Informed Consent in IBD Trials: Where We Are and Where We Need to Go

Address correspondence to: Michael Kurin, MD, University Hospitals Cleveland Medical Center, Wearn Building, Room 247, 11100 Euclid Ave, Cleveland, OH 44106 (michael.kurin@uhhospitals.org).

Division of Gastroenterology and Liver Diseases, University Hospitals Cleveland Medical Center and Case Western Reserve University School of Medicine, Cleveland, Ohio

Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, Ohio

Inflammatory Bowel Diseases, Volume 25, Issue 7, July 2019, Pages 1115–1119, https://doi.org/10.1093/ibd/izz067

Cite

Michael Kurin, Jeffry Katz, Eric Kodish, Bret Lashner, Informed Consent in IBD Trials: Where We Are and Where We Need to Go, Inflammatory Bowel Diseases, Volume 25, Issue 7, July 2019, Pages 1115–1119, https://doi.org/10.1093/ibd/izz067

Abstract

Patient enrollment is increasingly recognized as a major limiting factor to inflammatory bowel disease (IBD) clinical trial completion. Many IBD trials will fail to enroll enough patients to adequately power their study. This has led to a renewed multifaceted effort to encourage more patients to enroll in clinical trials. Although this is of clear importance, it is also important to ensure that all efforts to enroll patients in clinical trials do not compromise the quality and validity of the patient’s/study participant’s informed consent. Informed consent has 4 components: disclosure, voluntariness, understanding, and capacity. The application of informed consent to IBD clinical trials for biologic agents has not been previously studied. Yet the nature of clinical trials for biologics in IBD creates certain challenges to properly fulfilling the requirements of informed consent in the recruitment process that should be examined. In the following commentary, the components of informed consent are reviewed, challenges to their fulfillment in IBD trials are reviewed, and practical advice is offered.

INTRODUCTION

A recent review of randomized clinical trials (RCTs) for biologic agents showed that more than two-thirds of all inflammatory bowel disease (IBD) patients would have been deemed ineligible to participate in any of the trials based on their disease characteristics, leading some to question regarding the generalizability of IBD trial results. 1 Experts have also suggested that many patients who enroll in clinical trials do so after biologic therapy has failed to help them and that these individuals may not represent patients with a milder phenotype. 2 A survey of 200 IBD patients, of whom two-thirds were on biologic therapy, revealed that one-third would not be willing to consider participation in a clinical trial. 2 These concerns about inadequately powered and unrepresentative samples in IBD clinical research have led to a renewed interest in broadening trial enrollment. 2 For example, to increase patient awareness of clinical trials, an IBD Clinical Trials Community has been created by the Crohn’s and Colitis Foundation, in addition to other educational tools and a clinical trial ambassador program. 3 Surveys, focus groups, and expert panels have recently identified many barriers to patient enrollment and offered suggestions to overcome them, noting additional factors that motivate patients to enroll. 2, 4–6 Although we support this effort to increase IBD trial enrollment, in this commentary, we point to the need to ensure that all recruitment targets and tactics conform with important ethical principles, specifically those connected to informed consent.

There is an important distinction between clinical ethics and research ethics. In clinical medicine, there is a presumption that a physician will act in his/her patient’s best interest. In clinical trials, by contrast, the goal of the trial is to answer a scientific question for societal benefit. In some cases, this goal necessarily conflicts with the physician’s responsibility to offer the best possible care to each individual patient. 7 Many believe the function of informed consent is to resolve this conflict, as the investigator manifests respect for the patient/study participant by ensuring avoidance of harm, deceit, or inadequate disclosure of information to persuade them to take a particular course of action. 8, 9 As informed consent is necessary for the ethical validity of the clinical trial, it is important to ensure that the consent process is an ethically valid one.

Informed consent is a relative newcomer in the medical ethics literature. 10, 11 After the rise of patient autonomy, the laws and standards of informed consent were codified over the latter half of the 20th century. Informed consent has 4 requirements: disclosure, voluntariness, sufficient patient/study participant understanding, and decisional capacity. 12, 13 Lacking any of these 4 components disqualifies the informed consent. Each clinical trial has its unique set of circumstances and interventions, and thus a blanket approach to the validity of informed consent for all clinical trials is difficult. This issue has not yet been studied with respect to clinical trials of biologic therapy in IBD. We will examine and dissect each of the 4 components of informed consent, discuss potential threats to the fulfillment of each of them, and offer practical advice to allow for continued efforts to increase enrollment in an ethically acceptable way.

