Follow-On Biologics The New Regulatory Frontier

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

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

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® 3

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 4

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 5

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

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 7

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 Ø Need for clinical studies remains 8

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? 9

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. 10

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 11

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 12

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 13

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 14

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

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 16

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 17

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 18

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 19

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 20

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

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