Transcript Clinical trial design of authorized biosimilars in

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
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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?
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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withdrawn products)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
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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, ...
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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)
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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
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Results
Sample size PK/PD vs. phase III-trials
Epoetin
Alfa/Zeta
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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)
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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
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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
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Results
Endpoints, equivalence margins & statistical models : PK
Grastofil/Accofil: Study KWI-300-101
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Results
Endpoints, equivalence margins & statistical models : Phase III
 Endpoint, margins, statistical models are disease specific
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Results
Endpoints, equivalence margins & statistical models : Phase III
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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
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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
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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.
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Backup
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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
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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
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Time
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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)
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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
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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
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