Protecting Local REC Review and Decision-Making Authority

The importance of local context to REC review is well characterized in the literature.Reference Christakis²⁰ Scholarship on the most effective methods for incorporating local knowledge into REC review, however, varies widely.Reference Coleman and Bouësseau²¹ Attention to ethical, legal, and social issues relevant to proposed research studies have been traditionally served by localizing the review process amidst growing criticism about whether such localization measurably improves participant protections. Arguments against centralizing REC review generally falls into two categories. Ceding full board review to a centralized or single REC either wholly or in part can (1) compromise protections for local participants because the REC board of record lacks insight into local values, interests and priorities; and 2) robs local RECs of institutional autonomy they would otherwise maintain in single-site studies.

Sociologist Adam Hedgecoe was among the first to empirically study the tradeoffs of local versus centralized REC decision-making, claiming “local knowledge plays a vital yet largely overlooked role in how RECs make decisions.”²² Chair of the Médecins Sans Frontières Ethics Review Board, Raffaela Ravinetto, and colleagues confirm the protective benefits of maintaining a system of “double ethical review,” when RECs in both the sponsoring and host country conduct independent reviews of a multisite study.²³ Advocates for double ethical review contend it “de facto strengthens the protection of the study participants and their communities…Despite their universal character, ethical principles governing clinical research need to be translated into rules, procedures and practices, which may significantly vary among countries and regions.”²⁴

Studies involving REC members in Europe and North America similarly endorse local review of a multisite study when it includes international partners and where sociocultural differences warrant local input.Reference Klitzman²⁵ According to another study of REC members in The Netherlands, RECs manage bureaucratic tensions in the review process based on resource availability and institutional context. These differences help RECs develop what the authors call “situational authority” over when, how, and which studies proceed²⁶ and was a common theme identified in discussions with REC members represented in the COVID-19 Coalition when deciding the merits of centralizing multisite review of vaccine-related trials in the early stages of the pandemic.

Implicit in many of the above arguments rejecting single REC review are assumptions about how local RECs obtain, retain, and effectively apply local knowledge to ensure participant interests and values are duly served in the research. For instance, it presumes that the professional elites that dominate ethics committee deliberations adequately understand and represent the concerns of lay members of the population that they serve.

Proponents of single REC review challenge the assumption that full board review at each participating site is the most effective way for local values to be represented in the review process. For instance, Klitzman and colleagues²⁷ argue that conditions in the local context could be adequately captured in reviews conducted by a single REC of record. They identify four locally specific insights that any centralized body would need to have in order to conduct a quality and effective review:

• • Cultural and linguistic characteristics of prospective participants;

• • Geographic and socioeconomic issues;

• • Knowledge about specific researchers; and

• • Institutional differences across participating study sites.

Furthermore, Emanuel and colleagues claim that there is insufficient evidence to “substantiate the value of […] local knowledge or whether it can only be — or is best — gained through institution-based review.”Reference Emanuel²⁸ Put another way, one critical question is whether current models for incorporating local knowledge into reviews — namely by requiring site-specific review — successfully achieves the goal of community representation, and whether this purported benefit is at the expense of time-sensitive research during public health emergencies. Workflow improvements, such as standardized application and review forms,Reference Lidz²⁹ online submission and review portals, as well as software have been identified as recurring needs to streamline RECs process applications,³⁰ monitor progress and more directly incorporate input from community members on the REC at each stage in the review process from submission to continuing review.

Other scholars advocate for a new conceptual framework for multisite ethics review. For example, Townend and Dove propose RECs take a “sounding board” approach when serving as the board of record for international, multisite studies.Reference Townend and Dove³¹ The sounding board model places the onus on researchers to ensure local interests have been adequately considered and plans for protecting local participants are socioculturally appropriate. This model “obviates the need for a harmonised substantive ethics, which we believe is an intractable challenge” and instead emphasizes harmonization of those procedural elements common to all RECs.

Yet key to successful adoption and implementation of mutual recognition is, as we argue, empowering RECs to be responsive to local values while optimizing procedural efficiency in the review process. Discussants consulted for this report emphasized the point that local RECs should be directly involved in reviewing all multisite studies and expressed grave concern that a proposed system of ethics review mutual recognition would eliminate local input from decision-making. When asked how RECs modified pre-pandemic procedures to meet the new demand for multisite studies during the pandemic, each discussant acknowledged that the volume of new COVID-related protocols stressed local REC resources and reported that centralizing some component of the review with local authorization occurred. Discussants were also unclear how local input would be integrated into the final authorization of a multisite or multinational study, what authority local RECs would maintain if any, and the extent to which ethics review mutual recognition would affect community representation, more broadly. These are important concerns that will need to be addressed in the development or design of any system that proposes to centralise some of the REC review functions.

