COMMENTARY

A Reader Responds to "The Myth of Equipoise in Phase 1 Clinical Trials"

John H. Noble, Jr.

Disclosures

December 15, 2008

To the Editor:

Dr. Adil Shamoo does an admirable job of debunking the legitimacy of using "equipoise" to justify the conduct of phase 1 clinical trials and, by extension, phase 2 and 3 clinical trials.[1] To the extent that conflicts of interest abound that distort the design, implementation, and analysis of so much of all phases of clinical research, the use of the equipoise (uncertainty) argument to justify the conduct of research is essentially a moral balm applied to sooth the conscience of research sponsors and researchers alike. An equivalent argument is also falsely made through the consenting process to induce human research subjects to participate on the grounds that removing equipoise (uncertainty) will advance the future good of society.

Ironically, the failure of so much clinical research to scrupulously adhere to the basic tenets of scientific method serves to increase rather than diminish equipoise. Replicated research by AW Chan and associates[2,3,4] shows the magnitude of selective reporting of findings in the published clinical trial literature. Selective reporting of outcomes falls into 3 broad categories: withholding the results of a well-designed clinical trial, failure to report findings in sufficient detail to permit judgment about the validity of results, and selective reporting of favorable outcomes while suppressing unfavorable outcomes. Chalmers[5] regards all 3 as "underreporting" and thus "scientific misconduct." A strong case can also be made that the conduct of underpowered clinical trials that fail to produce reliable estimates of statistically significant small but dangerous adverse effects in the clinically relevant patient subpopulations to which the findings will be applied, as acknowledged by Psaty and Furberg[6] and Drazen[7] with regard to Vioxx, increases rather than diminishes equipoise.[8,9,10,11,12,13]

Dr. Shamoo's critique reveals the essential hypocrisy of the biomedical research enterprise in plying largely poor healthy individuals with money to participate in risky phase 1 clinical trials from which they derive relatively small sums of money that are in no way commensurate with the risk.[1] The moral balm of equipoise no doubt makes it possible to prey on the vulnerable in pursuit of the "future good of society," not to mention the billions of dollars of revenue that pharmaceutical and medical device companies derive each year from the successful marketing of US Food and Drug Administration-approved products. It is justifiable in the utilitarian calculus to sacrifice the few for the sake of the many.

Citing principles 5 of the Declaration of Helsinki (concern for the interests of the subject must always prevail over the interests of science and society) and 8 (the physician is obliged to preserve the accuracy of the results of research and reports of experimentation not in accordance with Declaration principles should not be accepted for publication), I have proposed a new scenario for the reform of the biomedical research enterprise.[14] In a recent article, I propose that all stakeholders -- researchers, research sponsors, Institutional Review Boards, journal editors and peer reviewers, government oversight agencies, and human research subjects -- seek to maximize the discovery and appropriate application of innovations, looking to the future good of society rather than maximizing the accrual of individual and corporate benefits while externalizing the full costs of producing innovations.[14] In the envisioned scenario there is no need for equipoise to justify research, only reliance on contracts among the stakeholders that are subject to the same standards of enforcement that apply to any commercial contract. Failure to satisfy contractual obligations at any place in the production of research findings would create third-party liability for damages that may accrue at any point down the line.

Ironically, the dynamic for reform in this case would be the quest to remove any and all legal equipoise in contractual obligations among the stakeholders to avoid the adverse consequences of not doing so!

John H Noble, Jr.
jhnoble@verizon.net

Editor's Note:
This letter was shown to the author, who has chosen not to respond.


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