Who to engage in HIV vaccine trial benefit-sharing negotiations? An empirical proposition of a framework.

BACKGROUND: A morally sound framework for benefit-sharing is crucial to minimize research exploitation for research conducted in developing countries. However, in practice, it remains uncertain which stakeholders should be involved in the decision-making process regarding benefit-sharing and what the implications might be. Therefore the study aimed to empirically propose a framework for benefit-sharing negotiations in research by taking HIV vaccine trials as a case. METHODS: The study was conducted in Tanzania using a case study design and qualitative approaches. Data were collected using in-depth interviews (IDI) and focus group discussions (FGD). A total of 37 study participants were selected purposively comprising institutional review board (IRB) members, researchers, community advisory board (CAB) members, a policymaker, and HIV/AIDS advocates. Deductive and inductive thematic analysis approaches were deployed to analyze collected data with the aid of MAXQDA version 20.4.0 software. RESULTS: The findings indicate a triangular relationship between the research community, researched community and intermediaries. However, the relationship ought to take into consideration the timing of negotiations, the level of understanding between parties and the phase of the clinical trial. The proposed framework operationalize partnership interactions in community-based participatory research. CONCLUSION: In the context of this study, the suggested framework incorporates the research community, the community being researched, and intermediary parties. The framework would guarantee well-informed and inclusive decision-making regarding benefit-sharing in HIV vaccine trials and other health-related research conducted in resource-limited settings.

Patient Consent for Medical Student Pelvic Exams under Anesthesia: An Exploratory Retrospective Chart Review.

AbstractObjective: We performed this study to examine patients' choices to permit or refuse medical student pelvic examinations under anesthesia (EUAs) during planned gynecologic procedures. DESIGN: We conducted an exploratory retrospective chart review of electronic consent forms at a single academic medical center using contingency tables, logistic regression, and nonparametric tests to explore relationships between patient and physician characteristics and consent. RESULTS: We identified and downloaded electronic consent forms for a census of 4,000 patients undergoing gynecologic surgery from September 2020 through calendar year 2022. Forms were linked to anonymized medical record information. Of the 4,000 patients, 142 (3.6%) were removed from analysis because consent forms were incomplete. Of 3,858 patients, 308 (8.0%) were asked for EUA consent more than once, 46 of whom were not consistent. Overall, 3,308 (85.7%) patients consented every time asked, and 550 (14.2%) refused or limited EUA consent at least once. Nine patients limited their consent to female students, and two patients refused medical student participation at all. We performed exploratory multiple logistic regression analyses exploring differences in rates of consent across patient and physician demographic groups. CONCLUSIONS: We find that some patients are more likely than others to refuse a pelvic EUA, magnifying the dignitary harm from a nonconsensual invasion of intimate bodily integrity and perpetuating historic wrongs visited upon vulnerable people of color and religious minorities. Patients' rights to respect and control over their bodies require that physicians take seriously the ethical obligation to inform their patients and ask them for permission.

What Is "Key Information"? Consideration of the Reasons People Do or Do Not Take Part in Research.

We performed a qualitative review of 50 consent forms posted on Clinicaltrials.gov, examining the content of key information sections. We found that key information disclosures are typically focused on procedures, risks, potential benefits, and alternatives. Drawing upon reviews of the large literature examining the reasons people do or do not take part in research, we propose that these disclosures should be based more directly on what we know to be the real reasons why people choose to take part or refuse participation. We propose key information language for consideration by researchers and institutional review boards.

Should HIV Vaccines Be Made Available at No or Subsidized Cost? A Qualitative Inquiry of HIV Vaccine Trial Stakeholders in Tanzania.

BACKGROUND: The world has come closer than ever to discovering a viable HIV vaccine. However, it remains less certain whether HIV vaccines should be made available to participants and communities in which trials are run no or subsidized cost. Hence the essence of this inquiry. METHODOLOGY: This is a case study design using in-depth interviews (IDI) and focus group discussions (FGD) with researchers of HIV vaccine trials, institutional review board (IRB) members, HIV advocates, a policy maker, and members of community advisory board (CAB) in Tanzania. Participants were purposively selected and data thematically analyzed using MAXQDA software. RESULTS: Hosting a vaccine trial and the financial incapacity of individuals at increased risk of HIV were among the reasons in favor of free access to HIV vaccines. In contrast, the view that vaccines should be provided at a subsidized cost was related to high costs of vaccine development, financial return expectations by investors, and the fear of labeling the free vaccine as less important. Moreover, apart from governments and international organizations, well-off individuals could share the cost burden. CONCLUSION: Stakeholders engaging in active discussion about sharing the viable vaccine ought to take the aforementioned concerns into account and ensure unhindered access to individuals and host communities in Tanzania and beyond.

