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Development Considerations Comparing Major Markets Including US, EU, Japan and China


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PAREXEL Consulting experts compare regulatory requirements in major drug development markets including the US, EU, Japan and China.

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Development Considerations Comparing Major Markets Including US, EU, Japan and China

  2. 2. © 2018 PAREXEL INTERNATIONAL CORP. / 2 AGENDA WELCOME • Development considerations: Comparing major markets including US, EU, Japan and China • Hear different approaches to similarity of quality attributes • Gain an understanding of navigating different clinical data requirements and their endpoints • What are the requirements for choice of reference product, interchangeability, ethnicity and need for data from local patients and conducting global studies?
  3. 3. © 2018 PAREXEL INTERNATIONAL CORP. / 3 NAVIGATING THE DIVERGING GLOBAL REGULATIONS OF BIOSIMILARS I want to see data in people from my country Reference product must come from my country If it is OK in your country it is OK with us US: This is not a biological in my country! Do not know what to do! Best I do nothing I do not care what others require – we need the data in drug naïve patients
  5. 5. © 2018 PAREXEL INTERNATIONAL CORP. / 5 Highly similar Notwithstanding minor differences in clinically inactive components No clinically meaningful differences in terms of the safety, purity, and potency (amino acid sequence same) Similarity in terms of quality, biological activity, safety and efficacy based on comprehensive comparability exercise Similar, in molecular and biological terms (amino acid sequence same) WHAT IS BIOSIMILARITY? USEU
  6. 6. © 2018 PAREXEL INTERNATIONAL CORP. / 6 The route of administration, the dosage form, and the strength of the biological product are the same as those of the reference product Posology and route of administration same Deviations as regards strength, pharmaceutical form, formulation, excipients or presentation require justification WHAT IS BIOSIMILARITY? USEU
  7. 7. © 2018 PAREXEL INTERNATIONAL CORP. / 7 REFERENCE PRODUCT •EU and US allow a sponsor to use data derived from animal or clinical studies comparing a proposed product with a non-U.S.- licensed product; often 3-way PK bridging is required. •Equivalent quality, safety and effectiveness to biotechnology applied drug already approved as a drug with a new active ingredient in Japan •China requires that reference product is sourced from the same manufacturer that supplies the Chinese market •Most other countries including Japan are satisfied by CMC bridging data or allow sourcing of reference product from defined regions
  9. 9. © 2018 PAREXEL INTERNATIONAL CORP. / 9 DEFINITION OF BIOLOGICAL MEDICINE Annex 1 to Directive 2003/63/EC ( produced by or extracted from a biological source and that needs for its characterisation and the determination of its quality a combination of physicochemical-biological testing, together with the production process for its control Section 351(i), PHSA, 42 U.S.C. § 262(i) a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, analogous product, protein (except any chemically synthesized polypeptide) and arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings
  10. 10. © 2018 PAREXEL INTERNATIONAL CORP. / 10 - 10 -THE EU REGULATORY SYSTEM Mixed MAA. Bibliographic + Own Data Similar Biological Medicinal Product Comparability Generic Medicine (Formerly Essentially Similar) Bioequivalence DIRECTIVE 2001/83/EC Annex I Directive 2003/63/EC Biosimilar data requirements 267 words 375 Words in EU Directives 7311 Words in US Act in US Well-Established Medicinal Use Bibliographic Amendment Directive Dir. 2004/27/EC 30/10/05 Biosimilar legal concept 108 Words
