Ethics review of multi-centre trials: where do we stand?

• Author: Saginur, Raphael

It has been a decade since the Office of the Inspector General, U.S. Health and Human Services (OIG), issued its landmark report, Institutional Review Boards: A Time for Reform. (1) The OIG report talked of major changes in the research environment, with more multi-centre trials (MCTs) and increased commercialization of research. The purpose of this article is to review recent developments in terms of ethics (2) review of MCTs within the Canadian context.

The OIG report described a number of important findings, all of which apply to the Canadian context as well:

* The number of studies reviewed by each REB has increased enormously, without a commensurate increase in resources and with continued lack of appropriate expertise on IRBs.

* Insufficient attention was given to monitoring the study after initial approval.

* Healthcare institutions have become dependent on revenues from commercially sponsored clinical research.

* There is concern about lack of independence of REBs and institutional pressure to approve trials, resulting in concern about conflict of interest.

* There was insufficient training for investigators and Board members.

The OIG called for a variety of measures to improve the system, including an increased role for Data Safety Monitoring Boards (DSMBs). However, the OIG did not advocate centralization of IRB function.

In a previous article in this journal, Enzle and Schmaltz reviewed the issue of MCTs in the Canadian context, and focused on the issue of centralization of ethics review. (3 They observed that article 1.2 of the Tri-Council Policy Statement (TCPS) (4) could be interpreted to limit the possibility of central review of MCTs. The TCPS initially assumed that an REB would be under the purview of an individual institution. Although this was later amended to allow delegation, Enzle and Schmaltz addressed multiple reasons why an institution might choose to use its own REB for ethics review of all studies involving the institution or its personnel, including regulatory compliance, management of liability, and quality of review. They noted that there was no regulatory or other requirement for ethics review within the institution. Rather, there was the requirement that the institution be accountable for research done under its auspices. Concern of the institution regarding liability was intertwined with a desire on the part of the institution to maintain control of ethics review as part of a broader administrative oversight of what is done in the institution. Finally, Enzle and Schmaltz addressed the inherent strengths and weaknesses of multiple ethics review. Strengths included a greater possibility of identification of key issues if more eyes observed a trial. However, concomitant weaknesses included redundant use of resources and inconsistencies between sites which could result in delays to the research. Although they reviewed examples of centralized REBs at that time, there was limited experience in this regard.

The key issue with moving toward centralized REB review can be summarized as follows. Under the current system of individual REB review, the opinion of each REB represents the consensus opinion of a number of individuals. However, centralizing ethics review to one REB necessarily means that there is only one consensus opinion. Multiple REB reviews mean that there will be more variability in response. A key issue is whether this variability is desirable.

Enzle and Schmaltz observe that differing REB opinions provide an opportunity for the critical study of a concern arising from a lone dissenter at a single REB, which could potentially be recognized by the REB as a whole in its decision. The authors however do not provide supporting data. There are abundant arguments to the contrary. (5) Numerous studies from disgruntled investigators address inefficiencies, inconsistencies and other negative consequences of multiple reviews of their trials. Burman et al. address consent form changes proposed by multiple REBs in a multi-centre trial of therapy of tuberculosis, resulting in errors and increased complexity to the forms. (6) Of the median 46.5 changes per form per REB, only 1.5% were thought to reflect local issues and only 1.7% were thought to be of potential general relevance to all sites. Gold and Dewa reviewed problems with ethics review of MCTs, and cite the huge costs, delays, and inconsistencies of institutional-based review. (7) They believe the differences are unrelated to substantive criteria. A systematic review by Greene and Geiger identified a total of 40 peer-reviewed articles and 6 commission or advisory reports regarding ethics review of MCTs. (8) The same problems were repeatedly identified in multiple studies. There were proposals for solutions with limited empirical data to support them. Of note, education and training of REB members and investigators were thought to be a key element of addressing MCTs. The problems with the REB system jeopardize research and squander scarce funds; costs are estimated at $1000 per site per review. (9)

Structurally, a negative response from one of a large number of institutional REBs reviewing a particular study does not impact the study as a whole; rather, it impacts that site, which will not participate, while the study goes ahead at the other sites. Dissenting opinions from individual REBs may be disregarded by the sponsors simply by bypassing the dissenting institution. The question arises, then, is the one review per centre model a source of quality or is it a reason for...