Sample size estimation for a paediatric clinical trial ...

[Pages:16]EMA EFPIA workshop, Break-out session no. 3

Case Study:

Sample size estimation for a paediatric clinical trial utilising external information

from historical trials in adults and children

Wolfgang K?pcke1, Joachim Ger?1, Raphael Koch1, Christoph Male2

1 University Clinic M?nster (Germany) Institute of Biometry and Clinical Research 2 Medical University Vienna (Austria), Department of Paediatrics

Objective

? Extrapolation of efficacy from adults to children ? Use of historical data from adults and children ? Modelling of clinical response data ? Age-appropriate dosing established

- Weight-based; adjusted by TDM to similar PD levels as in adults

Clinical setting Treatment of acute venous ? Venous thromthbrooemmbboolisemm: bolism

- Different triggers in adults vs children

- Common pathophysiologic pathway: thrombotic vessel occlusion, embolism

? Anticoagulants:

- mode of action: inhibition/reduction of clotting factors - Unfractionated heparin (UFH) versus low molecular heparin

(LMWH) - followed by Vitamin K antagonist (VKA) - Future development: new oral anticoagulants

? Endpoints: (during follow-up of 3-6 months)

- Efficacy: recurrent thrombosis

Historical data

UFH (+VKA) 10

Odds ratio 0.68 (95%CI 0.55-0.84)

5

LMWH (+VKA)

Odds ratio 0.53 (95%CI 0.05-4.0)

recurrent thrombosis

(%)

0 adults n=8122

Van Dongen, Cochr datab SR 2004

children n=76

Massicotte, Thromb Res 2003

Background & Rationale

Adult trial 1 Adult trial 2 Adult trial 3 Adult trial 4 Adult trial 5 Adult trial 6 Adult trial 7 Adult trial 8 Adult trial 9 Adult trial 10 Adult trial 11 Adult trial 12 Adult trial 13 Adult trial 14 Adult trial 15 Adult trial 16 Adult trial 17 Adult trial 18

All Adult trials pooled

Paediatric trial

Favours interventional treatment Favours standard treatment

0.1

0.5 1.0 2.0 5.0

Odds Ratio (log scale)

Background & Rationale

The available information of all historical trials shall be extrapolated to a future paediatric trial, that is planned in order to show that the interventional treatment is non-inferior (noninferiority margin =1.3) to the standard treatment in paediatric patients with venous thromboembolism.

Background & Rationale

? Bayesian meta-analytic-predictive approach

? Extension of the Neuenschwander et al. [3] model

? Data of control and interventional treatment

? Extrapolation to a planned paediatric trial with a potential shift in mean treatment effects between adults and children

M&S Assumptions

? Two important features of study-specific effects

? Random variation of study-specific effects (betweentrial variation)

? Possible difference in mean pooled effects between adults and children

? Determine the amount of evidence that the historical data contributes in a future trial

? The determined evidential weight can be translated to an estimated "prior effective sample size" (virtual

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