International Policy Frameworks for Consent in Minimal-risk Pragmatic Trials

Clinical research is our primary tool for evaluating health care; it is the method by which we innovate and create or refute evidence of utility for new and existing interventions. The highest level of clinical evidence comes from randomized controlled trials or meta-analyses of robust trials,¹  but these are expensive and time-consuming and there will never be enough of them to address even a small fraction of the important questions health services need to answer.

Alternatives to conventional randomized trials are thus of considerable interest. Novel designs have emerged that maintain the scientific rigor of randomized controlled trials while incorporating the real-world nature of observational studies.^2,3  Features such as real-time randomization at point of care,^1,4,5  with the collection of trial data from electronic health records⁴  or clinical registries,⁶  enable these trials to rapidly enroll large numbers of participants at considerably reduced cost.

Many such studies fall into the category of comparative effectiveness trials generally defined as head-to-head comparisons of commonly used clinical or public health interventions. Unlike traditional trials that evaluate efficacy in a well-defined and controlled setting, comparative effectiveness trials measure effectiveness—that is, the benefit of interventions in routine clinical practice. Their primary goal is to inform decision-making by providers and policymakers. Internationally, efforts are underway to strengthen capacity to undertake large-scale pragmatic comparative effectiveness trials.^7,8 

In this article, we provide an overview of contemporary thinking on the use of altered or waived consent for pragmatic comparative effectiveness trials; herein referred to as pragmatic trials.

To help investigators formulate their positions on the ethical acceptability of altered or waived consent, we summarize the ethical debate surrounding the use of these models and confirm which international ethical guidelines support their use.

We then establish whether the policy frameworks in three culturally similar countries—the United States, England, and Australia—permit six discrete consent models where consent is simplified, altered, or waived altogether. These countries were selected because, collectively, the authors have experience conducting trials in all three and are familiar with their policy frameworks. We cover both regulated trials (those under the purview of the U.S. Food and Drug Administration, the Medicines and Healthcare products Regulatory Agency in the United Kingdom, and the Therapeutic Goods Administration in Australia) and nonregulated trials governed by other legislation, federal policy, national guidance, or common law. We exclude trials conducted in emergency settings where patients are incapacitated, as altered consent in that context is already well established in many countries.

We then explore the reasons for the reported variability in ethics committee decisions around the use of altered or waived consent, including difficulties interpreting preconditions that must be satisfied before these models are permitted. We illustrate how these models have been operationalized by presenting three trials granted an alteration or waiver of consent.

Finally, we summarize key features and considerations into a framework for investigators planning the use of these models for their trials.

The current ethical framework for clinical research has emerged over the last century in response to a series of scandals such as the Tuskegee syphilis studies and atrocities committed during the Second World War.⁹  A key advance came in 1964 with the Declaration of Helsinki by the World Medical Association which positioned full disclosure and individual autonomy at the heart of ethical research.¹⁰  In the United States, the Belmont Report further clarified the principles to guide the resolution of ethical problems arising from human research by promulgating three ethical principles: respect for persons (including the requirement to acknowledge and respect autonomy); beneficence (including society’s moral obligation to do good to others); and justice (including the fair distribution of the benefits and burdens of research and the obligation to address inequalities in health care).¹¹ 

These documents codify the inherent tension between protecting individuals’ rights and doing research to support evidence-based care. For most trials, informed consent satisfies ethical mandates while allowing necessary research, but due to the very nature of some pragmatic trials, many experts report that traditional consent can compromise trial integrity or can render a trial impracticable for other reasons (table 1).^12–15  Thus, there is growing consensus that traditional consent may poorly suit pragmatic trials.^16–20  Some experts also question whether traditional consent is ethically necessary when existing practice is being evaluated.^21–24  Others note that lengthy and legalistic approaches to informed consent for minimal risk trials may result in an “injurious misconception,” where trial entry is rejected by potential participants because of an exaggerated and disproportionate perception of risk.^23,25 

The debate surrounding informed consent for pragmatic trials is hardly new. It has been more than 30 yr since Chalmers et al.^26,27  articulated a confused ethical analysis:

