Essay Predicting Harms and Benefits in Translational Trials: Ethics, Evidence, and Uncertainty Jonathan Kimmelman 1 , Alex John London 2 * 1 Biomedical Ethics Unit, Department of Social Studies of Medicine, McGill University, Montreal, Quebec, Canada, 2 Department of Philosophy, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America Introduction First-in-human clinical trials represent a critical juncture in the translation of laboratory discoveries. However, because they involve the greatest degree of uncer- tainty at any point in the drug develop- ment process, their initiation is beset by a series of nettlesome ethical questions [1]: has clinical promise been sufficiently demonstrated in animals? Should trial access be restricted to patients with refractory disease? Should trials be viewed as therapeutic? Have researchers ade- quately minimized risks? The resolution of such ethical questions inevitably turns on claims about future events like harms, therapeutic response, and clinical translation. Recurrent failures in clinical translation, like Eli Lilly’s Alzheimer candidate semagacestat, high- light the severe limitations of current methods of prediction. In this case, patients in the active arm of the placebo- controlled trial had earlier onset of de- mentia and elevated rates of skin cancer [2]. Various authoritative accounts of hu- man research ethics state that decision- making about risk and benefit should be careful, systematic, and non-arbitrary [3– 5]. Yet, these sources provide little guid- ance about what kinds of evidence stake- holders should use to ensure their esti- mates of such events ground responsible ethical decisions. In this article, we suggest that investigators, oversight bodies, and sponsors often base their predictions on a flawed and inappropriately narrow pre- clinical evidence base. Prediction and Ethical Decision- Making According to the core tenets of human research ethics, investigators, sponsors, and institutional review boards (IRBs) are obligated to ensure that risks to volunteers are minimized and balanced favorably with anticipated benefits to society and, if applicable, to the volunteers themselves [4,6]. Accurate prediction plays a critical role in this process. When research teams underestimate the probability of favorable clinical or translational outcomes, they undermine health care systems by imped- ing clinical translation. When investigators overestimate the probability of favorable outcomes, they potentially expose individ- uals to unjustified burdens, which may be considerable for phase 1 studies involving unproven drugs. In both cases, misestima- tion threatens the integrity of the scientific enterprise, because it frustrates prudent allocation of research resources [7]. Naturally, there are limits to the reli- ability with which forecasts based on experimental evidence predict clinical outcomes. However, in late stages of clinical development, forecasts underwrit- ing ethical and scientific decision-making have proven fairly reliable. Several analy- ses of cancer randomized controlled trials indicate that new interventions are just as likely to prove more effective than com- parator ones as they were to prove inferior [8–10]. Similar findings have been report- ed for other indications [11]. In the aggregate at least, researchers and review committees neither overestimate nor un- derestimate the medical benefits of allo- cating some patients to new interventions and others to standard drugs. Whether decision-makers utilize evi- dence as effectively when predicting out- comes in early phase research has not been systematically investigated. Never- theless, there are grounds for concern such that a systematic investigation is overdue. Highly promising preclinical findings in cancer, stroke, HIV vaccines, and neuro- degenerative diseases frequently fail clini- cal translation. In cancer, only 5% of products entering trials are eventually licensed [12,13]. In one study, approxi- mately 5% of high impact basic science reports were clinically translated within 10 years [14]. We suggest that these disap- pointments partly reflect two problems in the way evidence is used in predicting clinical outcomes. Preclinical Reporting and Validity First, decision-makers may not be adequately responsive to problems in preclinical research practice [15]. System- atic reviews repeatedly demonstrate that many animal studies do not enable reliable causal inference and clinical generalization because they do not address important threats to internal, construct, and external validity. With respect to the first, one recent analysis of animal studies showed that only 12% used random allocation and 14% used blinded outcome assessment [16]. Construct validity concerns the relationship between clinical implementa- tion of an intervention and implementa- tions evaluated in preclinical studies. A recent review found that clinical studies of cardiac arrest interventions applied treat- ment significantly sooner after cardiac events than in preclinical studies [17]. In the case of Astra Zeneca’s failed stroke drug NXY-059, use of normotensive The Essay section contains opinion pieces on topics of broad interest to a general medical audience. Citation: Kimmelman J, London AJ (2011) Predicting Harms and Benefits in Translational Trials: Ethics, Evidence, and Uncertainty. PLoS Med 8(3): e1001010. doi:10.1371/journal.pmed.1001010 Published March 8, 2011 Copyright: ß 2011 Kimmelman, London. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors were supported by Canadian Institutes of Health Research (EOG 102823) and a fellowship from the Andrew W. Mellon Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: ajlondon@andrew.cmu.edu Provenance: Not commissioned; externally peer reviewed. PLoS Medicine | www.plosmedicine.org 1 March 2011 | Volume 8 | Issue 3 | e1001010