Jonathan Kimmelman

Predicting Harms and Benefits in Translational Trials: Ethics, Evidence, and Uncertainty

First-in-human clinical trials represent a critical juncture in the translation of laboratory discoveries. However, because they involve the greatest degree of uncertainty at any point in the drug development 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 adequately 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 Lillys Alzheimer candidate semagacestat, highlight 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 dementia and elevated rates of skin cancer [2]. Various authoritative accounts of human research ethics state that decision-making about risk and benefit should be careful, systematic, and non-arbitrary [3]–[5]. Yet, these sources provide little guidance about what kinds of evidence stakeholders should use to ensure their estimates 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 preclinical evidence base.

Setting Global Standards for Stem Cell Research and Clinical Translation: The 2016 ISSCR Guidelines

The International Society for Stem Cell Research (ISSCR) presents its 2016 Guidelines for Stem Cell Research and Clinical Translation (ISSCR, 2016). The 2016 guidelines reflect the revision and extension of two past sets of guidelines (ISSCR, 2006, ISSCR, 2008) to address new and emerging areas of stem cell discovery and application and evolving ethical, social, and policy challenges. These guidelines provide an integrated set of principles and best practices to drive progress in basic, translational, and clinical research. The guidelines demand rigor, oversight, and transparency in all aspects of practice, providing confidence to practitioners and public alike that stem cell science can proceed efficiently and remain responsive to public and patient interests. Here, we highlight key elements and recommendations in the guidelines and summarize the recommendations and deliberations behind them.

Increasing placebo responses over time in U.s. clinical trials of neuropathic pain

Abstract Recent failures of clinical trials of novel analgesics designed to treat neuropathic pain have led to much speculation about the underlying reasons. One often discussed possibility is that the placebo response in these trials has increased in recent years, leading to lower separation between the drug and placebo arms. Whether this has indeed occurred has not yet been adequately addressed. Here, we extracted data from published randomized controlled trials (RCTs) of drugs for the treatment of chronic neuropathic pain over the years 1990 to 2013. We find that placebo responses have increased considerably over this period, but drug responses have remained stable, leading to diminished treatment advantage. This trend has been driven by studies conducted in the United States. Consideration of participant and study characteristics revealed that in the United States but not elsewhere, RCTs have increased in study size and length. These changes are associated with larger placebo response. Analysis of individual RCT time courses showed different kinetics for the treatment vs placebo responses, with the former evolving more quickly than the latter and plateauing, such that maximum treatment advantage was achieved within 4 weeks.

Distinguishing between Exploratory and Confirmatory Preclinical Research Will Improve Translation

Kimmelman and colleagues argue that the key to improving preclinical research lies in distinguishing between two different modes of research: exploratory vs. confirmatory.

Beyond Access vs. Protection in Trials of Innovative Therapies

Review of first-in-human trials should safeguard the integrity of the scientific enterprise through a focus on preclinical and clinical study quality. Over the past decade, researchers have initiated innovative, early-phase, clinical trials, including the first-ever testing in humans of cell therapies for myocardial infarction (1), as well as transplantation of embryo-derived tissues for spinal cord repair (2). The next decade promises more initiatives involving first-in-human trials of innovative therapeutic strategies (3).

Confronting stem cell hype

Against hyperbole, distortion, and overselling The way science is represented to the public can influence understanding and expectations, frame policy debates, and affect the implementation and use of emerging technologies. Inaccurate representations of research may, for example, lead to public confusion about the readiness of a technology for clinical application. As a result, the issue of science “hype”—in which the state of scientific progress, the degree of certainty in models or bench results, or the potential applications of research are exaggerated—is receiving increased attention from the popular press, the research community, and scientific societies (1). In newly issued guidelines on the ethical conduct of human pluripotent stem cell research and clinical translation (2), the International Society for Stem Cell Research (ISSCR) explicitly recognizes and confronts the issue of science hype. By placing a clear obligation on researchers, the ISSCR hopes to make balance in public representations of research a norm associated with scientific integrity. The focus on public communication, which is new to this version of the guidelines, is the result of both specific concerns regarding how stem cell research has been portrayed in the public sphere and the growing recognition that researchers play an important role in the science communication process.

