临床研究与生物伦理学杂志

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Addressing the Ethical Challenges of First-in-Human Trials

Audrey R. Chapman

Phase I clinical trials raise ethical challenges, particularly the Phase I trials that involve a novel therapy being tested in humans for the first time, usually termed first-in-human (FIH) trials. The ethical appropriateness of clinical research requires having a favorable risk-to-benefit ratio and protecting patients from excessive risk, but both of these standards may be difficult to assess and to achieve in Phase I trials. There are no widely accepted standards for judgments concerning risk, benefit, and value in Phase I trials. Also the question of how to conceptualize and compute benefit has been a subject of ethical debate, particularly for Phase I trials where the likelihood of therapeutic benefit to participants is very slight. Specifically, should regulators and institutional review boards approve Phase I trials in the absence of likely benefit to participants when these subjects are being exposed to an uncertain and potentially high level of risk. Then there is the question as to how to communicate accurate and meaningful information about the uncertainty, risk of adverse events, and the very limited, if any, prospect of therapeutic benefit to potential trial participants in order to promote a meaningful informed consent process. That FIH trials involving highly novel agents often enroll participants with serious unmet needs further complicates the process.
Very serious adverse reactions that occurred in the first-in-human trial of the monoclonal antipody TGN412 in Britain led to the issuing of several reports on first-in-human studies and the European Medicines Agency published a guideline on first-in-human trials shortly thereafter. In the past two years the (United States) Food and Drug Administration (FDA) has approved Investigational New Drug applications for three Phase I first-in-human clinical trials of candidate therapeutics derived from human embryonic stem cells (hESCs). Neither the FDA nor the National Institutes of Health have developed their own guidelines for the safety and ethics of first-in-human trials or guidelines for first-in-human trials with hESC derivatives.
The analysis in this paper highlights the need for more focused attention to the ethical issues that first-in-human, trials raise. The paper proposes identifying prerequisites for beginning trials with a novel and potentially high-risk intervention. Preferably, there should be clear-cut guidelines and/or review by a central body.