Franz Koenig Byron Jones Clinical trials for authorised biosimilars in the European Union A systematic review Introduction 2 A biosimilar medicine is a biological medicine ID: 933086
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Slide1
Johanna Mielke, Bernd
Jilma, Franz Koenig, Byron Jones
Clinical trials for authorised biosimilars in the European Union: A systematic review
Slide2Introduction
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 variabilityand any differences between it andits reference medicine will havebeen shown not to affect safety oreffectiveness.”
Source: Christian Schneider, Chair EMA Biosimilar Working Party: http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/2009/12/WC500020062.pdf
Slide3Introduction
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?
Slide4Methods
4EMA leading agency with 20 approved
biosimilars on 7 different biologicsFocus on approved biosimilars only (no refused, no withdrawn products)Some sponsors worked together and submitted identical clinical trials, but marketed the products separately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 z
eta
Silapo
(
Stada
Arzneimittel AG) - Retacrit (Hospira UK Ltd) 12 different applications
Slide5Methods
5Main source: European public assessment reports (EPAR)
Available online at http://www.ema.europa.eu Detailed information about the applicationDrug: Active substance, indications, ...
Non-clinical: Toxicology, ...Clinical development program: Studies, study design, endpoints, sample size, ...
Slide6Methods
6
Comparison of the submitted applications in terms ofSample sizeTrial design
EndpointsStatistical modelsEquivalence margins
N
umber of clinical trials
Approved indications, extrapolation to other indications
Route of administration
Number of doses (multiple dose, single dose)
Slide7Results
7
Overview
Active Substance
Originator drug name
Biosimilar
Haematopoietic growth factors
Epoetin
Alfa/Zeta
Eprex(EU), Erypo(Germany)Silapo/RetacritEpoetin Alfa Hexal/ Abseamed/Binocrit
FilgrastimNeupogenZarzio/
Filgrastim
Hexal
Tevagrastim
/
Ratiograstim
/
Biograstim
Nivestim
Grastofil
/
Accofil
Endocrinologically
acting drugs
Follitropin Alfa
Gonal-f
Ovaleap
Bemfola
Insulin Glargine
Lantus
Absaglar
Somatropin
Genotropin
Omnitrope
Anti-inflammatory blockers of
tumor
necrosis factor alpha
Etanercept
Enbrel
Benepali
Infliximab
Remicade
Remsima
/
Inflectra
Slide8Results
8Sample size PK/PD vs. phase III-trials
Epoetin
Alfa/Zeta
Filgrastim
Folitropin
Alfa
Others
Slide9Results
9Trial design
PK/PD:Guidelines: 2x2 crossover, mostly followedExceptions: 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)
Slide10Results
10Endpoints, equivalence margins & statistical models: PK
Metrics for bioequivalence testing: AUC, CmaxApproach: 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 intervalsMostly followed, exceptions:
Silapo
/
Retacrit
: wider equivalence range for
Cmax
Ovaleap, Benepali: no details given in EPAR and publication, unclear if formal testing was done
Slide11Results
11Endpoints, 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 limitsSponsor 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
Slide12Results
12Endpoints, equivalence margins & statistical models : PK
Grastofil/Accofil: Study KWI-300-101
Slide13Results
13Endpoints, equivalence margins & statistical models : Phase III
Endpoint, margins, statistical models are disease specific
Slide14Results
14Endpoints, equivalence margins & statistical models : Phase III
Slide15Results
15Endpoints, equivalence margins & statistical models : Phase III
Endpoint, margins, statistical models are disease specificVariation 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
Slide16Conclusion
16High variability between submitted trials
High variety also within an active substance case by case decision of the
regulatorsRecommendation 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
Slide17Thank 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.
Slide18Backup
18
Slide19Pre-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 m
9 – 12 m
2 – 4 yrs
4
3
2
1
Time
2
Introduction to biosimilar development
Results
20Indication & Extrapolation
Indications applied for are mostly the same as the one of the reference productExample for exception: Silapo/Retacrit “reduction of allogeneic blood transfusions in adult non-iron deficient patients prior to major elective orthopaedic surgery” was not
grantedReason: lack of shown equivalence for the subcutaneous (SC) administration routeMostly only studies in one therapeutically indication submitted (often reference to literature is given, modelling results are presented)
Slide21Results
21PK/PD vs. phase III-trials
PK/PD trials:
1-5 trials
mostly in healthy volunteers (exception:
Remsima
/
Inflectra
)
24-269 subjectsPhase III1-3 trials120-1295 subjects
Slide22Results
22Route of administration and single/multiple dose
Route of administration:Recommendation: subcutaneous routemostly followed, exception: Remsima/Inflectra – reference product can only be applied intravenously
Single dose/multiple dose:Recommendation: Single doseOften also multiple dose studies: justified if patients have to be used (ethical reasons)
s
ignal in some endpoints can also be measured after multiple doses