Healthy Skepticism Library item: 18372

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Publication type: Journal Article

Drazen JM, Wood AJJ
Don't Mess with the DSMB
NEJM 2010 July 7;
http://content.nejm.org/cgi/content/full/NEJMe1007445

Abstract:

If the lyrics of the popular Jim Croce song from the early 1970s were adapted for a clinical trialist anthem, the refrain would likely be

You don’t tug on Superman’s cape
You don’t spit into the wind
You don’t pull the mask off that old Lone Ranger
And you don’t mess around with the DSMB.
Since the DSMB (data and safety monitoring board) is charged with ensuring that clinical equipoise is maintained as trial data are accrued, it is considered very bad, even self-destructive, behavior for people who are involved with the study to interact with DSMB members on trial-related issues. Traditionally, there has been a wall between investigators, sponsors, and the DSMB. This wall prevents preliminary findings from leaking out in ways that would prejudice the trial. For example, if it was known that the DSMB was examining a marginal increase in cardiovascular risk in a trial, then trial investigators might bias future recruitment by excluding patients at risk for such events. In the proper performance of clinical trials, you “don’t mess around with the DSMB.”

Recently, a new type of problem has emerged that puts the integrity of the whole clinical-trial enterprise at risk. Two examples of this problem have appeared in the Journal in the past few years. In these cases, the integrity of the DSMB has been thwarted or violated.

In May 2007, we published a meta-analysis of randomized clinical trials showing an increased risk of cardiovascular adverse events among patients with diabetes who were receiving rosiglitazone, as compared with patients who were not receiving the drug.1 Shortly thereafter, the drug’s manufacturer, GlaxoSmithKline, went around the steering committee and the DSMB of an ongoing trial known as the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial (ClinicalTrials.gov number, NCT00379769 [ClinicalTrials.gov] ), an open-label comparison of antidiabetic regimens with and without rosiglitazone, and conducted an interim analysis of the trial data. We published that analysis in June 20072 but were not fully aware of GlaxoSmithKline’s manipulations until February of this year.3

What should have happened? The DSMB should have been informed of our May 2007 article and checked the trial data to be sure that patients receiving rosiglitazone in the RECORD trial were not having adverse events at an unacceptable rate. If clinical equipoise was still in play, the trial should have been allowed to continue undisturbed (i.e., without publication of the RECORD interim analysis), without public comment from the DSMB, without communication with investigators, and without disturbing the integrity of the trial. On the other hand, if in the opinion of the DSMB equipoise no longer existed, then the trial should have been terminated – that is the way it is supposed to work. The DSMB protects the participants in a trial. …