REC Organization

Ethical principles guiding responsible conduct of research involving humans emerged primarily in response to a troubled history of exploitation and abuse. While some of the earliest RECs operated in hospitals and research institutions in the 1960s, it was not until the early 1970s that the proposal for institutionalized RECs was written into the second revision of the Declaration of Helsinki and made a regulatory requirement for human subjects research in the UK, US, and Canada. The proposed constitution, structure, and oversight operations of institutional RECs remain largely unchanged. While membership may be broad, core REC members have professional expertise in fields such as ethics, medicine, law, and science, and many committees consult external experts to guide their review of studies with novel study designs, for example, or perhaps to gather informed input on how the study procedures align with the values of a prospective participation population. Importantly, community representatives help to represent the values and interests of the local population and their membership on the REC is mandatory in many countries.

Social, economic and political stability are, as some authors argue,³² key enabling factors for sustaining a robust REC system that greatly impacts the regulatory and institutional environments within which RECs operate. Figure 1 demonstrates various modalities for how RECs are embedded within these environments. RECs can be governed by national or regional authorities or by international organizations such as Médecins Sans Frontières and World Health Organization Headquarters and operate under rules outlined in ministerial mandates (e.g. health, research, education or equivalent). Some countries have a single national REC that serves as the official reviewing authority for all research involving humans performed in a country;Reference Hummel³³ others have many RECs. In some countries, the national REC only reviews certain types of research. Some RECs operate independently from institutions, but apply rules set forth by a country’s national health system. Finally, regional RECs may comply with national guidelines for human research protections but receive funding from or be mandated by a regional authority. Only in recent years have some national agencies introduced centralized or single ethics review for studies in which recruitment spans multiple institutions, including rapid response committees deployed during public health emergencies.³⁴

Figure 1 Four models of single or centralized ethics review for multisite studies adopted by RECs during the pandemic and represented in the Ethics Working Group of the Global COVID-19 Research Coalition.

Centralized committees may rely on institutional RECs to assess locally contingent elements of a protocol. These assessments can be both pragmatic and normative. Local REC review may be best positioned to evaluate the availability of human and material resources necessary to carry out study interventions and determine whether participant recruitment is appropriate and feasible. The arrangements by which scientific collaborations have traditionally been set up between researchers in the Global North and South can further distance researchers from the individuals and communities involved in the research. This distance is literal in that powerful information technologies allow researchers physically located in different geographies to collect, analyze, and share research data more than ever before. This distance is also metaphoric in that researchers may be culturally ignorant of the values and priorities of communities they recruit to the study, potentially affecting how effectively the REC of record can protect the interests of local communities. The concept of cultural distance is relevant to the success of ethics review mutual recognition insofar as members of the RECs of record need to demonstrate knowledge of, and sensitivity to the norms, values and priorities of communities within which local RECs are embedded and serve.

Many discussants articulated that the diversity in regulatory environments is a primary reason why establishing reciprocity among RECs — the second of two preconditions needed to support ethics review mutual recognition — is likely unrealistic and incompatible with applicable rules and laws in their home countries. For example, establishing reciprocity requires amendments to existing rules/laws for researchers and healthcare professionals because RECs are co-regulated with healthcare delivery in some countries, such as Brazil. In Nigeria and Ghana, discussants identified similar challenges in that adopting ethics review mutual recognition would require one system of governance for two otherwise distinct professional sectors within the Ministry of Health. All of these challenges suggest that the introduction of a system of ethics review mutual recognition is neither straightforward nor easily implemented.

Our discussions suggest that ethics review mutual recognition should be better integrated within existing legal and regulatory systems governing research involving humans regardless of their location if RECs are to feasibly implement it. However, such integration remains both a regulatory and logistical barrier to establishing reciprocity. A superior challenge arises with the introduction of a system of ethics review mutual recognition that spans the international arena. In the next section of the paper, we will speak specifically to one dimension of international collaboration that our discussants identified as a major obstacle to regulating ethics review internationally, namely trust between people from different nations.

