USA – When are RCTs Required for Breakthrough Drugs, HDEs? JAMA Study Investigates

A new study in JAMA Network Open finds that drugs and medical devices approved by the US Food and Drug Administration (FDA) based solely on non-randomized controlled trials (RCTs) exhibited larger effect sizes compared to products that required further study in randomized trials. But the authors called for greater FDA transparency to instill confidence that decisions about drug and device approvals based on observational data are appropriate.

The goal of the study, conducted by researchers including Stanford Professor John Ioannidis, Cochrane Founder Lian Chalmers and City of Hope Hematologist Benjamin Djulbegovic, was to identify how large treatment effects must be for regulators to consider data from non-RCTs sufficient for approval, as RCTs are considered the “gold standard” for generating clinical evidence for medical interventions.

“The main concern about non-RCTs is that it is currently challenging to predict with confidence when the results of RCTs will be concordant with those of observational studies. The consequences of such a discordance can sometimes be disastrous,” the authors write, pointing to a large randomized study conducted by the Women’s Health Initiative (WHI) to determine whether estrogen plus progestin could prevent coronary heart disease (CHD) and other chronic conditions in postmenopausal women. Contrary to earlier observational evidence, there were more cases of CHD and breast cancer in the treatment arm of the WHI study…