Currently there are no requirements that clinical trials of new pharmacotherapies specifically include persons with obesity; consequently, there are drugs marketed for a range of diseases and for disease prevention that may—or may not—be effective in individuals with obesity.
On Tuesday, 5 obesity advocacy organizations issued a joint statement asking the US Food and Drug Administration (FDA) to amend the dangerous omission and to “close gaps in the testing and approval process for new drugs intended for use by people with obesity.”
The Obesity Action Coalition, The Obesity Society, Stop Obesity Alliance, Obesity Medicine Association, and American Society for Metabolic and Bariatric Surgery said in the statement that individuals of higher body weights are routinely excluded from participating in clinical trials even though it is well known that body composition can materially alter pharmacokinetics. The result is “general population dosing instructions [that are] unsafe and/or ineffective for people with obesity” who now comprise 42% of the US adult population.
“Drug companies have an interest in reducing intersubject variability, because in narrower subsections, drugs are more likely to perform as expected, thereby increasing the odds of getting approved,” Jamy Ard, MD, president-elect of The Obesity Society, professor in the department of epidemiology and prevention at Wake Forest School of Medicine, co-director of the weight management center for Advocate Health Wake Forest Baptist said in the joint statement.
Clinical research policies for other subpopulations provide a “stark contrast,” the authors state. They point to FDA requirements that all drugs that could potentially be dangerous for persons with renal and liver impairment be evaluated specifically in these groups, groups a small fraction (2.2% and 1.7% respectively) of the size of the population with obesity.
The collaborative statement was released simultaneously with a special issue of the Journal of Clinical Pharmacology that includes a compilation of articles emphasizing the importance of studying persons with obesity as part of drug development. The focus for the series was sparked by a 2022 FDA workshop on the safety and efficacy of medications in individuals with obesity where in his opening remarks FDA Director Robert Califf was straightforward: “… there are generally no FDA regulatory requirements at present to evaluate weight as a specific issue. Consequently, they continue to be underrepresented in research and in clinical trials, making it difficult to obtain the necessary data to inform dosing of a newly marketed drug in individuals with obesity.”
Changes have been made in the past to population requirements for new drug testing the statement authors said, citing that until 1993 when the FDA and Congress required women to be included in clinical trials, drugs meant to be used by all adults were routinely tested only in men. Nearly a decade later, in the early 2000s, the FDA and Congress stepped in to mandate that drugs approved for adults could not be prescribed for children without separate clinical trials in the pediatric population.
In a second call to action, the group of advocacy organizations urged any companies marketing drugs with safety or efficacy issues in people with obesity when standard doses are used to update labeling immediately with correct usage instructions.
Authors describe 2 potentially dangerous issues with drug metabolism in people with obesity. Circulating levels of lipophilic drugs may be reduced by absorption into adipose tissue, extending the time to reach a therapeutic level or negating effect entirely; subsequent clinical decisions may be made in error, the authors caution, with risks to patients’ health and safety. Clinical trials of the antipsychotic agent brexpiprazole (Rexulti; Otsuka/Lundbeck) specifically excluded persons with elevated BMI despite evidence that more than half of people with schizophrenia are obese. Dosing changes were proposed based on post-marketing studies that found brexpiprazole takes significantly longer to reach therapeutic effects in persons with obesity; no changes have been made.
Obesity can significantly increase drug half-life, the second potential consequence of compromised drug metabolism the authors describe. The antifungal posaconazole (Noxafil; Merck) also was not fully evaluated in adults with obesity. The drug’s inhibition of cytochrome P3A4 already increases the risk of drug-drug interactions after stopping posacanazole; the additional lengthening of the agent’s half-life in the setting of obesity places those patients at risk for unintentional drug interactions for weeks after treatment cessation. Some chemotherapeutics do carry warnings to wait from 3 to 5 half-lives after stopping a similar drug before resuming normal dosing. Current labeling does not alert clinicians that this occurs in people with obesity.
“Drug companies don’t get a pass on people with obesity,” Angela Fitch, MD, president of the Obesity Medicine Association, associate director of the Massachusetts General Hospital Weight Center and an instructor of medicine at Harvard Medical School, said in the joint statement. “We must ensure drugs are safe and effective and labeled correctly for everyone for whom they are intended.”