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Rashomon revisited: two views of monitoring the Women's Health Initiative trials

For every generation of health scientists, there are touchstone clinical trials that shape their outlook on RCTs. From the 1960’s and 1970s, we still talk about the Health Insurance Program mammography trial [1], the Coronary Drug Project [2] and the University Group Diabetes Project (UGDP), the latter a trial featuring congressional hearings and a Supreme Court decision [3]. The late 1980s saw the counterituitive results of the CAST trial [4], now invoked as an almost talismanic corrective to undue faith in surrogate endpoints. For the new century, there could not be a more powerful reminder of the value and complexity of RCTs than the hormone replacement trials of the Women’s Health Initiative (WHI) (5,6). They had all the elements of powerful drama; politics, power (statistical), money (a lot), sex (one) and . . . statistics. Even now, three years after the publication of the second trial’s results, after literally thousands of journal and newspaper pages of subsequent commentary, scientific soul searching and clinical hand wringing, the principals involved are still writing in depth about the issues they encountered. In this issue of the journal, an extraordinary pairing of two such articles published [7,8]. The authors represent two different groups that lived with the evolving data in real time; the Clinical Coordinating Center (CCC) and the Data and Safety Monitoring Board (DSMB). As in the fabled movie Rashomon, we have one story told from two perspectives, stories that are tantalizing similar in broad outline, yet different in critical details. The details that differ are not the facts of the case. Both groups have been allowed to report the same data here so each article could stand alone, and to ensure that they told their story independently. It is their tone and overall focus, a difference striking enough make this pair required reading for current and future generations of trialists. This tone is mainly due to the different roles of a coordinating center and a monitoring board. For the CCC it was to be the guardians of the data, analysis, ‘proper’ scientific procedures, and to present the data to the DSMB and to the world. They struggled to develop monitoring procedures with the right degree of structure and flexibility. A telling phrase in their narrative is the rejection of procedures that they deemed ‘unduly’ ad hoc. This follows directly an exposition where they describe other approaches (eg, weighted versus unweighted statistics, multiplicity corrections) that had reasonable but informal justifications, and that might be described as ‘duly’ ad-hoc. That ad-hoc modifications needed to be made in the face of surprising and complex data is a given; but the line dividing ‘unduly’ from ‘duly’ ad-hoc is less clear. In contrast, DSMB exposition is distinctly personal. While they discuss many of the same methodologic issues mentioned in the CCC paper, they are accompanied with a distinctly different lexicon, eg, ‘struggle’, ‘internally conflicted’, ‘emergency’, ‘cohesiveness’ and ‘group dynamics’. Statistical boundaries, weighted statistics, and harm versus benefit tradeoffs aside, we are made privy to the extraordinarily difficult task of deciding for others whether to ‘knowingly’ expose them to further risk, and the cost to society of various decisions. Perhaps most telling is the story of the votes at the most critical junctures; 5–4 in both cases, with different persons in the majority, and nobody having more than 55% confidence in their decision. The knife edge does not get any sharper than that. Epistemologists, ethicists and historians of science – take note! Finally, we get a rare inside look at the politics of monitoring a high-stakes clinical trial, with the DSMB having to deal with not only the questions above, but the perspectives of the NIH, the NHLBI and the CCC. In a world where the main focus of conflict-of-interest is on industry-sponsored trials, the comments here on how structural relationships between government sponsors, DSMB and investigators can enhance or impair decision-making deserve special attention. These papers are an important addition to the literature on data monitoring [9–13] and highlight a number of inescapable DSMB dilemmas. First, there is the question of how a DSMB balances its dual Rashomon revisited: two views of monitoring the Women’s Health Initiative trials