Commercial considerations, rather than patient interests, could be driving a substantial increase in the number of cancer drug trials stopped early in recent years because the therapies involved started to show a benefit, a new analysis suggests.

The Italian study, published in the journal Annals of Oncology, has raised concerns about the early termination of cancer trials leading to premature and inflated claims for marketed drugs whose risk-benefit profile is still poorly defined.

Researchers from the Italian Medicines Agency and the Mario Negri Institute for Pharmacological Research in Milan assessed the use of interim analyses in randomised controlled trials (RCTs) of new anticancer drugs where the trial was terminated early because the treatment was showing a benefit rather than for reasons of harm (toxicity) or futility (lack of efficacy).

In the initial sample of 93 papers published between January 1997 and October 2007, 28 (30%) of trials were halted early for benefit, 28 (30%) for futility and four (4%) for harm. The final sample (i.e., trials stopped early for benefit) was 25 papers, with the drugs involved including Sutent (sunitinib, Pfizer), Herceptin (trastuzumab, Roche), Avastin (Roche) and Gemzar (gemcitabine, Eli Lilly).

The researchers found that 14 (56%) of the selected trials were published between 2005 and 2007, while 11 of them (79%) were used to support an application for marketing authorisation to the European Medicines Agency (EMEA) and the US Food and Drug Administration (FDA). “This suggests a commercial component in stopping trials prematurely,” the authors commented.

There was particular concern about five studies that had enrolled less than 40% of the patient sample planned for final analysis before they were halted early. “It is obvious that the risk of overestimating treatment effects increases markedly when the sample is small,” the authors noted.

While the researchers felt that the cancer trials analysed were well designed, they were less happy with the prevalence of early termination. “Given the serious and life-threatening nature of cancer and patients’ expectations, quicker clinical drug development is required by both patients and clinicians, but this may lead to an unclear and poorly defined benefit/risk balance of new drugs,” they wrote.

Addressing a news briefing held in London to publicise the analysis, Dr Giovanni Apolone, head of the Laboratory of Translational and Outcome Research in Oncology at the Mario Negri Institute, commented: “We are aware that trials stopped early because they are showing benefit may result in the identification of promising new treatments for patients. However, findings obtained following this strategy should be considered to be preliminary results that require subsequent confirmation.”

“We believe that only untruncated trials can provide the full level of evidence required to safely translate treatments into clinical practice,” Dr Apalone continued. “Without such evidence, unsafe and ineffective drugs could be marketed and prescribed, and patients’ health could be jeopardised.”

It could take several years for the long-term benefits or adverse side-effects of a treatment to become apparent, whereas the average study duration in the analysis published in Annals of Oncology was 30 months, with a range of between 12 and 64 months, Dr Apalone pointed out.

“If a trial is evaluating the long-term efficacy of a treatment of conditions such as cancer, short-term benefits, no matter how significant statistically, may not justify early stopping,” the researchers wrote.

“Data on disease recurrence and progression, drug resistance, metastasis, or adverse events, all factors that weight heavily in the benefit/risk balance, could easily be missed. An early stop may reduce the likelihood of detecting a difference in overall survival (the only relevant end point in this setting) because of the small sample, the possibility of crossing-over the experimental drugs, and contamination with other treatments.”

Decisions on halting clinical trials before completion called for “a complex of ethical, statistical and practical considerations, indicating that results of RCTs stopped early for benefit should be viewed with criticism and need to be further confirmed,” they concluded.