North-South Equity Relations and Manifestations in REC Review

The viability of ethics review mutual recognition is hindered by a trust problem among RECs working in LMICs when reviewing applications for sponsored research from well-resourced institutions in high income countries (HICs).³⁵ Scholars corroborate this lack of trust and emphasize the essential role that local REC review plays in representing not only communities but also national values, interests and priorities.Reference van Teijlingen and Simkhada³⁶ Enhancing opportunities for trust-building among RECs is a prerequisite to any functioning REC system based on mutual recognition.Reference Dove and Garattini³⁷ There are also often other tensions between government, researchers, and communities that inevitably affect the durability of such economies of trust.³⁸ Finally, while measures of REC review quality should include normative goals such as equity and inclusion, and performance goals like effectiveness and efficiency, recent analyses suggest that they rarely do.Reference Lynch³⁹

Most published articles available on centralized ethics review are primarily authored by REC actors/scholars based in high income countries in North America, Europe, and Australia. Absent a more globally balanced representation of REC experiences during the pandemic, the literature offers a skewed understanding at best about the merits and pitfalls of ethics review mutual recognition. Many discussants expressed healthy skepticism to this effect. The anticipated gains in efficiency afforded by centralizing reviews did not outweigh concerns about equity relations between RECs of record and local RECs. Rather, they precipitated fears that ethics review mutual recognition would further limit opportunities for meaningful engagement and community prioritization in REC decision-making. This issue was particularly salient when discussing North-South research collaborations.

There was broad concern about the extent to which international research conducted in LMICs continues to entrench unequal power relations characteristic of colonialism, corroborating findings from prior research.⁴⁰ While willing participants based in LMICs were enrolled in vaccine trials, reports indicate they have not equitably benefited.⁴¹ Few commitments by HICs to support global vaccine distribution has reinforced a perception that internationally, financial interests of wealthy countries take priority over values such as solidarity and health equity needed to achieve global herd immunity.Reference Katz⁴² Scholars from the global South have also argued that commitments as to vaccine research and equitable distribution were motivated not by genuine solidarity but rather by threats to the health and welfare of people in wealthy countries. Rate and trends of vaccine distribution and deaths are suggestive of gross inequities,Reference Bansal⁴³ which one retrospective modeling study found contributed to at least 1.3 million excess deaths worldwide.Reference Moore⁴⁴ Global vaccine trackers estimate that 12.8 billion doses of COVID-19 vaccines have been administered globally as of November 2022. Still more than 80 percent of people living in LMICs have yet to receive even one dose.⁴⁵ LMICs now lead the world in COVID-19 deaths per 100,000, and countries where fewer than 20 vaccine doses have been administered per 100 are located on the African continent.⁴⁶ Suspicions about the motivations of researchers and institutions based in wealthier countries, and experiences of scientific marginalization, mean that many scholars based in LMICs are deeply sceptical about efforts that may seem to eradicate the limited protections that exist in scientific research. From this perspective, national or local ethics review provides at least some safeguard against exploitation. A system of multinational ethics review needs to accommodate such concerns and actively promote technologies and approaches that are trustworthy and that promote accountability.

A second challenge confronting collaborative, multinational ethics review for several discussants was which ethics should govern transcultural clinical research.⁴⁷ Their perceptions differed from some reported in the literature whereby local RECs are seen to raise administrative (non-ethical) issues more frequently in ethical deliberations about biomedical research protocols.Reference Silaigwana and Wassenaar⁴⁸ Indeed, conceptual and theoretical frameworks underpinning today’s REC procedures and operations appeal to principlism and other predominantly Western paradigms of ethics. In so doing, indigenous and non-Western values with respect to responsible conduct of research involving humans could be discounted without opportunities to co-construct culturally-competent practices for REC review.Reference Bull⁴⁹ Barchi and colleagues highlight the effects of resulting resource- and power asymmetries between RECs in the Global North and South.⁵⁰ The authors claim that oversight of international research is “fertile terrain for mistrust” when “U.S. IRBs assume that host-country IRBs are unable to conduct adequate reviews, and the latter are skeptical that U.S. IRBs will be sensitive to their national concerns or place the needs of a local population above the imperatives of the U.S. research enterprise.” ⁵¹

Against such concerns, and where researchers or institutions have little opportunity to avoid exploitative research practices, ethics review can be co-opted as a source of resistance against the colonizing tendencies of international research.⁵² We propose, as others have,Reference Harman⁵³ that theories of reparative justice⁵⁴ could proactively inform approaches to enhancing equity in REC review by, for example, incorporating specific REC review related to benefit sharing,Reference Munung and de Vries⁵⁵ mandatory compensation for research-related injuries,Reference Larkin⁵⁶ and potentially adding retrospective REC review of the social impacts the research had on participant communities.Reference Dawson⁵⁷

REC Communication Lost in Translation

REC coordination and communication are well-evidenced problems which are exacerbated in the context of multisite, collaborative research.Reference Guner⁵⁸ Many practical and logistical challenges constrain the feasibility of implementing a system of mutual recognition for multisite, public health research in pandemic settings. First, delineating responsibilities could prove challenging between reviewing RECs of record and local authorizing RECs. Second, the absence of a central database listing all operating RECs globally makes it difficult for researchers to seek support from local RECs when preparing their protocol application. Third, RECs based in under-resourced settings often rely on paper-based filing for application intake and processing, whereas those in wealthy countries often employ inaccessible and costly submission and ethics review portals, which can complicate document sharing across RECs and participating institutions.