A response to Al et al. Trials 2023;24:233.

In their recent paper, Al and colleagues (Trials 2023;24:233) argue that manipulation of the methods of recruitment using well-known techniques in order to increase enrollment can be ethically acceptable. This brief response challenges that notion as an affront to voluntariness and a devolution of the ethics of human subjects research to the "ethics" of the marketplace.

A census of clinical trials conducted under the U.S. exception from informed consent rule.

BACKGROUND: The exception from informed consent (EFIC) rule was adopted in 1996, permitting waiver of informed consent for certain emergency research, including trials funded by the U.S. government. The rule requires prospective consent from patients or their legally authorized representative(s) (LAR) if practicable. For those enrolled without consent, the patient or their LAR must be given an opportunity to opt out from continued participation at the earliest opportunity. We sought to census the trials conducted under the EFIC rule to facilitate research to better understand how the rule is being used. METHODS: We conducted a multipronged search to identify all trials conducted under the EFIC rule, drawing on reviews, database searches, examination of the FDA's docket, posting an inquiry on the institutional review board forum, and email requests to lead authors of all published EFIC trials and related review articles. We describe the trials, when they were started and completed, and whether they were terminated early. RESULTS: We identified a total of 110 trials as of the end of April 2022: 78 complete, 13 recruiting, seven registered on clinicaltrials.gov but not yet recruiting, five trials that were abandoned before enrolling any subjects, and seven trials in early planning. Nine of the 78 completed trials were pilot or feasibility trials. Of 69 completed full trials, 30 (43.5%) were terminated early. The most common reason for early termination was futility (15 trials, 25.0%) followed by poor recruitment (10 trials, 14.5%). The rate of conduct of trials has been remarkably constant since 2001, with roughly 18 trials started in each 5-year period. CONCLUSIONS: We have compiled a census of trials conducted under the U.S. FDA's EFIC rule, the availability of which we hope will stimulate further in-depth data collection and analysis of this set of trials.

Can HIV vaccines be shared fairly? Perspectives from Tanzania.

BACKGROUND: For over 35 years, Africa has continued to host HIV vaccine trials geared towards overturning the HIV/AIDs pandemic in the continent. However, the methods of sharing the vaccines, when available remain less certain. Therefore, the study aims to explore stakeholders' perspectives in the global South, in this case, Tanzania, on how HIV vaccines ought to be fairly shared. METHODS: The study deployed a qualitative case study design. Data were collected through in-depth interviews and focus group discussions with a total of 37 purposively selected participants. This included researchers, institutional review board members, a policymaker, HIV/AIDS advocates, and community advisory board members. The data obtained were inductively and deductively analyzed. RESULTS: Findings indicate that HIV vaccines can be shared fairly under the principles of distributive justice (contribution, need and equality). Thus, contribution-based sharing ought to be utilized upon the necessity to prioritize vaccine access or subsidized trial benefits to host communities. Need-based sharing ought to be considered for non-host communities that are at an increased risk of HIV infection. Lastly, equal-based sharing would be useful at later stages of vaccine distribution or when the aforementioned principles are deemed morally inappropriate. However, none of the benefit-sharing approaches is free of limitations and a counterbalancing sense of unfairness. CONCLUSION: Fair sharing of HIV vaccines, when available, ought to be informed by the contribution, need and equality principles of distributive justice. Countries in the global south including Tanzania are likely to be prioritized during the distribution of the HIV vaccines due to their participation in HIV vaccine trials and due to the disproportionate HIV burden evident in the region.

Practicalities of Impracticability: An Interim Review of Randomized Controlled Trials.

