NEJM SEAS Early Release Perspective Is Out; Circulation Piece Re-Visited. . . .

The NEJM perspective I mentioned/teased this morning is now out (full-text; $$ req'd.) -- while I try to source a full-text version, it looks as though it will likely tread most of the same path worn here -- in Circulation (a JAMA property), last year, by Dr. Allen Taylor:

. . . .5. Does the Design of SEAS Move the Field Forward?

SEAS, begun in 2001, studied a reasonable hypothesis about the effects of lipid-lowering therapy on aortic stenosis. However, the design of this study was disappointing because of the absence of a simvastatin control arm. Accordingly, any observed benefit could be attributed to either component of the ezetimibe-simvastatin combination product. More disappointing is the fact that nearly all of the early trials of ezetimibe failed to examine the critical question of whether this agent adds any incremental value beyond that provided by simvastatin alone. In many ways, the absence of these critical data represent misjudgment by the US Food and Drug Administration, which approved ezetimibe on the basis of the ability of this drug to reduce low-density–lipoprotein cholesterol by a modest 15% to 18%. If the ezetimibe approval had been coupled with a mandate to perform appropriate outcome trials, we would not find ourselves in the current dilemma of questioning whether ezetimibe is effective or safe. At best, we will now learn, approximately a decade after introduction of this drug, whether ezetimibe offers any incremental benefits beyond statin monotherapy. For an agent taken by millions of patients, that’s far too long an interval. Consideration of control by the US Food and Drug Administration over biased clinical trial designs leading to de facto positive studies is needed to maximize the value of human volunteer participation and to inform the treated public with meaningful research results.

6. Is the Media the Most Appropriate Venue for Initial Presentation of Scientific Results?

Although the investigators are to be applauded for promptly bringing to public awareness the potential adverse-event signal (no doubt, a lesson learned from other recent delays in public disclosure of trial results), the answer to this question is most certainly "no". A simple survey of the vastly divergent headlines stemming from the media event, ranging from "Trial Intensifies Concerns About Safety of Vytorin" to "Vytorin Misses Primary End Point in SEAS Study," illustrates the potential for confusion. Venues exist for rapid, peer-reviewed dissemination of clinical trial results, and these venues should be preferred over carefully controlled and scripted media sessions and press releases. Many of the top-tier medical journals offer "expedited review," which enables publication within a few weeks after generation of the manuscript. If an "emergency press conference" were required to protect public health, it should not have been orchestrated by the sponsor, and it should definitely not have included other clinical trial results (eg, primary and secondary end point data from the study) beyond those necessary for immediate public disclosure to address safety concerns. . . .

To be fair, one of the authors of tonight's NEJM piece was associated with the SEAS study, so perhaps he takes a more pro-sponsor view. We will report, when more is known about the full content.