1. Follow-On Biologics: The New Regulatory Frontier [?] Michael S. Labson August 23, 2007

2. 2 The Small Molecule Generic Paradigm NDA Reference Listed Drug ANDA “Sameness” + bioequivalence CMC information Patent certification 30-mo. stay provisions 180-day exclusivity provisions + 505(b)(2) applications … Preclinical (e.g., toxicology) Clinical (safety & effectiveness) CMC information Patent listing

3. 3 Current Law & FDA Policy -- 505(b)(2) Limited pool of FDCA biologics Two-levels of the legal debate –Scope of 505(b)(2) generally –Special issues for biologics, especially manufacturing data FDA policy –Citizen petition response –Pfizer Norvasc® case came and went –Unigene Fortical® –Sandoz Omnitrope®

4. 4 Current Law & FDA Policy -- PHSA Reclassify biologics as drugs subject to FDCA 505? –“Biologics” are “drugs” Create a pathway within PHSA? But … significant legal barriers –PHSA sec. 351: “a product for which a license has been approved under subsection (a) shall not be required to have an approved application under section 505 of such Act” –FDA statements –Reinforced by FDA views on proprietary data

5. 5 The Pressure for Change Economic and political pressure as significant biologic products come off patent Scientific advances –E.g., better characterization of compounds Regulatory and administrative convergence –Review processes both driven by PDUFA –FDAMA creates unified BLA –CTD –2003 CBER/CDER reorganization European developments

6. 6 Europe Fewer legal barriers because no dual system for drugs/biologics General Guidance Documents Product-Specific Guidances –rDNA insulin – June 2006 –rDNA GCSF – June 2006 –Somatropin – June 2006 –rDNA EPO – July 2006 –Low molecular weight heparin – pending –rDNA alfa interferon – pending

7. 7 Europe Action on filings –April 16, 2006, Sandoz’s Omnitrope approved as biosimilar to Pfizer’s Genotropin –May 5, 2006, Biopartners’ Valtropin approved as biosimilar to Lilly’s Humatrope –June 30, 2006, CHMP issues negative opinion on Biopharma interferon alpha (Alpheon) –June 2007, CHMP recommends approval of three EPO products biosimilar to J&J’s Eprex Sandoz, Binocrit Hexal Biotech Medice Arzneimittel Putter, Abseamed

8. 8 FOBs – the “Scientific” Debate Advances/limitations on analytical characterization Relevance of innovator comparability protocols Immunogenicity risks Importance of manufacturing process Select cases cited pro/con: –Berlex Avonex® –Serono Pergonal® –Eprex® pure red cell aplasia episode –Raptiva® development  Need for clinical studies remains

9. 9 FOBs – the “IP” Debate Exclusivity –Debate around uncertainty of patents for biotech. Patents: incentive for invention Exclusivity: incentive to incur risk and bring product to market –Need for incentives for FOBs through exclusivity Patent –Link patents and regulatory schemes à la Hatch-Waxman? –Challenges with “listing” patents Takings –Reasonable investment-backed expectations –Kelo (S. Ct. 2005) Broadens “public use” concept, but not what is a taking and when must there be just compensation –Hatch-Waxman precedent from 1984?

10. 10 State of the Congress Senate FDARA “sense of the Senate” S. 1695 (Kennedy/ Clinton/Hatch/Enzi) marked up by HELP Comm. –May be further amended –Judiciary Comm. review may be needed for patent provisions House Not in FDARA H.R. 1956 (Inslee) H.R. 1038 (Waxman) Debate over what to use as base bill, including potentially a new bill August recess marches on – FDARA to be enacted in September.

