NEJM Editorial Faults Process Used In Merck's SEAS Release -- In July 2008

A new editorial in the prestigious New England Journal of Medicine finds fault with legacy Schering-Plough, and Old Merck, in the process surrounding the early release of the SEAS trial results, and the "early peek" at the IMPROVE-IT trial.

Though using a playful Jim Croce riff for the title, the issue is deadly-serious: potential manipulation of study independence by inappropriate contact with the study's DSMB, or data safety monitoring board. See here:

. . . .The. . . Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial. . . was designed to determine whether the cholesterol-lowering agent ezetimibe had a salutary effect in patients with aortic stenosis. Analysis of the data from the SEAS trial suggested an imbalance in incident cancers and cancer deaths among patients receiving ezetimibe and simvastatin as compared with those who were not receiving the drugs. The sponsors, Merck and Schering-Plough, appear to have interacted with the investigators and the DSMBs in two ongoing trials of ezetimibe, the Study of Heart and Renal Protection (SHARP) trial and the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), which resulted in the unblinding of data on cancer outcomes in these trials. In 2008, we published the outcome of this analysis but were not fully aware of the role of the trial sponsors and the extent of the interactions that had occurred among the sponsors, the DSMBs, and the trial investigators until we received information from one of the authors, outlining the process and the considerations that went into the unblinding of the data. In our opinion, the process should have maintained the primacy of the DSMBs of the SHARP and IMPROVE-IT trials: the sponsors should have informed the DSMBs about the cancer imbalance in the SEAS trial and allowed the DSMBs to perform the required analyses to determine whether clinical equipoise continued to exist. If it did, the trials could have continued without disturbing their integrity and with only a statement to that effect.

Given these experiences, the Journal will in the future carefully examine the independence of DSMBs when manuscripts are submitted that involve decisions that should appropriately have been taken by an independent DSMB. Examples include manuscripts reporting early stopping of a trial because of efficacy or toxicity and manuscripts reporting interim analyses of data. . . .

This is a very welcome first step. If followed, it would allow real-time analysis -- and commentary -- as opposed to the subsequent "footnoting" of a published article -- after the fact. The danger of overshadowing the DSMB's role is real -- and quite often these days, literally billions of dollars are riding on the "roles" of these dice.