The Challenges of Informed Consent in High-Stakes, Randomized Oncology Trials: A Systematic Review

Abstract

Importance. Oncology trials often entail high-stakes interventions where potential for morbidity and fatal side effects, and for life-prolongation or cure, intensify bioethical issues surrounding informed consent. These challenges are compounded in multistage randomized trials, which are prevalent in oncology. Objective. We sought to elucidate the major barriers to informed consent in high-stakes oncology trials in general and the best consent practices for multistage randomized trials. Evidence Review. We queried PubMed for original studies published from January 1, 1990, to April 5, 2018, that focused on readability, quality, complexity or length of consent documents, motivation and sickness level of participants, or interventions and enhancements that influence informed consent for high-stakes oncologic interventions. Exclusion criteria included articles focused on populations outside industrialized countries, minors or other vulnerable populations, physician preferences, cancer screening and prevention, or recruitment strategies. Additional articles were identified through comprehensive bibliographic review. Findings. Twenty-seven articles were retained; 19 enrolled participants and 8 examined samples of consent documents. Methodologic quality was variable. This body of literature identified certain challenges that can be readily remedied. For example, the average length of the consent forms has increased 10-fold from 1987 to 2010, and patient understanding was shown to be inversely proportional to page count; shortening forms, or providing a concise summary as mandated by the revised Common Rule, might help. However, barriers to understanding that stem from deeply ingrained and flawed sociocultural perceptions of medical research seem more difficult to surmount. Although no studies specifically addressed problems posed by multiple sequential randomizations (such as change in risk-benefit ratio due to time-varying treatment responses or organ toxicities), the findings are likely applicable and especially relevant in that context. Concrete suggestions for improvement are proposed.

Keywords: Informed consent; multistage trials; oncology; randomized trials.

Conflict of interest statement

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1

The mean number of words in informed consent forms from 1987 to 1989 was 338 (SD 67), from 2005 to 2007 it was 1087 (SD 594), and from 2009 to 2010 it was 3982 (SD 1320). Error bars show the standard deviations (SD).

Figure 2

Example of a multistage randomized trial where sequential consent or re-consent might be appropriate. Yellow circles refer to the randomizations. This trial examines whether patients who receive induction chemotherapy for acute myeloid leukemia (AML) and are then found to have measurable residual disease (MRD) should receive chemotherapy regimen A or B in an attempt to eradicate MRD. Nonresponders (i.e., persistently MRD-positive patients) are then randomized to allogeneic stem cell transplantation (C) or an experimental small molecule drug (D). All options have the potential for life prolongation or cure, but also carry very different and serious risks. Therefore, they are “high stakes” interventions. Patients may experience different trajectories: (1) A → MRD-negative → C, (2) A → MRD-positive → D, (3) B → MRD-negative → C, (4) B → MRD-positive → D. Complicating the consent process is the fact that allogeneic stem cell transplantation carries drastically different risks of cancer relapse for patients who enter transplant in an MRD-positive versus MRD-negative state, and the small molecule drug has a vastly different risk of cardiotoxicity for patients who previously received chemotherapy regimen A compared with those who previously received chemotherapy regimen B.