Towards Meeting the Obligation of Respect for Persons in Pragmatic Clinical Trials

Abstract

Research ethics oversight systems have traditionally emphasized the informed consent process as the primary means by which to demonstrate respect for prospective subjects. Yet how researchers can best fulfill the ethical obligations of respect for persons in pragmatic clinical trials (PCTs)—particularly those that may alter or waive informed consent—remains unknown. We propose eight dimensions of respect in PCTs: (1) engaging patients and communities in research design and execution; (2) promoting transparency and open communication; (3) maximizing agency; (4) minimizing burdens and promoting accessibility; (5) protecting privacy and confidentiality; (6) valuing interpersonal interactions with clinicians and study team members; (7) providing compensation; and (8) maximizing social value. While what respect requires in the context of PCTs will vary based on the nature of the PCT in question, the breadth of these dimensions demonstrates that respect obligations extend beyond informed consent processes.

Introduction

Patients, clinicians, and other stakeholders need high-quality evidence to guide healthcare decisions. Yet numerous barriers impede the ability of healthcare systems to efficiently generate needed evidence that is responsive to real-world needs. To overcome these barriers, many have advocated shifting towards learning health systems, in which clinical trials are embedded into clinical care, trial results are deliberately integrated into clinical care decisions, and clinical care informs the development of subsequent trials.¹ One aspect of advancing the learning health system vision involves pragmatic clinical trials, or PCTs, which are designed to efficiently evaluate the effectiveness of interventions under real-world conditions, to produce results that can be broadly generalized, and to inform both care delivery and policy development.²

To achieve these goals, PCTs are often embedded into routine clinical practice settings, which can both support the efficiency of research by eliminating the need for a separate research infrastructure and help ensure the generalizability of results. While embedding research into clinical care offers several advantages, it also presents ethical and regulatory challenges.³ Research has historically been understood as a distinct activity entailing distinct normative commitments, including the commitment to obtain explicit informed consent from individual participants for specific research projects. The deliberate integration of research into routine clinical practice settings challenges this paradigm, calling into question what is required for the ethical conduct and oversight of PCTs.⁴

One central challenge for the ethical conduct of PCTs is how to fulfill the ethical obligation of respect for persons in their capacity as research subjects, widely understood as a central requirement for the ethical conduct of human subjects research. The Belmont Report states that respect for persons incorporates “at least two ethical convictions: first, that individuals should be treated as autonomous agents, and second, that persons with diminished capacity are entitled to protection.”⁵ Research ethics oversight systems have traditionally emphasized the informed consent process as the primary means by which to demonstrate respect for prospective subjects, involving provision of written information, the opportunity for individual decision-making, and written documentation of that decision. However, obtaining written informed consent often poses a logistical challenge for PCTs, which may render such research impracticable, or introduce selection bias that undermines its generalizability.⁶ Furthermore, there is growing recognition that written consent alone may be neither necessary nor sufficient for meeting the ethical obligations of respect for persons. In fact, empirical scholarship in both clinical care and research identifies a range of considerations beyond informed consent that patients and/or subjects consider essential to fulfilling this requirement. These considerations include: referring to individuals by name as opposed to objectifying them through labels such as their diagnosis or room number, looking individuals in the eye to demonstrate genuine engagement, using relatable language in both spoken and written communications, and ensuring that study materials are inclusive and accessible.⁷ These empirical findings are consistent with normative scholarship on research ethics that has described respect for potential and enrolled subjects as involving both valuing individuals and acting in a way that reflects that value.⁸ Actions that express that value include a range of mechanisms beyond consent for study enrollment, including engaging patients and other stakeholders in the research process, permitting withdrawal from research, protecting privacy through confidentiality, informing subjects of newly discovered risks or benefits, informing subjects of research results, financial compensation, and maintaining subjects’ welfare.⁹

How then can researchers best fulfill the ethical obligation of respect for persons when at least some of the previously recognized mechanisms for demonstrating respect—particularly written informed consent—are not feasible in the context of PCTs? And how might the absence of certain respect-promoting features, such as obtaining prospective informed consent, alter downstream obligations in the context of a particular study? For example, if a PCT conducted under a waiver of consent reveals information that was not generated to address the study’s primary research question, but which may have health-related implications for individuals (termed a “pragmatic clinical trial collateral finding,” or PCT-CF), do researchers have different duties related to those findings than might exist if consent were obtained?¹⁰

