Just How Flexible Can a Prospective Clinical Trial Be? Donald A. Berry Donald A. Berry

2 2 Definition of flexible l Pliant l Characterized by a ready capability to adapt to new, different, or changing requirements l Pliant l Characterized by a ready capability to adapt to new, different, or changing requirements

3 3 With thanks to Mike Krams & Vlad Dragalin

4 4 Original question is not helpful Two kinds of flexibility: l Ad hoc (improvised) l Planned (prospective) Two kinds of flexibility: l Ad hoc (improvised) l Planned (prospective)

5 5 Original question is not helpful Two kinds of flexibility: l Ad hoc: okay for personal or internal company decisions l Planned: essential for external buy-in Two kinds of flexibility: l Ad hoc: okay for personal or internal company decisions l Planned: essential for external buy-in

6 6 New question 1: How to deal with ad hoc flexibility in a clinical trial? You cant!

7 7 New question 2: How to deal with planned flexibility in a clinical trial? l Design l The team on board? l Logistics l Regulatory l Design l The team on board? l Logistics l Regulatory

8 8 Design l Modeling--arbitrarily complicated l Efficacy and safety l Computation l OCs & comparisons n Type I error n Power n Sample size n Alternative designs l Modeling--arbitrarily complicated l Efficacy and safety l Computation l OCs & comparisons n Type I error n Power n Sample size n Alternative designs

9 9 The team on board? l You have to teach them l And you have to keep teaching them! l I dont want the DSMB making decisions such as whether to go to phase III. l DSMB as automaton l You have to teach them l And you have to keep teaching them! l I dont want the DSMB making decisions such as whether to go to phase III. l DSMB as automaton

10 Logistics l Data flow: Updating database l Clean data? (no, but model) n QA n Auxiliary variables n Central review l Missing data--same as above l What CRO? l Information leakage--who knows what and when? l Data flow: Updating database l Clean data? (no, but model) n QA n Auxiliary variables n Central review l Missing data--same as above l What CRO? l Information leakage--who knows what and when?

11 Logistics (contd) Adaptive design is a whole new ball game. If you dont know what you are doing, you can do some very bad things and damage the integrity of the trial, and of the whole process.

12 Who knows what & when? l Phase I or II vs Phase III l Dose-finding (The Pharmacist Knows) l Dropping arms or adaptive randomization (blinded vs open) l Seamless phase II/III n Simple line in the sand (Publish but continue to accrue?) n End of phase II meeting n Expanding accrual n One study or two? l Phase I or II vs Phase III l Dose-finding (The Pharmacist Knows) l Dropping arms or adaptive randomization (blinded vs open) l Seamless phase II/III n Simple line in the sand (Publish but continue to accrue?) n End of phase II meeting n Expanding accrual n One study or two?

13 Regulatory l CRCs and IRBs n Please explain in lay terms (Examples, examples, examples) n Informed consent? l FDA, EMEA n Meet early & as often as possible l CRCs and IRBs n Please explain in lay terms (Examples, examples, examples) n Informed consent? l FDA, EMEA n Meet early & as often as possible

14 The Bottom Line l Clinical trials will continue to become more complicated (such as I-SPY2) l This is good and bad l Trials must begin to address interactions between treatments and patient covariates l Clinical trials will continue to become more complicated (such as I-SPY2) l This is good and bad l Trials must begin to address interactions between treatments and patient covariates

15 The Bottom Line l Traditional trials are poorly suited for identifying treatments that benefit patients who have hetero- geneous diseases such as cancer l The adaptive path is treacherous, with mines every step of the way l Avoiding mines is challenging, but enormously rewarding... and fun! l Traditional trials are poorly suited for identifying treatments that benefit patients who have hetero- geneous diseases such as cancer l The adaptive path is treacherous, with mines every step of the way l Avoiding mines is challenging, but enormously rewarding... and fun!