More recently, the debate has been reinvigorated by recognition that both altered and waived consent models are fundamental to the successful development of a “learning healthcare system”; a concept first proposed by the Institute of Medicine,²⁸  in which knowledge generation processes are embedded into daily practice to continually improve care and deliver value. In essence, altered or waived consent would reduce disruption to normal clinical workflows, making trial integration into routine practice much more feasible. Thus, a number of groups have considered how informed consent could be adapted in such a health system. Kim and Miller propose a model that integrates research consent with the routine clinical discussion with patients.²⁹  Modi et al. advocate routine randomization as the default position and make the case for altered consent.²³  Myles et al. have adopted an altered consent model using postrandomization opt-out from further participation.²⁴  And finally, Faden et al. propose a new ethical framework where rigorous, systematic evaluation is considered part of normal practice and where patients and the public are better informed and accept that in some circumstances, individual consent may not be obtained.³⁰ 

Thus, experts appear undecided on the most appropriate models, particularly around the use of waiver of consent.³¹  While many accept that for some trials a waiver may be necessary, two camps have emerged:

• •

  Those who feel that respect for persons is the overriding ethical principle: waiver of consent is categorically indefensible in trials or should be limited to those trials that are minimal risk and truly impracticable without it.

• •

  Those who feel that although respect for persons is the central ethical principle, it is not the only ethical principle and cannot be considered in isolation: waiver of consent should be accepted in a wider group of minimal risk trials.

So how do international guidelines address the tensions between the rights of individuals and the needs of society and do they clarify when a prima facie duty such as respect for autonomy can be overridden by other obligations? Arguably, the Declaration of Helsinki is the most influential guideline. It permits research “without prior consent” in the emergency setting, but maintains the voluntary consent requirement for other types of clinical trial. However, the Declaration does permit investigators to, “consider the ethical, legal and regulatory norms and standards for research involving human subjects in their own countries.” The absence of a specific framework for minimal risk trials has prompted others to codify a set of ethical principles. For example, the Ottawa Statement³²  guides the ethical design and conduct of cluster randomized trials and acknowledges that when certain criteria are met, an ethics committee may alter or waive consent. This guidance highlights other relevant considerations such as, “Who is the subject when an intervention is applied at an organizational level?” This illustrates the complexity of the ethical decision-making process when these models of consent are being considered.

International Council for Harmonisation Good Clinical Practice Guidelines (Good Clinical Practice)³³  require written informed consent covering 20 elements. Although this guideline was primarily developed for “premarket” trials, its wide application to pragmatic trials has been criticized as a threat to their conduct,³⁴  although lobbying by an international group of investigators³⁵  may influence its proposed “renovation.”³⁶ 

The International Ethical Guidelines for Health-related Research Involving Humans, prepared by the Council for International Organizations of Medical Sciences and the World Health Organization,³⁷  describes suitable conditions under which an ethics committee may grant a waiver of consent. It recommends the use of three key criteria to support ethics committee decision-making:

The policy frameworks in the United States, England, and Australia describe several discrete consent models using a variety of terminology. In addition to the terms “simplified consent,” “altered consent,” and “waived consent,” the terms “broadcast consent,” “opt-out,” “limited disclosure,” and “deemed consent” are also used to describe aspects of these models. To enable comparison, we define six consent submodels representing the “best fit” across these countries (table 2).

Our analysis of policy frameworks and associated regulation (Supplemental Digital Content, https://links.lww.com/ALN/C77) quantifies the discordance across regulatory frameworks. In summary, the United States permits all six models in table 2 for both regulated and nonregulated trials when certain preconditions are met. These models are sanctioned by clear, research-specific policy. Although Australia has no national guidance that explicitly endorses the use of altered or waived consent for minimal risk trials, all six models appear to be permitted for nonregulated trials and regulated trials through de facto provisions. In contrast, if England adopts the European Clinical Trials Regulation³⁸  post-Brexit, waiver of consent will not be permitted in any situation other than the emergency setting and altered (opt-out) consent will only be permitted for a subset of cluster trials. Consent forms may be simplified, but verbal consent for trials will rarely be permitted. For nonregulated trials, only simplified consent is endorsed by explicit trial guidance.