Impracticability is an ethical standard for waiver of informed consent in research. We examine how well the criterion of impracticability appears to have been fulfilled in a set of 36 completed randomized controlled trials (RCTs) that secured consent from some subjects or LARs and employed waivers to enroll others. These trials were identified among 155 RCTs using waivers of consent in a convenience sample drawn from 7 systematic reviews. Recruitment data were available for 19 of the 36 trials, revealing an average of 41.6% of subjects (range 0.2-98.7%, 95% CI: 24.8-58.4%) were enrolled without consent. Six trials enrolled less than 10% of subjects without consent and an overlapping set of 9 trials sought consent from all subjects or LARs at some sites while waiving consent at other sites. We question whether these trials were practicable without waivers and identify issues for consideration by investigators and ethics review boards.

The History and Policy Evolution of Waivers of Informed Consent in Research.

We examine the evolution of policies permitting exceptions to or waivers of informed consent for research in the United States. This review reveals that (1) exceptions to the duty to secure informed consent were originally quite narrow; (2) there were two alternative approaches to allowing research on human subjects without their prospective consent: (i) exceptions in which individual capacity to consent is to be assessed and consent tailored to each person's abilities and (ii) waivers of the general requirement for a population of potential subjects, where securing prospective consent would "destroy or invalidate" critically important research; (3) waivers only appeared in the final rulemakings for research regulations issued by the National Institute of Education in 1974 and the Department of Health and Human Services in 1981, limiting the opportunity for the public to weigh in on the scope and use of waivers; and (4) rules adopted since 1981 have almost uniformly added extra requirements to justify waivers. Examples drawn from recent research show expansion of the use of waivers far beyond the bounds originally envisioned. Greater transparency about the use of waivers is needed for the public to weigh in on the standards for foregoing informed consent in human research.

Path Analysis of RCT Recruitment: Secondary Analysis of Results from a Systematic Review.

We examine recruitment processes for 71 pragmatic and comparative effectiveness trials identified in a systematic review, using path analysis to examine rates of refusal to screen, test, and consent to trial participation. Our analysis suggests that refusal rates might be on net slightly higher if potential subjects are screened or asked to undergo physical eligibility tests, but this was not significant in our sample of trials (p = .11 by Mann-Whitney test). We find that rates of refusing to provide informed consent are much lower for trials in which subjects have agreed to screening or testing (odds ratio = 0.40, Wilcoxon rank-sum z = 2.67, p = .008). We also observe that the overwhelming majority of trials examined secured consent after determining eligibility, even in trials involving screening or testing activities. The ethical implications and areas for future research are discussed.

Refusal rates and waivers of informed consent in pragmatic and comparative effectiveness RCTs: A systematic review.

BACKGROUND: Pragmatic and comparative effectiveness randomized controlled trials (RCTs) aim to be highly generalizable studies, with broad applicability and flexibility in methods. These trials also address recruitment issues by minimizing exclusions. The trials may also appeal to potential subjects because of lower risk and lower burdens of participation. We sought to examine rates of refusal and uses of waivers of informed consent in pragmatic and comparative effectiveness RCTs. METHODS: A systematic review of pragmatic and comparative effectiveness RCTs performed wholely or in part in the United States and first published in 2014 and 2017. RESULTS: 103 studies involving 105 discrete populations were included for review. Refusal data was collected for 71 RCTs. Overall, studies reported an average rate of 31.9% of potential subjects refused participation; on an individual basis, 38.4% of people asked to take part refused at some point during recruitment. 23 trials (22%) were performed, at least in part, with a waiver of informed consent, 7 (30%) of which provided any form of notice to subjects. CONCLUSIONS: Overall refusal rates for pragmatic and comparative effectiveness RCTs appear roughly the same as other types of research, with studies reporting about a third of people solicited for participation refuse. Moreover, informed consent was waived in 22% (95% Binomial exact Confidence Interval 13.9-30.5%) of the trials, and further study is needed to understand when waivers are justified and when notice should be provided.

High-impact RCTs without prospective informed consent: a systematic review.