  11. 11. © 2018 PAREXEL INTERNATIONAL CORP. / 11 - 11 -THE US REGULATORY SYSTEM Hormones (e.g. insulin, somatropin, FSH transition to PSA in March 2020 virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings. 375 Words in EU Directives 7311 Words in US Act in US Synthetic peptides ≤ 100 amino acids, recombinant peptides ≤ 40 and non proteins LMW heparin* remain under FD&C Act * = Biological in the EU Section 351 of the Public Health Service Act (42 U.S.C. 262) amended by The Biological, Price Competition & Innovation Act of 2009 Federal Food, Drug, Cosmetic Act Act) 1938
  12. 12. © 2018 PAREXEL INTERNATIONAL CORP. / 12 CHMP BIOSIMILAR GUIDELINES Similar biological medicinal products Biosimilar Non-clinical and clinical issues Biosimilar Quality issues Biosimilar recombinant granulocyte-colony stimulating factor Biosimilar low-molecular-weight heparins (not biosimilar in US) Biosimilar recombinant human insulin and insulin analogues Biosimilar interferon beta Biosimilar monoclonal antibodies: non-clinical and clinical issues Biosimilar erythropoietins Biosimilar recombinant follicle-stimulating hormone Biosimilar somatropin Orange = in US will be biosimilar in 2020
  13. 13. © 2018 PAREXEL INTERNATIONAL CORP. / 13 FDA BIOSIMILAR GUIDELINES NO PRODUCT SPECIFIC GUIDELINES Formal Meetings Final 11/17/15 Scientific Considerations Final 04/28/15 Quality Considerations Final 04/28/15 Clinical Pharmacology Data Final 05/13/14 Reference Product Exclusivity Draft 08/04/14 Biosimilars: Additional Questions and Answers Draft 05/12/15 Biosimilars: Questions and Answers Final 04/28/15 Interchangeability Draft 01/17/17 Statistical Approaches to Evaluate Analytical Similarity Draft 9/21/17
  14. 14. © 2018 PAREXEL INTERNATIONAL CORP. / 14 NEW US BIOSIMILAR LEGISLATION BIOLOGICAL, PRICE COMPETITION AND INNOVATION ACT OF 2009 • 12 years market exclusivity for the innovator product “Modification of structure” allows further 12 years provided gives added advantage • One year of market exclusivity for the first interchangeable biosimilar product • -- No such concept in EU • Confidential exchanges of detailed substantive patent contentions between biosimilar applicant and innovator BLA holder - No such concept in EU • Nomenclature - US: INN/USAN + random 4 letter suffix (unless IC?) - EU: INN – inverted black triangle indicates special ADE reporting
  15. 15. © 2018 PAREXEL INTERNATIONAL CORP. / 15 SUBSTANTIVE DIFFERENCES US VS. EU REGULATIONS US EU Regulations Extensive 7311 Words in US Act Light 375 Words in EU Directives supported by extensive guidance docs Biosimilar rDNA Peptide >25 aa/Protein rDNA Peptide/Protein; complex carbohydrates Originator Exclusivity 12 yrs market exclusivity for innovator “Modification of structure” alows further 12 years provided added advantage. EU is 10 years basic but new indications and paediatric development allows up to 12 years. Interchange- ability 1 yr market exclusivity for 1st interchangeable biosimilar No such concept Patent dance Confidential exchanges of detailed substantive patent contentions between biosimilar applicant and innovator No such concept Nomenclature INN/USAN + random 4 letter suffix (IC?) lNN – inverted black triangle indicates special ADE reporting
  16. 16. © 2018 PAREXEL INTERNATIONAL CORP. / 16 CMC REQUIREMENTS: US VS. EU US EU Approach Tiered statistical approach Less defined/more flexible Number of Batches Often >15 RP and >10 BS Less as no statistical equivalence Testing requirements Similar Acceptable differences Differences need to be justified
  17. 17. © 2018 PAREXEL INTERNATIONAL CORP. / 17 CMC DATA: POINTS TO CONSIDER • Variability of reference product • Batch-to-batch • Process change Test many batches over extended period • Testing Program • State-of-the-art • Orthognal • Reliable - accurate, precise and robust • Acceptability of differences • Understand impact of differences and justify • Biological activity needs to be closely matched FDA require statistically driven approach whereas CHMP do not 17
  18. 18. © 2018 PAREXEL INTERNATIONAL CORP. / 18 IMPACT OF CQA DIFFERENCES Efficacy PK Immunogenicity Safety Theoretical General literature Literature on reference product Studies on biosimilar Mass contribution
