Ethics Review of Multi-Centre Clinical Trials in Canada
Enzle, Michael E., Schmaltz, Rodney, Health Law Review
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. …