Encouraging adaptive designs in NiHR funded clinical trials

Professor Sallie Lamb

Chair, CET Board

Welcome and Housekeeping

• Bathroom facilities

• Break-out areas

• Coffee and lunch

• Fire alarm and drill

• Travel expenses

• Queries

Adaptive designs

• Most discussion has arisen from drug development and approval trials

• Most guidance is provided within this context

• Most methodological development has also been within this context

• Fit for purpose for NiHR trials (HTA) ?

• When indicated ?

• How facilitated ?

Adaptive designs

• Covers many different types of adaptation

• Futility and early stopping

• Treatment selection

• Dose response

• Sub-group refinement

• Interim sample size re-estimation

Adaptive designs

• Some applications not well understood

• Many myths – around speed, cost and method

• Widely accepted that operational issues are as important as statistical issues

NiHR funded research is different

• NiHR HTA programme – largest funder of academic clinical trials in the UK – pragmatic, phase III

• Commissioned and responsive mode

• NiHR EME programme – phase II/mechanistic

• NiHR programme grants

• NiHR fellowship applications

Trial phases

Pharmaceutical Industry HTA

To demonstrate superiority, or equivalence/n-i with better safety profile

To estimate superiority, equivalence, n-i with better safety profile

Risk of accepting null hypothesis to be minimised or eliminated prior to Phase III

Usually no risk to accepting null hypothesis - value of information remains high and investment worthwhile*

Drug trials for regulatory approval Few trials to support regulatory approval

Main driver of design – companies/regulator

Main driver of design – academics/funder

Outcomes - disease specific as primary

Various layers of outcome – disease specific, generic HQoL, cost

Comparators – placebo and/or active control

Comparators – usual care/ best current practice

Maximise effect prior to Phase III (a) Evaluate effect in everyday settings

O P E R A

OLDER PEOPLE’S EXERCISE IN RESIDENTIAL ACCOMMODATION

So what is today about

• Identify the issues• Methodological• Logistical – recruitment, ethics• Logistical - funding arrangements*• Talks – stats, trialist, and economics• Discussion – stick-its, group work• Workshops• Dissemination

Workshops

• What are the (applied) methodological questions that need to be addressed?

• What are the practical/organisational implications of using adaptive designs?

• What guide can we give for when adaptive designs should be considered?

• How should we encourage the greater use of adaptive designs in NiHR research?