  19. 19. © 2018 PAREXEL INTERNATIONAL CORP. / 19 US: CRITICALITY ASSESSMENT OF QUALITY ATTRIBUTES (CQA) Tier 1 • 2/3 representative CQAs that directly impact safety/potency • e.g. Rituximab = ADCC & CDC; Infliximab = anti-TNF binding & reverse signalling Tier 2 • Other CQAs that impact safety/ potency • e.g. non/low activity impurities Tier 3 • Little or no impact on safety and/or potency e.g. fully active variants These required to fall within +/- 1.5 SD for results from multiple reference product batches. It may be possible to justify broader limits. Quality range approach generally ±3SD based on multiple reference product batches. Descriptive Graphical display
  20. 20. © 2018 PAREXEL INTERNATIONAL CORP. / 20 •Defined as separate category in BPCI • Very high hurdle • “same clinical result in any given patient;” and risk of alternating or switching no greater than use of reference product • Not regulatory concept • Decision at national level • Initially general view biosimilars not as interchangeable but view shifting WHAT IS BIOSIMILARITY? US EU
  21. 21. © 2018 PAREXEL INTERNATIONAL CORP. / 21 DEMONSTRATING INTERCHANGEABILITY MEAN? • How much data? • Molecular complexity • Level of similarity • Knowledge of impact of differences • Known risks e.g. immune related reactions • Interchangeability study • Switch study generally required (unless e.g. single administration) – ------------------------------ US Reference-------------------------------- (>6 mths) – US Reference------Biosimilar-------US Reference–------Biosimilar (>6 mths) • 1 Endpoint: AUCτ and Cmax (steady state after last switch ; ensure reference washed out) – Margin 80 – 125% (Sample Size ~200) • 2 Endpoint: PD, Immunogenicity, Safety, Efficacy.
  22. 22. © 2018 PAREXEL INTERNATIONAL CORP. / 23 • Take into consideration - Any particular safety or effectiveness concerns associated reference product or putative interchangeable product - The specific condition of use and patient population, and patient exposure in the interchangeability development program. • Post marketing safety monitoring for an interchangeable product should also have adequate pharmacovigilance mechanisms in place DEMONSTRATING INTERCHANGEABILITY? POST -MARKETING SAFETY MONITORING CONSIDERATIONS
  23. 23. © 2018 PAREXEL INTERNATIONAL CORP. / 24 ACCEPTABILITY OF DIFFERENCES: RECENT US EXPERIENCE • Differences in formulation which had minor impact on PK accepted 1 • 1 new peak for ABP215 only = sequence variant due to a point mutation Ser121 to Ala stable and <1% not part of the complementarity determining region - ala will not perturb structure because switch from 1 small amino acid to another2 • Lower level of misformed S-S bonds increased in vitro potency but justified based on S-S reform correctly in vivo3 • Lower aggregate levels for ABP215 Amgen’s Mvasi (bevacizumab) HMWS 0.3% vs 0.46/7% 4 • Charge variants: ASN30>in US RMP; 2 additional peaks in MYL- 1401O related to oxidation at Met 255 and Asn30 deamidation 4 • 1 Sandoz Zarxio ODAC • 2 BLA 761028: ABP215, biosimilar to US-Avastin, ODAC Briefing Document 13 July 2017 • 3 Sandoz etanercept (Arthritis Adcom Transcript 15/7/16) • 4 BLA 761074 ODAC Briefing Document MYL-1401O, biosimilar to US-Herceptin 13 July 2017
  24. 24. © 2018 PAREXEL INTERNATIONAL CORP. / 25 ACCEPTABILITY OF DIFFERENCES: RECENT US EXPERIENCE • Slight change in levels of glycans –Do not preclude a determination of high similarity (Amgen’s adalimumab1 –Bevacizumab diff Mann5/6 and sialic acid unlikely to have a clinical impact as bevacizumab has predominantly soluble target 2 • Differences in ADCC accepted – Not considered a relevant MoA3 –Greater than 90 percent of lots of the proposed biosimilar are still within the quality range of the reference product 4 1 FDA Arthritis Adcom Slides 14July16 2 4 BLA 761074 ODAC BD MYL-1401O, biosimilar to US-Herceptin 13 Jul 2017 3 Sandoz etanercept: Arthritis Adcom transcript 15July16 4 Celltrion infliximab: Arthritis Adcom transcript 9Feb16.
