Is it time for updating the standards when it comes to informed consent for patients enrolling in clinical trials? When it comes to Phase I cancer clinical trials, particularly those with risk-targeting design in dose-finding, the answer is yes. That's the bottom line from a Comments and Controversies article published in the Journal of Clinical Oncology (2023; doi: 10.1200/JCO.22.01736).
"Is the informed consent process working? The consent form initially submitted when targeting toxicity is often peppered with words stating the goal is to find a 'safe dose' or 'well-tolerated dose'-or even the absurd 'safest dose,'" said the paper's lead author Paul Frankel, PhD, Research Professor in the Division of Biostatistics at City of Hope. "The need for this article has become increasingly important as we have seen a clear increase in Phase I cancer clinical trial designs seeking a dose where a substantial and pre-specified percent of patients will experience a severe or life-threatening adverse event in the first cycle (usually 28 days) of therapy (better known as dose-limiting toxicity)."
Informed consent of patients in clinical trials has been fundamental to medical research. The U.S. Department of Health and Human Services' Belmont Report, published in 1979, and the World Medical Association's Declaration of Helsinki, first published in 1964, provide the current basis for the informed consent process in the U.S. and elsewhere. The standards outlined in those reports have been refined and adapted since they first came out. But there's a need for more revision now, given the current clinical trial landscape, particularly for Phase I cancer drug trials, according to the new JCO paper.
Shortcomings of the Consent Process
The paper from Frankel and his colleagues focuses on Phase I clinical trials. "Issues with Phase II and III study consents are not covered in our discussion, but, as we note, the challenges with conducting a systematic review are readily apparent," Frankel said. He explained that dose-limiting toxicity-targeting Phase I clinical trial designs debuted in the early 1990s. "In our recent experience, the informed consent document and process has not adapted appropriately."
Some of the current issues with the informed consent process the paper points out include the following.
* There are consent forms stating the goal is to find a safe dose when the study design clearly indicates elsewhere that the goal is to find a dose where one in four is expected to experience dose-limiting toxicity.
* When a Phase I protocol specifically targets a dose-limiting toxicity rate and tests new or escalating doses to achieve it, there is no confirmation that this toxicity risk target is communicated to the patient.
What Would Work Better?
What is ultimately needed is transparency in Phase I cancer drug clinical trial design, as well as the risks associated with participation, according to the research. "In our opinion, there is little downside to such transparency. It is unlikely that a more thorough disclosure of risks will dissuade patients from enrolling in such studies if the level of risk is appropriate," the paper stated.
Frankel said one step in the right direction for improving the informed consent process for cancer clinical trials would be the publication of a consent model on clinicaltrials.gov. Other steps would likely involve more physician-patient interaction to discuss clinical trial participation, study design, and the risks, Frankel added.
Other researchers have come to this conclusion. A study published online in the journal PLoS One in 2017, for example, investigated patient understanding of key components of consent for their enrollment in contemporary cancer drug clinical trials. The trials involved the use of novel or conventional biologic or targeted therapies (doi: 10.1371/journal.pone.0172957). The researchers concluded that patients overall had a poor understanding of essential elements of the trials they were enrolled in at the time. Also, too much onus was put on the informed consent form itself to educate patients about the trial versus interactions with medical professionals.
"The failure to improve on the efficacy of informed consent forms over the past 20 years indicates that an adjustment to the classical conceptual framework of informed consent may be needed, de-emphasizing the role of the informed consent form as a replacement for medical counseling," the researchers noted in the paper. "The informed consent form is a part of the informed consent process, designed to complement, not replace, a discussion between researchers and subjects, but serves primarily as documentation rather than an educational tool."
Next Steps
According to Frankel, steps can be taken by different stakeholders to improve the informed consent process for patients participating in cancer clinical trials. Individual review boards can require more transparency on each protocol reviewed. That's already happening among some boards.
"As far as clinicaltrials.gov, whether there are unknown barriers to requiring a model informed consent or problems with uploading, a more accurate design summary is beyond our knowledge. However, from a site perspective, this is a minor addition to our reporting requirements," Frankel added.
And finally, practicing oncologists and cancer care providers who are informing patients about joining clinical trials should be aware of these issues.
"Practicing oncologists and cancer care providers who enroll patients in clinical trials should be aware when a study targets toxicity and participate when possible in regular conference calls to help guide the study team," Frankel said. "Oncologists who are lead investigators need to carefully consider the design of the Phase I study and make sure the consent form meets the ethical obligations required."
Sarah DiGiulio is a contributing writer.