1. Johanna Mielke, Bernd Jilma, Franz Koenig, Byron Jones Clinical trials for authorised biosimilars in the European Union: A systematic review

2. Introduction 2 “A biosimilar medicine is a biological medicine that is developed to be similar to an existing biological medicine (the ‘reference medicine’). [...] When approved, its variability and any differences between it and its reference medicine will have been shown not to affect safety or effectiveness.” Source: Christian Schneider, Chair EMA Biosimilar Working Party: http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/2009/12/WC500020062.pdf

3. Introduction 3  Questions: Which kind of clinical trials have to be undertaken for getting approval in Europe? How much and in which way do the development programs differ? Is there a unified approach for biosimilars with the same active substance?

4. Methods 4  EMA leading agency with 20 approved biosimilars on 7 different biologics  Focus on approved biosimilars only (no refused, no withdrawn products)  Some sponsors worked together and submitted identical clinical trials, but marketed the products separately Example: Biosimilar to active substance epoetin zeta Silapo (Stada Arzneimittel AG) - Retacrit (Hospira UK Ltd)  12 different applications

5. Methods 5  Main source: European public assessment reports (EPAR) Available online at http://www.ema.europa.euhttp://www.ema.europa.eu Detailed information about the application -Drug: Active substance, indications,... -Non-clinical: Toxicology,... -Clinical development program: Studies, study design, endpoints, sample size,...

6. Methods 6  Comparison of the submitted applications in terms of Sample size Trial design Endpoints Statistical models Equivalence margins Number of clinical trials Approved indications, extrapolation to other indications Route of administration Number of doses (multiple dose, single dose)

7. Results 7 Overview Active Substance Originator drug name Biosimilar Haematopoietic growth factors Epoetin Alfa/Zeta Eprex(EU), Erypo(Germany) Silapo/Retacrit Epoetin Alfa Hexal/ Abseamed/Binocrit FilgrastimNeupogenZarzio/Filgrastim Hexal Tevagrastim/Ratiograstim/ Biograstim Nivestim Grastofil/Accofil Endocrinologically acting drugs Follitropin AlfaGonal-fOvaleap Bemfola Insulin GlargineLantusAbsaglar SomatropinGenotropinOmnitrope Anti-inflammatory blockers of tumor necrosis factor alpha EtanerceptEnbrelBenepali InfliximabRemicadeRemsima/Inflectra

8. Results 8 Sample size PK/PD vs. phase III-trials Epoetin Alfa/Zeta Filgrastim Folitropin Alfa Others

9. Results 9 Trial design  PK/PD: Guidelines: 2x2 crossover, mostly followed Exceptions: -Remsima/Inflectra (parallel group design, but was allowed in product specific guideline) -Epoetin Alfa Hexal/Abseamed/Binocrit (pivotal PK/PD is a parallel group design, contradicts product specific guideline)  Phase III: Parallel group design recommended, followed except for Zarzio/Filgrastim Hexal and Grastofil/Accofil (single arm design, but accepted in product specific guideline)

10. Results 10 Endpoints, equivalence margins & statistical models: PK  Metrics for bioequivalence testing: AUC, Cmax Approach: Calculation of geometric mean ratio with confidence intervals, if confidence intervals fully lie within pre-specified limits  bioequivalence  Recommendation in guideline for PK studies: Equivalence margins: 80-125 % 90 % confidence intervals  Mostly followed, exceptions: Silapo/Retacrit: wider equivalence range for Cmax Ovaleap, Benepali: no details given in EPAR and publication, unclear if formal testing was done

11. Results 11 Endpoints, equivalence margins & statistical models : PK  If criteria are not fully fulfilled, approval is possible: Example Zarzio/Filgrastim Hexal: PK/PD-studies in five different doses, for lower doses and after multiple subcutaneous doses: AUC and Cmax not within limits Sponsor claimed “differences in level of purity”  adjustment to doses Nonetheless, for three settings outside of equivalence region Sponsor provided modelling results and explanations for mechanism of action  approval

12. Results 12 Endpoints, equivalence margins & statistical models : PK Grastofil/Accofil: Study KWI-300-101

13. Results 13 Endpoints, equivalence margins & statistical models : Phase III  Endpoint, margins, statistical models are disease specific

14. Results 14 Endpoints, equivalence margins & statistical models : Phase III

15. Results 15 Endpoints, equivalence margins & statistical models : Phase III  Endpoint, margins, statistical models are disease specific  Variation within a substance: Ovaleap and Bemfola (folitropin alfa) Same endpoint used (number oocytes retrieved) Ovaleap: Zero-inflated Poisson (ZIP) regression model Bemfola: Mann-Whitney TOST or Schuirmann’s TOST (data dependent)  Flexibility for the sponsors how to analyze the data

16. Conclusion 16  High variability between submitted trials  High variety also within an active substance  case by case decision of the regulators  Recommendation in product specific guidelines and overarching guidelines were mostly followed, but also exceptions  It is possible to gain approval although not all pre- specified primary endpoints meet the target

17. Thank you very much! 17 This project was supported by the Swiss State Secretariat for Education, Research and Innovation (SERI) under contract number 999754557. The opinions expressed and arguments employed herein do not necessarily reflect the official views of the Swiss Government. The project is part of the IDEAS European training network (http://www.ideas- itn.eu/) from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 633567.

18. Backup 18

19. Pre-clinic PK/PD Ph I/II Efficacy/Safety Ph III Post-approval Abbreviated toxicology, efficacy/ safety in relevant species models Demonstrate PK/PD equivalence in a sensitive population - can be healthy volunteers Design tailored to demonstrate biosimilarity, but not safety and efficacy de novo  Sensitive indication  Trial design might be different, e.g., endpoints Additional data to meet regulatory needs 6 – 12 m9 – 12 m2 – 4 yrs 4321 Time 2 Introduction to biosimilar development

20. Results 20 Indication & Extrapolation  Indications applied for are mostly the same as the one of the reference product  Example for exception: Silapo/Retacrit “reduction of allogeneic blood transfusions in adult non-iron deficient patients prior to major elective orthopaedic surgery” was not granted Reason: lack of shown equivalence for the subcutaneous (SC) administration route  Mostly only studies in one therapeutically indication submitted (often reference to literature is given, modelling results are presented)

21. Results 21 PK/PD vs. phase III-trials  PK/PD trials: 1-5 trials mostly in healthy volunteers (exception: Remsima/Inflectra) 24-269 subjects  Phase III 1-3 trials 120-1295 subjects

22. Results 22 Route of administration and single/multiple dose  Route of administration: Recommendation: subcutaneous route mostly followed, exception: Remsima/Inflectra – reference product can only be applied intravenously  Single dose/multiple dose: Recommendation: Single dose Often also multiple dose studies: -justified if patients have to be used (ethical reasons) -signal in some endpoints can also be measured after multiple doses