1. ANDAs – Key Regulatory and Legislative Issues June 4, 2003 Annual OCRA/FDA Education Conference Irvine, California Michael A. Swit, Esq. Law Offices of Michael A. Swit 539 Samuel Ct. Encinitas, CA 92024 760-815-4762; fax: 760-454-2979 mswit@fdacounsel.com FDA Counsel.com

2. 2 PART I – Power Protecting and Preserving A Drug Franchise Under Waxman-Hatch – Exclusivity and the 30-month Stay FDA Counsel.com

3. 3 Market Protections Available Patents (and extensions) Traditional enforcement Listing patents in FDA's "Orange Book" Statutory exclusivities/extensions under Waxman-Hatch Other strategies FDA Counsel.com

4. 4 Listing Patents in FDA's "Orange Book" Requires patent certification by generic competitors If approval sought pre-expiration, generic must notify sponsor of bases for alleged invalidity or non-infringement. Sponsor may sue for infringement and impose 30-month stay of generic approval. FDA Counsel.com

5. 5 Statutory Exclusivities Under Waxman-Hatch New Chemical Entity (NCE) Exclusivity Prohibits the filing of an ANDA (or 505(b)(2) NDA) for a product that contains the NCE for 5 years after approval of the first NDA. (4 years if ANDA includes a Paragraph IV challenge to listed patent) NCE: "a drug that contains no active moiety that has been approved by FDA in any other [NDA]." FDA Counsel.com

6. 6 Statutory Exclusivities … 3-Year Exclusivity Available for NDAs which contain: Reports of "new" "clinical trials" That were "essential to approval" of the NDA Conducted or sponsored by the applicant FDA may not approve an ANDA or 505(b)(2) NDA for 3 years after approval Applies for new indications, Rx  OTC switch, new dosing regimen, and some other labeling changes. Carve out for pediatric labeling. FDA Counsel.com

7. 7 Statutory Exclusivities -- Other Orphan Drug Exclusivity 7 year exclusivity Drugs for rare conditions (<200,000 people in U.S.) Pediatric Exclusivity 6-month extension of existing patent or Waxman-Hatch exclusivity 180-day generic (ANDA) exclusivity FDA Counsel.com

8. 8 Generic Defense Strategies Patent listing, litigation Development of follow-on/ancillary patents Strategy may be impacted by pending legislation Amendments seeking 3-year exclusivity New indication for original product (limited utility) Changed dosage form New dosing regimen New strength(s) FDA Counsel.com

9. 9 PART II – Problems with Power Federal Trade Commission Oversight of Patent Litigation Settlements Between Big Pharma and the Generic Industry and Other Alleged Nefarious Activity FDA Counsel.com

10. 10 Abbott – Geneva – 2000 Drug: Hytrin® (terazosin HCl) Alleged antitrust violation – Abbott paid Geneva to not sell an approved capsule version while the companies litigated patent issues on the tablet version not transfer or relinquish Geneva’s 180-Day “ANDA Exclusivity” rights – thus, keeping other generics off the market Resolution: consent order FDA Counsel.com

11. 11 Abbott – Geneva Consent order … bars agreements that: restrict ANDA applicant from giving up 180-day exclusivity; or restrict ANDA applicant from entering the market with a non-infringing product agreements to pay to stay off market done to settle patent litigation need court OK and FTC chance to comment required Geneva to waive its 180-day exclusivity rights on a Hytrin tablet so other generics could enter market FDA Counsel.com

12. 12 Schering – AHP/ESI & Upshur- Smith Drug – K-Dur® (potassium chloride) Alleged antitrust violation – agreements to settle patent litigation Upshur-Smith: for $$, agreed to stay off market; as first to file a Para. IV patent cert., had 180-day Exclusivity; its delay in marketing meant subsequent ANDA filers could not go to market Resolution – July 2002 – an FTC administrative law judge threw out the FTC action; saying deal was really procompetitive FDA Counsel.com

