Ethically designing research to inform multidimensional, rapidly evolving policy decisions: Lessons learned from the PROMISE HIV Perinatal Prevention Trial

Research in rapidly evolving policy contexts can lead to the following ethical challenges for sponsors and researchers: the study’s standard of care can become different than what patients outside the study receive, there may be political or other pressure to move ahead with unproven interventions, and new findings or revised policies may decrease the relevance of ongoing studies. These ethical challenges are considerable, but not unprecedented. In this article, we review the case of a multinational, randomized, controlled perinatal HIV prevention trial, the “PROMISE” (Promoting Maternal Infant Survival Everywhere) study. PROMISE compared the relative efficacy and safety of interventions to prevent mother to child transmission of HIV. The sponsor engaged an independent international ethics panel to address controversy about the study’s standard of care and relevance as national and international guidelines changed. This ethics panel concluded that continuing the PROMISE trial as designed was ethically permissible because: (1) participants in all arms received interventions that were effective, and there was insufficient evidence about whether one intervention was more effective or safer than the other, and (2) data from PROMISE could be useful for a diverse range of stakeholders. In general, trials designed to inform rapidly evolving policy issues should develop mechanisms to revisit social value while recognizing that the value of research varies for diverse stakeholders with legitimate reasons to weigh evidence differently. We conclude by providing four reasons that trials may depart from the standard of care after a change in policy, while remaining ethically justifiable, and by suggesting how to improve existing trial oversight mechanisms to address evolving social value.

Formalising the induction of patient and public involvement contributors on trial oversight committees

Background Clinical Trials Units are encouraged to integrate Patient and Public Involvement (PPI) into all aspects of trial design, running and oversight. This research explored the induction and training of PPI Contributors joining trial oversight committees and was used to update the Medical Research Council Clinical Trials Unit at University College London’s (MRC CTU at UCL) induction pack for new PPI Contributors. Methods Published and unpublished materials provided by other CTUs and research organisations on training for PPI Contributors on oversight committees were reviewed, with themes then triangulated to identify the most common topics covered in induction training. A face-to-face workshop with PPI Contributors from the MRC CTU at UCL reviewed a draft updated Induction Pack. Findings from these discussions were incorporated into a revised induction pack which was then re-reviewed by the workshop attendees. Results No published literature on this subject was found. However, several common themes were identified from unpublished materials. Workshop attendees agreed with most of the themes suggested in the initial draft pack based on the literature search and also provided a number of additional topics for discussion. Conclusions There is very little consistency in the induction of PPI Contributors on oversight committees. Whilst most local guidance explains the general role of a PPI Contributor, more context and background of the particular trial needs to be provided to allow for adequate induction of new committee members. The Induction Pack created provides a framework upon which trial managers can build a full picture of their study.

Integrating trials into a whole-population cohort of children and parents: statement of intent (trials) for the Generation Victoria (GenV) cohort

Background Very large cohorts that span an entire population raise new prospects for the conduct of multiple trials that speed up advances in prevention or treatment while reducing participant, financial and regulatory burden. However, a review of literature reveals no blueprint to guide this systematically in practice. This Statement of Intent proposes how diverse trials may be integrated within or alongside Generation Victoria (GenV), a whole-of-state Australian birth cohort in planning, and delineates potential processes and opportunities. Methods Parents of all newborns (estimated 160,000) in the state of Victoria, Australia, will be approached for two full years from 2021. The cohort design comprises four elements: (1) consent soon after birth to follow the child and parent/s until study end or withdrawal; retrospective and prospective (2) linkage to clinical and administrative datasets and (3) banking of universal and clinical biosamples; and (4) GenV-collected biosamples and data. GenV-collected data will focus on overarching outcome and phenotypic measures using low-burden, universal-capable electronic interfaces, with funding-dependent face-to-face assessments tailored to universal settings during the early childhood, school and/or adult years. Results For population or registry-type trials within GenV, GenV will provide all outcomes data and consent via traditional, waiver, or Trials Within Cohorts models. Trials alongside GenV consent their own participants born within the GenV window; GenV may help identify potential participants via opt-in or opt-out expression of interest. Data sharing enriches trials with outcomes, prior data, and/or access to linked data contingent on custodian’s agreements, and supports modeling of causal effects to the population and between-trials comparisons of costs, benefits and utility. Data access will operate under the Findability, Accessibility, Interoperability, and Reusability (FAIR) and Care and Five Safes Principles. We consider governance, ethical and shared trial oversight, and expectations that trials will adhere to the best practice of the day. Conclusions Children and younger adults can access fewer trials than older adults. Integrating trials into mega-cohorts should improve health and well-being by generating faster, larger-scale evidence on a longer and/or broader horizon than previously possible. GenV will explore the limits and details of this approach over the coming years.

STAKEHOLDER ENGAGEMENT IN A COMPARATIVE EFFECTIVENESS/IMPLEMENTATION STUDY TO PREVENT CA-MRSA INFECTION RECURRENCE: CA-MRSA Project (CAMP2)

Background Methicillin-Resistant (MRSA) or Methicillin-Sensitive (MSSA) Staphylococcus aureus skin and soft tissue infections (SSTIs) pose serious clinical and public health challenges. Few protocols exist for outpatient education, decolonization and decontamination. Objectives This trial implemented infection prevention protocols in homes via Community Health Workers/promotoras. Methods We engaged clinicians, patients, clinical and laboratory researchers, New-York-based Federally Qualified Health Centers and community hospital Emergency Departments. The Clinician and Patient Stakeholder Advisory Committee (CPSAC) convened in-person and remotely for shared decision-making and trial oversight. Results The trial consented 186 and randomized 119 participants with SSTIs with MRSA (n=59) or MSSA (n=59), completed home visits, obtained surveillance cultures from index patients and household members and sampled household environmental surfaces at baseline and three months. Lessons Learned The retention of the CPSAC during the trial demonstrated high levels of engagement. Conclusions CPSAC was highly effective throughout design and execution by troubleshooting recruitment and home visit challenges.