The ethics of human gene transfer.

Almost 20 years since the first gene-transfer trial was carried out in humans, the field has made significant advances towards clinical application. Nevertheless, it continues to face numerous unresolved ethical challenges — among them are the question of when to initiate human testing, the acceptability of germline modification and whether the technique should be applied to the enhancement of traits. Although such issues have precedents in other medical contexts, they take on a different character in gene transfer, in part because of the scientific uncertainty and the social context of innovation.

The attitudes of brain cancer patients and their caregivers towards death and dying: a qualitative study

BackgroundMuch money and energy has been spent on the study of the molecular biology of malignant brain tumours. However, little attention has been paid to the wishes of patients afflicted with these incurable tumours, and how this might influence treatment considerations.MethodsWe interviewed 29 individuals – 7 patients dying of a malignant brain tumor and 22 loved ones. One-on-one interviews were conducted according to a pre-designed interview guide. A combination of open-ended questions, as well as clinical scenarios was presented to participants in order to understand what is meaningful and valuable to them when determining treatment options and management approaches. The results were analyzed, coded, and interpreted using qualitative analytic techniques in order to arrive at several common overarching themes.ResultsSeven major themes were identified. In general, respondents were united in viewing brain cancer as unique amongst malignancies, due in large part to the premium placed on mental competence and cognitive functioning. Importantly, participants found their experiences, however difficult, led to the discovery of inner strength and resilience. Responses were usually framed within an interpersonal context, and participants were generally grateful for the opportunity to speak about their experiences. Attitudes towards religion, spirituality, and euthanasia were also probed.ConclusionSeveral important themes underlie the experiences of brain cancer patients and their caregivers. It is important to consider these when managing these patients and to respect not only their autonomy but also the complex interpersonal toll that a malignant diagnosis can have.

Unsuccessful trial accrual and human subjects protections: An empirical analysis of recently closed trials:

Background Ethical evaluation of risk–benefit in clinical trials is premised on the achievability of resolving research questions motivating an investigation. Objective To determine the fraction and number of patients enrolled in trials that were at risk of not meaningfully addressing their primary research objective due to unsuccessful patient accrual. Methods We used the National Library of Medicine clinical trial registry to capture all initiated phases 2 and 3 intervention clinical trials that were registered as closed in 2011. We then determined the number that had been terminated due to unsuccessful accrual and the number that had closed after less than 85% of the target number of human subjects had been enrolled. Five factors were tested for association with unsuccessful accrual. Results Of 2579 eligible trials, 481 (19%) either terminated for failed accrual or completed with less than 85% expected enrolment, seriously compromising their statistical power. Factors associated with unsuccessful accrual included greater number of eligibility criteria (p = 0.013), non-industry funding (25% vs 16%, p < 0.0001), earlier trial phase (23% vs 16%, p < 0.0001), fewer number of research sites at trial completion (p < 0.0001) and at registration (p < 0.0001), and an active (non-placebo) comparator (23% vs 16%, p < 0.001). Conclusion A total of 48,027 patients had enrolled in trials closed in 2011 who were unable to answer the primary research question meaningfully. Ethics bodies, investigators, and data monitoring committees should carefully scrutinize trial design, recruitment plans, and feasibility of achieving accrual targets when designing and reviewing trials, monitor accrual once initiated, and take corrective action when accrual is lagging.

Are outcome-adaptive allocation trials ethical?

Randomization is firmly established as a cornerstone of clinical trial methodology. Yet, the ethics of randomization continues to generate controversy. The default, and most efficient, allocation scheme randomizes patients equally (1:1) across all arms of study. However, many randomized trials are using outcome-adaptive allocation schemes, which dynamically adjust the allocation ratio in favor of the better performing treatment arm. Advocates of outcome-adaptive allocation contend that it better accommodates clinical equipoise and promotes informed consent, since such trials limit patient-subject exposure to sub-optimal care. In this essay, we argue that this purported ethical advantage of outcome-adaptive allocation does not stand up to careful scrutiny in the setting of two-armed studies and/or early-phase research.