Ethics review of multi-centre clinical trials in Canada.

• Author: Enzle, Michael E.
• Position: Special Issue: Canadian Governance for Ethical Research Involving Humans

Human research conducted at institutions receiving funding from any of the three federal Canadian funding agencies must be reviewed and approved in advance by a human research ethics board (REB). The Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (1) (TCPS) requires that each institution be fully responsible for the ethics review of human research conducted under its auspices (Article 1.2). (2) This provision has been interpreted to mean that one institution cannot pro forma accept the REB decision of another institution when the same research is proposed for conduct at both institutions. This interpretation is most clearly at issue in cases of multi-centre clinical trials, wherein researchers from two or more institutions are invited to participate in trials using standardized research protocols.

Many researchers, research ethics boards, clinical trial sponsors, and institutional administrators have complained informally about several inter-related consequences of TCPS Article 1.2. They argue that this Article has resulted in institutions and their REBs being concerned that reliance on another institution's REB decision would either constitute non-compliance with the TCPS, or would expose them to unknown, and therefore unacceptable, liability risks.

Other critics argue that the multiple reviews resulting from this state of uncertainty about institutional responsibility are unnecessarily redundant in view of the common standards for protection of human subjects established by the TCPS. They claim that this redundancy creates wasted human resources, wasted material resources, and wasted time.

Another concern centres on decision consistency, because it is possible for one REB to reject the same proposal judged acceptable in whole or part by another REB. Thus, the same protocol can be found acceptable for implementation at one site, but not at another.

Pharmaceutical companies and investigators (3) also complain that they receive many demands for protocol revisions from different REBs, some of which are diametrically opposed to one another. Such demands pose difficult challenges for the designers and sponsors of multi-centre trials, as homogeneity of methods across sites is a critical element of scientific control.

The critics of multiple REB reviews for multi-centre trials also cite a negative public health consequence: Research with important health implications may be delayed unnecessarily, or even discouraged, thereby indirectly depriving the populace of the best possible healthcare.

There have been three main reactions to these criticisms and warnings. One response is that redundancy and the attendant costs of multiple REB reviews is justified and desirable, as the effect is to enhance the protection of human research subjects. A second is that a national, centralized, system of review for multi-centre clinical trials should be established. The third reaction, a fait accompli, is an amendment to the TCPS Article 1.2 that permits institutions to form affiliations in which mutual acceptance of each other's REB findings can occur. (4)

1. Benefits of Redundancy

   Despite the apparent validity of the inefficiency and inconsistency arguments about multiple REB reviews, we have suggested elsewhere that multiple reviews may promote human research protections. (5) Critics of decentralized multiple reviewing implicitly claim that inconsistency among REB decisions amounts to poor reliability among REBs. They argue that a common, easily understood set of standards exist in the TCPS, and that inconsistency therefore represents a misapplication of the standards by REBs. This approach assumes, moreover, that minority opinion is wrong and reflects a lack of expertise or negligent application of ethics standards. We do not think that this is necessarily the case. Our reasoning stems from a common phenomenon at REB meetings--that in which a single REB member identifies a significant ethical issue, and persuades all remaining members of the REB that the protocol requires substantial changes or should be rejected. Thus, the minority opinion may be the incisive and decision-determining view for the local REB. The TCPS itself recognizes this possibility in its promotion of decision-making by consensus rather than by majority vote. (6) We believe that a similar dynamic might well operate at the level of multiple REBs. That is, the minority opinion of one or more REBs may sometimes be the better one. Where multiple REBs might overlook a subtle but significant point and approve a protocol, a small number of REBs might identify that critical point and reject the proposal, or call for revisions. The underlying problem is that although the TCPS does establish a common set of ethical principles, procedures and standards for researchers and REBs, there currently is no assurance system (e.g., accreditation) that establishes and oversees consistent implementation and application of those principles, procedures and standards.

2. Benefits of Centralized Review

   The 2000-2002 Health Canada Initiative

   Several years ago, Health Canada launched an ethics governance consultation process that included a multi-centre review trial balloon. This response appeared to accept the criticisms of multiple REB reviews as legitimate, but also reinforced that the primary concern of the TCPS was the protection of human research subjects. Discussion papers for that exercise cited a number of potential advantages for a national level of ethics review. (7) The Health Canada documents suggested that a national and central REB for multi-centre trials could provide a high level of review for proposals requiring specialized expertise, with a resulting enhancement of human subject protections. The papers also focused on increasing efficiency by reducing multiple reviewing of multi-centre trials. A key component of the system would have been a quality assessment and improvement system designed to ensure that all accredited REBs, including a national central REB for multi-centre trials, would meet a common and high level of human subject protections.

   The consultation papers suggested that the centralized review envisioned by the Health Canada actors of the day would have been a two-stage process. Protocols for multi-centre trials would have begun with a central national review mechanism followed by local review. In other words, a central REB could be created which would be expert in the review of pharmaceutical...