Do Some Randomized Controlled Trials Stack the Deck?

Neil Osterweil

July 27, 2023

Randomized controlled trials in oncology can make or break an investigational drug, with both patient lives and pharmaceutical company profits at stake.

These trials typically pit two options against each other, an investigational therapy and a control therapy — often a standard of care — to see which has greater benefit.

But there are ethical gray areas in trial designs that may, intentionally or inadvertently, tip the balance in favor of the experimental arm of a trial. These biases may result in substandard care for trial participants, even harm, and can invalidate or dilute scientific findings.

One major issue is whether participants in the control arm of a trial receive the standard of care or active therapy after disease progression. In clinical trial parlance, this practice is called crossover.

Patients who do not receive standard-of-care therapy after disease progression may be "unfairly disadvantaged," according to experts in a commentary published in late June.

What's worse, optimal crossover does not always happen, commentary author Edward R. Scheffer Cliff, MBBS, MPH, from Brigham and Women’s Hospital in Boston, Massachusetts, told Medscape Medical News.

A recent example comes from the ADAURA trial comparing adjuvant therapy with osimertinib (Tagrisso) to placebo following complete resection of localized or locally advanced stage IB-IIIA non–small cell lung cancer (NSCLC) harboring EGFR mutations.

The trial, which began in November 2015, was unblinded early and halted on the recommendation of the independent data-monitoring committee because osimertinib was associated with a nearly 80% reduction in the risk of disease recurrence or death. This data led to the Food and Drug Administration's 2018 approval of osimertinib as first-line treatment in this setting.

The recent overall survival data from ADAURA, presented at the 2023 American Society of Clinical Oncology (ASCO) annual meeting, helped confirm the drug's benefit: osimertinib was associated with a 51% reduced risk for death compared with placebo.

But critics of this report were troubled by the fact that, despite the reported benefits of osimertinib, only 79 of 205 patients (38.5%) in the control arm who relapsed received the drug — now considered standard of care in this setting.

The low rate of osimertinib crossover represents a serious flaw in the trial design and potentially an ethical problem.                                                                                                                            

In the commentary, Cliff, alongside colleagues Aaron S. Kesselheim, MD, JD, MPH, and William B. Feldman, MD, DPhil, MPH, detailed the ethical issues associated with substandard crossover in clinical trials.

"In the ethical design of clinical trials, patients make important sacrifices to participate, and in exchange, the academic and clinical communities owe them optimal treatment both during the intervention part of the trial and, if they progress, after progression, especially when it is directly in the control of the trial sponsor as to whether a drug that they produce is made available to a clinical trial participant," Cliff and colleagues wrote.

The authors highlighted 10 clinical trials — including SHINE, ZUMA-7, CLL14, ALCYONE, and JAVELIN 100 —  that had problematic crossover. In the SHINE trial, for instance, 39% of control arm patients with mantle cell lymphoma received BTKi therapy post-progression, while in the ALCYONE trial of multiple myeloma, only 10% of control patients received daratumumab at first progression. The VISION trial had the lowest crossover rate, with only one control arm patient (0.5%) with metastatic castration-resistant prostate cancer receiving lutetium-PSMA-617 after progression.

"Depriving control arm patients access to standard-of-care post-RCT therapy also has important scientific implications," Cliff and colleagues wrote. In oncology, "if patients in the control arm do not receive standard-of-care therapy after disease progression, then they are unfairly disadvantaged, and it becomes difficult to assess whether the intervention has indeed improved quality of life or survival."

Clinical trials should be designed with both ethical behavior and scientific integrity in mind, Cliff told Medscape. It's incumbent on everyone directly or peripherally involved in randomized trials to ensure that they are designed with mandatory unblinding at the time of disease progression, and that crossover is both allowed and funded by the trial sponsor and mandated by the trial investigators and FDA.

When it comes to clinical trials and the sacrifices patients make to participate, "I think everyone needs to lift their game," Cliff said.

The commentary by Cliff and colleagues was supported by Arnold Ventures. Cliff disclosed institutional funding from the firm. Kesselheim reported reimbursement for expert testimony. Feldman reported consulting for Alosa Health and Aetion, and expert testimony on litigation.

J Clin Oncol. Published online June 21, 2023. Full text.

Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.

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