1. Comments on “Adaptation and Heterogeneity” by Armin Koch Paul Gallo, Willi Maurer PhRMA Adaptive Design KOL Lecture Series November 14, 2008

2. 2 PhRMA Adaptive KOL Lecture Series / November 14, 2008 Bottom line  We agree with many of Armin’s bottom-line statements.  Differences in opinion or perspective largely boil down to questions of degree. oe.g., how heavy is the burden of proof ?

3. 3 PhRMA Adaptive KOL Lecture Series / November 14, 2008 Motivation  Not simply a matter of obtaining lower standards for sponsor advantage.  Statistical issues: subsets / subgroups always present challenges, and there can be a tendency in many contexts to over-react to signals.  No party wants to falsely invalidate or substantially undervalue meaningful results.  How do we go about this most rationally?

4. 4 PhRMA Adaptive KOL Lecture Series / November 14, 2008 Scope  Our scope: changes which do not strongly structurally change the nature of the data. oe.g., SS re-estimation, dropping an arm (as in seamless II / III), changing randomization allocation, etc.  More substantial structural changes, e.g., involving the nature of endpoints, would likely raise much more challenging issues with regard to any possibility of combining information to test a common hypothesis.

5. 5 PhRMA Adaptive KOL Lecture Series / November 14, 2008 “One trial or two?” A big question:  Where is within-trial heterogeneity important to investigate / understand? oAll trials? (but we don’t, and there don’t seem to be standards) oGroup sequential trials? (information leakage more easily envisioned, and evidence more accessible, but seems not routinely explored) oAdaptive trials?

6. 6 PhRMA Adaptive KOL Lecture Series / November 14, 2008 Meta-analyses (slides 9-10)  Is there an implication that meta-analyses are in some sense less important than confirmatory trials?  Meta-analyses can affect medical practice.  Not all are the same, but we would start from a view that both can be important within their contexts, and the question is one of most accurately interpreting the results.

7. 7 PhRMA Adaptive KOL Lecture Series / November 14, 2008 Meta-analyses (continued)  We may know that trials within a meta- analysis differ in many identifiable aspects: oinvestigators following different protocols and procedures, monitoring standards, calendar times, information from other trials out in the open, “therapeutic drift”, etc., etc.

8. 8 PhRMA Adaptive KOL Lecture Series / November 14, 2008 Meta-analyses (continued)  Adaptive trials without major structural changes may have none of these problems.  When interpreting whether or not non- definitive but potentially important signals of interaction might be real, shouldn’t there be an important role for plausibility / rationale ?

9. 9 PhRMA Adaptive KOL Lecture Series / November 14, 2008 “Natural reasons” (slide 11)  Because other factors can lead to some heterogeneity, “can we ignore the problem?”  No, but this highlights a difficulty and points toward caution in interpretation.  The concern: results might potentially be invalidated by a signal (real or not) unrelated to the adaptation, which would not have raised a concern had it arisen in a conventional trial.

10. 10 PhRMA Adaptive KOL Lecture Series / November 14, 2008 “Natural reasons”  Underlying minor heterogeneity can increase the chance of a formal test flagging a signal.  e.g., a 0.15 level interaction test may have a higher effective false positive (interaction) rate, because its homogeneity null hypothesis is already not true.

11. 11 PhRMA Adaptive KOL Lecture Series / November 14, 2008 Relationship to effect size (slide 12)  This seems not unlike how some important subgroup issues might be viewed.  A situation with a signal of heterogeneity, but with each subgroup showing benefit, would often be judged differently from one in which there was a subgroup that did not appear to benefit. oSome relationship to quantitative / qualitative issues.

12. 12 PhRMA Adaptive KOL Lecture Series / November 14, 2008 “Information leakage” (slide 14)  We “can’t prove that (good procedures) have been followed”  True, but we wouldn’t say that this alone would be sufficient; it’s just one part of the case.  Evidence of confidentiality / compliance, numerical strength of the signal, scientific plausibility or explanation, etc., are all part of the story.

13. 13 PhRMA Adaptive KOL Lecture Series / November 14, 2008 “Price to be paid” (slide 16)  Generally there are statistical prices to paid, but these are usually easily handled.  “Further investigation” of signals because of the added complexity in an adaptive design, as a price, seems fine also.  But the goal should be to most accurately draw conclusions from the data at hand; to falsely discount meaningful results at some non-trivial frequency may not be a good price to pay.

14. 14 PhRMA Adaptive KOL Lecture Series / November 14, 2008 Practical implementation issues  Don’t lose sight of the challenges inherent in implementing an investigation.  Defining stages is not always as clear as it might sound initially. oe.g., the DMC dataset is not the same as the point of implementation.

15. 15 PhRMA Adaptive KOL Lecture Series / November 14, 2008 Practical implementation (continued)  What’s the relevant unit for definition of stages? opatients (when they are randomized) or events (when they occur)?  Too much unstructured exploration with regard to these types of questions may increase the chance of false signals.  Time-to-event analyses may present special challenges because of confounding with non-proportional hazards.

16. 16 PhRMA Adaptive KOL Lecture Series / November 14, 2008 Pre-specification  Not only with regard to methodology...  What am I concerned about in advance, i.e., what’s the mechanism by which a change might be induced, and is it consistent with what I later see in the data?  Shouldn’t a signal be taken more seriously if consistent with sound pre-stated concerns?  Of course we do have to leave room for exploration of unanticipated signals.