In England and Australia, the limited use of altered and waived consent may, in part, be due to the absence of clear, trial-specific policy. In both countries, investigators and ethics committees considering the use of these models are left to interpret an array of legislation. To establish a defensible position, they must “deconstruct” informed consent into its component parts: (1) consent to process data; (2) consent to treatment: and (3) consent to enter a trial. In both countries, mechanisms exist that allow waiver of consent to process data for research. In both countries, there are common law requirements for consent to treatment that require disclosure of material risk and reasonable alternatives which for pragmatic trials would mirror what would have been appropriate outside the trial setting. For waiver of consent to disclose trial entry, common law requires patients to understand the nature and purpose of the treatment being offered. If, for individual trials, patients are not made aware of the research purpose (namely to generate better evidence through “randomization”), patient engagement through trial awareness activities should be considered. For example, the widespread broadcast of an institution’s reasons and arguments for embedding trials into routine care would increase awareness that trials are conducted primarily to improve care. If patients understand and accept that the goals of research (generating knowledge) and the goals of clinical care (treating patents) are converging, the risks related to nondisclosure of the research component of treatment and its adverse impact on patient autonomy would be minimized.

One common theme in the literature is the lack of consistency in ethics committee decisions around the use of altered and waived consent, particularly in the United States where these models are most widely used.^39–40,17  We present three trials (two from the United States and one from Australia) that illustrate how investigators justify the use of alteration or waiver of consent (table 3). We also discuss why ethics committees have difficulty interpreting the preconditions present in the legislation that must be satisfied before these models; particularly waiver of consent can be used.

Much of the variation in ethics committee decision-making is attributed to the wide interpretation of two key preconditions present in both research and privacy regulation: the requirement for trial risk to be minimal and the requirement for the trial to be impracticable without alteration or waiver of consent.

An ethics committee needs adequate information about the relative risk of a patient’s treatment inside and outside the trial. But how should they use this information to determine trial risk? Without clear guidance, ethics committees may well question how a trial involving the use of high dose dexamethasone during open heart surgery (Trial 1) could ever be considered low risk. Lantos et al. make a strong case that the risks posed by existing standard of care (which in Trial 1 was high dose dexamethasone) should not be part of the trial risk determination.³⁹  Importantly, all three countries in our review support this position and have attempted to provide clarity. Table 4 provides extracts from national policy or guidance that directs ethics committees to consider “trial risk” as the risk that is incremental to the risk posed by standard medical care for the condition being treated.

However, Kim and Miller have cautioned that even if the incremental risk is low, nondisclosure of trial entry may adversely affect patient welfare if the treatments being compared have different types of risks and benefits that would be important to patients, as would be the case for a trial comparing sedation versus general anesthesia or open versus laparoscopic surgery.⁴¹  Welfare concerns may also diminish if patients have no real choice outside the trial. This is especially true for trials investigating components of complex interventions where in routine practice, tacit consent is assumed. This is illustrated in Trial 2 where the oxygen concentration chosen for surgery would neither be discussed nor subject to patient choice. As is commonly the case with all clinical trials, welfare considerations are especially relevant when trials involve disenfranchised or disadvantaged populations who may be less able to express free choice about participation. For example, poor literacy would render some consent models unsuitable. Investigators and ethics committees should consider whether special protections are needed for such participants.³² 

Trial 1 illustrates that it may be appropriate to make independent risk determinations for individual study arms (rather than the whole trial). Such provisions can be found in both the United States and Australian guidance.^42,43 

In the United States, the Secretary’s Advisory Committee on Human Research Protections has published guidance on the rationales that may be used to justify the second key precondition; trial impracticability⁴⁴ :

Although this wording is not present in the revised Common Rule, it provides useful clarification on the types of rationales that may make a trial impracticable. It also highlights that not all justifications provided for our trials may fully meet the “impracticability” test. For example, the discomfort generated when doctors tell patients that they do not know what treatments are best is unlikely to make a trial impracticable. While this rationale alone may not meet the legal precondition for alteration or waiver, it may well support an ethics committee’s overall assessment of the balance of risks, burdens, and benefits.