DISCLOSURE

Although the other 3 requirements focus on the patient’s/study participant’s decision-making, disclosure focuses on the physician’s obligation to the patient/study participant. Most patients want to hear information about clinical trials that are available from their physicians or even research teams, but only 25% of patients actually receive this information. 14 Clinicians may not be providing this information due to lack of awareness, lack of time, and/or lack of knowledge and skillset to discuss protocols and safety mechanisms of trials. 6 Educating providers can remedy this and allow for discussion of risks, benefits, and alternatives. However, this alone may be insufficient for the physician to discharge his/her obligation to the patient/study participant.

Special care must be taken to avoid a particular form of inadvertent deception or misrepresentation that is commonly present in clinical trial enrollment known as therapeutic misconception (TM), wherein the patient/study participant believes that the purpose of their participation in the trial is for their own treatment benefit, when in reality the purpose of the trial is to answer a scientific question for the benefit of society, on occasion even at the expense of the patient/study participant. 15 Ill patients not responding to available therapy are at highest risk of therapeutic misconception. 16 There is some evidence that this may be an issue in IBD trials. In an IBD patient/study participant focus group, it was discovered that patients’/study participants’ main motivation for participation in a trial was the possibility of improving their own health. 6 Physicians may not be correcting the misconception, and may be reinforcing it. Some experts have suggested that physicians should reinforce to patients/study participants that they will get better care in a clinical trial than otherwise because of enhanced monitoring, 2 an example of the purported inclusion benefits of study participation. 17 We disagree with this approach; in reality, the purpose of enhanced monitoring is to obtain objective data points. It does not necessarily offer clinical benefit to the patient/study participant.

Failing to correct TM may undermine the informed consent altogether if the impetus for informed consent is the principle of respect for persons, 12 because allowing the misconception about the trial’s motives may not show sufficient respect to the patient/study participant being recruited. A mainstream view advocated recently by some authors gives a dual purpose of informed consent: to determine whether participation in the trial is fitting with their interests and to give the patient/study participant the right to be protected from exploitation and harm. 18 Allowing the therapeutic misconception to persist is at least not fitting with the spirit of protecting the patient/study participant from exploitation, even if the other functions of informed consent are fulfilled.

Practical Advice

We recommend ensuring that TM is searched for and corrected in all recruited patients/study participants. Previous authors in other contexts have urged investigators to inform patients/study participants that the primary purpose of the research is not to provide the best care for them, but to answer a question for the general population while making every effort to minimize any risks to the patient/study participant. 19 Similarly, the researcher or physician should explain to the patient/study participant any differences between the standard of care and what the patient/study participant will receive in the trial. 19 We agree with previously made suggestions that recruiters should be careful to use appropriate terms for a clinical trial, including researcher or investigator rather than doctor, and trial or experiment rather than treatment. 16 Although making every effort to disabuse clinical trial candidates of TM, it is in our view ethically acceptable to emphasize to patients/study participants that they themselves may benefit in the future from having additional biologic agents available. 2

VOLUNTARINESS

The decision to participate in a clinical trial must be the patient’s/study participant’s own without coercion or undue influence. Advice from the primary gastroenterologist continues to hold sway, as perhaps the strongest encourager of participation in clinical trials is a recommendation from a trusted physician. 6 A high percentage of physicians enrolling children in phase I trials use persuasive language when attempting to enroll a patient/study participant without realizing that they are doing so. 20 Furthermore, many patients feel that they will be disappointing their physician if they do not enroll in the trial and that this may hinder their relationship with their physician in the long term. 21

Beyond this, the main challenge to voluntariness comes with the compensation package associated with participation in a clinical trial. The possibility that financial compensation to enroll may constitute undue influence on the patient’s/study participant’s decision to enroll has been raised in the context of so-called “guinea pigs,” who repetitively enroll in research studies for financial gain. 22 In that context, the concern of exploitation and coercion stems from the assumption that there is more supply than demand of such subjects and that they are desperate for finances. Given this poor bargaining position, they are likely to be forced to agree to unfavorable terms of a trial if the researcher makes use of the leverage he or she has.

