Many breast cancer clinical trials that are described as comparing a new treatment with a standard-of-care therapy do not actually make such a comparison, University of Sydney researchers argue.
That’s because they fail to follow U.S. or European clinical practice guidelines on control treatments, the team contended. The risk of doing this is generating a biased assessment of a new drug, they said.
“An inappropriate comparator, such as a drug or dose that is less effective than the standard of care, may result in a new treatment appearing more effective than it really is,” Dr. Rachel F. Dear said in a press release.
“Another type of inappropriate comparator may be a treatment that may not be inferior but is not provided or accepted as the standard of care, which will result in outcomes that are difficult to interpret and implement in the context of multiple standards across multiple trials,” she added.
She was the lead author of the team’s article in the Journal of the NCCN titled “‘Standard Care’ in Cancer Clinical Trials: An Analysis of Care Provided to Women in the Control Arms of Breast Cancer Clinical Trials.”
To examine how those conducting clinical trials defined standard of care, the team looked at 210 trials that recruited 229,182 women worldwide. They compared the trials’ standard of care or control treatments with what U.S. and German guidelines call for. The U.S. standards are in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. The German standards, which researchers consider a good representation of European Union-wide standards, are in the German Gynecological Oncology Group guidelines.
The researchers discovered that 29 percent of all trials had failed to define standard of care according to either set of guidelines.
U.S. trials were better at complying with guidelines, with only 13 percent not having control groups that failed to follow recommendations. In contrast, 21 percent of trials outside the United States failed to follow either U.S. or European guidelines.
Most of the trials that failed to comply with guidelines used a standard-of-care treatment not included in the recommendations. Forty-two percent used recommended treatments — but at a different dose or dosing schedule than guidelines called for.
“Inconsistency of choice of control arm undermines the quality of evidence generated by clinical trials, which in turn impacts systemic reviews, the development of clinical practice [treatment] guidelines, planning of future trials, and, ultimately, patient care and outcomes,” Dear said.
Researchers also found that studies that began between 2012 and 2014, that covered women with early-stage breast cancer, or that were held in four or more countries did a particularly poor job of complying with guidelines.
On the other hand, trials of new treatments for ER-positive breast cancer were more likely to follow recommendations.
Dear’s team said the results indicate that it is essential to look at how researchers choose and describe the standard-of-care therapies they administer to clinical trial control groups.
“This study highlights the complexity when defining ‘standard care’ for the control arm of phase III clinical trials,” said Dr. Meena Moran, director of the radiation breast program at Yale Cancer Center/Smilow Cancer Hospital.
“Other factors that need to be considered include how new fluxes of information make capturing standard of care in real time difficult, and controversies surrounding trials conducted outside of the United States,” she said. “Nevertheless, this body of work provides a great starting point for identifying any deviations from ‘standard care’ in clinical trials that, with further investigation, may prove to be clinically relevant or detrimental for patients.”