Coronavirus Disease 2019 (COVID-19) Clinical Trial Oversight at a Major Academic Medical Center: Approach of Michigan Medicine

Clinicians, eager to offer the best care in the absence of guiding data, have provided patients with coronavirus disease 2019 (COVID-19) diverse clinical interventions. This usage has led to perceptions of efficacy of some interventions that, while receiving media coverage, lack robust evidence. Moving forward, randomized controlled clinical trials are necessary to ensure that clinicians can treat patients effectively during this outbreak and the next. To do so, academic medical centers must address 2 key research issues: (1) how to effectively and efficiently determine which trials have the best chance of benefiting current and future patients and (2) how to establish a transparent and ethical process for subject recruitment while maintaining research integrity and without overburdening patients or staff. We share here the current methods used by Michigan Medicine to address these issues.

Improving the Induction of PPI Contributors on Trial Oversight Committees

Clinical Trials Units are encouraged to integrate Patient and Public Involvement (PPI) into all aspects of trial design, delivery, oversight and dissemination. This research explored the induction and training of PPI Contributors joining trial oversight committees. It was used to create an induction pack for new PPI Contributors at the Medical Research Council Clinical Trials Unit at University College London’s (MRC CTU at UCL). We have made this resource available to all researchers and in this we report describe the methodology behind its production.

A third trial oversight committee: Functions, benefits and issues

Background/aims: Clinical trial oversight is central to the safety of participants and production of robust data. The United Kingdom Medical Research Council originally set out an oversight structure comprising three committees in 1998. The first committee, led by the trial team, is hands-on with trial conduct/operations (‘Trial Management Group’) and essential. The second committee (Data Monitoring Committee), usually completely independent of the trial, reviews accumulating trial evidence and is used by most later phase trials. The Independent Data Monitoring Committee makes recommendations to the third oversight committee. The third committee, (‘Trial Steering Committee’), facilitates in-depth interactions of independent and non-independent trial members and gives broader oversight (blinded to comparative analysis). We investigated the roles and functioning of the third oversight committee with multiple research methods. We reflect upon these findings to standardise the committee’s remit and operation and to potentially increase its usage. Methods: We utilised findings from our recent published suite of research on the third oversight committee to inform guideline revision. In brief, we conducted a survey of 38 United Kingdom–registered Clinical Trials Units, reviewed a cohort of 264 published trials, observed 8 third oversight committee meetings and interviewed 52 trialists. We convened an expert panel to discuss third oversight committees. Subsequently, we interviewed nine patient/lay third committee members and eight committee Chairs. Results: In the survey, most Clinical Trials Units required a third committee for all their trials (27/38, 71%) with independent members (ranging from 1 to 6). In the survey and interviews, the independence of the third committee was valued to make unbiased consideration of Independent Data Monitoring Committee recommendations and to advise on trial progress, protocol changes and recruitment issues in conjunction with the trial leadership. The third committee also advised funders and sponsors about trial continuation and represented patients and the public by including lay members. Of the cohort of 264 published trials, 144 reported a ‘steering’ committee (55%), but the independence of these members was not described so these may have been internal Trial Management Groups. Around two thirds of papers (60%) reported having an Independent Data Monitoring Committee and 26.9% neither a steering nor an Independent Data Monitoring Committee. However, before revising the third committee charter (Terms of Reference), greater standardisation is needed around defining member independence, composition, primacy of decision-making, interactions with other committees and the lifespan. Conclusion: A third oversight committee has benefits for trial oversight and conduct, and a revised charter will facilitate greater standardisation and wider adoption.

PO 8300 REGIONAL CENTER FOR REGULATORY EXCELLENCE IN CLINICAL TRIAL OVERSIGHT – TRAINING 2017

BackgroundThe competencies of the various national medicines regulatory agencies (NMRAs) in Africa vary which leads to generally porous regulatory systems for clinical trial oversight. Consequently, many trials have been conducted under unacceptable conditions compromising participants’ safety and data credibility and resulted in questionable outcomes that are used for making scientific judgement in addressing issues of public health in Africa.To improve the safety and quality of health technologies in Africa, the New Partnership for African Development (NEPAD) agency launched a programme to designate Regional Centres of Regulatory Excellence (RCOREs) with the specific objective of bridging existing gaps between African NMRAs through strengthening regulatory capacity of African Union member states. The Food and Drugs Authority (FDA), Ghana, was designated as RCORE for Clinical Trials oversight in May 2014.MethodsTo achieve the RCORE objectives, the FDA collaborated with the School of Public Health (SPH), University of Ghana to develop a training manual and piloted a training programme with funds from the International AIDS Vaccine Initiative (IAVI) through NEPAD.The programme, consisting of 4 compulsory modules, was organised from 6–30 November 2017 for 10 participants from Zambia, Sierra Leone, Liberia, Rwanda and Ghana. Interactive training methods in the form of theoretical and practical sessions were employed.ResultsThe pilot RCORE training was successful with expected training objectives achieved. Participants gained hands-on experience through activities like observing Good Clinical Practice inspection and a Technical Advisory Committee Meeting. Participants were given template tools to assist in developing regulatory guidelines and forms in their respective countries.A follow-up questionnaire was circulated to participants to assess the impact of the training on their work. Feedback „indicates that regulation of clinical trials has improved in their respective institutions.ConclusionThis pilot fellowship training was successful, „leading to the improvement of clinical trial regulation in the participating countries.