There is a need to improve transparency with informed consent in Phase I oncology trials, according to the authors of a recently published paper.1 “Clarifying the targeted toxicity rate from a clinical perspective can minimize undisclosed risks to participants,” asserts Paul H. Frankel, PhD, the paper’s lead author and a research professor in the division of biostatistics at City of Hope Comprehensive Cancer Center.
If researchers state, “We seek a target dose-limiting toxicity (DLT) rate of 25%,” this comment probably will not grab the attention of participants. “But if written out in common language, it has an entirely different impact,” Frankel says.
For example, if a study targets a 25% DLT rate and the evaluation period is a 28-day cycle, the consent form should include that information. The form also should explain what it means in easily understood language. For instance, the consent form might state, “This study is designed to find the dose where it is expected that one in four patients will experience a particularly concerning severe adverse event within the first 28 days.”
Such clarification can improve communication among patients, principal investigators, and statisticians.
“It can ensure alignment between the clinical goals and the statistical language in the protocol. For researchers, the key thing is to question the design [of the study protocol],” Frankel says. “Is it really designed appropriately? Is it risk-targeting when it should be risk-limiting?”
For IRBs, it is challenging to question the scientific design of the study protocol. “But it is easy for IRBs to require sufficient transparency in the consent process regarding the targeted risk to the patient,” Frankel notes.
A one-size-fits-all approach does not work for informed consent in oncology trials that pose unique risks.2 Researchers interviewed 34 cancer patients and analyzed 25 consent forms. The clinical trials included “first-in-human” (trials where researchers are giving the initial use of a novel compound to study participants) and “window of opportunity” (trials where researchers give an investigational agent to treatment-naïve patients after diagnosis and before surgery). Both types of clinical trials pose unique risks to study participants.
“Window trials may postpone standard of care surgery. For first-in-human trials, we have no preliminary safety data in humans,” explains Rebecca D. Pentz, PhD, a professor of research ethics at the Winship Cancer Institute at Emory University in Atlanta.
Pentz and colleagues wanted to learn how patients preferred important information about risks to be presented in consent forms for these trials.
“We must be very careful in informing potential participants about any unique risks a trial might have. That needs to be highlighted in the consent document and explained carefully during the consent process,” Pentz stresses. “Standard informed consent forms, which often are designed by following generic templates, do not prompt investigators to mention the unique risks.”
For example, the National Cancer Institute consent document template was created based on patient advocate feedback. “But it is generic — and, thus, does not address unique risks,” Pentz says.
Many consent forms Pentz and colleagues analyzed did mention the unique risks posed by the clinical trials. “But the unique risks were not highlighted and were buried in the consent,” Pentz reports.
For example, 95% of the “first-in-human” consent forms included information about the fact the trial was “first-in-human” in the risks section, and 71% of patients wanted it in that section. However, 82% of patients also wanted the “first-in-human” information in the “purpose” section of the consent form. Only one-fourth of consent forms mentioned it in that section.
About half (53%) of “window of opportunity” patients wanted information on the unique risks to be included early in the consent form, before the “risks” section (60% of consent forms did include the information there). “Getting potential participant feedback is key to creating consent templates for trials that have unique risks,” Pentz observes.
For both types of clinical trials, patients wanted to see information about unique risks highlighted early in the consent form. If consent forms do that, and also mention the unique risks several times, it increases the chance potential participants will be aware of them. Study investigators also should make the unique risks clear during discussions with participants. “The consent conversation, not just the form, is also crucial,” Pentz says.
To ensure ethical informed consent, researchers must present potential benefits and risks to prospective participants in a balanced, accurate manner. “Researchers should avoid overpromising what participation in the trial might deliver,” warns Steven Joffe, MD, MPH, chair of the department of medical ethics and health policy and chief of the division of medical ethics at the University of Pennsylvania Perelman School of Medicine.
For example, researchers should avoid stating or implying they know the intervention under investigation in a clinical trial is the best way to treat the patient’s cancer. Another ethical concern is researchers sometimes present trial participation as the default option. If researchers offer trial participation as the first option, then present other treatments as alternatives that frames trial participation as the default option. “Joining the trial should always be an active choice as compared with receiving treatment outside a trial,” Joffe emphasizes.
For many patients with advanced cancer, symptom-directed care (or palliative care) alone may be a reasonable choice. In such cases, investigators always should present trial participation as just one option. “Researchers should ensure that if patients do decide to join the trial, they will simultaneously receive excellent palliative care,” Joffe adds.
Joffe says there are two ways to improve the informed consent process for oncology trials:
• Researchers should describe the potential benefits and risks of participating in the trial compared with potential benefits and risks of receiving standard treatment outside the trial. This allows participants to assess what additional risks they might be accepting and what additional benefits they have a chance of enjoying if they do decide to participate. “Researchers should clearly distinguish between the procedures, risks, and benefits that patients would receive anyway — if they didn’t join the trial — and those that are truly unique to the trial and, therefore, are most salient to patients’ decisions,” Joffe explains.
For example, clinical trial participation might involve a biopsy for research purposes that would not be necessary outside the trial. In other cases, trial participation involves adding a new drug the patient would not receive unless they joined the trial. That new drug might offer new possible benefits (or new possible risks) that would not exist outside the trial. “It’s those new possible benefits and new risks that the researchers need to focus on during the consent process,” Joffe says.
• Researchers should strive to write consent forms that highlight the key issues involved in the decision to join a trial. Even if researchers did write shorter, readable consent forms, however, many sponsors, IRBs, and lawyers would force them to add additional language. That makes consent forms longer and more complicated. “IRBs, sponsors, and lawyers are often a barrier to better forms,” Joffe argues. “They need to help researchers by becoming less of a barrier.”
REFERENCES
1. Frankel PH, Groshen S, Beumer JH, et al. Ethics and clinical research: Improving transparency and informed consent in phase I oncology trials. J Clin Oncol 2023;41:2155-2158.
2. Avinger AM, Sibold HC, Campbell G, et al. Improving oncology first-in-human and window of opportunity informed consent forms through participant feedback. BMC Med Ethics 2023;24:12.
Researchers should describe the potential benefits and risks of participating in the trial compared with potential benefits and risks of receiving standard treatment outside the trial. Also, strive to write consent forms that highlight the key issues involved in the decision to join a trial.
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