In this paper, we build upon prior scholarship on informed consent in PCTs as well as respect in clinical care and clinical research to propose eight dimensions of respect for persons that can be used to guide the ethical design, conduct, and oversight of PCTs (see Table 1). These dimensions are intended to be context-dependent goals that can provide guidance on key considerations beyond the level of generalization presented in The Belmont Report and related codes for the ethical conduct of human subjects research, but should not be understood as absolute obligations that are required for all PCTs. Nevertheless, these dimensions can support a process evaluation, facilitating researchers’ ability to consider—and justify—how they are fulfilling their obligations of respect along these dimensions, within the context of their specific PCT. We present these dimensions in roughly chronological order, charting from the beginning stages of study design through dissemination of results, but we recognize that these dimensions may be interrelated and the obligations not time-limited.

Table 1.

Eight Dimensions of Respect for Persons in PCTs

Dimension	Respect-promoting practice(s)
Engaging Patients and Communities	Actively involve patients and communities throughout the lifecycle of research
Promoting Transparency & Open Communication	Provide information about research activities and the study purpose and communicate about study progress
Maximizing Agency	Recognize and promote the decisional rights of individuals, including but not limited to decisions about research enrollment
Minimizing Burdens & Promoting Accessibility	Minimize perceived subject burdens and facilitate research enrollment by those with differing abilities and situational contexts
Protecting Privacy & Confidentiality	Ensure data shared only “under appropriate conditions, to appropriate parties, and for appropriate reasons”
Valuing Interpersonal Interactions	Show kindness and appreciation in interactions with patient-subjects and take interest in their perspectives
Providing Compensation	Offer payment as reimbursement for costs incurred as result of research participation or as compensation for additional time, effort, or inconvenience
Maximizing Social Value	Deliberately design research to enhance likelihood it can generate future improvements in health or well-being

Dimensions of Respect in PCTs

We propose the following eight dimensions of respect for persons in PCTs: (1) engaging patients and communities in research design and execution; (2) promoting transparency and open communication; (3) maximizing agency; (4) protecting privacy and confidentiality; (5) minimizing burdens and promoting accessibility; (6) valuing interpersonal interactions with clinicians and study team members; (7) providing compensation; and (8) maximizing social value. While these dimensions are also relevant to conventional clinical and sociobehavioral research, the attributes of PCTs can shape their application in practice, which we describe below.

Engaging Patients and Communities in Research Design and Execution

Various calls have been made to increase the engagement of patients, communities, and stakeholders throughout the lifecycle of research. Among the numerous arguments offered in support of engagement is that it respects individuals (and their communities), recognizing them as partners in the co-production of knowledge, rather than merely as objects to be studied.¹¹ Viewing patients or those included in research as partners recognizes that patients and other stakeholders have an interest in excellent care, and that their views on research to advance that goal should shape both the nature and prioritization of research questions, as well as the study designs used to explore them. Several mechanisms exist for engagement, ranging from community consultation (as is currently required for emergency clinical research conducted under an exception from the requirement to obtain informed consent),¹² engagement in decision-making about research priorities or study design, and inclusion in study oversight, such as through patient representation on institutional review boards (IRBs) and data and safety monitoring boards (DSMBs). Patients or potential subjects might also be engaged in decisions about whether or not specific studies should proceed. Examples of robust approaches to engagement include Good Participatory Practice Guidelines, developed by the Joint United Nations Programme on HIV/AIDS (UNAIDS) and AVAC Global Advocacy for HIV Prevention for biomedical HIV prevention trials and subsequently adapted for tuberculosis research, as well as community based participatory research.¹³

The processes and mechanisms for engaging patients or potential subjects in PCTs parallel those for engaging patients in research more generally. For example, in a Veterans Affairs (VA)-funded study of complementary and integrative health therapy interventions for chronic pain, veterans contributed to study design and provided input on intervention components and meaningful study outcomes.¹⁴ In another VA study examining chiropractic care, veterans provided feedback via interviews to inform treatment scheduling protocols.¹⁵ Other proposals for patient engagement in embedded PCTs include intentionally engaging patients in ethical decisions about study implementation, including study-specific decisions about the appropriateness of waivers or alterations of informed consent, and in ensuring research portfolios are responsive to the needs of the patient community, such as through the use of community advisory boards or patient and family councils.¹⁶ Involving patients in decisions about disseminating study updates and results has been also proposed as a means to address longstanding shortcomings in sharing information with subjects and affected communities, grounded in the expectation that patients and affected communities might be able to better tailor messages and communication channels so as to better retain and respect participants and their communities.¹⁷ Engagement therefore can serve a process function, advancing other dimensions of respect (such as transparency, discussed below), while also demonstrating respect independent of any specific secondary benefit it might help secure.

