On behalf of the American Society for Metabolic and Bariatric Surgery, the Obesity Action Coalition (OAC), the Obesity Medicine Association, the STOP Obesity Alliance, and The Obesity Society (TOS), we call on the FDA to close gaps in the testing and approval process for new drugs intended for use by people with obesity.
Currently, there is no requirement that new drugs be specifically tested in people with obesity prior to approval. What’s more, specific exclusion criteria routinely bar people at higher body weights from participating in these trials. Yet it is well known drug kinetics can materially change in larger bodies, making general population dosing instructions unsafe and/or ineffective for people with obesity. That puts people with obesity, who make up 42% of the U.S. population, at unnecessary risk of poorer health outcomes and adverse events, including death. This practice is in stark contrast to drug policies for other sub-populations. For instance, all drugs must be evaluated for differences in people with renal and liver impairment, and significant incentives exist for testing to be undertaken in children once drugs have been proven safe and effective in adults.
In addition, we call on drug companies that are currently marketing drugs that have issues with safety or effectiveness for people with obesity at standard doses to update their labeling immediately to provide correct usage instructions for people with obesity.
We are releasing our joint statement of support to coincide with a special issue of the American College of Clinical Pharmacology’s Journal of Clinical Pharmacology, which includes a collection of articles addressing the need to study people with obesity as part of the drug development process. The need for this special issue grew out of an FDA workshop[1] on drug efficacy and safety in people with obesity held in November 2022, where the research on the following page was presented. This topic has been highlighted since the workshop in recent publications and conferences by Caroline Apovian, MD, Co-Director, Center for Weight Management and Wellness Professor of Medicine, Harvard Medical School[2], and William H. Dietz, MD, PhD, and director of the STOP Obesity Alliance, George Washington University[3]. FDA Director Califf opened the conference directly calling out the problem, “…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.”
“People with obesity deserve to know if the drugs they use are safe and effective for them—and so do their doctors,” says Joe Nadglowski, President and CEO of OAC, an 80,000-member advocacy organization for people with obesity. “These drugs are used every day by people who don’t know they might not be effective, and include treatments for depression, schizophrenia, emergency contraception, preventing organ transplant rejection, infections, and cancer.”
Not all drugs behave differently in the bodies of people with obesity, but some clearly do. In people with obesity, lipophilic drugs can be absorbed by fat, reducing the level of drug circulating in the blood. A lower level of drug in the bloodstream means the drug may require a longer time to become effective, or it may never reach effective levels. This effect can lead to the mistaken conclusion that the drug is ineffective, which can pose serious risks.
For example, the drug brexpiprazole, marketed under the brand name Rexulti, is used to treat schizophrenia and depression. The studies conducted to demonstrate Rexulti’s safety and efficacy prior to launch specifically excluded people with higher BMI’s,[4] despite reports showing 58% of people with schizophrenia have obesity.[5] More recent studies, whose co-authors include two former FDA review division heads, revealed that brexpiprazole takes significantly longer to reach effective levels in people with obesity, and those who are also CYP2D6 poor metabolizers never reach effective levels.[6] These experts proposed dosing changes for such patients that have never been acted on. Underdosing may lead patients and their doctors to conclude the drug is ineffective and discontinue the medication, or unknowingly continue its use at an ineffective level. A person with untreated or undertreated schizophrenia can be at risk of harming themselves or others or committing suicide.
A second consequence of obesity can be a significant increase in drug half-life. An increased half-life may lead to inadvertent drug-drug interactions. For example, posaconazole, an antifungal marketed under the brand name Noxafil, was not fully tested in people with obesity prior to approval. The half-life of posaconazole is significantly longer in patients with obesity than in patients at a normal BMI.[7] Because posaconazole is a strong inhibitor of CYP3A4, a liver enzyme that metabolizes a high percentage of all drugs, people with obesity are at risk of prolonged drug-drug interactions for weeks after stopping posaconazole. For instance, numerous cancer drugs already carry warnings to wait 3-5 drug half-lives after stopping a drug like posaconazole before resuming normal dosing. But drug labeling does not advise doctors that this phenomenon occurs in patients with obesity.
“Drug companies have an interest in reducing inter-subject variability, because in narrower subsections, drugs are more likely to perform as expected, thereby increasing the odds of getting approved,” says Jamy Ard, MD, FTOS, President-Elect of TOS, the leading professional society focused on obesity science, treatment, and prevention. “Unfortunately, variation in body size is easy to identify and as a result, drug companies often structure clinical trials to exclude people with obesity.”
Congress and the FDA have the power to require drug companies to test new drugs on relevant subsections of the population prior to approval. Drugs meant for use by all adults were routinely tested only on men until the FDA and Congress required them to be tested on women as well in 1993. Drugs meant for use by children in addition to adults weren’t routinely tested on children until the FDA and Congress required it in the early 2000s. More recently, the FDA provided clear guidance that drugs that might have certain adverse effects on the kidneys or liver to be tested on people with kidney or liver disease, respectively. Given that 42% of U.S. adults have obesity compared to 2.2% with kidney disease and 1.7% with liver disease[8], it should be required that drug companies assess relevant drugs for safety and efficacy in people with obesity.
This failure to attend to the needs of people with obesity is both harmful and erodes the trust they have in healthcare. “You’re either invisible, or the answer is to lose weight, even with mental health,” says a failed Rexulti user after learning that the drug was not tested on people with obesity.
“We must ensure drugs are safe and effective and labeled correctly for everyone for whom they are intended,” says Angela Fitch, MD, FACP, FOMA, Dipl. ABOM, and President of the OMA, the largest organization of physicians, nurse practitioners, physician assistants, and other health care providers working every day to improve the lives of patients affected by obesity. “Drug companies don’t get a pass on people with obesity.”
[1] https://cersi.umd.edu/event/17455/fdam-cersi-workshop-drug-efficacy–safety-to-the-obese
[2] Apovian CM, et al. Incomplete Data and Potential Risks of Drugs in People with Obesity. Current Obesity Reports (manuscript accepted).
[3] Chow CR, Greenblatt DJ, Dietz WH. Assessments Of Drug Safety And Effectiveness Continue To Fail People With Obesity. Health Affairs Forefront, August 30, 2023.
[4] Application Number: 205422Orig1s000 and 205422Orig2s000 Clinical Pharmacology and Biopharmaceutics Review(s). US Food and Drug Administration Center for Drug Evaluation and Research (FDA CDER). https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/205422Orig1Orig2s000ClinPharmR.pdf
[5] Annamalai A, Kosir U, Tek C. Prevalence of obesity and diabetes in patients with schizophrenia. World J Diabetes 2017;8:390. https://doi.org/10.4239/wjd.v8.i8.390.
[6] https://accp1.onlinelibrary.wiley.com/doi/abs/10.1002/jcph.1946
[7] Greenblatt DJ, Harmatz JS, Ryan MJ, Chow CR. Sustained Impairment of Lurasidone Clearance After Discontinuation of Posaconazole: Impact of Obesity, and Implications for Patient Safety. J Clin Psychopharmacol 2018;38:289–95. https://doi.org/10.1097/JCP.0000000000000892.
[8] Centers for Disease Control. Summary Health Statistics for U.S. Adults: National Health Interview Survey, 2018 n.d. https://www.cdc.gov/nchs/fastats/kidney-disease.htm (accessed May 8, 2023).