Among the new drugs approved between 2005 and 2012 that are most commonly used in the primary care setting, three-quarters of pivotal trials supporting FDA approval did not provide sufficient information in publicly available FDA documents and corresponding publications to determine if they were conducted in primary care settings. Based on the information available, we determined that 8% of trials were partially conducted in primary care settings—none exclusively so. Our results suggest that the approval of these new drugs were predominantly supported by evidence generated in subspecialty settings, despite that most end users of these therapies will likely be patients and prescribers in primary care settings.
Evaluating drugs in settings that do not resemble where they will most often be used may result in outsized estimates of benefit—because of the risk-treatment paradox 4—as well as safety risk, since patients with more comorbidities who are taking more medications—and thus more likely to require specialty care—are more likely to experience adverse drug events 5. The Randomized Aldactone Evaluation Study was one instance; following publication, the rate of hospitalization for hyperkalemia increased from 2.4 to 11.0 per 1000 patients (P < 0.001), and the associated mortality increased from 0.3 to 2.0 per 1000 patients (P < 0.001) from 1994 to 2001, presumably due to the different patient populations seen in trial and practice settings 6. There are other important differences in care processes between primary care and specialty care settings that may affect medication management, including visit length, ancillary staff availability, and educational support.
Our estimates are deliberately conservative, as the descriptive text provided in FDA documents and publications was often vague. It is possible that settings described ambiguously as “clinics” were in fact primary care clinics, but without explicit detail; we categorized these as indeterminate. This information could be clarified through the FDA’s Drug Trials Snapshots initiative (www.fda.gov/Drugs/InformationOnDrugs/ucm412998.htm), which provides demographic characteristics of trial participants of newly approved drugs, offering additional regulatory transparency and information to patients and clinicians. Future efforts should encourage trial recruitment in clinical settings in which the drugs will most commonly be used, ensuring new drug evaluations that can best inform patient care.