Promoting Transparency and Open Communication

Transparency about research activities and the reasons underlying them respects individuals by making them aware that the research is taking place and of the rationale for research activities.¹⁸ Transparency also respects individuals by recognizing them as persons who should be offered genuine explanations about practices that affect them, rather than solely as instruments or objects. Additionally, transparency about a study respects individuals by supporting their decisional rights (discussed below), for example, by potentially providing an opportunity for a subject to request withdrawal of their data. Researchers can promote transparency through open communication, including the use of such practices as providing information to subjects about study progress and adverse outcomes, and about the uses (and misuses) of data.

Various strategies have been advanced for promoting transparency in PCTs and related contexts. In the Reduce MRSA trial, a PCT that compared three contemporary strategies for preventing healthcare-acquired infections within adult intensive care units (ICUs), the IRB waived the requirements for prospective individual informed consent. However, they required that notices about the study be posted in each ICU room. Through this “broad notification” approach, potential subjects and their families were provided with information about the study, its procedures, and the underlying rationale.¹⁹ Similarly, several transparency-promoting mechanisms have been proposed in the context of learning health systems as means for demonstrating respect beyond traditional informed consent processes, including through the use of diverse media approaches such as newsletters, video monitors throughout clinics, or postings on institutional websites to promote awareness of specific trials that are planned or underway within a health system, as well as broader, non-study specific disclosures of an institution or health system’s commitment to deliberate integration of research into ongoing clinical care so as to improve the quality and efficiency of knowledge generation.²⁰ Efforts to promote transparency may be taken independent of any decision regarding consent approach or ability to opt-out, and may have value regardless of whether subjects have a choice regarding enrollment.

Maximizing Agency

Respect also involves policies and practices that maximize the agency of prospective subjects by recognizing their decisional rights. Traditionally, efforts to respect the decisional rights of prospective subjects have emphasized the informed consent process. Within the informed consent process, relevant components include providing information about putative risks, benefits, and the purpose of the study to enable individuals to assess whether participation is (or is not) consistent with their respective preferences, interests, and values, permitting individuals to choose whether or not to participate, and documenting that choice regarding participation (such as via a signature). However, maximizing agency and supporting decisional rights does not end at the time of study enrollment. Several post-enrollment practices also can support agency, including informing subjects of newly discovered risks, benefits, or alternatives that emerge during the trial that may shape subjects’ interest in continued participation, and permitting study withdrawal.

The scope and means for respecting decisional rights in PCTs will vary based on study-specific characteristics. For example, some PCTs may alter traditional informed consent processes to provide information about study-specific participation via oral or multimedia approaches as opposed to via written forms. Others may shift the default for the choice regarding participation from opt-in to opt-out, or document an individual’s choice regarding participation using electronic means, rather than a handwritten signature.²¹ While the basic desire to maximize agency is no different conceptually in PCTs than in other research contexts, the study design of PCTs may present greater constraints on practicality. Furthermore, the nature of the compared treatments in PCTs may render the differences in risk and benefit associated with research participation less meaningful than for explanatory trials.

Minimizing Burdens and Promoting Accessibility

According to The Belmont Report, respecting autonomy requires giving weight to an autonomous persons’ considered opinions, such as through informed consent processes that recognize an individual’s decisional rights regarding research participation. Among the ways to show a lack of respect for autonomy includes, according to Belmont, “to deny an individual the freedom to act on [their] considered judgments.”²² Minimizing burdens is also supported by non-autonomy-based considerations, including a recognition of the psychological, physical, and economic hardships that may be associated with research participation—impacts that deserve attention regardless of their ultimate influence on one’s ability to act on their considered judgments.

