Study Raises Concern Over Risk of Bias in EMA-Approved Cancer Trials



A new study shows that approximately half of clinical trials that supported approvals for new cancer drugs in Europe were judged to be at high risk of bias, meaning that some treatment effects might have been exaggerated.

The study conducted by the British Medical Journal focused on trials and approvals between 2014 and 2016. In its report, the BMJ said the findings raise concerns about “low standards of evidence” that supported the approval of new oncology treatments. The study raises concerns over the clinical trials of the approved oncology treatments that do not include overall survival as a primary endpoint.

During the three year period covered by the evaluation, the European Medicines Agency approved 32 new cancer treatments. The approvals were supported by 54 different clinical studies. Of those, 41 studies were randomized controlled trials, with 39 of those had publications regarding the trials, BMJ said. In its report, BMJ noted that of those 39 trials that included published attachments, only 10 included overall survival as its primary endpoint. The remaining 29 evaluated indirect measures of clinical benefit, BMJ said, which it added: “do not always reliably predict whether a patient will live longer or have a better quality of life.”

BMJ said since 1995 there have been concerns regarding “deficits” in clinical trial design that can affect trial results. Those concerns, BMJ said, are particularly pertinent regarding cancer trials due to those drugs being among the most-often approved treatments.

“Most cancer drugs enter the market on the basis of their effects on surrogate endpoints, rather than clinical outcomes that matter to patients and their caregivers – overall survival and quality of life. Cancer drugs that appear effective on surrogate endpoints may turn out to have no effect on overall survival,” the report said.

As an example, BMJ pointed to several drugs of concern, including bevacizumab for glioblastoma; bevacizumab for metastatic breast cancer; bevacizumab for advanced ovarian cancer; axitinib for advanced renal cell carcinoma; everolimus for metastatic breast cancer; and atezolizumab for urothelial cancer.

The report shows that some cancer drugs that appear effective on surrogate endpoints may actually have detrimental effects on survival. As an example, the BMJ study pointed to the BELLINI trial conducted by Genentech assessing the efficacy of venetoclax on multiple myeloma patients. BMJ said patients who received venetoclax had shorter survival than those who received a control treatment, “even though venetoclax appeared more effective than the control on the basis of commonly-used surrogate endpoints like progression-free survival and response rate.”

The analysis put forward by the BMJ researchers includes additional trial examples for which it raises concern.

Looking at the trials it studied for the report, BMJ said 19 of them, 49%, were considered to be at high risk of bias “because of deficit in their design, conduct or analysis.” Trials that evaluated overall survival were at lower risk of being considered having a bias, the report said. The report goes on to show that 10 of the 32 drugs approved during this time have had some problems surface.

In 2017, the organization Cancer UK conducted a study that showed some cancer drugs approved by the European Medicines Agency might not have provided sufficient evidence of survival benefits. According to that study, only about half of the approvals from 2009 to 2013 showed evidence that the medications improved survival or quality of life.

In their criticisms, BMJ noted that there are some limitations to the analysis. As an example, the publication said the researchers who undertook this task did not include clinical study reports. Those reports contain detailed information regarding the conduct of the trial and its results. Also, the study focused on the risk of bias as opposed to bias itself, which the researchers said could be a flaw in the design of their analysis. The BMJ researchers said it’s a “possibility that the methodological deficits identified by the authors did not lead to biased findings.” The study points to the need to “improve the design, conduct, analysis, and reporting of cancer drug trials” in Europe, BMJ said.



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