11. 11 Key Issues for Legislation Approval standards –Characterization requirements –Data/study requirements –Data for all indications –Post-approval requirements FDA procedure –Treatment of FDCA biologics –E.g., Use of guidance documents Substitution/therapeutic equivalence/ interchangeability –Nomenclature Exclusivity –Innovator –Supplemental approvals –FOB Patent provisions/linkage

12. 12 Biologics Price Competition and Innovation Act (S. 1695) Sens. Kennedy, Clinton, Hatch, Enzi Approval standards (new PHSA 351(k)) –Analytical studies to show “highly similar” to RLB –Animal studies –Clinical study(ies) for 1 or more RLB use –Same MOA(s) (to the extent known) –Previously approved conditions of use –Same dosage form, strength, route of adminstr’n –Facility meets standards for safety, purety, potency

13. 13 Biologics Price Competition and Innovation Act (S. 1695) Approval standards (new PHSA 351(k)) –Analytical studies to show “highly similar” to RLB –Animal studies –Clinical study(ies) for 1 or more RLB use FDA may determine unnecessary + avoid needlessly duplicative or unethical clinical testing + FOB may reference publicly available info and prior findings for RLB

14. 14 S. 1695 (cont’d) Interchangeability –Biosimilar + expected to produce the same clinical result as the RLB + no increased risk of safety or diminished efficacy due to switching FDA procedure –Same review division as RLB –Same REMS authority as for innovators –User fees FDA to develop recommendations for Congress Transition provions –FDA may issue guidance documents Gen’l or specific, and public comment Guidance not required for FOBs to be submitted or approved –PHSA 351(k) is exclusive pathway for FOBs Limited exception for FDCA biologics, expiring in 10 years

15. 15 S. 1695 Patent Provisions FOB Confidential Access RLB Patent List FOB Certification & Supp’l Patents RLB Response  Special negotiation period  Mechanism for RLB suit  Prior notice of FOB marketing & mechanism for PI  Limitations on DJs

16. 16 S. 1695 (cont’d) Innovator exclusivity –12-year bar on FOB approval –4-year bar on FOB filing First interchangeable exclusivity –No further interchangeability finding until the earlier of: 1 year after first commercial marketing 18 mos. after appeals court decision or dismissal in case brought under new patent provisions 42 mos. after approval if sued and case still pending at 36 months 18 mos. after approval if not sued

17. 17 Patient Protection and Innovator Biologic Medicines Act (H.R. 1956) Rep. Inslee Product-class specific guidance –Anyone may request –Notice & comment process, with adv. comm. input and timelines Required data and information –Manufacturing process –Stability, compatibility and integrity of active –Data fully characterizing FOB v. RLB (active and product) –Comparative nonclinical studies (PK, PD, tox., immunogenicity) –Comparative clinical trials –Postmarketing monitoring (incl. re immunogenicity) Data for all indications

18. 18 H.R. 1956 (cont’d) FDA procedure –New PHSA 351(k) is exclusive pathway, including for FDCA biologics –Same review division as RLB No therapeutic equivalence and unique name required –Reports to Congress on future feasibility of therapeutic equivalence determinations Innovator exclusivity –No FOB submitted for 12 years –No FOB approved for 14 years, plus 1 for clinically sign. supplement No patent provisions

19. 19 Access to Life-Saving Medicine Act (H.R. 1038) Rep. Waxman Approval standards –Comparability based on non-clinical data and necessary confirmatory clinical study(ies) for one or more condition of use No unnecessary duplicative testing –Highly similar principal molecular structural features, but “minor” differences in heterogeneity, impurities, degradation, post-translational events, glycosylation, etc. permitted –Same MOA(s) if known –Same dosage form, strength and route of administration –Manufacturing facilities meet standards –505(b)(2)-type application also permitted

20. 20 H.R. 1038 (cont’d) Interchangeability –FDA makes determination for each FOB based on expectation of clinical equivalence FDA to issue guidance on standards –FOB and RLB shall have same designated official name Exclusivity –Exclusive interchangeability period for first interchangeable FOB (including bar on authorized FOBs) –No innovator exclusivity Patents –FOB request for patent list at any time –FOB notice at any time, incl. par. IV-type notice –RLB may bring infringement action within 45 days for listed patents only – bar on RLB DJs prior to commercial marketing Limitations on RLB citizen petitions

21. 21 Will We See “Shark Fin” 2? Sales Time generic entry

22. 22 Questions ? Michael S. Labson Covington & Burling LLP (202) 662-5220 mlabson@cov.com