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2. © Copyright 2015 Quintiles FDA/EMA Current Thinking on Totality of Evidence for Biosimilar Approvals Kamali Chance, MPH, PhD, RAC Vice President Head, Global Biosimilars Regulatory Strategy Quintiles, Inc.

3. 3 Disclaimer The views expressed in this presentation are the personal views/assessments by the author and do not necessarily represent the views of Quintiles, Inc.

4. 4 Regulations/Guidances – USA and EU Totality of Evidence ›CMC ›Nonclinical ›Clinical US Updates EU Updates Summary Agenda

5. 5 2004 2005 2006 2009 2010 2011 2012 2014 2015 EMEA Legislative Pathway EMEA Regulatory Guidance [Overarching Guideline] Product Class Specific Guidelines: Low molecular weight heparin, recombinant Interferon- alpha Product Class monoclonal antibodies- non-clinical and clinical issues Guidelines under revision: Follicle stimulating hormone, Interferon-beta Product Class Specific Guideline: Recombinant Erythropoietin Quality Guideline; Non-Clinical & Clinical Guideline Product Class Specific Guidelines: Recombinant Insulins, G-CSF, Somatropin Product Class Immunogenicity assessment of monoclonal antibodies PHS Act amended to allow the approval of biosimilars Overarching Draft Biosimilar Guidelines Nonclinical and clinical guidelines revised http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c The BPCI Act appears in Title VII, subtitle A of the Patient Protection and Affordable Care Act, March 2010. US FDA: Guidances for industry. Quality and Scientific considerations in demonstrating biosimilarity to a reference product and Q & A final Guidances 2015. Europe United States Biosimilar Regulations/Guidelines in EU and USA The EU pioneered the development of biosimilar regulations Biosimilars Clinical Pharmacology Overarching and Q&A guidances revised and finalized. Additional Q&A guidance issued + Nonproprietary Naming of Biological Products Quality guidelines revised Labeling for Biosimilar Products 2015 2016

6. 6 Stepwise Development Same amino acid sequence, higher order structures, including secondary, tertiary, and quaternary structure using state of the art orthogonal methods Post-translational modifications, charge variants, N or C terminal truncations, other variants, degradants and impurities Functional activities: specific activity; receptor mediated activity, etc. Selective and targeted approach to animal and/or clinical testing CMC Non-clinical Clinical Comprehensive and robust comparative structural and functional characterization

7. 7 Head-to-head similarity assessment In-depth chemical, physical, and bioactivity comparisons with side-by-side analyses An in-house reference standard(s) As a scientific matter, as with 351(a) BLAs, a type II Drug Master File (DMF) for a drug substance, drug substance intermediate, or drug product would not be acceptable for a 351(k) application Tests used to characterize the product during development do not necessarily need to be validated but should be scientifically sound Totality of evidence basics - analytical

8. 8 Comparative accelerated and stress stability studies under multiple stress conditions Sufficient real time, real condition stability data If manufacturing changes are made after completing the initial analytical similarity assessment or after completing clinical testing, the sponsor should perform an additional analytical similarity assessment: ›with lots manufactured by the new process and the reference product and ›with lots manufactured by the old and new manufacturing processes Totality of evidence basics - analytical

9. 9 Comparative in nature In vitro studies- generally performed to assess any possible differences in bioactivity ›Binding to target antigen ›Binding to receptors ›Fab associated functions (e.g., neutralization, receptor activation or receptor blockade) ›Fc-associated functions (ADCC and CDC assays, complement activation) In vivo studies-depend upon the need for additional information, and the availability of a relevant animal model ›In vivo nonclinical studies should be conducted in a sensitive animal model and should include full animal pathology, histopathology, PK, PD, and immunogenicity assessments. ›If non-human primates are the only relevant species, the conduct of standard repeated dose toxicity studies is usually not recommended. If appropriately justified, a repeated dose toxicity study with refined design (e.g., using just one dose level of biosimilar and reference product and/or just one gender and/or no recovery animals) or an in-life evaluation of safety parameters may be considered Totality of Evidence Basics - Nonclinical

10. 10 Human PK/PD (if PD biomarker is available) similarity data required ›Even if relevant PD measures are not available, sensitive PD endpoints may be assessed if such assessment may help reduce residual uncertainty about biosimilarity. PD measures should be: »Relevant to clinical outcomes »Measurable after dosing to ascertain PD response »Have sensitivity to detect clinically meaningful differences ›If there is a meaningful correlation between PK and PD results and clinical effectiveness, convincing PK and PD results may make a comparative efficacy study unnecessary. Efficacy and safety similarity data generally expected ›If the MOA is the same for all indications, then likely one confirmatory trial would be needed ›If MOA for the various indications is different, then likely more than one confirmatory trial would be needed Immunogenicity similarity data expected ›Nature of immune response (anaphylaxis, neutralizing antibody, etc.), clinical relevance, and severity of consequences needs to be assessed Totality of Evidence Basics - Clinical

11. 11 Clinical data should be generated using biosimilar product derived from the commercial manufacturing process. The proposed biosimilar and the reference product should be assessed in the same assay with the same patient sera whenever possible. Generally, FDA/EMA expect a clinical study or studies designed to establish statistical evidence that the proposed product is neither inferior nor superior to the reference product by more than a specified margin. Totality of evidence basics - clinical

12. 12 Typical standalone clinical development programs Confirmatory efficacy, safety, immunogenicity trial Proposed biosimilar US reference PK(PD) two-way comparison, single dose in healthy volunteers (HV) Proposed biosimilar EU reference Proposed biosimilar EU reference Proposed biosimilar US reference

