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CANCER DRUG TRIALS: QUITTING WHILE YOU’RE AHEAD – PART I

April 20th, 2008

From time to time you hear about a clinical trial for a new cancer treatment that proves so stunningly effective that evaluators are obliged to end the trial prematurely so that all the participating patients can share in the new breakthrough. Typically this kind of news is portrayed as an example of progress, a welcome glimmer of hope.
However, some cynics have quietly speculated that the real purpose of stopping such trials is not to ensure that the few hundred trial participants who are receiving the current standard treatment are given access to the new drug, but to massively benefit the drug companies sponsoring the trial. When a trial is halted prematurely, researchers are deprived of the opportunity to determine whether the drug in question might eventually prove less valuable if the trial were allowed to proceed to completion. Crudely put, by stopping clinical trials early, the trial directors might be quitting while they are ahead.
Now a European study has added some substance to that cynical view. According to this report, published in Annals of Oncology, an increasing number of cancer drug clinical trials are being stopped early, on the basis of very preliminary (and possibly misleading) evidence, and this ultimately puts patients in general at risk.
Researchers at the Mario Negri Institute for Pharmacological Research in Milan, looked at all cancer trials published in the decade between 1997 and 2007 in three major medical journals. They identified 25 that were stopped early because the drugs in question appeared, initially at least, to be working well. The trials’ reviewers thereupon demanded an early trial closure so that all participating patients could get the new medicines as soon as possible. Significantly, the Milan researchers found that about 80 percent of trials that are stopped prematurely were linked to an application for a marketing license in Europe or the United States.
“That suggests that companies have a commercial interest in stopping these trials, which may not be good for patients,” said Giovanni Apolone, MD, Head of the Laboratory of Translational and Outcome Research the Mario Negri Institute. “Without enough information [i.e., the kind that can only come from a completed trial, ed.], we don’t know if patients are really benefiting from these new drugs.” Dr. Apolone is an important voice in the field of medical ethics. In addition to his position at Mario Negri, he is Vice-President of the Ethics Committee of the European Institute of Oncology and is a National Expert at the European Agency for the Evaluation of Medicinal products (EMEA) in London (UK).
Apolone also told the British newspaper The Independent: “This suggests a commercial component in stopping trials prematurely. 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 in this way require subsequent confirmation. Without such evidence, unsafe and ineffective drugs could be marketed and patients’ health could well be jeopardized.”
Some of the drugs whose trials were stopped early are among the most heavily promoted new treatments, including Herceptin (trastuzumab) for breast cancer, Avastin (bevacizumab) for colon, kidney and breast cancer, Camptosar (irinotecan) for lung and bowel cancer, Sutent (sunitinib) for kidney and gastrointestinal cancer, Nexavar (sorafenib) for kidney cancer, and TaxolCarbo (carboplatin) for ovarian and lung cancer (Laurance 2008).
Dr Apolone said it could take years for the long-term benefits or dangerous adverse effects of a drug to become evident, but the average duration of the 25 trials that were stopped early was just 30 months. Five of these trials had enrolled less than 40 per cent of the planned number of patients. This means that decisions on drug approval and availability were based on under-powered clinical trials that were halted well before information on long term safety and effectiveness could be gathered.
In the online edition of Annals of Oncology, the Milan researchers added: “If a trial is evaluating long-term efficacy of a treatment of conditions such as cancer, short-term benefits – no matter how significant statistically – may not justify early stopping. Data on disease recurrence and progression, drug resistance, metastasis, or adverse events, all factors that weigh heavily in the benefit/risk balance, could easily be missed” (Trotta 2008).
Stuart Pocock, professor of medical statistics at the London School of Hygiene and Tropical Medicine, also told The Independent that stopping trials that showed early evidence of benefit skews the overall results and exaggerates the benefits of new anticancer drugs.
“Overall, there is an underlying bias towards exaggeration [of the results]. We can pretty reliably claim there is exaggeration going on. This is not as sober an environment as it should be. It has an aura of hot-headedness about it” (Laurance 2008).
Defenders of the early trial closure system say that these decisions to pull the plug on cancer drug trials are not made by pharmaceutical companies, and not even by the researchers who head the trials. They are generally made by outside data monitoring committees, which routinely review trial information and periodically assess progress. The data monitoring committees then make recommendations to the sponsoring pharmaceutical companies. Indeed, in the Apolone study, 19 out of the 25 trials halted early were overseen by such independent data monitoring committees.
While ideally a data monitoring committee should not include any members with contractual or financial ties to the trial’s sponsor or to the contract research organization conducting the trial, it can be difficult to find experts in the field who have no such ties. Furthermore, there is nothing to say that such outside experts are not ideologically biased in favor of quickly approving new anticancer drugs. A lot of oncologists feel that the more new drugs that are available in their armamentarium, by definition the better off they and their patients will be.
The system is thus designed in such a way that evaluators generally rush to judgment to approve new agents.
Ralph Moss, 20/04/2008. CancerDecisions.com

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