1. Encouraging adaptive designs in NiHR funded clinical trials Professor Sallie Lamb Chair, CET Board

2. Welcome and Housekeeping Bathroom facilities Break-out areas Coffee and lunch Fire alarm and drill Travel expenses Queries

3. 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 ?

4. Adaptive designs Covers many different types of adaptation Futility and early stopping Treatment selection Dose response Sub-group refinement Interim sample size re-estimation

5. 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

6. 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

7. Trial phases Phase 1 First in man Phase 2 Learn Phase 3 Confirm Evaluate

8. Pharmaceutical IndustryHTA 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 approvalFew 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

10. 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

11. 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?