  25. 25. © 2018 PAREXEL INTERNATIONAL CORP. / 26 NON CLINICAL • Need for in vivo data based on tiered risk based approach • Generally require only in vitro data • Need for in vivo data often questioned • In vitro data generally not considered in non clinical section • In vivo data required if first in humans studies to be done in US • Existence of clinical data may eliminate need for non clinical data Some other jurisdictions require more comprehensive non clinical data e.g. India, Japan, China.
  26. 26. © 2018 PAREXEL INTERNATIONAL CORP. / 27 PK/PD • Following much debate in early days HV studies preferred globally • Ctrough data from patients also required • CHMP will compare with historic data • 3-way PK bridge: Test vs. EU RP vs. US. RP – FDA: 3-way PK equivalence study waived in favour of separate 2-way studies on the basis that two studies performed in same Unit using same methods and similar protocol. – CHMP have accepted CMC bridge without 3-way PK
  27. 27. © 2018 PAREXEL INTERNATIONAL CORP. / 28 PD CONSIDERATIONS Response Dose Steep part of dose response curve May need to test at several doses Endpoint may not need to be validated but must be relevant + show clear dose/concentration response relationship. Occasionally may replace clinical trial
  28. 28. © 2018 PAREXEL INTERNATIONAL CORP. / 29 EARLY US APPROACH: SURROGATE CLINICAL ENDPOINTS • Coherus PegFilgrastim • Entire program in healthy volunteers • Single dose PK/PD study • Immunogenicity – two doses in ~300 patients • FDA did not request additional clinical study to be performed in oncology patients GABI OnLine 11/11/2016: FDA accepts application for pegfilgrastim biosimilar from Coherus; - 29 -
  29. 29. © 2018 PAREXEL INTERNATIONAL CORP. / 30 HOW MUCH CLINICAL DATA? NON CLINICAL AND CLINICAL GUIDELINE (EMEA/CHMP/BMWP/42832/05) • Usually comparative clinical trials required • Safety data must be sufficient • Clinical comparability margins should be pre-specified and justified, primarily on clinical grounds • Assay sensitivity (see ICH topic E10) has to be ensured • If a clinical comparability trial design is not feasible, other designs should be explored and their use discussed with the competent authorities • Clinical safety of similar biological medicinal products must be monitored closely on an ongoing basis
  30. 30. © 2018 PAREXEL INTERNATIONAL CORP. / 31 CLINICAL TRIAL DATA: FDA VS. EU US EU Trial Population Most sensitive – but views on this can differ Endpoints Views may differ Equivalence margin Risk Ratio Proportions Preserve >50% effect > Putative placebo effect 90% CI 95%CI Switching May be required Discouraged Study duration 12 months 12 months
  31. 31. © 2018 PAREXEL INTERNATIONAL CORP. / 32 IMMUNOGENCITY • Immunogenicity usually secondary endpoint • Sometimes FDA will require a formal immunogenicity study • “a one-sided design will ordinarily be adequate to compare clinical immunogenicity of the proposed product and reference product.” • Setting margin can be challenging as one cannot rely on historical data – need to consider adaptive trials Kozlowski et. al. “the FDA will evaluate immunogenicity in a risk-based manner.”
