More than half of studies testing anticancer drugs against each other have rules about dose modification and myeloid growth factors that favor the experimental drug arm, a new analysis suggests.
This kind of "unfair" or "unequal" trial design leaves open the question of whether the new drugs are truly superior to the older ones or if the outcomes are due to more aggressive dosing or growth factor support, the investigators say.
In other words, some trials may be "rigged" in a way where the new therapy appears more effective, first author Timothée Olivier, MD, Geneva University Hospital, Switzerland, and University of California San Francisco (UCSF), told Medscape Medical News. "We found it sobering that this practice is so common."
Olivier, along with UCSF coinvestigators Alyson Haslam, PhD, and Vinay Prasad, MD, MPH, report their findings in the European Journal of Cancer.
"Highly Concerning"
When testing new cancer agents, different drug modification rules or growth factor support guidance may affect the results of randomized controlled trials (RCTs).
For the current study, Olivier and colleagues performed a cross-sectional analysis of all 62 head-to-head registration RCTs of anticancer drugs in the advanced or metastatic setting that led to US Food and Drug Administration (FDA) approval between 2009 and 2021.
The authors compared dose modification rules or myeloid growth factor recommendations in the study arms, and assessed potential imbalances in drug modification rules, myeloid growth factor recommendations, or both.
The team discovered that 40 of the 62 trials (65%) had unequal rules for dose medication, granulocyte colony-stimulating factor (G-CSF) use, or both.
Six trials (10%) had rules favoring the control arm, while 34 (55%) had rules favoring the experimental arm. Among these, 50% had unequal drug modification rules, 41% had unequal G-CSF rules, and 9% had both.
For example, the authors pointed to the KEYNOTE-042 trial, which compared first-line pembrolizumab versus platinum-based chemotherapy for advanced or metastatic non-small cell lung cancers. Patients in the control group did not receive prophylactic G-CSF, which may have led to worse toxicity or worse outcomes overall. In addition, the researchers noted, some trials may be designed to push dose intensity only in the experimental arm.
"Of course, many of these agents are highly active and life prolonging and might have still yielded superior outcomes even if rules were equal; however, the existing literature does not tell us which drugs are better compounds and which drugs succeeded merely because of greater dose intensity," the authors write.
Overall, the results of this analysis are "highly concerning," Olivier said. When investigating the effect of a new drug, "you don't want to have a false sense of a drug's effect because of other factors not directly related to the drug's efficacy."
Is There a Fix?
Olivier said that the fact that most registration trials are industry-sponsored is likely the primary reason for these findings.
"Industry-sponsored trials may be designed so that the new drug has the best chance to get the largest 'win' because this means more market share and more profit for the company that manufactures the drug," Olivier noted.
The drug industry runs on a business model that "naturally aims to gain more market share and more profit," he said. And "it is the role and duty of regulators to reconcile industry incentives with the patients' best interests." However, he noted, accumulating data show regulators are failing to do so.
Addressing this problem will likely take buy-in from multiple stakeholders.
Awareness of the problem is a first step and understanding the influence of commercial incentives in drug development is key as well, Olivier said.
Institutional review board and drug regulators could systematically evaluate drug dosing modification and supportive medication rules before a trial gets under way. Regulators could also incentivize companies to implement balanced rules between arms by not granting drug approval based on trials suffering from such flaws.
However, enforcing this level of oversight may be challenging, and potential conflicts of interest remain prevalent. For instance, a recent study from coauthor Prasad found that when hematology-oncology medical reviewers working at the FDA leave the agency more than half end up working or consulting for the pharmaceutical industry.
"Financial conflict of interest is present at many levels of drug development," Olivier said.
Eur J Cancer. Published online July 10, 2022. Full text
The study was funded by Arnold Ventures LLC, through a grant paid to UCSF. Olivier and Haslam have no relevant financial relationships. Prasad receives royalties from Arnold Ventures.
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Medscape Medical News © 2022
Cite this: Are Head-to-Head Cancer Drug Trials 'Rigged'? - Medscape - Jul 26, 2022.
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