Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Clinical trials for authorised biosimilars in the European Union: A systematic review Johanna Mielke, Bernd Jilma, Franz Koenig, Byron Jones Introduction “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 2 Introduction 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? 3 Methods 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leading agency with 20 approved biosimilars on 7 different biologics Focus on approved biosimilars only (no refused, no withdrawn products) Some sponsors worked together and submitted identical clinical trials, but marketed the products separately • Example: Biosimilar to active substance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 4 Methods Main source: European public assessment reports (EPAR) • Available online at http://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, ... 5 Methods 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) 6 Results Overview Active Substance Originator drug name Haematopoietic growth factors Epoetin Alfa/Zeta Eprex(EU), Erypo(Germany) Filgrastim Neupogen Endocrinologically acting drugs Follitropin Alfa Gonal-f Biosimilar Silapo/Retacrit Epoetin Alfa Hexal/ Abseamed/Binocrit Zarzio/Filgrastim Hexal Tevagrastim/Ratiograstim/ Biograstim Nivestim Grastofil/Accofil Ovaleap Bemfola Insulin Glargine Lantus Absaglar Somatropin Genotropin Omnitrope Anti-inflammatory blockers of tumor necrosis factor alpha Etanercept Enbrel Benepali Infliximab Remicade Remsima/Inflectra 7 Results Sample size PK/PD vs. phase III-trials Epoetin Alfa/Zeta 8 Filgrastim Folitropin Alfa Others Results 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) 9 Results 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 10 Results 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 11 Results Endpoints, equivalence margins & statistical models : PK Grastofil/Accofil: Study KWI-300-101 12 Results Endpoints, equivalence margins & statistical models : Phase III Endpoint, margins, statistical models are disease specific 13 Results Endpoints, equivalence margins & statistical models : Phase III 14 Results 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 15 Conclusion 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 prespecified primary endpoints meet the target 16 Thank you very much! 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.ideasitn.eu/) from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 633567. 17 Backup 18 Introduction to biosimilar development 6 – 12 m 1 9 – 12 m 2 Pre-clinic Abbreviated toxicology, efficacy/ safety in relevant species models 2 – 4 yrs 3 PK/PD Ph I/II Demonstrate PK/PD equivalence in a sensitive population - can be healthy volunteers Efficacy/Safety Ph III Design tailored to demonstrate biosimilarity, but not safety and efficacy de novo Sensitive indication Trial design might be different, e.g., endpoints 2 Time 4 Post-approval Additional data to meet regulatory needs Results 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) 20 Results 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 21 Results 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 22