Various aspects of study design can influence the ability or interest of an individual to participate in research by influencing their assessments of how accessible—or conversely, how burdensome—a study is.²³ Respect for persons can therefore be understood as also requiring efforts to minimize the perceived and actual subject burden associated with study enrollment, and recognizing and responding to individuals’ unique needs, enabling participation by those with differing abilities and situations.

In some cases, embedding PCTs into ongoing care supports the goals of minimizing burdens and promoting accessibility, thereby enabling wider participation with few if any additional procedures that would be commonplace in a comparable explanatory clinical trial. Other PCTs, however, may add burdens for individuals as compared to usual care that may not be offset by the prospect of direct clinical benefits, such as through the collection of patient-reported outcomes (PROs) or similar surveys, or through assignment to trial arms that may take more time to complete.

Notably, the embedded nature of PCTs means that access to clinical care will shape the accessibility of research—and likely also the patient-subject’s experiences of feeling respected, both within and beyond the course of a research study. While researchers cannot be expected to remediate broader patterns of inequity in access to health research or health care through design of a single study, they nevertheless have an obligation to be aware of the impact of these barriers on subjects and their experiences of feeling respected, and to design study procedures to minimize them.

Protecting Privacy and Confidentiality

Researchers also respect persons by protecting the privacy and confidentiality of their health-related information. Because health data can be personal and intimate, privacy about that information is an important component of respect.²⁴ Respecting persons therefore demands that sharing of those data occur “under appropriate conditions, to appropriate parties, and for appropriate reasons.”²⁵ Furthermore, protecting privacy reduces the risk that health information will be misused, such as by interfering with an individual’s insurance access or employment.²⁶

Many of the mechanisms to protect privacy and confidentiality of health data in PCTs resemble those within health research more generally. For example, researchers should collect and share the minimum amount of data necessary for the research in question. They should also secure identifiable health information, remove identifiers, and establish systems of accountability for data breaches or other harms. However, PCTs can make some of these mechanisms less feasible. For example, when research is embedded into clinical care and when research data are abstracted from electronic health records, it may not be practical to insist upon de-identification. Accountability mechanisms for promoting privacy and confidentiality may also pose challenges, since they often include disclosing to individuals how their data may have been compromised and the steps that are being taken to remedy the problem. If individuals did not know that they were in a research study, notifying them about a data breach and its remedies may reveal the underlying research activity—a disclosure that might reasonably be expected to evoke distrust among at least some research subjects. This challenge underscores the value of transparency regarding research activities (described earlier), even—or perhaps, especially—when prospective informed consent is not obtained for particular research activities.

Valuing Patient-Subjects’ Interpersonal Interactions with Clinicians and Study Team Members

In non-PCT research settings, empirical research indicates that research subjects consider interpersonal interactions with study team members to be an important component of respect.²⁷ Examples of respectful interactions include study staff members showing kindness towards research subjects, taking interest in their perspectives, and showing appreciation for their contributions to the research. Empirical data in the setting of clinical care has found patients similarly emphasize the importance of interpersonal interactions for respect, including listening carefully, asking questions to convey interest, recognizing the value of patients’ time, and using explanations that facilitate understanding.²⁸ There is little reason to think that patient-subjects included in PCTs have different expectations. In fact, this sort of respect may be even more important in PCTs, because subjects are not always asked for their express, prospective permission to be included. However, as PCTs are embedded in ongoing clinical care settings, the relevant interpersonal interactions may include not only those with members of the research team, but also—if not predominantly—with those involved in the delivery of clinical care.

Providing Compensation

Investigators may offer payment to research subjects for a number of reasons, including reimbursement for out-of-pocket costs incurred as a direct result of participation (e.g., parking or transportation for study appointments), compensation for time, effort, or inconvenience experienced as a result of the research, and compensation for resultant harm.²⁹ Offers of payment may respect research subjects by ensuring that individuals need not pay to contribute to the social good of research, and by treating them in accordance to what would be expected outside the research context.³⁰ Because most interventions in PCTs are low risk and/or commonly used in clinical care, issues about discrete research-related harms may not be commonly encountered. Nevertheless, ensuring that patients are not adversely affected as a result of research enrollment is important.

