Self-Designing Trials: Further Thoughts & Advances

1. Self-Designing Trials: Further Thoughts & Advances Lloyd D. Fisher, Ph.D. Professor Emeritus, Biostatistics, University of Washington Biostatistical Consultant

2. Outline of Talk • A clue as to the method • Simple Example & Verbal Handwaving • Combing with usual sequential monitoring • The “How is clear” • Practicalities • Introduction into the middle of a study without prior planning • Back to the basic idea • Practicalities

3. Outline Continued • Survival Data • PhD nominally working on this • One method (somewhat like group sequential) • Comments on the way we do business • Pharmaceutical, Biologics and Devices statisticians don’t bother to fasten seatbelts? Vaccinate children? Like to stand under trees in lightening storm? • Long past time for a change, good for society and also industry – as well as in accord with our statistical traditions

4. Example - 1

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13. Example – 10

14. The Principle • From an hypothesis testing point of view: at any point in the RCT experiment can modify the design, data used for testing, etc. as long as the conditional probability of rejection under the null hypothesis is the same or larger as for the “original design” using all the past data (including by treatment arm).

15. Combining Self-Designing Randomized Clinical Trials, SDRCTs, with a Lan-DeMets Spending Function, O’Brien-Fleming Boundary, Etc. • In many, perhaps most, situations the interim looks at data require extreme data so as to preserve the power of the study. • If this is so the using for example, the Bonferroni inequality, can use SDRCT with the more classical looks.

16. SDRCT with Lan-DeMets • Practicalities • “Extending” studies involves resources; in a commercial or NIH type setting someone with authority needs to have access to data as well as resources • At beginning get a statistical idea of the length of a study • Uncertainty is superior to “beginning” from scratch with a barely negative study

17. SDRCT with Lan-DeMets - 2 • Possible DSMB/C set-up • Open meeting with blinding intact • Restricted unblinded meeting with sponsor and DSMB • Restricted unblinded meeting for DSMB only • Industry/FDA interactions have improved tremendously over the last 20 years • Need for even more during ongoing studies

18. Introducing SDRCTs Without Preplanning During a Trial • Remember the basic principle!

19. Introducing SDRCTs Without Preplanning During a Trial - 2 • Remember the basic principle! • Practicalities: • Worry about mischief • Clear documentation, e.g. dated, witnessed and securely archived files, material and decisions • Another reason agency involvement would be useful • Clearly a totally independent DSMB cannot do this • For IRB review and informed consent need to have the possibility in the protocol

20. Time to Event Endpoints • Comparing two groups the log-rank test compares observed and expected numbers of events • By dividing the exposure and events up into disjoint groups we can weight “new” exposure depending upon the past experience – thus effectively changing the sample size

21. A Few Limitations • Designs are (as expected) not as efficient as if have correct alternative initially • “Don’t you believe in the sufficiency principle?”

22. Comments on the way we do business • The essence of science is to learn from past experience – rocket ship to mars analog • Why use seat-belts? Vaccinate our children? • Why not reduce risk in an acceptable way • As you have and will hear there are multiple ways now to approach things more appropriately. Now is the time.

23. References • Fisher LD. Self-Designing Clinical Trials. Statist. Med. 17:1551-1562, 1998. • Shen Y, Fisher LD: Statistical Inference for Self-Designing Clinical Trials with a One-Sided Hypothesis. Journal of the International Biometric Society55(1):190-197, 1999. • Thach C, Fisher LD: Self-designing two-stage trials to minimize expected costs. In press, Biometrics, 2002.