Historically, randomized controlled trials have served as the state-of-the-art method for determining the efficacy and safety of new, innovative treatment regimens for patients with cancer and other diseases. It is imperative that such trials are carefully designed to ensure that they are scientifically and ethically sound and that experimental regimen is, indeed, superior or comparative to the current standard of care. Now, however, researchers from The University of Sydney, led by Rachel F. Dear, MBBS, PhD, found that 29% of breast cancer clinical trials reviewed failed to establish a control arm meeting the current standard of care.
Dr. Dear and colleagues published their findings in the September 2017 issue of JNCCN – Journal of the National Comprehensive Cancer Network.
"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 guidelines, planning of future trials, and, ultimately, patient care and outcomes," said Dr. Dear.
The Declaration of Helsinki, which is a set of ethical rules regarding human experimentation such as clinical trials, states that the "benefits, risks, burdens, and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods." Therefore, modern clinical trial design should include control arms representing the most current, evidence-based treatment standards at the time of implementation.
To investigate the frequency of inappropriate comparators, the researchers analyzed phase III randomized controlled clinical trials in breast cancer-;the most frequently studied cancer type worldwide. Taking studies from 2004 – 2014 comparing drug treatments to "standard of care," the team compared the control arm drugs and dosing to the concurrent recommendations within the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for U.S. studies, and the German Gynecological Group (AGO) for European studies.
There were more than 229,000 patients enrolled in 210 trials analyzed. Sixty of the trials failed to provide control group treatment in line with the concurrent standard of care. Among trials recruiting in the United States, the control arm was not considered standard in (11/83; 13%)-;a much lower proportion than the overall cohort (60/210; 29%). In contrast, a higher proportion of trials that recruited exclusively outside of the United States were not consistent with the NCCN Guidelines (49/127; 39%).
"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. 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," said Dr. Dear.
In a multivariable model, it was less likely for the control arm to be consistent in trials that began in 2012–2014; involved women with early-stage breast cancer; or involved four or more countries of recruitment, or if the trial was not recruiting in the United States. Randomized breast cancer trials that included ER-positive disease were more likely to use control arms consistent with the NCCN Guidelines®.
To ensure that clinical trials achieve the ultimate goal of obtaining the best information to guide patient management, further investigation must be done as to the process of determining the optimal standard of care for clinical trial control groups, the researchers note.
"We were somewhat surprised to find little guidance available internationally to help trial investigators decide what care is appropriate to give women who are randomized to the comparison or "standard care" arm of clinical trials. Better guidance needs to be available to investigators to ensure provision of the best current care to patients in control groups of clinical trials," Dr. Dear said.
"This study highlights the complexity when defining 'standard care' for the control arm of phase III clinical trials," said Meena Moran, MD, Director of the Yale 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. 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."