This is discussion forum for physicians, researchers, and other healthcare professionals interested in the epistemology of medical knowledge, the limitations of the evidence, how clinical trials evidence is generated, disseminated, and incorporated into clinical practice, how the evidence should optimally be incorporated into practice, and what the value of the evidence is to science, individual patients, and society.
I just stumbled across this and think it's worth musing over it a bit. The recently published ACT I trial by Rosenfield et al is a noninferiority trial of an already approved device, the "emboshield embolic protection system" used in conjunction with the "Xact carotid stent system" both proprietary devices from Abbott. I'm scrutinizing this trial (and others) to determine if adequate justification is given for the noninferiority hypothesis around which the trial is designed. One thing I'm looking for is evidence that there are clear secondary advantages of the novel or experimental therapy that justify accepting some degree of worse efficacy, compared to the active control, which falls within the prespecified margin of noninferiority. This is what the authors (or their ghosts) write in the introduction:
"Most carotid revascularization procedures in the United States are carotid endarterectomies performed for the treatment of asymptomatic atherosclerotic disease. Revascularization is also performed by means of stenting with devices to capture and remove emboli (“embolic protection” devices).3,4 In the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), no significant difference was found between carotid endarterectomy and stenting with embolic protection for the treatment of atherosclerotic carotid bifurcation stenosis with regard to the composite end point of stroke, death, or myocardial infarction.5 CREST included both symptomatic and asymptomatic patients, and it was not sufficiently powered to discern whether the carotid endarterectomy and stenting with embolic protection were equivalent according to symptomatic status. The primary aim of the Asymptomatic Carotid Trial (ACT) I was to compare the outcomes of carotid endarterectomy versus stenting with embolic protection in patients with asymptomatic severe carotid-artery stenosis who were at standard risk for surgical complications."
That's a mouthful, to say the least, and probably ought to be expectorated.
Debut VideoCast for the Medical Evidence Blog, explaining non-inferiority trial design and exposing its inherent biases:
In this related blog post, you can find links to the CONSORT statement in the Dec 26, 2012 issue of JAMA and a link to my letter to the editor.
Addendum: I should have included this in the video. See the picture below. In the first example, top left, the entire 95% CI favoring "new" therapy lies in the "zone of indifference", that is, the pre-specified margin of superiority, a mirror image of the "pre-specified margin of noninferiority, in this case delta= +/- 0.15. Next down, the majority of the 95% CI of the point estimate favoring "new" therapy lies in the "margin of superiority" - so even though the lower end of the 95% CI crosses "mirror delta", the best guess is that the effect of therapy falls in the zone of indifference. In the lowest example, labeled "Truly Superior", the entire 95% confidence interval falls to the left of "mirror delta" thus reasonable excluding all point estimates in the "zone of indifference" (i.e. +/- delta) and all point estimates favoring the "old" therapy. This would, in my mind, represent "true superiority" in a logical, rational, and symmetrical way that would be very difficult to mount arguments against.
Added 9/20/16: For those who question my assertion that the designation of "New" versus "Old" or "comparator" therapy is arbitrary, here is the proof: In this trial, the "New" therapy is DMARDs and the comparator is anti-tumour necrosis factor agents for the treatment of rheumatoid arthritis. The rationale for this trial is that the chronologically newer anti-TNF agents are very costly, and the authors wanted to see if similar improvements in quality of life could be obtained with chronologically older DMARDs. So what is "new" is certainly in the eye of the beholder. Imagine colistin 50 years ago, being tested against, say, a newer spectrum penicillin. The penicillin would have been found to be non-inferior, but with a superior side effect profile. Fast forward 50 years and now colistin could be the "new" resurrected agent and be tested against what 10 years ago was the standard penicillin but is now "old" because of development of resistance. Clearly, "new" and "old" are arbitrary and flexible designations.