13. 13 Hoechst-Marion-Rousell & Andrx Drug – Cardizem CD Alleged antitrust violation – agreements to settle patent litigation by which, for $$: Andrx agreed to stay off the market Andrx agreed to not relinquish its 180-day Exclusivity rights Resolution – consent order -- FDA Counsel.com

14. 14 Hoechst-Marion-Rousell & Andrx … Consent order … (similar to Hytrin®) barred from agreeing to NOT relinquish 180-day exclusivity rights (which, if kept, can preclude subsequent generic filers from marketing even if approved and even if patent expired) barred from agreeing to restrictions on entering market with a non-infringing generic Interim patent litigation settlements involving payments to generics require Court OK and notice to FTC FDA Counsel.com

15. 15 Other Alleged Nefarious Activity – Biovail Patent Listing Case Drug – Tiazac® (diltiazem) Alleged violative activity: filing a patent in Orange Book (O.B.) that did not claim marketed drug – effectively kept generic off due to need to certify to new patent illegal exclusive marketing license with patent holder (differed from Biovail) FDA Counsel.com

16. 16 Other Alleged Nefarious Activity – Biovail Patent Listing Case … Resolution – consent order: Biovail to divest part of exclusive patent license Biovail to not enforce any rights that would trigger a 30-month Waxman-Hatch barred from wrongfully listing patents in O.B. FDA Counsel.com

17. 17 Part III – Regulatory and Statutory Solutions to Power Problems FDA October 2002 Rule McCain-Schumer Legislation FDA Counsel.com

18. 18 FDA 30-Month Rule No need to give notice to a patent that claims a use for which ANDA applicant is not seeking approval More specifically defines those patents that should be listed by brand name companies Drug substance – must be same as that which is subject to a pending or approved NDA FDA Counsel.com

19. 19 FDA 30-Month Rule Drug product patents – must be subject to a pending or approved NDA Method of Use patents – only those indications or “conditions of use” that are in a pending or approved NDA “Patent Declaration” required by brand names relative to patents to be listed FDA Counsel.com

20. 20 Orange Book Listing Patents that "claim the drug for which the application was approved," or Patents that claim an approved method of use, Must be submitted to FDA within 30 days of NDA approval, or 30-days of issuance (if issued post-approval) FDA Counsel.com

21. 21 Late Listing Penalty Failure of NDA holder to timely list will bar patent holder (who may be different person) from enforcing the patent against any person who has filed an ANDA or 505(b)(2) NDA, or manufactures, uses, or sells an approved generic or 505(b)(2) drug. FDA Counsel.com

22. 22 Listing Challenges ANDA applicants can bring civil lawsuit seeking correction or removal of listed patent information. Only pending applicants may sue. Only applies to patents listed at time of NDA approval. No "damages" allowed. FDA Counsel.com

23. 23 Claim-by-Claim ¶-IV Certifications For patents that Include both product claim and method of use claim(s), or Contain multiple method of use claims, Paragraph IV Certifications, and "viii statements" must be claim-specific. FDA Counsel.com

24. 24 30-Month Stay Limitation The 30-month stay of Paragraph IV ANDA approval may only be imposed with respect to patents listed at time of initial NDA approval, not post-approval patents. For "other patents" "not described in clause (iii)"** but listed in the Orange Book, innovator must seek PI within 45 days; If PI denied, immediate approval possible. If PI granted, approval delayed until case resolved. FDA Counsel.com

25. 25 One-Shot Patent Enforcement In addition to not being able to enforce late-listed patents, if no lawsuit is brought within 45 days of a Paragraph IV Notification to a listed patent, a patent owner is "barred from bringing a civil action for infringement" with respect to drug under the ANDA. FDA Counsel.com

26. 26 Generic Exclusivity Eligibility Reverts to prior FDA requirement that first Paragraph IV applicant must be sued to get exclusivity. Appears to maintain patent-by-patent exclusivity approach. FDA Counsel.com

27. 27 Generic Exclusivity Triggers Reverts to "final" court decision trigger rule to start 180-day exclusivity period. Adds settlement or consent decree as a triggering event if it contains a specific finding of invalidity/non-infringement. FDA Counsel.com

