Princeton-Trenton ASA Seminar on Missing Data in Clinical Trials

This seminar included presentations on analysis methods and a panel discussion on issues from design through sensitivity analyses for missing data mechanism assumptions in clinical trials. The largely pharmaceutical audience also included a few FDA experienced members, so very practical and patient centered issues were raised. The recent report on Missing data in Clinical Trials by the NRC panel on Missing data was cited frequently as a valuable contribution to the field.

Statisticians often point out the limitations (bias in effect and standard error estimates) that accompany per-protocol analyses where patients who drop out are omitted from the study, relative to analyses of the full ITT population. However, a good point to consider is the purpose of the trial and of the treatment under evaluation: it is usually to improve outcomes for those patients who can tolerate that treatment. In practice, no one treats patients as if once assigned a treatment they must comply with that treatment. If a treatment produces an adverse reaction or does not help, a patient will switch.

Recognizing this, newer designs were discussed. For example, in one design patients first participate in a "run-in" phase with a low dose of drug, and only those patients who tolerate the low dose are randomized. This eliminates only one source of dropout; the book includes other examples of designs.

There were some good suggestions for "sensitivity analyses" related to assumptions and methodological choices made in handling the missing data in the analysis of trial data. Slides should be posted soon. One suggestion was to relax the assumption of a single mechanism and to assume instead that there were two groups of patients, each having a different missing data mechanism. Then this analysis is conducted and compared to the primary analysis.

The simple idea of using as many potentially divergent estimators as possible in a sensitivity analysis was agreed to be sensible, but perhaps not feasible for a trial protocol where a primary and specific sensitivity analysis are required.

David Bristol gave his farewell lecture, complete with stories of ancient technologies (chalk & blackboard, for example). He described how different missing data mechanisms in treated and placebo groups can lead to bias: placebo group experiences placebo effect for several visits, but then loses patients for LOE (loss of efficacy). The completers in this group show definite improvement using LOCF analysis. The treatment group loses patients early if tolerability issues arise; they do not improve in such a short time. Dropout of this kind can bring the treated and control group means so close together that significance is lost, even when the drug "works" on those who can tolerate it. I had never thought about that. I now see why design of these studies needs to change. I need to think about the NI trial and perhaps come up with a NI trial design for non-pharmacologic interventions that would have this kind of run-in as part of the design. I also have a new respect for per-protocol analyses.

Statistician Greg Ridgeway: New Deputy Director of National Institute of Justice

I have admired Greg's work for a long time. His career path was shaped by a field where little statistical work was being done, and he managed to address important questions using data in innovative ways. He made some great contributions to the field of criminal justice, and will now bring his insights and his unique perspective to the National Institute of Justice.  I remember seeing funding proposals on the NIJ web site back in 2005 when I was a graduate student in statistics. My research advisor was reluctant to submit for funding there, because of our lack of expertise in criminal justice. Greg's story seems to weigh against that inhibition - how interesting!

Here's the article

Statistician Greg Ridgeway: New Deputy Director of National Institute of Justice