Studies highlight risks of excluding people with obesity from drug trials

People with obesity often go underrepresented in drug development trials, a critical gap that researchers say leaves drugmakers and doctors unsure of efficacy or risks in that patient population.

“Patients and providers are not aware of how some drugs may act differently in people with obesity,” said Christina Chow, the head of research at Emerald Lake Safety, an institution that conducts independent research to make pharmaceuticals safer. “People with obesity are underrepresented in clinical trials for drug approval.”

Chow and other researchers are presenting data at the ObesityWeek conference in Dallas this week about such omissions and their effects. They reviewed 201 drug approval studies in clinicaltrials.gov that occurred in 2022, and found that 64% did not include weight or BMI-based inclusion/exclusion criteria, which does not ensure the representation of people with obesity in these studies. Moreover, of the 72 studies that did have a weight or BMI-based inclusion/exclusion criteria, 75% of the trials used the criteria to exclude patients with obesity.

Caroline Apovian, the co-director at the Center for Weight Management and Wellness at Brigham and Women’s Hospital and the lead author of this poster, said that given the stigma associated with obesity, patients with a BMI over 30 are often reluctant to volunteer themselves for clinical trials even if they are a part of the inclusion criteria.

The Food and Drug Administration has previously noted that, to reduce the observed variability of early-phase trials, sponsors and regulators of trials often exclude participants who have a BMI over 30, fail to recruit people with obesity, and fail to report rates of obesity among their study samples. However, for some drugs, the clinical differences in people with obesity can lead to negative effects, said Chow.

Chow and her colleagues have researched the pharmacokinetics and pharmacodynamics of lipophilic or fat-soluble drugs commonly prescribed in people with obesity.

“One reason this occurs is that increased body fat mass increases the deposition of lipophilic drugs in body fat, thereby lowering the plasma concentration of the drug. Consequently, a longer time may be required to achieve the appropriate plasma level of the drug,” they wrote in an August commentary published in Health Affairs.

They observed this while investigating brexpiprazole, marketed under the brand name Rexulti, a drug that is indicated for use in patients with schizophrenia and depression. The drug took extensively longer to reach effective levels in people with obesity, and in some patients it never even reached effective levels, according to their study published in The Journal of Clinical Pharmacology.

“After following standard dosing instructions, providers may end up concluding that Rexulti is ineffective and ultimately discontinue the drug in patients with obesity, but that could lead to harmful effects. Patients with schizophrenia left untreated or under-treated are at a higher risk of harming themselves,” said Chow, who engaged in focus groups and interviews with patients with obesity who took brexpiprazole.

The findings of her team, also presented in a poster at ObesityWeek, were that patients with obesity who took brexpiprazole expressed negative sentiments, disappointment, and frustration with its lack of effectiveness and concern that it was not tested in people like them.

“You’re either invisible, or the answer is to lose weight, even with mental health,” one patient said.

Earlier research shows examples of the incomplete data. A study conducted by researchers at Texas Tech and University of Mississippi examined 69 randomized controlled trials for antibiotic drug approvals in acute bacterial skin and skin structure infections. This review, published in March in Open Forum Infectious Diseases, found that only 30% of newly approved drugs mention patients with obesity, despite the skin infections affecting approximately 50% of people with obesity in the United States.

In 2022, the FDA hosted a virtual workshop on drug safety and efficacy in people with obesity, where Commissioner Robert Califf recognized that in clinical trials “there are generally no FDA regulatory requirements at present to evaluate weight as a specific issue.” However, a major gap remains in the safety and effectiveness of drug therapy in people with obesity.

“The FDA needs to issue a mandate of including people with obesity in clinical trials to hold pharmaceutical companies accountable,” said Apovian. She said inclusion of such patients should be mandated for sponsors and regulators, just as they have to include patients with liver and kidney disease in their trials — a part of the population that’s still less than approximately 42% of Americans who have obesity.

In addition to calling for a mandate, researchers are advocating for drug manufacturers to include information on the effects of obesity on specific drugs in the drug package insert itself. This can help increase awareness among practitioners, Chow said.

William Dietz, the director of the STOP Obesity Alliance at the Milken Institute School of Public Health at George Washington University, calls for a reporting system for adverse events relating to drug metabolism in people with obesity to enable the FDA and drug manufacturers to identify and track issues.

“As a criterion for the approval of such drugs, manufacturers must include people with obesity in their drug trials, and the outcomes in people with obesity should be analyzed and reported separately,” he said.