One important question for pragmatic trials is whether “cost” can be used as a primary reason to justify a trial’s impracticability. This debate is articulated by Gelinas et al.,⁴⁵  McKinney et al.,¹⁸  and by Kim⁴⁶  who writes:

Considering the size of the three trials we present (especially Trial 3), all may have been prohibitively expensive without alteration or waiver of consent. Gelinas et al. support the inclusion of cost as a justification for impracticability and take the position that research that infringes participant rights may be justified if, the gravity of the rights infringement is minor and outweighed by the expected social value of the research. Kalkman et al. also conclude that publicly funded investigator-led trials with high social value may have a stronger claim of “impracticability” than trials supported by commercial companies as investigator-led trials are less likely to have the resources to overcome these impracticability issues.⁴⁷  The group also propose a means for ethics committees to judge a trial’s social value by defining its determinants: (1) the extent to which the research question has real world relevance; (2) the trial design’s ability to generate a real world answer; and (3) the probability of direct uptake of the results by decision-makers in practice.⁴⁸ 

Although incurring some expense to obtain consent is not by itself considered a justification for impracticability, some privacy laws do permit excessive cost to be used as a primary justification for waiver of consent to process data for observational research; including data relating to genetic material.^49,50  One could argue that in some cases, the risks posed by the disclosure of data may be no less than the risks posed by randomization in minimal risk trials. If ethics committees can take into account excessive cost when waiving consent for observational research but not for clinical trials, the disparity would seem a double standard. As articulated by Zeps et al., in times of major economic rationalization of healthcare services, the use of valuable resources required to obtain individual consent could in itself be seen as unethical.⁵¹ 

Most pragmatic trials are feasible without alteration or waiver of consent, especially if the consent process is simplified and investigators craft concise and readable documents.^52,53  But, in specific situations, it may be necessary to depart from traditional consent, leading to tensions between the rights of individuals and the needs of society that ethics committees must reconcile (fig. 1).

For every trial, investigators and ethics committees must assess the potential risks and benefits of trial participation. But the risks and benefits to individual participants are not the only consideration. The consequences of trial participation for individuals should be balanced against the risks of unstudied health care to both current and future patients. Those seeking altered or waived consent often point to a pragmatic trial’s high social value to justify the use of these models. For pragmatic trials comparing routine therapies, where the incremental risk of physical harm is established as minimal, the risk determination focuses on the potential for psychologic harm arising from infringements of a patient’s right to autonomous choice. If a trial’s high social value is used to justify the use of these models, an ethics committee will need to be reassured that its social value adequately counterbalances its potential harms.⁵⁴  So how should a trial’s social value be quantified? Based on the determinants developed by Kalkman et al.,⁴⁸  we propose that social value can be considered as the ability of the trial to generate real-world evidence that has substantial potential to improve care or reduce healthcare costs, and a high probability of uptake by decision-makers.

However, even when an ethics committee deems an alteration or waiver ethically defensible, policy frameworks should ensure that those decisions are made transparently and accountably.

The potential loss of public trust in the health system from widespread and uncontrolled nondisclosure of trial entry is a valid argument for limiting the use of alteration and waiver of consent. If patients no longer support research due to a loss of trust, this in itself may impact patients’ welfare. As discussed earlier, Kim and Miller also caution that patient welfare is not only impacted by safety considerations such as the risks of the intervention, but also by the removal of a person’s ability to make decisions based on their expectations and perspectives. Thus, the degree to which a patient would be expected to have preferences about the various treatment options is a key welfare consideration. Kim rightly warns that ethics committees should not treat all trials involving standard of care interventions as a “monolithic category of special ethical status” and that patients’ reasonable expectations should be considered.^41,46 

Although the wider use of these models brings with it a greater risk of uncontrolled use of alteration or waiver; lessons can be learned from the use of waiver of consent for the processing of data for observational research. This is well established and sanctioned by law in many countries and proceeds under conditions which are transparent and tightly controlled to avoid scope creep. The open publication of information on all trials granted an alteration or waiver would provide the public with assurance that the rules around the use of these models continue to be strictly observed.

