Elizabeth F. Krakow, MD, encountered some unexpected ethical challenges with informed consent after designing a sequentially randomized trial for patients with newly diagnosed acute myeloid leukemia.

The objective was to assess the utility and optimal timing of allogeneic stem cell transplantation compared to alternative treatment options.

“The treatments and timing of the treatments offered in the trial would depend on the disease response,” explains Krakow, a researcher at Fred Hutchinson Cancer Research Center in Seattle.

Changing Risk-Benefit Ratio

The traditional informed consent model required researchers to explain possible trajectories at the outset; however, this was not appropriate for the study. “When it came time to select a subsequent treatment, it would be difficult for patients to remember a conversation that occurred weeks beforehand,” says Krakow.

Conceivably, patients might refer to the original consent form as a reference, assuming they kept it — and understood it. “These documents are dense and long,” notes Krakow. “And much of the information would not be relevant to the treatment choices at hand.”

Even if patients fully understood all the complexities, an important piece of information still was missing.

“The risk-benefit ratio of the treatments proposed could not possibly be known at the outset since many clinical events would occur in the interim,” says Krakow.

Some people initially appear to be good candidates for transplant. But complications of treatment, such as renal insufficiency, may develop — changing the risk-benefit analysis. It became apparent that a repeat consent conference was necessary before each sequential randomization.

This change raised broader questions of how best to inform cancer patients about the decisions they face in any randomized trial. As someone who regularly seeks patient consent for high-stakes experimental oncologic interventions, Krakow puts a lot of thought into how these trials are presented to patients: “Yet, I still don’t think I communicate the nature of clinical trial participation well enough.”

Krakow and a colleague sought answers in a recent analysis of 27 studies.1 None of the studies specifically addressed problems posed by multiple sequential randomizations, but many of the issues were relevant. Some of the identified barriers to informed consent could be addressed fairly easily, including shortened consent forms or provision of a concise summary.

Deeply ingrained, flawed perceptions of medical research are considerably more challenging. “Beliefs such as the ‘therapeutic myth’ often lead patients to filter what they hear, and prove difficult to change,” says Krakow.

The paper was rejected by two leading oncology journals. “The editors sent almost apologetic rejection letters,” says Krakow. “They did not cite flaws in the paper, but noted that the findings would not surprise their readership.”

To the researchers, this was an indication that problematic informed consent processes are commonplace. “This leads to the question of why we allow these inadequate methods of soliciting informed consent to persist ubiquitously,” says Krakow.

Consent forms and processes may provide some legal protections to clinicians. However, they are not serving the needs of patients, concludes Krakow.

The paper suggests that researchers consider newer, lesser-used methods, such as:

  • animated videos;
  • decision aids developed with the help of patients;
  • the presence of trained patient advocates during patient/physician discussions on treatment options.

It is not uncommon for a provider to become aware of a significant change in the patient’s medical or psychosocial condition from the time the consent form was signed. In this case, another conversation is needed about whether the patient wishes to remain in the study, says Krakow.

This is especially important if study-mandated treatment is ongoing, says Krakow. “The possible risks and benefits of receiving treatment might have changed substantially.”


  1. Nathe JM, Krakow EF. The challenges of informed consent in high-stakes, randomized oncology trials: A systematic review. MDM Policy Pract 2019;1:2381468319840322.