Research

Australian expert rejects criticism of oncology trials bias


An Australian expert has rejected claims that oncology clinical trials are increasingly compromised by use of surrogate outcomes and industry funding.

A new review has noted a swing in recent years to greater use of surrogate end points along with a “massive shift” to pharmaceutical industry sponsorship.

The study of trends in randomised controlled trials (RCTs), published in JAMA Oncology, also raises concern about the increasing use of professional medical writers, with the authors saying this could “unduly influence” trial results.

However, Australian cancer triallists contacted by the limbic were sceptical about some of the review’s conclusions, saying they were not borne out in the Australian context.

Led by Dr Joseph C. Del Paggio of the University of Toronto, the review authors analysed 289 Phase III RCTs involving more than 300,000 patients with breast, colorectal and non small cell lung cancers reported in seven high-profile journals during the decade to 2020.

Major findings included a leap in pharmaceutical industry funding to 89% of the total RCTs reviewed in the 10-year period to 2020  – up from 78% in 2005-2009 and 57% in 1995-to 2004. In the 1970s and 1980s, government grants had supported most RCTs (60%).

The review also found that trials were increasingly likely to be palliative in nature and almost half of new trials used progression-free survival (PFS) as their primary end point. Palliative and PFS-oriented trials were more likely to be ‘positive’.

The marked rise in use of PFS outcomes was of particular concern, the authors said.

“While there are some contexts in which the PFS is an appropriate end point, this is the exception and not the rule; in most contexts, PFS is not a valid surrogate for QOL (quality of life) and OS (overall survival),” they wrote.

QOL data was evident in only half of the palliative intent trials.

“We believe that all trials in non-curative settings should measure QOL; failure to do so severely limits application of results to patient care,” the authors said.

“This cohort study suggests that contemporary oncology RCTs now largely measure putative surrogate end points and are almost exclusively funded by the pharmaceutical industry.”

One limitation of the study, however, was that trials were “dichotomised as industry: yes/no”, not distinguishing partial funding, such as the provision of a study drug, from full funding or sponsorship.

“Given current interests in promoting high-value care, our community needs to reflect on the use of PFS  and whether effect sizes  targeted in the trial designs are are large enough to change clinical practice,” the authors concluded.

“Finally, the oncology community needs to consider how we can answer fundamental questions in our field that will be of low priority for the pharmaceutical industry.”

Australian context

Professor John Simes, a medical oncologist, clinical epidemiologist and biostatistician, and an international leader in clinical trials research based at Sydney University, rejected the notion that pharmaceutical industry support would necessarily sway clinicians regarding appropriate therapy for patients.

“There are some people in the medical community who basically have a view that if information is coming from industry, it can’t be trusted, because they have a vested interest in selling their drugs. My view is that it’s in their best long-term interests to present the evidence as clearly as possible,” Professor Simes said.

If a study showed an impact on progression-free survival but not on overall survival, it should be given less weight than another that was able to show an impact on survival, “but you would do that based on the quality of the evidence rather than on the source who funded the study,” he added.

Professor Simes also noted the paper’s findings might reflect a certain bias, in that it looked only at studies published in high-profile journals which may have been more disposed towards accepting studies showing positive results for experimental therapies and thus did not reflect all studies undertaken.

While there may be an increase in industry-led trials internationally, the ratio between industry and non-industry sponsorship in Australia appeared to be stable, he said.

“In fact, some of the increase in smaller studies (in Australia) appears to be in non-industry as much as the industry studies,” he told the limbic.

Professor Simes said work was under way here to see if the trend towards smaller studies reflected a shift to more personalised medicine with clinicians looking at more niche treatments over time, or if the shift should give reason for caution.

“Does it relate to appropriate change in design, or is it raising questions about whether trials are now going to be undersized to answer the questions they were set out for?” he said.

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