Two new papers examine what sham-controlled trials suggest, how to reduce risks, and whether patients are truly informed.
Sham controls can be an integral part of CV device trials, providing a unique way to overcome the placebo effect, but they also represent an ethical minefield of concerns that deserve careful consideration, a new editorial argues.
“If doing a sham procedure is the right thing to do for science, why does it feel so wrong?” asks Dr. Alexander Postalian (Texas Heart Institute, Houston) in the paper, published online Monday in JACC: Cardiovascular Interventions.
Years ago, as a cardiology fellow, he first came face to face with the realities of what this aspect of clinical trial design meant in real-world practice. The other day in the catheter lab, he encountered an elderly woman undergoing the sham procedure who had severe coronary artery atherosclerosis and ischemic cardiomyopathy that were deemed unsuitable for revascularization. She ended up doing well after the make-believe procedure—but, as Postalian posits in her piece, what if she hadn’t?
At the time, “it kind of hit me that it was, it feels weird,” Postalian told TCTMD, referring to the ethical issues involved. That sentiment stayed with him and was the motivation behind his new editorial.
Although his perspective has evolved over the years, with mock procedures carrying less of an emotional punch, “I still think it’s important not to forget the humanity of patients. . . . I mean, we do procedures all the time and we stop feeling the little emotions,” he said, noting how easily people who are “patients” can slip into being seen as “subjects.”
That doesn’t mean there isn’t a role for sham-controlled trials, Postalian stressed. “I think all interventionists agree that sham procedures are extremely important. They are essential to the advancement of science and to preventing the widespread use of useless or even harmful procedures. Otherwise, I would not have participated in these studies [as a researcher]”, he commented. “But I think we have to recognize the trust they have in us as individuals who have more information about the nuances of their condition and the procedure they’re going to undergo.”
Importantly, the Postalian writes in its paper, the use of sham “allows us to challenge the dogma of established paradigms and potentially avoid much of the morbidity and even mortality of patients by ending unfavorable procedures that carry risk.” Prime examples in cardiovascular medicine include SYMPLYCITY HTN-3 and ORBITA, whose use of sham controls was not without controversy.
Neal W. Dickert, MD, PhD, who along with Chandan M. Devireddy, MD (both of Emory University, Atlanta, GA), co-authored an editorial that offered a counterargument to the Postalian article, noted that the suitability of a fake controlled trials is a problem that has “pervaded” cardiology for several decades.
After that, ORBITA and SYMPLICITY HTN-3 “brought this issue to the fore, and I think people have to think more about the need for fake guns now than they would have if you went back 10 years,” Dickert said in an interview with TCTMD. He cites the FAME 2 trial, comparing optimal medical therapy with or without FFR-guided PCI in patients known to have at least one flow-limiting lesion, as an example of where a sham control was not used, but perhaps was it should have been.
Dickert and Devireddy, in their view, clarify their position that sham controls are a necessary element of cardiovascular research. But conducting such research properly requires consideration, they emphasize: a clear understanding of the possible consequences of any sham intervention, ethical standards that recognize what level of scientific benefit and social value might justify that particular exposure to risk, and recognition of the harms. which can occur when unproven interventions see clinical use.
Perhaps where the two editorials differ most is whether fraud constitutes fraud.
“In its simplest deconstructed interpretation,” Postalian states, “a sham procedure involves intentionally injuring an individual under the false pretense of possibly improving their health, all for the potential benefit of the general population.”
Dickert and Deviredy, however, say this characterization is “incorrect and unhelpful.”
“There are also no ‘false claims’ in ethically conducted sham studies that are supported by a robust informed consent process,” they wrote. “It is clear that informed consent plays a critical role and there is a need to explore how best to conduct consent processes in sham trials to promote understanding and avoid therapeutic misconceptions or misjudgments.” However, there are no ‘false claims’ in a well-designed and well-conducted sham-controlled trial.”
Postalian, on TCTMD, admitted that his wording might be dramatic, but reiterated his point. “Intentional injury does not mean malice or vicious intent, and false does not mean lying.” But [with] the theatrics involved in fake procedures, you’re trying to make the patient believe you’re doing something [and] it is certainly trying to deceive the patient,” he said.
Where the two papers overlap is the shared message that if a sham trial design is to be pursued, trial participants need to exercise caution.
Informed consent is critical in situations such as those where study participants agree to undergo some degree of physical intervention beyond simply taking medication. Every single person goes through this consent process during trials, though it’s no guarantee the message will get through, Postalian warned.
“The problem is, what is their internal perception and their internal hopes? Because we want to believe that we have achieved perfectly informed consent: that the patient understands the minute details of both their condition and the planned procedure, and they participate in the fictitious process from a position of selflessness for the betterment of others,” he said. “But we probably have to accept the much more likely scenario, which is that they have limited information about the nuances of their condition and planned procedure. And the only reason they agree to participate is to hope to feel better or live longer.”
Postalian added, “Once you’re directly involved in talking to these patients, you realize that most of the time it’s more likely the second scenario.”
Dickert noted that while the sham procedure itself misleads people about what they are actually getting, “the consent process for a sham control trial does not involve deception. This does not include hiding from people that you will be randomized into one of two arms, one of which will be a sort of procedural placebo.
How patients perceive sham-controlled trials is an area ripe for research, he added. Still, “it is not wrong for a patient to sign up for a sham-controlled trial, knowing that there may be a false response and hoping for a benefit. Those two things, they don’t cancel each other out. . . . I don’t think that hoping for benefit and understanding research are necessarily at odds.”
Besides informed consent, Dickert highlighted two main elements that should support sham-controlled studies. “One really important problem from a design point of view is achieving a false effect with as little risk as possible,” he said. “The second part, I think, is a closely related concept: by ensuring that all elements of studies that are done primarily for research purposes that impose a level of risk, we need to be sure that the scientific value of the information produced by those components is robust .”
For operators performing the procedures, there may also be relatively simple ways to reduce the risk of harm to patients, the Postalian paper suggests. It may be possible to reduce the invasiveness of the intervention while maintaining the placebo effect, such as by performing a venipuncture and using the smallest sheath size allowed, or perhaps even simply injecting a local anesthetic. Finally, he says, it may be possible to devise statistical methods that could predict the placebo effect, as a means of improving the external validity of research results and in some cases eliminating the need for a dummy control approach.
Dickert and Deviredy dispute this latter suggestion, calling it “grossly unscientific,” adding that it greatly overestimates what we know about likely placebo (or nocebo) effects in a specific context. It is also unrealistically optimistic about the strength of the statistical adjustment,” they comment.
Postalian, while agreeing that it would be challenging to pull off, said it was not impossible: “We shouldn’t be afraid to explore advances in statistics and improve our understanding of the placebo effect and help quantify it. determination and prediction.’
Despite the many points and counterpoints, Postalian believes that the two documents should not be presented as “dueling views”, as they overlap more than they diverge. “I think we’re all on the same page, to be honest,” he said.
The key takeaway is that sham controls need to keep the patient in mind, Postalian concluded. “We know that a patient undergoing a sham procedure will gain no benefit, only risk. So our duty is not only to make the risks ‘low’, but to reduce them to the absolute minimum possible.”