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ACI’s Conference on Follow-on Biologics Defining Biosimilars: Proving (or Disproving) Interchangeability and Biosimilarity June 21, 2010 Brian J. Malkin Partner 212-588-0800 [email protected] ©2010 CONFIDENTIAL Frommer Lawrence & Haug LLP Methods for Determining Similarity: Safety, Purity, and Potency Biosimilars Act defines “biosimilar” in two parts: • “[T]he biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components” PHSA § 351(i)(2)(A) - • “[T]here are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product” - PHSA § 351(i)(2)(B). Data supporting biosimilarity includes: • “[A] clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in 1 or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biological product.” - PHSA § 351(k)(2)(A)(i)(I)(cc). 2 ©2010 CONFIDENTIAL Frommer Lawrence & Haug LLP Methods for Determining Similarity: Safety, Purity, and Potency (cont’d) PHSA regulations define safety, purity, and potency: • Safety: “[T]he relative freedom from harmful effect to persons affected, directly or indirectly, by a product when prudently administered, taking into consideration the character of the product in relation to the condition of the recipient at the time” - 21 C.F.R. § 600.3(p) • Purity: “[R]elative freedom from extraneous matter in the finished product, whether or not harmful to the recipient or deleterious to the product. Purity includes but is not limited to relative freedom from residual moisture or other volatile substances and pyrogenic substances” - 21 C.F.R. § 600.3(r) • Potency: “[T]he specific ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner intended, to effect a given result” - 21 C.F.R. § 600.3(s). 3 ©2010 CONFIDENTIAL Frommer Lawrence & Haug LLP Methods for Determining Similarity: Safety, Purity, and Potency (cont’d) Manufacturing changes requiring comparability protocol (pre-approval) 4 • Increase/decrease batch size affecting equipment size • Modification in fermentation parameters (time, temperature, pH, dissolved oxygen) • Adding, deleting, substituting raw materials (e.g., buffer, media) • Mode changes (equipment oriented, e.g., tangential flow filtration to centrifugation) • New working cell bank using modified procedure • Reprocessing drug substance/product • Addition, deletion, or rearrangement of production steps • Other facility-related changes established in BLA See FDA Guidance for Industry: Comparability Protocols – Protein Drug Products and Biological Products – Chemistry, Manufacturing, and Controls Information (Draft 2003); FDA Guidance for Industry: Q5E Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process (2005). ©2010 CONFIDENTIAL Frommer Lawrence & Haug LLP Methods for Determining Similarity: Safety, Purity, and Potency (cont’d) Process-specific considerations for comparability protocol • Complexity of product structure • Ability to characterize physiochemical, biochemical, immunological, microbiological, and biological properties • Ability to detect differences in product characteristics • Degree of product heterogeneity • Effect of potential changes in impurities on product safety • Robustness of product (ability to remain unaffected by process changes) • Rigorousness of process controls 5 See FDA Guidance for Industry: Comparability Protocols – Protein Drug Products and Biological Products – Chemistry, Manufacturing, and Controls Information (Draft 2003); FDA Guidance for Industry: Q5E Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process (2005). ©2010 CONFIDENTIAL Frommer Lawrence & Haug LLP Methods for Determining Similarity: Safety Head-to-head clinical trials • Clinical trials providing direct evidence of safety, e.g., Phase III studies for Omnitrope® [Note: Omnitrope has “BX” rating.]. Immunogenicity assays • “Low and acceptable level of immunogenicity”, e.g., antibody levels for Omnitrope® • Neutralizing antibodies assays may be necessary See Miacalcin® (Salmon calcitonin nasal spray) citizen petition (FDA-2005-P-0367) [Note: 2 “AB”-rated generics for Miacalcin® nasal spray using chemical synthesis as with referenced product, one 505(b)(2) NDA (Fortical®) for the recombinant-derived product; none for Miacalcin® injection.]. Toxicological studies [Required for 505(b)(2) NDA (Fortical®) but not ANDAs.] 