Ethical Considerations for Phase I Trials in Oncology

Abstract

Phase I trials often represent the first occasion where new cancer strategies are tested in patients. Various developments in cancer biology, methodology, regulation, and medical ethics have altered the ethical landscape of such trials. We provide a narrative review of contemporary ethical challenges in design, conduct, and reporting of phase I cancer trials and outline recommendations for addressing each. We organized our review around four topics, supplementing the first three with scoping reviews: (1) benefit/risk, (2) research biopsies, (3) therapeutic misconception and misestimation, and (4) reporting. The main ethical challenges of conducting phase I trials stem from three issues. First, phase I trials often involve higher research burden and scientific uncertainty compared with other cancer trials. Second, many patients arrive at phase I trials at a transitional point in their illness trajectory where they have exhausted standard survival-extending options. Third, phase I trial results play a major role in informing downstream drug development and regulatory decisions. Together, these issues create distinct pressures for study design, ethical review, informed consent, and reporting. Developments in methodology, regulation, cancer biology, and ethical awareness have helped mitigate some of these challenges, while introducing others. We conclude our review with a series of recommendations regarding trial design, ethical review, consent, and reporting. We also outline several unresolved questions that, if addressed, would strengthen the ethical foundation of phase I cancer trials.

Should Children Be Included in Human Challenge Studies?

“…74 One point of broad agreement-which is particularly instructive for pediatric human challenge studies-is that the ethics of children's inclusion in phase I oncology trials should be guided by necessityto answer a scientific question and to the patient once options offering the prospect of direct medical benefit have been exhausted. Phase I oncology trials are a necessary step between preclinical studies and evidencebased improvements to medical practice and patient outcomes, 75 and cannot be conducted effectively with adults only, given the differences in drug tolerance and pharmacokinetics between children and adults, and the limitations of extrapolations from adult studies. 76 Pediatric human challenge studies should also be guided by necessity.…”

Travel Time and Distance and Participation in Precision Oncology Trials at the National Cancer Center Hospital

“…The number of genes amenable to genotype-matched trials has been steadily increasing over the past 2 decades, 11 and the response rate in phase 1 trials has surged by nearly 2-fold to 15% to 25% without an increase in treatmentrelated death, which has therapeutic implications. [11][12][13][14][15] Therefore, an inequity in accessibility to these trials suggests an ethical problem. 12 Several factors can reduce the likelihood of participation in cancer clinical trials, including eligibility and socioeconomic status.…”

“…[11][12][13][14][15] Therefore, an inequity in accessibility to these trials suggests an ethical problem. 12 Several factors can reduce the likelihood of participation in cancer clinical trials, including eligibility and socioeconomic status. 16,17 The burdens of time and costs associated with travel to the trial sites also account for the low likelihood of cancer clinical trial participation.…”

“…Participating in clinical trials can help patients with cancer gain access to new and potentially life-saving therapies that may otherwise be unavailable. The number of genes amenable to genotype-matched trials has been steadily increasing over the past 2 decades, and the response rate in phase 1 trials has surged by nearly 2-fold to 15% to 25% without an increase in treatment-related death, which has therapeutic implications . Therefore, an inequity in accessibility to these trials suggests an ethical problem …”

Statistics in Oncology

“…Moving beyond the statistical design, another key consideration of phase I trials is conveying the risk/benefit of an investigational agent to patients. Bittlinger et al 6 provide a narrative review of ethical issues in contemporary phase I clinical trials. They illustrate how the main ethical challenges stem from three issues: phase I trials have greater uncertainty and burden than later-phase cancer trials; they may offer less prospective benefit from the experimental intervention than later-phase trials; and their patient population is different than later-phase trials.…”