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OBR OncologyControversy Over Crossover Access in Clinical Trials: Should Changes Be Mandated?

The Ethical Quandary of Crossover in Oncology Clinical Trials

Oncologists are increasingly alarmed by the problematic use, or absence, of crossover in randomized clinical trials. The issue not only jeopardizes the interpretation of trial outcomes but also raises ethical questions concerning patient care, especially when the control arm is not given access to the best available treatment at disease progression.

HCN Medical Memo
The growing concern over crossover in oncology studies is a crucial ethical and scientific issue. The absence of mandated crossover not only limits the interpretability of trial results but also questions the ethical integrity of depriving the control arm of beneficial treatments. As the medical community navigates more targeted and complex therapies, a renewed focus on ensuring ethical and scientifically sound crossover protocols is urgently needed.

Key Points:
  • Bishal Gyawali, MD, PhD, from Queen’s University, Ontario, highlights in a Nature Reviews Clinical Oncology commentary that the lack of mandated crossover confuses clinical trial results and can be ethically compromising.
  • The ADAURA trial, presented at the 2023 ASCO Annual Meeting, allowed but did not mandate crossover to osimertinib for patients in the control arm, making the comparator arm unrepresentative of the current standard of care.
  • Another example is the NATALEE trial, which also lacked mandated crossover to ribociclib, the standard care at disease relapse.
  • Edward R. Scheffer Cliff, MBBS, MPH, questioned the ethics of not providing standard-of-care postprogression therapy and emphasized its importance for the scientific integrity of the trial.
Additional Points:
  • Trials conducted internationally or in countries where the drug is not yet approved face challenges in providing the US standard of care but can still be designed to include crossover.
  • A study found that only 36.4% of trials had assessable postprogression data reported between January 2018 to December 2020.
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“To me, every step of the process is failing patients. The drug companies, trial investigators, peer reviewers, journals, and the FDA and other regulators are all failing patients when they don’t insist on crossover in appropriate scenarios.”
– Edward R. Scheffer Cliff, MBBS, MPH, Brigham and Women’s Hospital in Boston

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