For all countries, particularly those without a current framework for altered or waived trial consent, increased public engagement to improve trial awareness and acceptance will not only enable consumers to join the debate, it will help create a “reasonable expectation” for the use of data for research and the use of randomization to make some quality improvement activities more robust. Notably, different communities will have differing levels of trust and any campaign should carefully consider how to engage communities that are especially distrustful of research or the medical establishment and also how best to build that trust.⁵⁵  As advocated by Kass et al., more information about the views of informed and engaged consumers is needed.⁵⁶  Recent studies are already providing useful insights^56–60  indicating that generally, patients wish to be informed that they are entering a study, but are also accepting of consent models that reduce autonomy—especially when socially valuable research would be impracticable without their use.⁶¹  The development of infrastructure to support increased levels of consumer involvement in research means investigators can now partner with consumers to coproduce their trials. This in itself will enhance our understanding of whether consumers and their communities are prepared to tolerate reduced autonomy.^62,63 

Ethics committees should be provided with tools to effectively manage the need to uphold basic ethical principles without unnecessarily impeding socially valuable research. A clear research-specific framework that describes a range of consent models would be a prerequisite for their wider acceptance. For countries that permit altered and waived consent, we summarize the key considerations from this review (table 5). A set of preconditions for alteration or waiver, derived from ethical guidelines or policy frameworks, guide the ethical and regulatory acceptability of these consent models—although their use in countries outside this review will be subject to the requirements of local policy frameworks.

The number of large-scale pragmatic trials adopting flexible approaches to informed consent is increasing. Most experts agree that healthcare systems that wish to embed pragmatic trials need to adopt consent models that more closely parallel those used in routine clinical practice. Most also agree that in some circumstances, altered or waived consent is ethically defensible, but the extent to which these models should be used is still widely debated. This discordance is reflected in international policy frameworks and key ethical guidance.

Of the three countries studied, the policy frameworks in the United States best support pragmatic trials. These frameworks are harmonized and permit altered and waived consent when certain preconditions are met. Importantly, these frameworks are research-specific and sanctioned by law. Not only does this provide investigators with the unequivocal assurance that altered or waived consent is legal, it also supports efforts to improve public acceptance of these consent models. In contrast, England appears to have the least supportive frameworks. If adopted post-Brexit, the European Union Clinical Trials Regulation³⁸  will regulate all medicinal product trials in England and will require prospective, written informed consent for all but a small subset of cluster trials. Such a strict approach highlights a marked contrast in the “current thinking” of the Food and Drug Administration and the European Medicines Agency. Although differing cultural norms are likely to underlie policy differences, the extent of discordance is surprising, particularly as both regions are founding members of the International Council for Harmonisation whose stated mission is to achieve greater consistency worldwide. Adjustments to the least supportive frameworks appear necessary to align with the prevailing views of the research community and would support international efforts to conduct large, collaborative pragmatic trials that are currently hampered by “regulatory inconsistency.”

Pragmatic trials are also hampered by “regulatory uncertainty,” particularly difficulties interpreting the preconditions for alteration and waiver of consent, which many cite as the reason for the considerable variation in ethics committee opinion. To support ongoing international efforts to provide clarity on this topic, we summarize key points into a rudimentary framework, primarily to assist investigators in navigating the ethical and regulatory minefield that surrounds the use of these models and to facilitate discussions with their ethics committees. In countries that permit the use of altered or waived consent, we call for explicit and risk-proportionate guidance for these socially valuable trials.

Our review of interlinking regulations, particularly privacy laws, is not comprehensive. It is, therefore, possible that factors we did not identify influence the approaches to waiver in our countries and may also explain why certain legislation appears especially conservative. Trial activities such as the collection of tissue, trigger consideration for other laws not discussed herein. Although our analysis was reviewed by legal experts, none of the authors is a lawyer, much less with special training in this relatively arcane regulatory area. Our summary of relevant law is brief and thus necessarily omits detail and nuance. Our framework is rudimentary, but we hope it will contribute to international efforts to improve the environment in which pragmatic comparative effectiveness trials are conducted.

The authors thank Colin J. H. Thomson, A.M., B.A., L.L.B., L.L.M. (Hons), University of Sydney (Sydney, NSW, Australia), and Malcolm Crompton, A.M., F.A.I.C.D., C.I.P.P., of Information Integrity Solutions (Sydney, NSW, Australia) for their insightful comments and suggestions.

The work was entirely funded internally. Professor Myles is supported, in part, by an Australian National Health and Medical Research Council Practitioner Fellowship (Canberra, Australia; GNT1135937).

The authors declare no competing interests.