Discussants with direct experience reviewing multisite/national studies related to COVID-19 in countries with and without centralized models of ethics review described significant issues in coordination and communication between reviewing RECs, local RECs, and researchers. Because communication was poor between RECs from the same region and in pre-pandemic times, discussants expected such challenges to scale when RECs from different countries as “research ethics committee would not wish to regard itself as being subservient to another, or to give up control over its current areas of jurisdiction.”Reference Aarons⁵⁹ Saxena and colleagues underscore the negative effects that territorial local RECs may have on communication and coordination. They argue that since RECs do not proactively communicate with other RECs evaluating the same protocol, there is a

Continued efforts to strengthen communication, reporting and collaborative partnerships among RECs and their governing authorities across countries (see for example the work of Fogarty InternationalReference Strosberg⁶¹ ) is a necessary first step to enhancing willingness among RECs to work together.

AVAREF Case Example

The AVAREF (African Vaccine Regulatory Forum) joint review model is one example from which the REC community can learn how a system of ethics review mutual recognition could potentially scale for multisite clinical trial research. The AVAREF joint review model remains the only operational, extra-jurisdictional system of ethics review and approval based on mutual recognition to our knowledge, and motivates its inclusion as a case study of interest here. The AVAREF model also practically demonstrates how regulators across countries can achieve the two conditions under which we hypothesize ethics mutual recognition is most likely to succeed, namely by adopting procedural standards (condition 1) for REC review, and establishing reciprocity between participating sites that recognize the decisions of the joint committee (condition 2).

AVAREF was established by the WHO in 2006 to enhance human research protections, REC capacities, and biomedical research collaboration on the African continent. It has since issued nine consensus guidelines to guide quality and effective review of clinical trials for vaccine development, specifically. Representatives to AVAREF from 55 member states reviewed and approved the guidelines in October 2019, marking a “shift to standardized clinical trial applications and assessments, and proof of ongoing harmonization initiatives on the continent, which will ultimately lead to shorter timelines for product development.”⁶² The AVAREF guidelines outline processes and procedures for joint review of multisite/multi-national vaccine trials, including how to plan, organize, and conduct joint reviews to reduce redundancies and improve efficiency of multisite clinical trial applications in Africa. Before a joint review committee convenes, the trial sponsor agrees to procedural, transparency, and communication requirements. Notably, a candidate medical product such as a vaccine under review must be deemed to have high public health value to African countries from the perspectives of participating representatives serving on the committee. Next, representatives from participating sites convene a joint committee meeting. They apply equivalent procedural standards for REC review of vaccine trials (condition 1) through AVAREF templates, tools, criteria as well as WHO Guidelines on Clinical Evaluation of Vaccines: Regulatory Expectations. Subject-matter experts and a neutral proctor are invited to the meeting in addition to participant observers. The joint committee issues a final decision which is recognized by public health authorities from countries represented on the panel (condition 2). Local RECs retain the authority to accept the joint committee’s review or to opt out of the study/trial.

The AVAREF model demonstrated success most recently in July 2020, when it was leveraged to review trials investigating the safety and efficacy of COVID-19 vaccine candidates. One goal of the AVAREF COVID-19 Action Plan was to accelerate research and development of effective therapeutics and diagnostics, and it committed to finalizing its joint committee ethics review within 10 working days. The first joint review committee of a multinational COVID-19 vaccine trial on the continent included reviewers from 14 African Member States, 12 of which were able to deliver a decision in less than 25 days. AVAREF also elaborated on challenges encountered in this multinational effort, which included reasons for review delays. The organization reported that “delays in ethics decisions and in some cases by National Regulatory Authorities (NRAs) were responsible for the unmet timelines. Another major cause of delay was additional queries raised by some countries outside the joint review process, in some cases ignoring adequate responses to queries which sponsors had provided during the joint review.”⁶³

The AVAREF joint committee model demonstrated practical advantages to site-specific REC review. It allowed for representatives of participating sites to collectively review safety and efficacy data for vaccine candidates, and to openly discuss relevant ethical issues participating sites were likely to face in participant recruitment, retention, and post-trial access to vaccines. The model also advantaged trial sponsors, who were able to submit a single protocol for review that could then be replicated across participating sites, enhancing rigor and protocol consistency. Representation from trial sites as part of the joint review process is a key feature of the model that helps to ensure the protocol aligns with local values and resources, and respects members’ authority to opt out of the trial if they are maligned.