There are many ways that offers of payment could be integrated into PCTs. Largent, Joffe, and Miller have suggested that, in embedded health research, different copay structures might be implemented based on patient willingness to enroll in trials that involve no more than minor net risk over that of usual clinical care, with patients who refuse to enroll facing higher copays than those that agree to participate.³¹

While PCTs do not add new rationales for research payments as compared to those in the explanatory trials, several features of PCTs may alter their feasibility or appropriateness. For example, PCTs can also be very large, so that each patient’s contribution is small, but the administrative cost of paying them all is high, thereby jeopardizing the financial feasibility of the study. Finally, the study design of some PCTs may include subjects who are unaware of their participation in the research—a requirement that would limit the potential scope for certain payment approaches as respect-promoting practices in PCTs.³²

Maximizing Social Value

Ethical clinical research must have social value; it must be likely to generate improvements in health or well-being. Requiring research to have social value respects persons by ensuring that they are not subjected to potential harms without the possibility for social or scientific benefit.³³ Research activities should be well-designed and must be able answer the questions they seek to answer—functions that can be supported through appropriate review processes.

The underlying rationale for PCTs—to generate real-world data that is directly applicable to decision-making by different stakeholders—suggests that PCTs will generally have social value. Furthermore, the design of PCTs generally means that the research-related risks and harms will be low. There are even arguments that PCTs may be more likely to yield direct value than explanatory trials, given they are intended to be more immediately applicable to practice.³⁴ Shona Kalkman and colleagues have proposed three determinants of social value for PCTs: (1) the real-world relevance of the research question; (2) the design’s ability to provide a real-world answer; and (3) the probability of direct uptake of the results.³⁵ Kalkman and colleagues’ analysis suggests several mechanisms by which researchers can maximize the social value of a given PCT, including using patient-centered outcomes and clinically relevant endpoints, maximizing generalizability, validity, and precision, and committing to proactive and sustained engagement with target end-users of research results to facilitate uptake of study findings.³⁶ These arguments are consistent with those of Nancy Kass and Ruth Faden, who have proposed that respect within learning health system-type research requires health systems to make it a “proactive priority” to translate knowledge gained from that research, including through the development and implementation of established procedures and systems to ensure that care actually improves.³⁷

An additional set of mechanisms for maximizing benefit include those related to sharing data to facilitate reuse, which, it has been argued, can better honor trial subjects by increasing the opportunities to generate knowledge from their contributions.³⁸ Data sharing might also respect future subjects, by shielding them from unnecessary risk by avoiding redundant trials. However, maximizing social value through data sharing may be in tension with other dimensions of respect, including protecting privacy and confidentiality and enabling individual control over future data uses.

Practical Applications for Ethical Oversight and Conduct of PCTs

Mapping these eight dimensions of respect in PCTs suggests several practical applications. First, informed consent processes are neither necessary nor sufficient for advancing respect for persons. While informed consent has been the dominant mechanism used to help ensure respect for persons in clinical research, appropriate regard for subjects extends well beyond promoting decisional rights at the time of study enrollment. Respectful practices in research are varied and continue throughout the study, and even after its conclusion.

Second, respect for persons looks different depending on the context.³⁹ What respect requires in the context of PCTs will vary based on the nature of the PCT in question. In some circumstances, alterations of consent may be more ethically appropriate than traditional regulatory consent practices.⁴⁰ For example, a PCT conducted in the context of an emergent health event (e.g., myocardial infarction) may not be able to utilize a traditional consent process. Furthermore, the use of traditional, lengthy research consent processes might be inapt for PCTs comparing two or more treatments in wide use, such as antihypertensive medications for elevated blood pressure, given these studies generally pose only minimal additional risks or burdens beyond what patients would experience in clinical care.⁴¹ Potential subjects may view such consent conversations as interfering with the delivery of their clinical care, especially during time-pressured primary care visits. Consequently, satisfying the requirement of respect for persons in some PCTs may be better achieved with a simplified consent or opportunity for “informed refusal,” rather than traditional regulatory consent mechanisms.⁴² However, traditional consent approaches may still be important for other PCTs, such as those in which there is greater uncertainty about the risks and benefits of the compared treatments, those in which there are substantial qualitative differences between treatment arms, and those that involve interventions posing more than minor net risks to subjects, such as a randomized PCT comparing tonsillectomy with conventional medical treatment for children with recurrent sore throats.⁴³