For IBD trials, however, the context is drastically different. There are currently >1500 available clinical trials in IBD, but most will fail to enroll enough participants to be completed. 6 Each day a drug’s approval is delayed costs the company up to $8 million. 6 Furthermore, the majority of trial participants are not of the lowest economic demographic. If one recent randomized controlled trial (RCT) on telemedicine in inflammatory bowel disease (IBD) serves as an example, 92% of the study population was Caucasian, two-thirds had commercial insurance, and only 7% were either uninsured or on medical assistance. 23 Without leverage at the disposal of the investigator, the concerns for exploitation and coercion are less likely to apply to IBD trials. Therefore, some amount of financial compensation to participate in trials can remain ethical, especially as others have questioned the assumption that incentives to participate in clinical trials are ever unethical. 24

However, even without exploitation or coercion, a lucrative compensation package can still exert undue influence and undermine voluntariness when it causes the patient/study participant to neglect important decisions about their health. Moreover, the simple act of paying a patient/study participant to participate in a study treats them as a means to an end rather than an end in themselves. As described above, one of the purposes of informed consent is to ensure that patients/study participants are treated as an end in themselves, and financial compensation may threaten the ability of informed consent to fulfill this function.

Practical Advice

Every effort must be made by the physician to reassure the patient/study participant that they will not harm the doctor–patient relationship by declining to participate in a trial. Although a large financial incentive to encourage trial participation is unethical, certain forms of compensation already in practice remain ethically acceptable. For example, a benefits package that covers the cost of the biologic agent and all endoscopic procedures associated with the trial, provides family care for times when participants are at a required office visit or colonoscopy, and even provides compensation for lost salary for time away from work would not detract from voluntariness. These are more accurately understood as means to mitigate the disincentives of trial participation rather than offering an extra reward. Removing barriers is ethically distinct from seductive incentives. A small financial reward to offset the inertia of automatically declining trial participation but not large enough to cause undue influence should remain ethically acceptable. The exact dollar value of such a stipend would need to be clarified with additional research.

UNDERSTANDING

The researcher must ensure adequate patient/study participant understanding of the clinical trial. Despite being the simplest criterion conceptually, it is the most difficult to fulfill in practice. Unfortunately, current practice does a poor job of ensuring patient/study participant understanding. Data suggest that patients/study participants have a poor understanding of the informed consent document even after they have signed it. 18, 25 Previous authors have suggested that the informed consent document is outdated, 18 overly lengthy, and difficult to understand. 21 It has been posited that the reason the informed consent document has persisted despite these flaws is that the informed consent process has become more about protecting the physician and/or sponsor from future litigation than about a true attempt to give the patient/study participant the information he/she needs to make an autonomous decision. 26

Practical Advice

Fortunately, the informed consent process is becoming modernized, and there is an opportunity for IBD trials to adopt more effective approaches to obtaining consent that allow for greater patient/study participant understanding. Informed consent is increasingly moving to electronic platforms, and some data show that electronic consents are more effective and are preferred by patients/study participants. 18 This can involve the use of multimedia videos, built-in quizzes to assess patient/study participant understanding, opportunities for patients/study participants to connect to the clinical investigators by phone or via online chat for any questions, and videos that explain the trial protocol. Such an approach has already been implemented successfully in clinical trials for coronary disease. 27 This approach to obtaining informed consent can allow for recruitment of patients/study participants from locations too distant to recruit in person, can standardize the process of informed consent to eliminate variability among different practitioners, and can also eliminate any concern for inadvertent persuasive speech by the physician.

Another evolution in informed consent shifts the focus of the process away from a lengthy list of all risks, benefits, and alternatives, toward broadly outlining the reasoning behind a recommendation to participate in the trial in broad terms, then allowing the patient/study participant to direct further discussion toward his/her particular questions or concerns. 26

An alternative new approach to consent with promising results has been termed continuous consent, a process in which consent is obtained in multiple stages throughout the recruitment process, and even during the trial. 16 Giving information in small doses as it becomes relevant is likely to achieve better patient/study participant understanding than the current approach. Thus, there are a number of attractive ways to improve patient/study participant understanding of the research process.

CAPACITY

The most complex component of informed consent from an ethical perspective is capacity. Decisional capacity itself has 4 components: understanding, expression of a choice, appreciation of how risk and benefit data apply to oneself, and ability to provide reasoning that is logically consistent with that choice. 28 Adding to the complexity is that decisional capacity is not a binary concept and must be assessed on a sliding scale depending on the seriousness of the decision at hand. 12 The absence of any of these 4 components has the potential to invalidate informed consent for that particular decision.

One challenge to decisional capacity in the cognitively intact IBD patient/study participant is termed information overload, an effect of the need to analyze a large and complex amount of information to make a decision that leads to emotional overwhelm. 12 This could threaten the patient’s/study participant’s ability to understand and synthesize data and to reason logically. Being in the throes of an acute illness or poorly controlled chronic disease compounds this effect. 12 That said, in theory it should be possible for a talented educator to present even the most complex medical information to a patient/study participant in a way that can be understood on a basic level of relevance to them, even if some of the finer details are omitted from the presentation.