28. 28 Generic Exclusivity Forfeiture Failure to market w/in 60 days of final approval or court decision (whichever is later) Withdrawal of ANDA Amendment from ¶IV to ¶III Failure to obtain tentative approval w/in 30 months. Failure to challenge newly listed patents. FTC finds unlawful conduct by applicant FDA Counsel.com

29. 29 "Rolling" Generic Exclusivity If first challenger forfeits exclusivity, all subsequent ANDAs eligible for approval. If first subsequent ANDA to get effective approval was also the first subsequent filer (i.e., second overall filer), then it receives exclusivity. No other subsequent ANDA eligible. FDA Counsel.com

30. 30 Bioequivalence Provisions The 1992 amendments to 21 C.F.R. Part 320 "shall continue in effect as an exercise of authorities under [FDCA] sections 501, 502, 505, and 701," but may be amended by FDA. "This section shall not be construed to alter the authority of [HHS] to regulate biological products under the [FDCA] (21 U.S.C. § 301 et seq.). Any such authority shall be exercised under that Act as in effect on the day before the date of enactment of this Act." FDA Counsel.com

31. 31 Part IV – the Future – Generic Biologics??? No consensus view exists that any current legal mechanism can be used to support approval of a generic biologic Why? Legally, biologics licensed under Public Health Service Act, not Waxman-Hatch Difficulty (alleged?) in characterization FDA Counsel.com

32. 32 What is a 505(b)(2) Product ? Not a completely new product, Not a generic, A product with some differences from a previously approved product. Approval requires clinical data, but the studies may have been conducted by others. FDA Counsel.com

33. 33 “Generic” “Biologics” "One cannot completely characterize the biological product and that in itself is an issue, and quite frankly with biological products you really don’t have a homogeneous product, you have a defined range of biological components for which you find consistency in a particular clinical outcome. The challenges of analytical technology are still very great for characterizing biologics." -- Katherine Zoon, CBER FDA Counsel.com

34. 34 “Generic” “Biologics” Under 505(b)(2)? For Biologics originally approved under an NDA, FDA will accept a 505(b)(2) for a “generic” version Examples include naturally-derived active ingredients (from animal or botanical sources) or those derived from recombinant technology (e.g., insulin, HGH) For BLA-approved products, no generic approval pathway FDA Counsel.com

35. 35 How is 505(b)(2) Different? The applicant and FDA may rely on prior FDA safety and efficacy determinations, based on studies conducted by someone else even though the applicant does not have a right of reference to the data. 21 U.S.C. § 355(b)(2) Safety and efficacy can also be supported by published reports FDA Counsel.com

36. 36 Types of 505(b)(2) NDAs New Chemical Entity (rarely) Changes to a Previously Approved Drug New dosage form, dosing regimen, strength, or route of administration New indication New active ingredient New inactive ingredient that requires studies beyond limited confirmatory studies Rx  OTC switch (Claritin) Duplicates of approved drugs that cannot be approved under an ANDA FDA Counsel.com

37. 37 Patent and Exclusivity Issues 505(b)(2) NDA must include patent certification(s). 505(b)(2) NDA must also list any relevant patent(s). Same Paragraph IV challenge system as ANDAs, EXCEPT, no 180-day exclusivity period. FDA Counsel.com

38. 38 Patent and Exclusivity Issues A 505(b)(2) product may itself qualify for 3 or 5 years of new drug exclusivity 3-year exclusivity requires: New clinical studies (other than BE studies) Conducted by the applicant Essential to the approval of the application 5-year exclusivity for "New Chemical Entities" NCEs can be old drugs (i.e., ingredient never approved under an NDA) FDA Counsel.com

39. 39 Patent and Exclusivity Issues Waxman-Hatch Exclusivities block ANDAs and 505(b)(2) NDAs, but cannot block a "full" NDA. 3-year exclusivity blocks other pending 505(b)(2)s, regardless of filing date; creates race to approval. Only the first 505(b)(2) for a change can receive exclusivity. Studies for later applications deemed not essential for approval. 5-year exclusivity does not block other 505(b)(2)s that were filed before first approval. FDA Counsel.com

