Obesity is a national health issue, with a prevalence that
has increased from 30% to 43% in adults in the United
States during the past 20 years. Importantly, obesity is
also associated with increased risks for other comorbid
diseases such as diabetes, hypertension, cardiovascular
disease, respiratory failure and cancer. As such, the
American College of Clinical Pharmacology® (ACCP)
is issuing a call for action aimed toward the timely
inclusion of obese participants in clinical trials during
the drug development process. A road map is proposed to recommend the inclusion of obese participants within clinical trials with the consideration of disease epidemiology, comorbidities, pharmacokinetics (PK), pharmacodynamics (PD), efficacy and safety of the investigational agent and encourages evidence synthesis through model-informed data integration to optimize the posology of therapeutics and maximize benefit versus risk in the intended patient population.
Epidemiological data indicate a growing prevalence of obesity in the general population worldwide and in the United States. Ideally, label recommendations for drugs are meant to reflect both the population studied and provide generalizable knowledge that can be applied to a broader population who will use the therapy. Therefore, the inclusion of obese participants in clinical studies during drug development should be considered and actively discussed among clinicians, sponsors and regulators in the context of the prevalence of obesity and related comorbidities in the target patient population. The assessment of expanding or actively enabling inclusion of obese participants in a clinical drug development program requires careful evaluation of potential effects of obesity on PK, PD, efficacy and safety of the specific investigational agent. The assessment needs to consider the physicochemical properties, mechanisms of disposition, mechanism of action, efficacy and safety profiles and anticipated therapeutic index of the investigational agent in relation to the anticipated comorbidities and sensitivity to potential adverse events in the obese population.
A suggested good practice for clinical development is to incorporate inclusion of a subset of overweight or obese participants in early Phase 1 studies to specifically determine PK parameters as a function of body size descriptors. This should set the stage for inclusion of obese patients in proof-of-concept (ie, Phase 2a) trials, and subsequently in the pivotal Phase 2/3 program, with appropriate dosing and risk management in these trials to ensure safe evaluations. Taken together, sufficient data should be available in obese patients and assessed on the basis of body size descriptors. The practice of actively but carefully and responsibly including obese patients in clinical studies during drug development will enhance the understanding of the benefit-risk profile of new drugs in the intended patient population. This will eventually help clinicians make informed dosing decisions for new drugs entering the market.
The ACCP proposes the following roadmap in support of a call for action to promote the safe inclusion of obese participants throughout the drug development cycle to optimize dosage and maximize benefit versus risk of medicines in obese patients:
- Learn and characterize the effect of obesity on the PK, PD, efficacy, and safety of drugs through all phases of the clinical development program, leveraging applicable MIDD tools.
- Expand the inclusion and exclusion criteria of clinical studies to enable inclusion of obese participants when data are available to support doing so safely.
- Include dosing information in relation to body size descriptors in drug labels when appropriate to guide their safe use in obese patients.