioequivalence”Attack: • Fisons/Intal/the nebulizer version (93P-0010) --asked for an in vivo bioequivalence standard requiring well-controlled clinical trials. • FDA: • here, the key was that the drug met the bioequivalence regulations (21 CFR Part 320) criteria for a waiver of in vivo studies as it was in solubized form • also stressed that comparative clinical studies are “the least accurate, sensitive and reproducible” of the general approaches to bioequivalence. 14

15. Citizen Petitions – The “You Must Have the Same Inactives and Labeling As Us”Parley • Diprivan • Reformulated to use a preservative • Clinicals – 3-year Waxman-Hatch Exclusivity • You must use same inactive and, btw, your label contains a different warning • FDA • Selected generic preservative OK • Different warning reflects “different mfr.” carve-out of Waxman-Hatch 15

16. Citizen Petitions -- Others • The “Your Generic Sustained Release Must The Same release mechanism as us to be the same dosage form”Gambit: • Pfizer/Procardia XL • FDA: release mechanism is not relevant to dosage form determination. • The “You have to meet the new disso-lution specification that FDA forced us to meet” Maneuver • Roche/Klonopin -- withdrawn by Roche for unstated reasons 16

17. Citizen Petitions – “Winners” -- The “Active ingredient(s) must be fully characterized” Parley • Wyeth-Ayerst/Premarin -- “full” story on FDA’s web site • Lovenox – still pending, but has worked for 4 years – low molecular weight heparin • EU – regards as a biologics • Pergonal – exception, but limited by its facts • “Different isoforms” did not relate to key structure; protein backbone and amino acid sequences were identical • No data to show clinical significance of isoform differences 17

18. Citizen Petitions – “Winners” – Active Ingredient Characterization • Generic biotech products – • this parley still forms basis for a prime source of opposition to efforts to secure regulatory or legislative solutions to absence of generic biotech products; • Even if there is legislation, characterization will remain a central form of attack to influence FDA’s discretion • General Rule – FDA wins in courts on scientific issues 18

19. Reformulations – The Moving Target • The backdrop: • Waxman-Hatch – ANDA’d drug must be same as “reference listed drug” • The Gomer Pyle Syndrome – right before patent/exclusivity expiry, the formulation changes [“surprise, surprise, surprise”] 19

20. Reformulation -- Example • Tricor (fenofibrate) • Original NDA – 67 mg & 200 mg. capsules • Teva sued for patent infringement; 30-month stay • Abbott reformulated to 54 & 160 mg. tablets • Pulled capsules • Abbott reformulated again to 48 & 145 mg. tablets, andgot a label change to remove requirement product be taken with food • Teva – was able to approval, but its product was not AB-rated to Abbott’s 20

21. Other “Reformulations” • Rx-to-OTC Switches • But, fight back – “forced switch” petitions • Nexium® -- change to different active ingredient that is barely different from Prilosec 21

22. Generic vs. Generic Tactics • ANDA Suitability Petitions • ANDA Exclusivity • Morphing into “Brand Name” Drug Development 22

23. ANDA Suitability Petition • Standard – FDA must approve unless clinical investigations required • Examples • Dosage form -- tablet to capsule change • Strength – usually lower or intermediate if consistent with labeled dosing regimen; higher – rare • Route of administration – possible, but rarer • PPA Patch -- denied • Ingredient – only a single ingredient in a combination drug • Different salts – not allowed • Advantage – product line extension – e.g., Roxane • Disadvantages • no exclusivity; anyone else can do same thing; timing is important • Public process • Pediatric studies – under PREA – may need to do 23

24. Elements for ANDA Exclusivity • First Person to Submit Complete ANDA (“First to File”) • Containing a Paragraph IV Certification • Challenging a Patent as Invalid or Not Infringed • Notice to Patent Holder and NDA Holder (if different) • Eligible for 180 Days of Exclusivity 24

25. Medicare Modernization Act of 2003 -- Impact on Exclusivity • Trigger for Start of Exclusivity • Before Aug. 18, 2003: Earlier of Date of Favorable Court Decision in a Patent Lawsuit, or Date of First-to-File’s First Commercial Marketing • After Aug. 18, 2003: First-to-File’s First Commercial Marketing (Only) • Timing of Notice to NDA/Patent Holder • Before Aug. 18, 2003: At ANDA Applicant’s Discretion • After Aug. 18, 2003: Within 20 Days After ANDA Applicant Receives Word From FDA That ANDA Is Acceptable to Be Received 25

26. Medicare Modernization Act of 2003 -- Impact on Exclusivity • After December 8, 2003, 180-Day Exclusivity May Be Forfeited – Section 505(j)(5)(D) • Grounds for Forfeiture • Withdrawal of ANDA • Amendment or Withdrawal of Paragraph IV Certification • Failure to Obtain Tentative Approval Within 30 Months • Collusive Agreement with Another ANDA Applicant, NDA Holder or Patent Owner • Expiration of the Patent • Failure to Market Within 75 Days of: ANDA Approval, 30 Months Since ANDA Submission, Final Court Decision, Lawsuit Settlement, Withdrawn Patent 26

27. Historical Controversies Over180-Day Exclusivity • What is a “Complete” Application? • Must First Filer Be Sued? • Must First Filer “Successfully Defend” Lawsuit? • What is a “Court Decision” That Triggers 180-Day Exclusivity? • 1999: FDA Regulation Said Appellate Court • 1997-2000: Court Rulings Said Trial Court • 2000: FDA Guidance Said First Court That Decides the Patent Is Invalid, Unenforceable or Not Infringed • After Aug. 18, 2003: No Court (Only Trigger Is First Filer’s First Commercial Marketing) 27

