Sunday, April 3, 2011

The Costs of Ethical Review, Part II

Researchers on both sides of the Atantic are trying to measure how the delay due to ethics review in medical research can harm or kill those who would benefit from innovative therapy.

[Ian Roberts, David Prieto-Merino, Haleema Shakur, Iain Chalmers, Jon Nicholl, "Effect of Consent Rituals on Mortality in Emergency Care Research," Lancet 377, no. 9771 (26 March 2011): 1071-1072, doi:10.1016/S0140-6736(11)60317-6; S. N. Whitney and C. E. Schneider, "Viewpoint: A Method to Estimate the Cost in Lives of Ethics Board Review of Biomedical Research," Journal of Internal Medicine 269, no. 4, (April 2011): 396-402, doi: 10.1111/j.1365-2796.2011.02351_2.x See also The Costs of Ethical Review. Hat tips to Rebecca Tushnet and Simon Whitney.]

Writing in the Lancet, Ian Roberts, David Prieto-Merino, Haleema Shakur, Iain Chalmers, and Jon Nicholl report on the CRASH-2 trial, in which tranexamic acid was administered to trauma patients at risk of significant bleeding. Because this was a clinical trial, hospitals were required to secure written consent from relatives before administering the treatment. The authors estimate that this process delayed treatment by about an hour or two, reducing the benefit: "Whereas the relative risk of death from bleeding with tranexamic acid was estimated in the CRASH-2 trial as 0·85 (95% CI 0·76—0·96), the corresponding relative risk in the presence of a 1-h delay is 0·96 (0·86—1·08)." Moreover, they argue, "the delay in starting treatment can obscure a real treatment benefit from the administration of a time-critical treatment. In the CRASH-2 trial, the requirement for written informed consent probably means that the trial has underestimated the beneficial effect of tranexamic acid in trauma patients with bleeds, which would be given without delay in normal clinical practice."

They conclude that "the need for an urgent trial treatment, even in patients who are conscious and whose relatives are available, by itself excludes the possibility of fully informed consent. If consent rituals delay the start of a trial treatment such that the treatment effect could be reduced or obscured, we maintain that seeking consent is actually unethical."

Meanwhile, Simon Whitney and Carl Schneider offer a more general exploration of the costs of ethics review. Building on the work of Collins, Doll, and Peto, they note that major studies, like the ISIS-2 trial of the effect of thrombolytics on the mortality of hospitalized heart attack patients, can radically change the standard of care for a given condition. Since differences across countries suggest that detailed consent procedures can delay recruitment for such trials, they conclude that these procedures delay the eventual introduction of new therapies, costing thousands of lives.

Whitney and Schneider conclude that "the cost of research-ethics regulation is great enough" to require urgent inquiry into the number of lives lost to regulatory delay.

Commentators on both projects note that one can imagine a system of ethics review that offers more flexible consent procedures, thus securing the benefits of ethics review at a lower cost in lives. Responding to an account of the Lancet study [Ben Goldacre, "When Ethics Committees Kill," The Guardian: Bad Science, 26 March 2011], a commenter ("Dingleford") suggests that a problem with the way ethics committees handle emergency treatment does not discredit the system as a whole. And a response to the Whitney and Schneider piece [S. Holm, "Commentary: Systems, rules and the costs of being ethical – a response to D. Chalmers and to S. Whitney and C. Schneider," Journal of Internal Medicine 269, no. 4, (April 2011): 403-406, doi: 10.1111/j.1365-2796.2011.02351_3.x] suggests that the problem lies not with the principles of the Helsinki Declaration or the concept of ethics review, but rather "a belief that all decisions need to be consistent, and wrongly believing that consistency is, in this case, a matter of linguistic conformity," resulting in long and hard-to-understand consent forms.

While any improvement is welcome, I think that these comments overlook a basic finding of the two articles: that regulators have failed to assess either the costs or the benefits of ethics review. Whitney and Schneider offer a 2007 statement by Greg Koski, the former director of OHRP: "We still don’t have direct evidence that the current process is actually preventing harm. We need solid empirical research on whether the IRB process is actually working." If a regulatory regime has demonstrably deleterious effects on human health and no clear evidence of benefit, does it not make sense to devote some public resources to exploring its worth and that of possible alternatives?

It will be harder to make the case that the restrictions on social science kill people, but I don't think it is out of the question. Had Scott Atran been allowed to interview more failed suicide bombers, might he not have helped avert a bombing, saving dozens or hundreds of lives? Had Robert Dingwall had an easier time studying the reuse of single-use surgical and anaesthetic devices, might he not have prevented more deaths from post-operative infections?

More typically, though, the real, unmeasured cost of IRB review of the social sciences comes in lives diminished, not lost. Had Linda Thornton and Martin Bergee been able to conduct a richer study of why students major in music education, they would have prevented no hemmorages, heart attacks, infections, or suicide bombings. At most, they might have gained insight that would have helped some people avoid a career not suited for them, and steered other young people with the knack toward a life as a music teacher, bringing song, joy, and enhanced cognitive skills to hundreds of children over the course of decades. I would like to think that this, too, merits attention.


Anonymous said...

Research is not therapy! Thinking otherwise is falling victim to therapeutic misconception. Until you've done the research you don't know that the drug or intervention is effective. That's the whole point of clinical trials, to figure out if it works or it doesn't. And most of them don't work or worse. And it's often a big problem getting people, both patients and often the doctors conducting the trials, to understand this.

Of course in some situations the researchers may be doing research on an intervention that's already in common use to establish whether it works or not. (A lot of medical practice has undergone rigorous evaluation--and a lot of it isn't good for you.) In those cases the researchers shouldn't be asking for consent to do the intervention if it would have been done anyway.

Zachary M. Schrag said...

Thank you for these comments.

I don't think that either the Roberts article or the Whitney article claim that research is therapy. Rather, they claim that research saves lives, and that, by hampering research, ethics review and consent requirements cost lives. Though their examples are studies that proved the benefits of certain treatments, their claim would be true even for studies that show that a given intervention is ineffective or harmful. The sooner we learn that, the better off we will be. The costs of ethics review must be measured against whatever gains can be established for it.

By contrast, Beauchamp does claim that the distinction between research and therapy has been taken too far. "The distinction between therapeutic and nontherapeutic research has a considerably diminished presence in biomedical ethics today," Beauchamp writes. "No doubt we need to be cautious about this distinction, but I am not convinced that the language of ‘therapeutic research’ is illogical or a poor way to understand how research functions in many settings. Instead of abandoning the therapeutic-nontherapeutic research distinction, we might consider resuscitating it for today’s medical environment."