  32. 32. © 2018 PAREXEL INTERNATIONAL CORP. / 33 IMMUNOGENCITY Coherus PegFilgrastim: FDA rejected BLA requesting a ‘re-analysis of a subset of subject samples with a revised immunogenicity assay’ GABI online 07/07/2017: FDA rejects pegfilgrastim biosimilar from Coherus
  33. 33. © 2018 PAREXEL INTERNATIONAL CORP. / 34 EXTRAPOLATION TO OTHER USES? • Extrapolation accepted in guidelines in EU, USA, Canada and Japan • Requires adequate justification • Immunomodulator and anticancer (cytotoxic) antibody, extrapolation more challenging (CHMP Guidance) • Antibody-dependent cytotoxicity (ADCC) appears to be more important in some indications than in others • Should extrapolate immunogenicity findings from sensitive to non sensitive populations: e.g. not immunosuppressed and more liable to produce antibody response • In contrast to EU, FDA require pediatric plan with biosimilar application unless interchangeable status granted
  34. 34. © 2018 PAREXEL INTERNATIONAL CORP. / 35 NEED FOR DATA IN LOCAL POPULATION • US: EU patients not essential but justify studied population representative of EU • EU: EU patients not essential but justify studied population representative of EU • India: Variable, figure 100 Indian patients often cited • Russia: Variable, often OK to include Russian patients in trial or perform small separate study in Russia • Mexico: Request some local patients to be included • Japan: Require exposure of some Japanese subjects • China: Full program in China no longer required need to justify extrapolation from non Chinese population and likely need some patients ex China
  35. 35. © 2018 PAREXEL INTERNATIONAL CORP. / 36 JAPAN • Need ethno-bridging data • PK/PD study in Japanese patients (suitability of HVs should be discussed with MPA) • OR Include adequate Japanese patients in global study • OR Include Japanese subjects in PK equivalence trial • Provide CMC bridge to Japanese reference product and reference product used in the trial • US/EU directed program may be suitable but need to discuss with MPA – differences in dosage, ethnic response, approved indication could complicate bridging.
  36. 36. © 2018 PAREXEL INTERNATIONAL CORP. / 37 CHINA Major Changes • Lower regulatory hurdle, much faster approval timeline • New drug definition to encourage company to put China into the first round of global registration by favoring re- imbursement • Faster & Cheaper Clinical development in China • Aim to align with ICH requirements; in parallel will also take China specific requirements into consideration. • CMC: China pharmacopoeia & guidance; “establish condition” • Chinese safety & efficacy profile must be well address by taking ICH E5&17 into consideration • Guidelines for biosimilars such as bevacizumab
  37. 37. © 2018 PAREXEL INTERNATIONAL CORP. / 38 • “Foreign clinical data” can be conditionally accepted to support China registration: • Efficacy and safety are well addressed with foreign data and expanded to Chinese • Ethnic sensitivity should be well addressed • All the sites comply with ICH GCP requirements and ready for CFDI • China local clinical data must generate for China registration and “foreign clinical data” can only use for reference CHINA: ACCEPTANCE OF FOREIGN CLINICAL DATA AFTER CHANGEBEFORE CHANGE More science based negotiation with CFDA could be expected! Underline means it can be implemented after new DRR is in force.
  39. 39. © 2018 PAREXEL INTERNATIONAL CORP. / 40 REPRESENTATIVE GLOBAL BIOSIMILAR PROGRAM – PLAN AHEAD 3-way PK study with BS vs. EU RMP vs. US RMP Separate ethnicity trials in Chinese, patients?? Global patient study USA EU RoW India, Russia HV PK/PD bridging study in Japan Global Efficacy Study vs. EU RMP 1 or 2 year Safety Extension China, Japan PK/PD study
  40. 40. © 2018 PAREXEL INTERNATIONAL CORP. / 41 CONCLUSIONS • EU and US apply very definitions to “Biological Medicine” • EU and US regulatory systems very different • 375 Words in EU Directives vs 7311 Words in US Act • EU more reliant on guidelines • EU decisions based on consensus; FDA based on Division opininion • US regulations introduce concepts novel to EU • Patent dance • Interchangeability • Despite Efforts towards harmonisation FDA and CHMP can take take different stances • Important to discuss requirements with Agencies at early stage