The prevalence of randomized controlled trials (RCTs) performed without fully informed prospective consent from subjects is unknown. We performed this study to estimate the prevalence of high-impact RCTs performed without informed consent from all subjects and examine whether such trials are becoming more prevalent. We performed a systematic review of English-language RCTs published from 2014 through 2018 identified in Scopus and sorted to identify the top 100 most highly cited RCTs each year. Text search of title and abstract included terms randomized controlled or clinical trial and spelling variants thereof, and excluded metaanalyses and systematic reviews. We independently identified the most highly cited RCTs based on predefined criteria and negotiated to agreement, then independently performed keyword searches, read, abstracted and coded information regarding informed consent from each paper and again negotiated to agreement. No quality indicators were assessed. We planned descriptive qualitative analysis and appropriate quantitative analysis to examine the prevalence and characteristics of trials enrolling subjects with other than fully informed prospective consent. We find that 44 (8.8%, binomial exact 95% CI 6.5% to 11.6%) of 500 high-impact RCTs did not secure informed consent from at least some subjects. The prevalence of such trials did not change over the 5 years (OR=1.09, z=0.78, p=0.44). A majority (66%) of the trials involved emergency situations, and 40 of 44 (90.9%) of the trials involved emergency interventions, pragmatic designs, were cluster randomized, or a combination of these factors. A qualitative analysis explores the methods of and justifications for waiving informed consent in our sample of RCTs.

What gives them the right? Legal privilege and waivers of consent for research.

Waivers of informed consent for research participation are permitted in the United States under the Common Rule, the Health Insurance Portability and Accountability Act regulations, and the US Food and Drug Administration's Exception from Informed Consent rule for emergency research. We assess the novel question regarding what legal right researchers have to carry out research procedures on or about another person, be it experimental medical intervention, psychological or social manipulation, or invasion of privacy, without the permission of their subjects. Our analysis frames waivers of consent as a species of presumed consent, and we address the underlying empirical question of whether it is reasonable to believe that subjects from whom no consent is sought would in fact agree, if asked. A scoping review of what is known about participation and refusal rates in United States-based research suggests that a large minority, on average, do not agree to take part in research. Refusal rates vary widely. This suggests that, while researchers may assert the social utility of their studies are high enough to justify waivers, there is reason to suspect that many who would be enrolled under a waiver of consent would not want to be enrolled. We conclude that waivers should be rare and that institutional review boards and researchers must explicitly address study acceptability in the community at large and the target population of their proposed research.

"The keeping is the problem": A qualitative study of IRB-member perspectives in Botswana on the collection, use, and storage of human biological samples for research.

BACKGROUND: Concurrent with efforts to establish national and regional biorepositories in Africa is widespread endorsement of ethics committees as stewards of the interests of individual donors and their communities. To date, ethics training programs for IRB members in Botswana have focused on ethical principles and international guidelines rather than on the ethical dimensions of specific medical technologies and research methodologies. Little is known about the knowledge and concerns of current and prospective IRB members in Botswana with respect to export, reuse, storage, and benefit-sharing of biospecimens. METHODS: This qualitative study examined perspectives of IRB members in Botswana about the collection and use of biospecimens in research. Forty-one IRB members representing five committees in Botswana participated in discussions groups in March 2013. Transcriptions of audiotapes and field notes were analyzed to identify issues of concern that might be alleviated through education and capacity-building, and areas that required ongoing discussion or additional regulatory guidance. RESULTS: Areas of concern included lack of understanding among patients and providers about the use of biospecimens in clinical care and research; reuse of biospecimens, particularly issues of consent, ownership and decision-making; export of specimens and loss of control over reuse and potential benefits; and felt need for regulatory guidance and IRB-member training. Local belief systems about bodily integrity and strong national identity in the construct of benefits may be at odds with initiatives that involve foreign biorepositories or consider such collections to be global public goods. CONCLUSION: Education is needed to strengthen IRB-member capacity to review and monitor protocols calling for the collection and use of biospecimens, guided by clear national policy on priority-setting, partnerships, review, and oversight. Engagement with local stakeholders is needed to harmonize fundamentally different ways of understanding the human body and community identity with the aims of contemporary biomedicine.

Fostering IRB collaboration for review of international research.

This article presents a review of the literature, summarizes current initiatives, and provides a heuristic for assessing the effectiveness of a range of institutional review board (IRB) collaborative strategies that can reduce the regulatory burden of ethics review while ensuring protection of human subjects, with a particular focus on international research. Broad adoption of IRB collaborative strategies will reduce regulatory burdens posed by overlapping oversight mechanisms and has the potential to enhance human subjects protections.