Blood cancers

Blood cancer drugs approved on the basis of flimsy trial data


The quality of clinical trials for new cancer therapies leaves room for improvement, according to an article in the latest BMJ.

An analysis of 54 pivotal studies, which led to the European Medicines Agency (EMA) approval of 32 novel targeted therapies and immunotherapy drugs for cancers between 2014 and 2016, found almost half the trials (49%) were at high risk of bias.

Bias was determined using a Cochrane bias tool that is widely used in systematic reviews. It incorporates bias across five domains of randomisation, deviation from intended interventions, missing outcome data, outcome measurement and selection in reporting results.

The study found most of the pivotal trials (76%) were randomised controlled trials however only seven cancer drug approvals were supported by two or more RCTs.

In addition, a minority of the pivotal trials (26%) used overall survival as a primary endpoint.

“Progression free survival was the primary endpoint in 21 randomised controlled trials (54%), whereas the remaining trials evaluated disease response, event free survival, or safety endpoints,” the study said.

Using progression-free survival enables trials to be completed faster than those based on overall survival but may “overestimate the magnitude of benefit associated with new cancer drugs”.

“Recent systematic review showed that progression free survival and disease response do not consistently translate to survival gains or quality of life benefits.”

Regulators also identified additional problems with 10 of the 32 newly approved drugs (31%), but these concerns rarely surfaced in the scientific literature.

An accompanying editorial in the BMJ authored by Australian academics said the findings highlight the need to improve the design, conduct, analysis, and reporting of cancer drug trials.

“Uncertainty and exaggeration of the evidence that supports approval of cancer drugs causes direct harm if patients risk severe or fatal adverse effects without likely benefit, or forgo more effective and safer treatments,” wrote Associate Professor Barbara Mintzies, from the University of Sydney, and Dr Agnes Vitry from the University of South Australia.

“Inaccurate evidence also leads to intangible harms if it encourages false hope and creates a distraction from needed palliative care.”

Extending clinical trials to include overall survival probably only required an extra year compared to the time required for surrogate outcomes,  they noted.

“A year may seem a long wait for a patient with advanced life threatening disease. However, several policy options have been proposed to facilitate earlier access to experimental treatments, such as clinical trial participation, compassionate access programmes, or managed entry agreements with ongoing funding conditional on more solid evidence.”

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