By David Tuller, DrPH
Researchers are planning yet another trial of a rehabilitative exercise program for Long COVID—but, in this one, they propose to lie to all the participants about the nature of the study and the intervention being investigated. BMJ Open has recently published a paper called “Pursuing Reduction in Fatigue After COVID-19 via Exercise and Rehabilitation PREFACER: a protocol for a randomised feasibility trial.”
The intervention, called COVIDEx, is “a novel, remotely delivered, multimodal rehabilitation programme specifically designed for Long COVID fatigue.” According to the investigators, “COVIDEx integrates patient-centred strategies, including energy conservation techniques, cognitive behavioural approaches and structured pacing principles, to mitigate PEM [post-exertional malaise] risks while improving functional capacity.”
The investigators, largely from Western University in London, Ontario, indicate that their clinical trial uses a “modified Zelen design.” This refers to a controversial approach outlined by Marvin Zelen, a Harvard biostatistics professor, in a 1979 paper in the New England Journal of Medicine.
In Zelen’s design, trial participants are not consented before randomization. After randomization, only those slated to receive the experimental intervention are informed about it and consented. The members of the control group receive standard care and only after-the-fact are they informed that they had been enrolled in a clinical trial. At that point, they are retroactively asked for consent to use their data.
The rationale for not telling some participants that they’re in a clinical trial is that depriving them of this knowledge eliminates the possibility of certain kinds of bias. However, this use of deception obviously raises serious ethical questions. However, at least those who receive an experimental intervention are alerted to that salient detail, and given the chance to accept or reject the opportunity to be in the trial before undergoing treatment.
In the case of the new exercise trial, the “modifications” in Zelen’s design create more headaches for ethicists. The investigators, it seems, plan to lie to everyone, not just the half of the sample in the control group, as would happen under Zelen’s original proposal.
Here’s the plan: “All patient participants will be informed that they are part of an observational study designed to follow the natural progression of Long COVID and to evaluate the costs associated with standard post-COVID-19 treatments. This includes both the COVIDEx and usual care groups…A research coordinator or assistant will telephone each participant on completion of the participant’s study procedures and disclose the deception to participants.”
It is hard to understand what would justify this sort of flagrant deception. COVIDEx is not a “standard post-COVID-19 treatment.” The study describes it as a “novel” intervention—the opposite of standard. If it were standard, it wouldn’t need to be trialed.
In other words, the investigators are testing an experimental intervention on patients without telling the patients they’re being experimented on. This approach certainly seems to constitute a violation of research principles on informed consent, including those outlined in the Declaration of Helsinki. (The Declaration of Helsinki is an international human rights document that was created in the wake of Nazi atrocities to protect the rights of human research subjects.)
The investigators provide the following explanation for their decision: “Blinding patients to the presence of the experimental group will mitigate the effects of feeling disappointed, frustrated or discouraged about being assigned usual care. This is important given that the study is also assessing fatigue, a subjective, patient-reported outcome measure. This approach can also reduce the likelihood that participants in the usual care group begin self-motivated programmes trying to mimic the intervention.”
This explanation makes some sense. That is, if you overlook the fact that the investigators are delivering an experimental intervention to patients and lying about it in order to achieve their research aims.
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A focus on post-exertional malaise
Which brings us to post-exertional malaise (PEM). Unlike the many Long COVID exercise trials that ignore PEM, as recently reported by The Sick Times, these investigators recognize its significance and place great emphasis on monitoring for PEM among participants. The intervention’s design seeks to minimize the possibility that the program will trigger PEM.
The attention to PEM is welcome. But the bottom line is this: The investigators are trialing a rehabilitative exercise intervention among a patient population in which a significant proportion experience PEM. Informed consent involves telling participants about potential risks of an intervention. Is there a plan to tell those receiving the intervention of the risk that it might trigger PEM in susceptible individuals? Doesn’t sound like it, since they’re being told the intervention is “standard” treatment, as far as I can tell.
In a rapid response published this week, Todd Davenport, a professor of physical therapy at University of the Pacific in Stockton, California, and colleagues, offered a solid rebuttal to the protocol. As they write, the proposed trial “undermines informed consent, increases risks for harms, exploits the vulnerability of participants, and erodes trust in science and health care, all while exploring a question that already has been asked and answered satisfactorily enough to inform clinical recommendations.”
Here’s a key passage:
“Physical activity is a common trigger for post-exertional malaise (PEM), which is common in people living with long COVID. PEM involves an impaired recovery response from exertion that is distinct from deconditioning. The hallmark of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is PEM. Exercise is no longer recommended in contemporary clinical guidance for ME/CFS, because an accumulation of evidence from research and lived experience suggests it is likely to cause avoidable harms. Exercise prescription without adequate safeguards for PEM even may be considered negligent practice. The protocol acknowledges people living with PEM often worsen with exercise dosages that may be appropriate for other conditions. Several of the authors of this protocol also previously published a systematic review acknowledging risks of exercise in people with long COVID related to PEM. However, the authors did not adequately justify using deception in this study even while clearly acknowledging the risks of the intervention they proposed.”
Davenport and colleagues are right. It is not sufficient for the investigators to tell themselves—and protocol readers—that their methodology includes safety mechanisms to protect participants from PEM. Whether or not that is true, it is irrelevant to the question of consent. Research subjects have the right to decide for themselves if they have any interest in undergoing a “novel” intervention, and they have a right to be informed of any potential risks. Period.