Pressure Grows for More Inclusive Clinical Trials

Health policymakers, academic researchers, and regulators are clamoring for biomedical studies to fully examine how new drugs and medical products affect a broad spectrum of patient populations, including women, minorities, children, and older individuals with chronic diseases. Despite multiple FDA guidances and rules over the years advising sponsors to include all demographic groups in clinical trials, many subgroups remain underrepresented. A 2011 report from FDA found that African-Americans constitute 12% of the U.S. population, but make up only 5% of clinical trial participants; the disparity is even greater for Hispanics, which account for 16% of Americans, but only 1% of research subjects.

One response from the Pharmaceutical Research and Manufacturers of America (PhRMA) is a collaboration with the National Minority Quality Forum to increase awareness and participation in clinical trials of minority populations.

Meanwhile, FDA is developing an action plan for improving demographic subgroup data collection and analysis for regulated medical products, as required by the FDA Safety & Innovation Act of 2012 (FDASIA). As a first step, FDA issued a report last August on the subject. The study formed the basis of a public hearing on April 1 to hear from stakeholders on best approaches for encouraging subgroup enrollment in clinical trials and for capturing race and ethnicity data in studies. FDA is accepting comments on these issues until May 16 to help develop its plan for moving forward.

Sex and chronic diseases

Sex differences in drug response also raise questions about sufficient female enrollment in clinical trials. Last year, FDA lowered the dose for women of the sleep aid zolpidem. More recently, the agency turned down approval of a new drug, flibanserin, to treat low female sexual desire, calling for additional clinical trials to evaluate drug-drug interactions and drowsiness. Researchers at the Brigham and Women's Hospital in Boston recently issued a report calling for more women in clinical trials, especially for cardiovascular drugs, and to better assess how hormonal responses in women affect treatment for depression and Alzheimer's disease. The researchers urge FDA to require sponsors to include adequate numbers of women in clinical trials or clearly explain why not.

Sandra Kweder, deputy director of the Office of New Drugs at the Center for Drug Evaluation and Research (CDER), noted in a recent blog post on http://fda.gov/ that the agency requires equal enrollment of men and women in most trials except where there is a known lack of response by one sex to certain treatment. And FDA-approved drug labels routinely discuss dose considerations or side effects related to patient age, health problems, and sex.

Pregnancy safety measures

Collecting information on drug response during pregnancy is even more challenging. An FDA public meeting in May will address methods for evaluating the safety of drugs and biological products during pregnancy, focusing on the design and implementation of pregnancy registries and other post-approval evaluation strategies. Issues related to response differences and dose selection based on age, ethnicity, pregnancy, and other factors was the topic of another FDA workshop on March 10. Experts from the agency and pharma companies discussed the uses of physiologically-based pharmacokinetic (PBPK) modeling in predicting drug-drug interactions and PK response for different patient groups.

FDA also is taking steps to implement a broader Health and Human Services initiative to ensure that clinical trials include more individuals with multiple chronic conditions (MCCs). The program was launched in 2009 to encourage drug development programs to address "real world" health situations.

An FDA-HHS study completed in August 2011 found that 71% of some 147 clinical studies submitted in market applications excluded patients with some psychiatric disorder; patients with a heart disorder were blocked from 66% of studies, and many trials ruled out patients with atherosclerosis or diabetes. Sponsors routinely institute such exclusions for fear such patients will drop out of trials or experience drug-drug interactions or negative results.

In response, CDER issued an internal policy last December calling for inclusion of broad patient populations in clinical trials, particularly those with MCCs. The agency will use end-of-Phase-II meetings to check whether sponsors' planned studies include all appropriate patient groups, and that any exclusion criteria are appropriate and necessary.

Robert Temple, deputy director of CDER for clinical science, explained at a January briefing that clinical trials should encourage broad participation of all subgroups in order to fully understand how a new drug may affect all potential users. Temple said that drugs tend to work similarly in most patients, but "if there are real differences in response among population subgroups, clinicians should know that."