28. Problems Interpreting 180-Day Exclusivity • Does Later Filer Ever Get ANDA Exclusivity? • What About Patents Not Filed Promptly With FDA (“Late Listed” Patents)? • Can There Be “Shared” Exclusivity? • Based on Differing Product Characteristics • Based on Multiple Patents • Based on Same-Day Filing of ANDAs • Can exclusivity be “sold”? 28

29. Problems Interpreting 180-Day Exclusivity • Can the ANDA Applicant Force a Patent Infringement Suit? • Possibly, via Declaratory Judgment Action • What Are the Potential Consequences of Settling the Patent Lawsuit? • Risk of Lawsuit by Plaintiff’s Lawyers, Patient Groups, Shareholders, Competing Generic Companies, FTC • After Jan. 4, 2004: Must Notify FTC & DOJ Within 10 Business Days of Settlement 29

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31. Complicated Area • Amlodipine Besylate Exclusivity Issues – the FDA Front • Posted: 28 Mar 2007 02:14 PM CDT • The Federal Circuit’s March 22, 2007 decision invalidating Pfizer’s patent on NORVASC (amlodipine besylate), and Mylan’s commercial launch of its generic version approved under ANDA #76-418 later that day triggering the company’s 180-day exclusivity period has set off a flurry of activity, both in the courts and at FDA. This case raises several interesting issues about the availability of 180-day exclusivity once a patent expires and the applicability of pediatric exclusivity. FDA is being asked to address these issues in three recent citizen petitions submitted to the Agency concerning amlodipine drug products. • Yesterday, the Orange Book Blog reported on the United States District Court for the District of Columbia’s order granting Mylan’s Emergency Application for a Temporary Restraining Order and/or Preliminary Injunction, in which Mylan argues that “[i]n the past, the FDA has taken the position that 180-day generic exclusivity does not survive patent expiration [and that there] is no basis in the Hatch-Waxman Act for such a limitation.” Pursuant to the court’s order, FDA is enjoined from approving any other ANDAs for generic NORVASC until at least April 13, 2007 at 5:00PM, and after FDA “solicit[s] the views of other interested parties on this matter by April 4, 2007 [to] render an agency decision on April 11, 2007.” The Federal Circuit also ordered Pfizer and Mylan “to respond, no later than 10 a.m. on Monday, March 26, 2007, concerning how the invalidity determination affects the pediatric exclusivity period and the ANDA approval.” • Simultaneous with FDA’s solicitation and consideration of views on this 180-day exclusivity issue, the Agency must now also consider several citizen petitions concerning amlodipine drug products. • On March 26, 2007, Mylan submitted a petition to FDA (Docket No. 2007P-0116) requesting that FDA stay the approval of any additional ANDAs for generic amlodipine products until after Mylan’s 180-day exclusivity expires on September 23, 2007. Mylan’s arguments hew closely to those the company made in its Emergency Application. • On March 21, 2007, Pfizer submitted two petitions (Docket Nos. 2007P-0110 and 2007P-0111) requesting that FDA enforce pediatric exclusivity rights for amlodipine, and that FDA stay approval of any and all supplements to LOTREL concerning amlodipine and pediatric exclusivity, respectively. LOTREL is Novartis’s brand name version of the combination of amlodipine besylate and benazepril hydrochloride. Although Pfizer’s petitions do not concern Mylan’s ANDA approval specifically, they do raise raise issues concerning the applicability of Pfizer's pediatric exclusivity for amlodipine, and whether the LOTREL NDA is a 505(b)(2) application subject to that exclusivity. 31

32. Generic Tactics – Morphing Into a “Brand Name” Company • Teva – Copaxone® -- 1996 • Duramed -- Conjugated Estrogens – Cenestin® -- 1999 • 120 women • 12 week study • No animal tox needed • Par – Megace ES® • 625/5 ml vs. 40 mg./ml (Bristol Myers) • Not possible via ANDA Suitability • But, still only did a bioequivalent study 32

33. Take Home Messages • Be Prepared – monitor what’s going on • FDA Dockets – Petitions • News • Your Own Review Documentation – can give hints • Be Prepared to Be Aggressive • Anticipate the Unexpected • Know Your Product • Very Complicated Scenarios 33

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35. Questions? Call, e-mail, fax or write: Michael A. Swit, Esq. Vice President, U.S. Pharmaceuticals 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 D.C. Office 202.730.4123 michael.swit@weinberggroup.com www.weinberggroup.com 35

36. About your speaker… Michael A. Swit, Esq., is Vice President for U.S. Pharmaceuticals 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. 36

37. 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. 37

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39. State Regulation of Clinical Trials5th National Conference on Managing Legal Risks in Structuring and Conducting Clinical Trials American Conference Institute Boston September 27, 2006 Michael A.Swit, Esq.Vice President, Life Sciences

40. MOST ACTIVE CLINICAL RESEARCH STATES 40

41. HOW CAN WE KNOW ALL THE STATES’ LAWS? • You can’t (easily) • One general source: State-by-State Clinical Trial Requirements Reference Guide, Sept. 2004, Serio, et al., Editors, Barnett Educational Services • Focus on key states -- e.g., see our chart • Work with your IRBs – they are required to know local conditions under federal law – thus, protocols and consents should be tailored by them to meet local rules 41

42. California v. Texas -- Age of Consent 42

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48. LEGALLY AUTHORIZED REPRESENTATIVE 48

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50. IRBS 50