A Good Number of Cancer Patients in Mid-Stage Trials Get Drugs Later Approved

One in six patients in phase II oncology clinical trials received a treatment that was eventually approved by the FDA, according to a longitudinal study.

In a sample of 400 phase II trials that included 25,000 participants, a total of 4,045 patients (16.2%) received a treatment that advanced to FDA approval, reported Jonathan Kimmelman, PhD, of the McGill University School of Population and Global Health in Montreal, and colleagues in the Journal of the National Cancer Institute.

That proportion increased to 19.4% when considering treatments that received off-label recommendations in National Comprehensive Cancer Network (NCCN) guidelines and decreased to 9.3% for FDA-approved regimens that are considered to have substantial clinical benefit using the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS).

Kimmelman and colleagues also observed that the proportion of patients receiving approved treatments in phase II trials is much greater than that previously estimated for phase I trials (1.2%).

“This suggests that phase I trials do a good job at protecting patients downstream from unsafe and ineffective cancer treatments,” they wrote.

“Regarding design and ethical review, our findings suggest that, when evaluating risk, reviewers should direct their focus on the expected scientific value of the study,” they concluded. “Specifically, they should consider the strength of the scientific justification and the soundness of design.”

“With respect to consent, many educational materials emphasize that trials present an opportunity to receive tomorrow’s treatments,” they added. “Our findings move beyond such nondescript statements to meaningful statements — namely, that by entering a phase II trial, a patient has a 1 in 6 chance of receiving a treatment that will later be approved for their condition.”

In an editorial accompanying the study, Howard S. Hochster, MD, of the Rutgers Cancer Institute in New Brunswick, New Jersey, suggested that the benefit rate of 16.2% calculated by Kimmelman and colleagues is likely understated.

Hochster pointed out that the study showed that if the definition of benefit was broadened even further — if the criteria were whether the drugs were FDA approved for any indication and dose — the proportion of patients who benefit in these trials rises to 37.7%, and to 50.9% if considering inclusion in NCCN guidelines.

“The need to continue oncology new drug development using expansion cohorts and/or phase II trials is not debatable,” Hochster wrote. “Every approved and beneficial oncology drug has been through a phase II type of study to demonstrate activity by response or time to progression. We can improve the individual patient and regulatory approval rates by using more appropriately designed trials, ensuring correct patient selection and use of biomarkers reflecting the best evidence-based understanding of tumor biology and the mechanisms of actions for the new agent.”

According to Kimmelman and colleagues, while a number of studies have assessed the risk/benefit balance for treatments in phase I trials, little is known about the extent to which patients benefit by enrolling in phase I dose expansion or phase II clinical trials.

In this study, the authors randomly sampled 400 trials initiated from November 2012 to November 2015 — allowing 7.5 years after trial launch for a drug to proceed to regulatory approval.

These were interventional phase II cancer trials that tested drug-indication pairings that were not FDA approved at the time the trial started. The authors excluded trials with ambiguous product names, adjuvant or neoadjuvant trials, trials without an efficacy endpoint, trials without a registered primary completion date, and trials addressing symptoms of treatment.

These trials had a total patient enrollment of 25,002 patient-participants in 608 specific treatment cohorts testing 332 drugs. The median enrollment per trial was 62 patients. Most patients (73%) had advanced or metastatic disease.

Regulatory approval was granted to 71 drug regimens in the tested indication, 24% of which involved accelerated approvals.

Kimmelman and colleagues said their analysis suggests certain types of trials provide a greater chance a therapy will advance to approval. Phase II trials involving biomarker enrichment or immunotherapy increased the probability of receiving a later-approved therapy to one in four, and trials testing unapproved drugs showed a therapeutic proportion of one in five, compared with one in 11 for trials testing approved drugs in a new indication.

The authors acknowledged several limitations to their study. For example, since cancer research is constantly evolving, they suggested its longitudinal design meant there was no guarantee that the therapeutic percentages based on the cohort of drugs in this study would be sustained in present-day cohorts.

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