Cognitively intact acutely ill patients/study participants may enter a state of temporary cognitive dysfunction that lessens their ability to understand, appreciate, and logically reason. Eric Cassel remarked, “Illness robs patients of their autonomy and it’s given back to them when they are healed.” 29 A study of consent for trial enrollment of acutely ill infants showed that a high number of parents surveyed did not remember being informed about side effects or believed that they were told there were no side effects of the treatment, despite the fact that these were indeed discussed. 13 A patient/study participant in the throes of an IBD flare or frustrated by the failure of several approved biologic agents may experience a similar phenomenon. In a small focus group study, one patient/study participant explicitly noted that he enrolled in a trial because, being in a severe IBD flare, he was more willing to try a new drug that might work. 6

The capacity to consent can also be negatively influenced by impaired application of even properly analyzed data to oneself. In what has been termed unrealistic optimism, some patients/study participants believe they have a higher chance of getting benefit or a lower chance of incurring the risk of a certain therapy than other patients/study participants with the same characteristics. 7 Here the patient/study participant has sufficient understanding, can express a choice, and can reason logically but has difficulty appreciating how the synthesized data apply to him/herself.

Unrealistic optimism and emotional overwhelm from illness or information represent subtle impairment of decisional capacity, placing the patient/study participant at risk of making an impulsive decision. Catastrophic thinking of the emotionally overwhelmed patient/study participant can block the ability to properly deliberate. 16 In a sense, a person in such a mental state is akin to one who decides under coercion that the coercion comes from within rather than from an external source. If we posit that the true wishes of the patient/study participant are the decisions he or she would make with their full mental capabilities, this “coercion” may invalidate the decisional capacity and perhaps even voluntariness.

Therefore, a clinician could be justified in barring the overwhelmed patient/study participant from enrolling in a trial, as his or her informed consent is provided only under the influence of these internal forces that overwhelm the ability to reason. On the other hand, most decisions are made within a context, one that is often influenced by life’s stresses. Should this type of influence make our decisions illegitimate, we would be paralyzed from living most of our lives. This is not merely an argument of pragmatism. As decisions in a vacuum free of any contextual influences are a near impossibility, it must be the case that decisions under some degree of situational influence are legitimate. Perhaps as long as one is able to offer logically consistent reasoning behind a decision, it meets criteria for informed consent and decisional capacity, even if others believe the patient’s/study participant’s decision would be different under less stressful circumstances.

Practical Advice

To prevent emotional overwhelm from information overload, investigators in IBD trials should focus on ways to present the relevant information to the patient/study participant in the most understandable fashion possible, perhaps using some of the tools discussed in the previous sections including the continuous consent model. From an ethical perspective, acutely ill patients/study participants with emotional overwhelm and those with unrealistic optimism are best left out of clinical trials. 7, 30 Instead, investigators should focus on altering the terms of clinical trials to be more favorable to patients/study participants who are otherwise less likely to enroll by eliminating relevant barriers. This could include changes to the protocol that would ensure continuity of care through the study. Moreover, trial design could be made more favorable to the patient/study participant through use of asymmetric allocation to minimize the odds of being randomized to the placebo arm, providing an open-label extension, or allowing patients/study participants access to drugs after the trial is complete, or even changing the study type to a cluster randomization trial or noninferiority trial. 2 Trial designers could increase convenience by providing after-hours office visit times, providing family care for participants when needed, or providing work excuse forms. Trial safety could be improved through providing access to a rescue medication if a participant develops a flare during a trial. 6

CONCLUSIONS

Although we continue to work on ways to increase enrollment in IBD clinical trials, we must be careful to ensure that our recruitment process allows for proper informed consent in a patient/study participant population in whom trial enrollment is appropriate. There are challenges to achieving proper informed consent from all 4 of its components in IBD trials, yet in most circumstances proper informed consent remains possible. Rather than increasing enrollment by recruitment practices that are ethically questionable, investigators and sponsors could focus on improving the study protocol and benefits to participants in the ways outlined above. Those designing clinical trials should focus on revamping and modernizing the informed consent process to meet the aspirational goals of high-quality informed consent. Physicians and investigators should be careful about how they discuss trial enrollment with their patients, using appropriate language to avoid therapeutic misconception. Finally, studies to measure the quality of informed consent will help to foster continuous improvement in this important area for gastroenterologists, clinical investigators, and our patients/study participants.