Third, informed consent processes respect prospective subjects in several ways—inclusive of but not limited to respecting autonomy. As argued elsewhere, consent practices do more than merely authorize, and other practices may serve the concomitant functions better.⁴⁴ For example, traditional informed consent provides transparency to current or prospective subjects about study activities, but transparency can be achieved through numerous mechanisms, with varying degrees of likely reach and impact.⁴⁵ Similarly, consent processes can express the value that a system places on individuals and their contributions, communicating that they are being treated as ends in themselves, and not solely as means. However, while asking individual permission to participate in research is one mechanism to communicate this regard for individuals, it is not the only means by which to do so; some respect-related goals can be advanced through a wide variety of mechanisms, and researchers should consider implementing a wider range of these mechanisms to satisfy the ethical principle of respect for persons.

Fourth, and relatedly, other practices beyond consent will often advance multiple dimensions of respect. Engaging patients and communities in research design and execution, for example, offers the opportunity to also improve transparency, informing researchers about strategies to improve dissemination. Such engagement may also help to identify ways to minimize burdens and promote accessibility through advancing understanding of contextual features of patients, families, and communities that may shape their study-specific experience with research participation.

Fifth, waivers or alterations of informed consent—while in some cases permissible—may “up the ante” for researchers to address other dimensions of respect. For example, Nancy Kass and Ruth Faden have argued that if consent is streamlined or waived for learning health system-style research, additional respect-promoting actions are ethically required. These ethically required actions include robust engagement with patients, both about how patient-subjects should be informed about research activities, and in decisions about when alterations or waivers of consent are appropriate; as well as robust transparency practices to make patients aware of ongoing research within the health system. They also argue for the importance of accountability, understood as a commitment to proactively prioritize not only that the research has social value, but that any resulting evidence generated from that research is deliberately and systematically translated into changes to improve future care delivery processes.⁴⁶

Considering these applications in a case illustrates several ways in which study procedures can demonstrate respect, even with a waiver of consent. For example, an institution-level cluster-randomized PCT comparing two different approaches to hydration to prevent kidney failure in children met the regulatory criteria for a waiver of informed consent. Several approaches could nevertheless be incorporated into the study design to reflect dimensions of respect, including promoting transparency, engaging parents of potential subjects, and maximizing agency. Potential approaches include: having clinicians present an information sheet about the study, including to which arm their institution is being randomized and that clinicians do not know which approach is better (promoting transparency); engaging parents in shared decision-making with their clinicians about which of the two interventions to receive, with the option to elect the alternative approach from that which was assigned (engaging parents and maximizing agency); and soliciting permission for data collection and specimens once treatment has been initiated (maximizing agency).

Open Questions

We have argued that PCTs should include a broad range of respect-promoting practices. However, the scope and application of these practices, and how they should be applied to the design of specific PCTs, are questions that should be informed by future scholarship. Prior empirical data from both research and clinical care contexts, discussed above, suggests several components of what it means to respect persons. As others have previously observed, these components imply that respect requires much more than maximizing agency through informed consent.⁴⁷ Yet we do not yet know whether and how the embedded nature of PCTs shapes patient-subjects’ expectations for respectful treatment, nor do we know how deviations from standard research practices in various contexts—such as alterations of informed consent—will affect their perception of what constitutes respectful conduct. Such data could play a vital role in supporting the ethical design of PCTs, informing which features are most important to individuals, how varying contexts shape those perceptions, and how people weigh the relevant trade-offs for the efficiency and feasibility of research.

Conclusion

While the rise of PCTs has fostered robust debate regarding the necessity of informed consent and the appropriateness of waivers or alterations to consent, consent is neither necessary nor sufficient for fulfilling the ethical obligation of respect for persons in all PCTs. We have proposed eight dimensions of respect in PCTs to support the ethical design, conduct, and oversight of pragmatic research. The breadth of these dimensions demonstrates that respect obligations extend well beyond policies and practices to promote decisional rights at the time of study enrollment and extend throughout the lifecycle of research. However, the particular design and implementation of study-specific practices to fulfill the ethical obligation of respect will vary based upon the trial context. While prior scholarship in clinical research and clinical care contexts can inform some of these decisions, further work is necessary to understand how best to respect patient-subjects in PCTs.