By Mark Yarborough
Imagine that you suffered from a fatal neurodegenerative disorder like Alzheimers or ALS, or that you had a serious chronic condition like hypertension or heart disease. Imagine further that you were asked to participate in a clinical trial related to your disease. Finally, imagine that the person recruiting you into the trial reassured you that the study had been vetted by a research ethics committee (REC) tasked with protecting your welfare, rights, and interests.
Of course, countless people in these exact same circumstances routinely get recruited into REC-approved trials. While many or perhaps even most of them may have never heard of RECs and the role they play in clinical research, they nevertheless are likely to implicitly trust that the trials they are being recruited into are both important and ethical to conduct. Such trust should be warranted since that is what REC approval is meant to certify.
But does REC approval reliably certify this? I suspect that many readers of this journal believe that they do and thus rarely if ever truly ponder the question. I know this used to be true for me, in large part due to my own personal experiences working on RECs and seeing the hard work and dedication of committee members and staff. Today, though, I am convinced that the question is one of the most central ones there is in research ethics. After all, the trustworthiness of the clinical research endeavour is in large part a direct outcome of the strength of the accountability measures in place to support it and REC review is at the heart of those accountability measures.
Why the shift in my thinking? It is the result of spending many years trying to learn as much as I can both about what makes biomedical research deserving of the public’s trust and how well accountability measures, such as utilization of sound research design and methods, as well as regulatory oversight, actually work. I’ve spent a lot of time consulting the literature that reports about research on research to see what it shows. This has proven to be a real eye-opener that woke me from my “dogmatic slumber” of implicit confidence in the status quo.
Two articles in particular, both of which I refer to in my article, catalysed the shift from major confidence in RECs to real worry that REC review may well be fundamentally broken. One article is of particular relevance to the people who suffer from the kinds of serious neurodegenerative disorders I mentioned above. It was a meta-analysis done to estimate the extent of excess significance bias in preclinical neurosciences studies. It drew from several thousand preclinical studies that informed 160 early phase clinical investigations, each of which was fuelled by the volunteerism of the trial participants. The authors concluded that, based on their examination, only 8 of the 160 clinical investigations should have been done. Of all the questions this conclusion prompts, the most critical one for me is, how is it possible that all 160 trials received REC approval. The other article is of particular relevance to the other people I mentioned above who suffer from chronic disorders. It was an analysis of several dozen randomly selected later phase head-to-head trials comparing competing drugs, devices, and biologics. These trials collectively were fuelled by several hundred thousand volunteer research participants. The authors of the article concluded that, due to features of the design of the trials, less than half a dozen of them were capable of producing truly meaningful findings. This conclusion also prompts many questions, with the most critical one for me being, again, how is it possible that RECs approved all of the trials, rather than just some of them.
My current article only somewhat probes these questions because it is, for the most part, an attempt to make the case that the REC status quo is deeply flawed, as well as explore what we might do to strengthen it. I think this focus is warranted given all the inertia behind the status quo. A necessary step for resisting that inertia is recognition of problems and their scope. So, in my article I try to show that there are major ones across the entire spectrum of clinical trials that call the ethical conduct of countless trials into question that somehow continually elude recognition by RECs.
If I were to speculate, and this is nothing more than speculation on my part, about the major propellants of the inertia, I would point to three. First is a set of basic facts pertaining to RECs: they too often limit their objectives to complying with regulatory mandates; they work one application at a time (they miss the forest for the trees); they have full meeting agendas and thus are always pressed for time; they either reside in institutions whose mission is to conduct research and/or they are paid by research sponsors to review their trials; and what they consider in their deliberations is largely a function of the paper placed in front of them.
Second, with respect to REC review of early trials, I think too many REC members get cowed by the prior decisions of regulatory agencies such as the FDA and EMA because they fail to appreciate just how narrow the scope of review done by those agencies actually is. For example, as I touch upon in my article, just because the FDA or EMA grants permission to conduct human studies on a novel treatment modality, that does not mean that any given human study of it is ethically warranted. Rather, all it means is that the regulatory agency is satisfied that the new modality is safe enough to initially test in humans. But there is still the more fundamental ethical decision to make, which is “are the possible benefits of conducting a clinical test of a new modality reasonable in relation to the risks?” It is almost always the case that RECs are the only ones tasked with answering this ethically essential risk/benefit question. Thus, when RECs treat regulatory assessments about safety as if they are equivalent to a risk/benefit analysis, there is no assurance that a trial has the potential for producing benefit that is sufficient to offset its risks.
Third, with respect to REC review of later phase industry-sponsored trials, while no doubt many REC members may be quite sceptical or even cynical about the large companies that sponsor the trials, I am not sure that they fully appreciate the track record showing the extent to which these companies can hijack the trappings of science and hoodwink research participants in order to gain a leg-up on their competitors, sometimes even when, as I discuss in my article, this occurs at the expense of patient health. Greater appreciation of this track record might heighten REC members’ interest in knowing whether or not any later phase industry-sponsored trial they happen to be reviewing is tainted by any of the factors that have led to the worrisome track record in the first place.
The article itself, however, is not mere speculation. It is an analysis of a robust body of evidence that raises fundamental concerns about current REC practices. Readers may disagree with my analysis of the evidence. That is fine. All that I ask is that they avail themselves of the evidence itself and I worry that too many in the research oversight and research ethics communities currently are not.
Author(s): Mark Yarborough
Affiliations: University of California Davis Bioethics Program
Competing interests: None