13. 13 Biosimilar Clinical Development Program Confirmatory efficacy, safety, immunogenicity trial PK(PD) three-way comparison, single dose in healthy volunteers (HV) Proposed Biosimilar EU Reference US Reference Proposed Biosimilar EU Reference

14. 14 Transition Study Design Test Reference n 1 1 Test.5 Important to consider duration of exposure to test product is generally 12m for chronic indications Reference product can be from US or EU

15. 15 Interchangeability Study Design W52 n 2 2 T Test Switches should occur at the end of each cycle of chemotherapy, not during. Also should represent worst case dosing scenario. There is no washout period. Reference T R Reference product has to be US licensed and sourced product

16. 16 The mechanism of action in each condition of use for which licensure is sought: ›The target/receptor(s) for each relevant activity/function of the product ›The binding, dose/concentration response, and pattern of molecular signaling upon engagement of target/receptor(s) ›The relationship between product structure and target/receptor interactions ›The location and expression of the target/receptors The PK and bio-distribution of the product in different patient populations; PD measures may provide important information on MOA Differences in expected toxicities in each condition of use and patient population Data requirements for extrapolation

17. 17 Is interchangeability designation possible in an original 351(k) application? ›Yes, however highly unlikely at this time Fulfilling pediatric study requirements under PREA ›Extrapolation from reference product to proposed biosimilar depends upon: »If adequate pediatric information in the reference product labeling it can be extrapolated to proposed biosimilar with adequate scientific justification. »If PREA requirements were deferred for the reference product for those indications, a biosimilar applicant should request a deferral. »If PREA requirements were waived for the reference product for those indications, a biosimilar applicant should request a partial or full waiver. »If the submitted scientific justification for extrapolation under the BPCI Act is inadequate, a biosimilar applicant must submit appropriate data to fulfill applicable PREA requirements. ›Applicant should submit the PSP no later than 210 days before initiating confirmatory trial Pediatric requirements do not apply, if your product is found to be interchangeable FDA Updates

18. 18 For injected products, how can an applicant demonstrate that its proposed biosimilar product has the same “dosage form” as the reference product? ›For proposed biosimilar products intended to be injected, FDA considers “injection” (e.g., a solution) to be a different dosage form from “for injection” (e.g., a lyophilized powder). ›For purposes of section 351(k)(2)(A)(i)(IV) of the PHS Act, FDA also considers emulsions and suspensions of products intended to be injected to be distinct dosage forms. Nonproprietary Naming of Biological Products ›Biological products licensed under the PHS Act to bear a nonproprietary name that includes an FDA-designated suffix ›Applicable to all biologics, not just biosimilars ›FDA is considering whether the nonproprietary name for an interchangeable product should include a unique suffix, or should share the same suffix as its reference product. ›FDA seeking input from stakeholders on potential approaches for designating and incorporating suffixes retrospectively and prospectively into the nonproprietary names of all biological products. Labeling of Biosimilars ›Indicate that it is a biosimilar to already licensed reference product by name and include indications specifically authorized for the biosimilar ›Incorporate relevant data and information from the reference product into the biosimilar label and include appropriate product-specific modifications FDA Updates

19. 19 The biosimilar guidelines applicable to highly purified products that can be thoroughly characterized such as biotechnology-derived products Deviations from the reference product as regards strength, pharmaceutical form, formulation, excipients or presentation require justification. Any difference should not compromise safety Improvements in efficacy are not compatible with the biosimilarity approach. However, a biosimilar can have a better safety profile such as lower levels of impurities or lower immunogenicity Regarding quality data, biosimilar must meet all requirements for Module 3 and satisfy EP, and ICH guidelines Premarketing manufacturing changes will require comparison against the reference product and post marketing manufacturing changes will not. For pharmacovigilance monitoring the brand name and batch number of the biological product should be clearly identified for a suspected adverse reaction report EU Updates

20. 20 Clinical data cannot be used to justify substantial differences in quality attributes An in vivo nonclinical study may be necessary, if product-inherent factors that affect PK and/or biodistribution, like extensive glycosylation, cannot sufficiently be characterized on a quality and in vitro level Correction for protein content may be acceptable on a case-by-case basis if pre-specified and adequately justified, with the results from the assay of the test and reference products being included in the protocol. If the selected PD marker/biomarker is an accepted surrogate marker for clinical outcome, comparative PK/PD studies may be sufficient to demonstrate clinical comparability. Examples: » ANC >GCSF; »Early viral load reduction in chronic hepatitis C to assess the effect of alpha interferons »Euglycaemic clamp test to compare two insulins »Magnetic resonance imaging of disease lesions can be used to compare two β-interferons in multiple sclerosis The analytical assays should preferably be capable of detecting antibodies against both the biosimilar and the reference molecule. Increased immunogenicity as compared to the reference product will question biosimilarity. However, a lower immunogenicity is acceptable EU Updates

21. 21 FDA and EMA both have guidelines in place for approval of biosimilars They both emphasize stepwise development of biosimilars: analytical > nonclinical > clinical FDA has provided much needed clarity in the updated Quality and Scientific Consideration guidances as well as old and new Q&A guidances FDA has issued Nonproprietary Naming of Biological Products draft guidance and Labeling Guidance for Biosimilars EMA has provided clarity on overarching biosimilar guidelines as well as nonclinical and clinical issues There are some differences in the development of Biosimilars in the US vs EU ›Transition study ›Interchangeability ›Pediatric Study Plan In Summary

22. 22 Let us meet again.. We welcome you to our future conferences of Conference Series LLC through 6 th International Conference and Exhibition on Biologics and Biosimilars October 19-21, 2016 Houston, TX, USA http://biosimilars- biologics.pharmaceuticalconferences.com/europe