40. 40 Pfizer/Pharmacia Petition Statement of Grounds Reliance on proprietary data not authorized by FDCA for 505(b)(2) NDAs Published Studies vs. Proprietary Data vs. FDA Findings of Safety/Efficacy Reliance on proprietary data would be an unconstitutional “taking” “A” ratings not permitted for 505(b)(2) drugs FDA Counsel.com

41. 41 Which Way is the Generic Biologics Wind Blowing ?? No 505(b)(2) approved yet for a biotech product FDA Guidance on “Well-Characterized Biologics” – a manifesto for action? Transfer of CBER therapeutics review divisions to CDER – a harbinger of a bureaucracy being repositioned to handle generic biologics? FDA Counsel.com

42. 42 Which Way is the Generic Biologics Wind Blowing ?? No 505(b)(2) approved yet for a biotech product FDA Guidance on “Well-Characterized Biologics” – a manifesto for action? Transfer of CBER therapeutics review divisions to CDER – a harbinger of a bureaucracy being repositioned to handle generic biologics? FDA Counsel.com

43. 43 A Few Predictions and Questions FDA will not do it on its own; will require statutory authorization McCain-Schumer will not be the vehicle, but may be regarded by some as necessary itself to be enacted before tackling generic biologics Is the generic industry ready to challenge technologically? FDA Counsel.com

44. 44 Generic Biologics -- A Few Predictions and Questions … Where does the science of characterization and replication stand on large molecules? How will bioequivalence be judged? Are the “drug” models relevant? If not, will generic biologics always require comparative clinical studies? FDA Counsel.com

45. 45 OTC’s – Key Issues Wellpoint Petition – forced Claritin OTC Will FDA file its own petitions? T.E.A. Rule – foreign data can now be used to support an OTC Switch What studies are sufficient to support Waxman-Hatch Exclusivity? Make sure they’re essential – Minoxidil More than one similar product can get exclusivity FDA Counsel.com

46. 46 Questions? Call, e-mail, fax or write: Michael A. Swit, Esq. Law Offices of Michael A. Swit 539 Samuel Ct., Suite 229 Encinitas, California 92024 760-815-4762 ♦ 760-454-2979 (fax) mswit@fdacounsel.com http://www.fdacounsel.com FDA Counsel.com

47. 47 About the speaker... Michael A. Swit has extensive experience in all aspects of FDA regulation with a particular emphasis on drugs and medical device regulation. In addition to his regulatory law experience, Mr. Swit also served for three and a half years as vice president and general counsel of Pharmaceutical Resources, Inc. (PRI) a prominent generic drug company and, thus, brings an industry and commercial perspective to his representation of FDA-regulated companies. While at PRI from 1990 to late 1993, Mr. Swit spearheaded the company’s defense of multiple grand jury investigations, other federal and state proceedings, and securities litigation stemming from the acts of prior management. Mr. Swit then served from 1994 to 1998 as CEO of Washington Business Information, Inc. (WBII) a premier publisher of FDA regulatory newsletters and other specialty information products for the FDA publishing company. Before starting FDACounsel.com, he was with Heller Ehrman from May 2001 to May 2003, and also twice in private practice with McKenna & Cuneo, from 1988 to 1990 and, most recently, from 1999 to 2001, first in that firm’s D.C. office and most recently, in its San Diego office. He first practiced FDA regulatory law with the D.C. office of Burditt & Radzius from 1984 to 1988. Mr. Swit has taught and written on a wide variety of subjects relating to FDA law including, since 1989, co-directing a three-day intensive course on the generic drug approval process, serving on the Editorial Board of the Food & Drug Law Journal, and editing a guide to the generic drug approval process, Getting Your Generic Drug Approved, published by WBII. Mr. Swit holds an A.B., magna cum laude, with high honors in history, in 1979, from Bowdoin College, and earned his law degree from Emory University in 1982. He is a member of the California, Virginia and District of Columbia bars. FDA Counsel.com