Pragmatic trials raise some new ethical issues that need greater attention, according to the authors of a recent study.1

“Existing ethics guidance is not well-suited to pragmatic trials,” says Stuart Nicholls, PhD, the study’s lead author and a senior clinical research associate at Ottawa Hospital Research Institute in Ontario, Canada.

Pragmatic trials aim to evaluate interventions under real-world conditions. “The current empirical ethics literature does not reflect the full range of stakeholder perspectives,” Nicholls says. Previous studies focused on a narrow range of topics, such as when written consent approaches may be modified.2-6 “We aimed to explore more broadly what ethical challenges may arise in the design and conduct of pragmatic trials,” Nicholls explains.

Nicholls and colleagues interviewed 45 stakeholders, including ethicists, clinical investigators, methodologists, and patients. Participants reported ethical concerns about how “minimal” risk is determined, when it is appropriate to alter traditional informed consent practices, and how to distinguish between quality improvement and research.

They also expressed concern about determining what protections are owed to the broader populations the trial affects and the diversity of participants. During interviews, Nicholls and colleagues heard feedback regarding justice and equity. “This is particularly important, given the potentially heterogeneous populations within pragmatic trials,” Nicholls notes.

There is a general feeling that more pragmatic trials are needed, says Spencer Phillips Hey, PhD, another of the study’s authors and a faculty member at the Harvard Medical School Center for Bioethics. Mainly, the creators of clinical trials enroll people who are most likely to benefit from what is studied. “A drug that looks really promising in an idealized trial might not actually work so well in clinical practice,” Hey observes.

Pragmatic trials give a better idea of how an intervention’s going to work in the real world. Including groups that are excluded often from research is another potential benefit. “Getting more people, particularly historically under-represented groups of people, involved in research is an encouraging feature of some pragmatic trials,” Hey offers.

One unresolved ethical issue is how researchers are going to protect the interests of these broader participant groups. “We have not really come to a clear consensus on how to handle this move toward pragmatism while still appropriately protecting the rights of the participants,” Hey laments.

Traditional informed consent is not always going to be possible in these studies. This means investigators have to find other ways to protect participants. “We still have to think about how to best show respect and safeguard their interests, even if we are not getting consents,” Hey suggests. Exactly when it is ethically permissible to waive consent in the first place is debatable, too. “This is probably the biggest area of controversy,” Hey notes.

One condition in the Office for Human Research Protections regulations for waiver of informed consent notes securing traditional consent is “impracticable.” Some people might interpret this to mean if there is not enough money to obtain informed consent from everyone, that means consent is impracticable, and a waiver is needed. “But cost alone is not a sufficient justification,” Hey cautions.

For some pragmatic trials, traditional informed consent remains ethically necessary. “There seems to be a push from some investigators [who say] that just because a trial is pragmatic, it’s taken as justification to not get consent. That is very much putting the cart before the horse,” Hey explains. Whether consent is needed depends on multiple ethical considerations, such as whether the individual’s welfare is adversely affected. If it turns out informed consent is needed after all, researchers have to either find a way to do it, or perhaps conduct a smaller study than they planned. In other cases, the study design has to be re-evaluated. “You may have to tweak the questions a bit, and then it’s ethically acceptable to get a waiver,” Hey suggests. There are various types of pragmatic trials, each with its own ethical considerations depending on the study design. “Pragmatic trials mean different things to different people,” Hey observes.

One study might use electronic health record data to prospectively follow patient outcomes. Another randomizes huge numbers of patients at dozens of hospitals with no opportunity for the patients to opt out. “Both of those things can be pragmatic trials. But the ethical consequences that flow from those study design choices can be different,” Hey explains.

As it stands, investigators often struggle to find guidance on the particular ethical questions their study raises. “My worry is that it’s not practical to have to go to the literature and comb through dozens of studies to find out what you need to do,” Hey shares. There is no searchable online resource for investigators to plug in the parameters of their intended trial and find answers to relevant ethical questions. “That would be really compelling and valuable,” Hey says. “That’s the guidance and support that’s missing right now.”

REFERENCES

  1. Nicholls SG, Carroll K, Zwarenstein M, et al. The ethical challenges raised in the design and conduct of pragmatic trials: An interview study with key stakeholders. Trials 2019;20:765.
  2. Weir CR, Butler J, Thraen I, et al. Veterans Healthcare Administration providers’ attitudes and perceptions regarding pragmatic trials embedded at the point of care. Clin Trials 2014;11:292-299.
  3. Whicher D, Kass N, Faden R. Stakeholders’ views of alternatives to prospective informed consent for minimal-risk pragmatic comparative effectiveness trials. J Law Med Ethics 2015;43:397-409.
  4. Topazian RJ, Bollinger J, Weinfurt KP, et al. Physicians’ perspectives regarding pragmatic clinical trials. J Comp Eff Res 2016;5:499-506.
  5. Kass N, Faden R, Fabi RE, et al. Alternative consent models for comparative effectiveness studies: Views of patients from two institutions. AJOB Empir Bioeth 2016;7:92-105.92.
  6. Goldstein CE, Weijer C, Brehaut JC, et al. Ethics issues in pragmatic randomized controlled trials: A review of the recent literature identifies gaps in argumentation. BMC Med Ethics 2018;19:14.