6 • Comparative carcinogenic potential • Comparative reproductive toxicity. ©2010 CONFIDENTIAL Frommer Lawrence & Haug LLP Methods for Determining Similarity: Purity Common impurities in peptide products include modifications arising from oxidation, deamidation, epimerization, or N-1 deletion. HPLC analysis may determine an absence of any peptide-related impurities to a low detection threshold. (Miacalcin®) Peptide-related impurities should be comparable (not necessarily identical) to the reference product. (Miacalcin®) • See also Pergonal® (follicle-stimulating hormone and luteinizing hormone from urine of post-menopausal women) where uncharacterized urinary proteins were treated as impurities rather than additional components [Note: Generic versions of Pergonal® obtained “AB” rating.] Immunogenicity study may be required if significant impurity levels or aggregation not found in the reference product. (Miacalcin®) 7 ©2010 CONFIDENTIAL Frommer Lawrence & Haug LLP Methods for Determining Similarity: Potency One or more measurements of product integrity: • Quantitative biological assay (“bioassay”) A bioassay measures “the activity of the product related to its specific ability to effect a given result.” In vitro organ, tissue, or cell-based culture systems In vivo tests in relevant animal models e.g., rat bioassay for Pergonal® (menotropins) (USP). • Non-biological analytical assays Immunochemical, biochemical, or molecular attributes correlated to product-specific biological activity. See Miacalcin®; see also FDA Guidance: Potency Tests for Cellular and Gene Therapy Products (Draft 2008). 8 ©2010 CONFIDENTIAL Frommer Lawrence & Haug LLP Examples of Manufacturing Changes Where Similarity Was Questioned Myozyme® (alglucosidase alfa) • Genzyme intended to market both a 160L and 2000L scale enzyme product (α-glucosidase) (GAA) • But comparability data in GAA knockout mice revealed AUC was 30% lower for 2000L scale product • Resulted in withdrawal of 2000L scale product from BLA. (Note: FDA approved the BLA for Genzyme’s Framingham, Massachusetts facility, but FDA’s approval letter indicated Genzyme would manufacture its final product at Genzyme’s Allston, Massachusetts facility.) 9 ©2010 CONFIDENTIAL Frommer Lawrence & Haug LLP Examples of Manufacturing Changes Where Similarity Was Questioned (cont’d) Raptiva® (efalizumab) • Genentech developed cell line and process for monoclonal antibody for psoriasis and transferred to XOMA, which manufactured clinical grade material and performed clinical trials for Genentech • But when XOMA transferred to Genentech for scale-up and commercial requirements, minor analytical differences in the product were confirmed with a finding of significant PK profile differences • Forced Genetech to perform another clinical trial with a larger patient subset for safety and efficacy. (Note: Withdrawn in 2009 for post-approval safety reasons – rare life-threatening neurological viral disease.) 10 ©2010 CONFIDENTIAL Frommer Lawrence & Haug LLP Examples of Manufacturing Changes Where Similarity Was Questioned (cont’d) Eprex® (erythropoietin alpha) • Ortho Biologics (J&J) reformulated its glycoprotein hormone that controls erythropoiesis (red blood cell production) in Europe following the mad cow scare to remove human-sourced material (human serum albumin) and replace it with sorbitol (polysorbate 80) • Following reformulation, 200+ patients developed pure red cell aplasia (PRCA) as a result of neutralizing antibodies generated against erythropoietin, preventing new red blood cell production and requiring transfusions • Animal evidence suggests that sorbitol caused certain organic compounds to leach from the rubber stoppers, increasing erythropoeitin immunogenicity • Ortho started using specially-coated stoppers and changed route of administration from S.C. to I.V., resulting in return to baseline event profile. 11 ©2010 CONFIDENTIAL Frommer Lawrence & Haug LLP Applying for Similarity Determinations Existing comparability protocol may pave way for biosimilar pathway. FDA has no legal requirement to develop guidance but may develop with public input. FDA unlikely to provide guidance by letter requests as occurred in late 2009 for ANDA products. 12 ©2010 CONFIDENTIAL Frommer Lawrence & Haug LLP Applying for Similarity Determinations (cont’d) Biosimilar applicant may request pre-IND or CMC-specific meetings to discuss 13 • Data required for approval • Cell lines and characterization • Physiochemical and biological characterization • Removal of impurities (misfolded proteins, aggregates, host cell proteins, nucleic acid) • Bioactivity of product-related substances and impurities • Facility design • Other validation or assay considerations. See FDA Guidance for Industry: IND Meetings for Human Drugs and Biologics – Chemistry, Manufacturing, and Controls Information (2001); FDA Guidance for Industry: Formal Meetings Between the FDA and Sponsors or Applicants (2009). ©2010 CONFIDENTIAL Frommer Lawrence & Haug LLP Questions? 14 ©2010 CONFIDENTIAL Frommer Lawrence & Haug LLP