Johanna Mielke, Bernd Jilma - PowerPoint Presentation

Slide1

Johanna Mielke, Bernd

Jilma, 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

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

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?

Methods

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biosimilars on 7 different biologicsFocus on approved biosimilars only (no refused, no withdrawn products)Some sponsors worked together and submitted identical clinical trials, but marketed the products separately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

Methods

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, ...

Methods

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)

Results

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

Results

8Sample size PK/PD vs. phase III-trials

Epoetin

Alfa/Zeta

Filgrastim

Folitropin

Alfa

Others

Results

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)

Results

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

Results

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

Results

12Endpoints, equivalence margins & statistical models : PK

Grastofil/Accofil: Study KWI-300-101

Results

13Endpoints, equivalence margins & statistical models : Phase III

Endpoint, margins, statistical models are disease specific

Results

14Endpoints, equivalence margins & statistical models : Phase III

Results

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

Conclusion

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

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.

Backup

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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 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)

Results

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

Results

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