Clinical trials are instrumental for health science community to test and evaluate interventions. Trials can be broadly categorized in two classes, i.e. pragmatic and explanatory; where the former are designed to evaluate the efficacy of interventions in real-life routine practice conditions, whereas the latter aim to test whether an intervention works under optimal situations. Outcomes from pragmatic trials can be generalized and applied in routine practice settings. Since most of the findings of exploratory trials cannot be broadly generalizable, the “pragmatic design” has gained significant importance. (1)

However, researchers hypothesize that there may be a tension between the goals of pragmatic randomized controlled trials (RCTs) and the traditional ethical rules governing RCTs. The main challenge then is the traditional regulatory informed consent process (referred to as “regulatory consent”), (2) which usually requires lengthy consent forms and procedures that significantly alter the routine workflow of “real-world” clinical settings, thus compromising the pragmatic nature of the trial. (3) Therefore, some have argued that in some types of pragmatic RCTs where the risks are very low and patient expectations are not violated, the regulatory procedures for obtaining informed consent could be altered or even waived. (4)

The principle of informed consent makes the foundation for ethics in clinical research. This process provides crucial trial information to potential participants in order for them to make a rational and informed decision about participation. However, advancements in medical research have generated complex medical protocols resulting in elaborate and complicated information to be conveyed during the informed consent process. The complexity of consent documents also stems from the fact that sponsors as well as investigators view it as a legal and symbolic document of participant’s agreement to participate in the research study. This results in an informed consent process that is legally right, but often inadequate in terms of simplicity and ease of understanding for the study participants. (5)

Pragmatic trials are typically associated with standard-of-care comparisons, and yet their value is not limited to treatments already used in clinical practice. Early pragmatic trials (EPTs) generate real-world effectiveness data by comparing new interventions with existing standards. This data can be valuable to health care decision makers even at the time of regulatory approval. Currently, ways to facilitate the design and conduct of EPTs to bridge the “efficacy-effectiveness gap” are being extensively explored. In this context, EPTs can study unapproved treatments in the pre-market phase (premarket EPTs) as well as newly approved treatments in the early post-market phase (post-market EPTs). (6)

On the other hand, there is no well-established ethical framework for interpreting the criteria and little specific guidance on how to interpret them. This lack of guidance is evidenced by the fact that, as recently as 2008, the Secretary’s Advisory Committee on Human Research Protections (SACHRP) recommended the Office for Human Research Protections to issue specific guidance on the topic. (7) Lack of guidance is especially acute in applying the waiver criteria to pragmatic RCTs, because historically these criteria have been applied to medical records research or to studies with special research designs (such as, experiments requiring deception). Thus, pragmatic RCTs, which compare individual medical interventions, are a novel setting for waivers or alterations of regulatory consent. (8)

The most important reason for an ethical framework for waiver and alteration of informed consent is that the regulations lump together waivers and alterations, making important ethical distinctions ambiguous. Altering regulatory consent by leaving out a single consent element (e.g., whom to contact for information) is ethically quite different from waiving consent to RCT participation, which could involve actively concealing from someone that he is enrolled in a RCT; yet the regulations require the application of the same criteria for these two ethically different departures from regulatory consent. This is problematic, as it opens the door to over-regulation (unnecessarily prohibiting ethically acceptable alterations by holding them to the same standard as for a complete waiver) as well as to under-regulation (erroneously permitting unethical waivers by holding them to the same standard as for a minor alteration). Clearly, a principled ethical framework is necessary to prevent such mistakes. (8)

Evidence suggests that the increased interest in standard-of-care pragmatic trials has led to the debate between if and how traditional regulatory consent can be ethically modified- either waived entirely or altered in some way to ethically achieve the goals of pragmatic trials. Indeed, some changes in certain research regulations explicitly accommodate “simplified” procedures for obtaining consent for some types of pragmatic clinical trials. However, there are many factors that necessitate the modification of informed consent process, such as research risks, impracticability of the regulatory consent, and ensuring non-violation of patients’ rights and interests.

In the end, we would like to sum up our observations as follows: No pre-market EPT can be conducted with either a waiver of or an alteration to regulatory consent. Although no post-market EPT can be conducted with a waiver of regulatory consent, some may be conducted ethically with an alteration to the regulatory procedure. To add to this, thinking about EPTs can help further pinpoint morally relevant issues in pragmatic trials across the different stages of a drug’s life cycle.

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  1. Patsopoulos NA. A pragmatic view on pragmatic trials. Dialogues in Clinical Neuroscience. 2011; 13(2):217-224.
  2. Kim SY, Miller FG. Waivers and alterations to consent in pragmatic clinical trials: respecting the principle of respect for persons. IRB 2016; 38:1–5
  3. McKinney RE Jr., Beskow LM, Ford DE, et al. Use of altered informed consent in pragmatic clinical research. Clin Trials 2015; 12:494–502.
  4. Faden R, Kass N, Whicher D, et al. Ethics and informed consent for comparative effectiveness research with prospective electronic clinical data. Med Care 2013; 51(Suppl 3):S53–7.
  5. Sreenivasan G. Does informed consent to research require comprehension? Lancet 2003; 362:2016-8.
  6. Kalkman S, Kim SY, van Thiel GJMW, et al. Ethics of informed consent for pragmatic trials with new interventions. Value Health 2017; 20:902-908.
  7. Secretary’s Advisory Committee on Human Research Protections (SACHRP). Recommendations related to waiver of informed consent. 2008.
  8. Kim SY, Miller F. Waivers and alterations to consent in pragmatic clinical trials: Respecting the principle of respect for persons. IRB. 2016; 38(1):1-5

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