1. © Frommer Lawrence & Haug LLP BIOSIMILARS: ALTERNATIVE REGULATORY PATHWAYS American Conference Institute FOLLOW-ON BIOLOGICS June 22, 2010 Charles J. Raubicheck 745 Fifth Avenue New York, New York 10171 Phone: (212) 588-0800 Fax: (212) 588-0500

2. © Frommer Lawrence & Haug LLP 1 BIOSIMILARS UNDER HATCH-WAXMAN Section 505(b)(2) Added by Hatch-Waxman Clinical Studies Not Conducted By or For the NDA Applicant and No Right of Reference 505(b)(2) Applicant Can Rely on Clinical Data it Does Not Develop (Innovator’s S/E Data) Section 505(b)(2) Regulatory Approval Pathway

3. © Frommer Lawrence & Haug LLP 2 HATCH-WAXMAN: 505(b)(2) NDA (cont’d) Types of data for Reliance Published Literature (previous “Paper NDA”) FDA Finding of Safety and Effectiveness for a Drug Approved Under a Full NDA 505(b)(2) Applicant Relies in Part on Innovator’s S/E Data (505(b)(1)), Plus Data the Applicant Itself Generates FDA’s Rationale: Preclude Unnecessary Clinical Studies for What is Already Known About a Drug

4. © Frommer Lawrence & Haug LLP 3 HATCH-WAXMAN: 505(b)(2) NDA (cont’d) Announcements of 505(b)(2) Approach 1987 Parkman Letter (Modifications When Clinical Data Required) Preambles: 1989 and 1992 ANDA Regulations 1999 Section 505(b)(2) Guidance Guidance – (b)(2) Applies to Changes to Drugs Previously Approved Under a FULL NDA

5. © Frommer Lawrence & Haug LLP 4 HATCH-WAXMAN: 505(b)(2) NDA (cont’d) Bridging Studies: Usually Several Clinical Trials At Least One Phase II or Phase III Conference with FDA re Protocol Rare: Bioequivalence

6. © Frommer Lawrence & Haug LLP 5 HATCH-WAXMAN: 505(b)(2) NDA (cont’d) Examples of Types of Changes Active Ingredient Dosage Form Strength Route of Administration Dosing Regimen Combination Product Indication

7. © Frommer Lawrence & Haug LLP 6 HATCH-WAXMAN: 505(b)(2) NDA (cont’d) Naturally Derived or Recombinant Active Ingredient Change to prior approved Active Ingredient that is Chemically Synthesized or Derived from Another Source Clinical Bridging Studies: Required to Show that Active Ingredient Is the Same As the Active Ingredient in a Drug Covered by an Approved Full NDA Also, (key here):

8. © Frommer Lawrence & Haug LLP 7 SECTION 505(b)(2) NDA: CHALLENGES Proprietary Data (Clinical and CMC) FDA Only Refers Internally Data Protected: No Public Disclosure Statute Doesn’t Preclude Reliance on Innovator’s S/E Data No Unconstitutional Taking No Expectation of Confidentiality (Highly Regulated Field) REJECTED BY FDA

9. © Frommer Lawrence & Haug LLP 8 SECTION 505(b)(2) NDA: BIOSIMILARS No Statutory Exclusion Biologic Is a “Drug” Highly Similar Active Ingredient Precedent: Insulin (Historical) Need for Biosimilar Pathway

10. © Frommer Lawrence & Haug LLP 9 SECTION 505(b)(2) NDA: BIOSIMILARS (cont’d) 2005 – HYLENEX (Recombinant Hyaluronidase): Increases Absorption and Dispersion of Other Injected Drugs Reliance: Amphastar ® (bovine-derived) 2005 – FORTICAL (Recombinant Salmon Calcitonin): Ostoporosis Reliance: Miacalcin ® (Synthetic) Recent 505(b)(2) Approvals

11. © Frommer Lawrence & Haug LLP 10 SECTION 505(b)(2) NDA: BIOSIMILARS (cont’d) 2006 – OMNITROPE (Recombinant Somatropin): Human Growth Hormone (rhGH) Reliance: Genotropin ® CASE STUDY: OMNITROPE Citizen Petitions (Pfizer, BIO, Genentech) Denied FDA Rationale 505(b)(2): Chemical Structure of Active Ingredient “Highly Similar” (as in Biosimilars Act) (“Sameness” Not Required)

12. © Frommer Lawrence & Haug LLP 11 SECTION 505(b)(2) NDA: BIOSIMILARS (cont’d) rhGH a Relatively Simple Recombinant Protein (Characterization, Purification) Highly Similar Characteristics: Pharmacokinetic, Pharmacodynamic, Bioavailability Clinical Experience and Published Literature on rhGH Bridging Studies PK/PD Studies Phase III Clinical Trials (4)

13. © Frommer Lawrence & Haug LLP 12 ANDA APPROVAL VEHICLE ANDA Must Be Filed for: Same Active Ingredient, Dosage Form, Strength, Route of Administration, Indications Drug Product which Differs From Innovative Product in One of the Above Respects, but Has an Approved Suitability Petition Allowing the Change Does Not Require S/E Clinical Studies Can’t Be a 505(b)(2)

14. © Frommer Lawrence & Haug LLP 13 ANDA APPROVAL VEHICLE (cont’d) Ferring’s REPRONEX (Menotropins) for Infertility Active Ingredient: Follicle-Stimulating Hormone (“FSH”) Citizen Petition Opposition: Serono’s Pergonal ® FSH in REPRONEX Different From FSH in Pergonal ® (Different Isoforms of Hormone) ANDA Route Improper Example

15. © Frommer Lawrence & Haug LLP 14 ANDA APPROVAL VEHICLE (cont’d) FDA Denied Citizen Petition: Natural Variation in Carbohydrate Elements (Leading to Different Isoforms of Hormone) “Not Clinically Significant” (Similar to “No Clinically Meaningful Difference” in New Biosimilar Definition) “Sameness” Standard Satisfied when Same Primary Chemical Structure, Amino Acid Sequence, Potency, and Degree of Batch to Batch Uniformity Unusual for a Biologic

16. © Frommer Lawrence & Haug LLP 15 ANDA APPROVAL VEHICLE (cont’d) D.C. Circuit (upholding FDA): “Same Active Ingredient”: Chemical Identity to Extent Possible (Not Complete Identity) Isoform Variations Permissible under FDA’s “No Clinical Significance” Criterion Reasonable Interpretation under Chevron: Deference to FDA ANDA Vehicle Unlikely Now, due to Biosimilars Act

17. © Frommer Lawrence & Haug LLP 16 TRANSITIONAL PROVISIONS 505(b)(2) NDAs Permitted: For Biologics in Same Product Class as Biologics Previously Approved under (b)(2) Submitted Before Enactment Date (March 23, 2010), or Within 10 Years Thereafter All Biologics After Enactment Date: BLA or ABLA

18. © Frommer Lawrence & Haug LLP 17 TRANSITIONAL PROVISIONS (cont’d) All 505(b)(2) Approved Products: Deemed to Have Approved BLAs 10 Years after Enactment Date (Follow-On Products Then Need ABLA) Until then, 505(b)(2) Procedures Apply (including Patent Certification)

19. © Frommer Lawrence & Haug LLP 18 BIOSIMILAR VIA FULL BLA Full BLA Alternative Pathway NEUTROVAL (Filgrastim; Similar to Neupogen ® ) Treatment of Neutropenia (Increases White Blood Cells to Prevent Infection in Patients Undergoing Chemotherapy) Accepted by FDA (February 2010): pre- Biosimilars Act Supported by 5 Clinical Studies 780135