Anticipate regulatory expectations: Fill evidence gaps and mitigate risks

This article is part of Parexel's "Navigating to 2030" playbook series on differentiating next-generation obesity therapies. This series offers strategic insights across trial design, regulatory considerations, clinical operations, and patient retention strategies to support sponsors in this rapidly evolving and competitive market.  

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The rise of GLP-1s has revolutionized the treatment of Type 2 diabetes mellitus (T2DM) and obesity, offering promising avenues for weight management and metabolic control. However, their usage over longer periods and expansions into off-label and new patient populations raise new safety and regulatory considerations. Ensuring patient safety and maintaining public trust requires proactively mitigating risks and ensuring compliance with evolving regulatory frameworks.

Longer-term safety of GLP-1s for weight loss and T2DM remains to be established.

To date, there are no data on the overall safety of taking GLP-1s for a lifetime for type 2 diabetes, obesity, or other cardiometabolic conditions. Data from clinical trials of approved therapies suggest that patients regain most, if not all, of the weight they lose once they stop taking the drugs, so long-term administration or microdosing may be necessary. 

GLP-1s are increasingly being used in circumstances not studied in clinical trials, such as off-label for cosmetic weight loss by people who are mildly overweight or of normal weight but want to lose a few pounds. These populations may have unknown comorbidities and take a variety of concomitant medications. Therefore, the safety of approved GLP-1s in these persons is not yet understood. In addition, as a result of shortages of approved GLP-1s due to high demand, many patients take compounded GLP-1s. Although compounding of drugs is appropriate in certain circumstances, they are not FDA approved: the FDA does not review compounded drugs for safety, effectiveness or quality.¹  There have been reports of adverse events associated with the use of compounded GLP-1s, primarily due to dosing errors or use of doses higher than in the labeling of the FDA-approved GLP-1.  

Post-marketing surveillance and real-world data are essential for the early identification of safety signals from long-term and off-label use, with care taken to distinguish safety of approved GLP-1s from that of compounded versions.

Earlier planning for testing of next-generation GLP-1s in pediatric patients is critical.

The prevalence of overweight and obesity among children and adolescents has progressively increased. Therefore, availability of safe and effective treatments in pediatric populations is important. In the US, under the 2003 Pediatric Research Equity Act, all new drug applications (NDAs) for novel agents and supplemental NDAs for new indications, dosage forms and regimens, or new routes of administration must contain safety and efficacy trials of the product in pediatric patients unless this requirement is waived, deferred, or inapplicable. The FDA issued a draft guidance for drugs to treat obesity and overweight in January 2025, outlining key pediatric patient considerations.² In the EU, the Paediatric Regulation also requires sponsors to develop pediatric investigational plans (which may include waivers or deferrals) for all novel molecules. 

Regulatory requirements for pediatric studies have been applied to approved GLP-1s.  For example, when it first approved Ozempic in 2017, the FDA required postmarketing studies in pediatric patients aged 10-17 (scheduled to be completed in December 2026) but waived the requirement for trials in ages 0-9 because “necessary studies are impossible or highly impractical.”³ In the EU, studies for children down to 6 years of age were required.⁴ Three of the marketed GLP-1s, Victoza, Saxenda, and Wegovy (all from Novo Nordisk), have been approved by the FDA and the EMA for use in pediatric patients with diabetes or obesity. 

Many pediatric endocrinologists prescribe GLP-1s in younger children due to the dire downstream effects of pediatric-onset diabetes, overweight, and obesity. Once obesity is established, it rarely resolves after adolescence, inflicting physical and mental harm before adulthood and after—including infertility, cancer, cardiovascular disease, and diseases of the liver and kidneys.⁵ Therefore, formal studies of the efficacy and safety of GLP-1s in the current off-label pediatric populations are essential.
In general, efficacy and safety data in adults should be available before a new drug is studied in children. Typically, this has meant that pediatric studies of a drug have not been initiated until after the drug was approved for use in adults. However, earlier initiation of certain pediatric studies (such as pharmacokinetic trials) is possible in the pre-approval setting when there are adequate supportive data from adult trials.  

Pediatric trials of weight loss medications are challenging. For example, growing children gain weight, and adolescents undergo accelerated growth, so determining a clinically relevant BMI reduction can be complex, and sponsors must track the long-term impact of therapies on developing muscular and skeletal systems. Adolescents also undergo puberty, during which they are resistant to insulin. And because minors must have parental consent to enroll in trials, the decision to participate is made by family units. Some parents are interested in clinical research, while others may be skeptical. Despite the challenges, at Parexel, we encourage sponsors to consider conducting pediatric trials before approval in adults because adolescent obesity is still a substantial unmet medical need.

Careful assessment of the safety of GLP-1s in other indications will be key.

The known effects of GLP-1s must be factored into the benefit-risk considerations for new treatment populations. For example, in studies to explore GLP-1s as treatment of alcohol and opioid use disorders, the patient selection criteria should account for the appetite suppression and weight loss effects of GLP-1s. In such studies, enrollment of overweight/obese persons would be more appropriate than those with low or normal body weight.  Determining the appropriate dosing, eligibility criteria, and patient monitoring in non-obesity trials is critical.

The duration of the pre-market safety studies is also essential. Some new indications for GLP-1s already require multi-year efficacy studies (for example, MASH, which progresses slowly over time, necessitating long-term studies to observe the full impact of treatments on disease progression, including liver fibrosis and cirrhosis).⁶ Therefore, pre-market safety studies in those indications will likely extend beyond the standard 12 months typical of drugs for chronic diseases.⁷ Companies must make data-driven, indication-specific arguments to explain why the proposed duration of safety studies is relevant and appropriate. 

In addition to providing appropriate safety information to support regulatory approval, sponsors of GLP-1 agonist drugs must fully address the safety information required by payers. At Parexel, we advise sponsors to design their studies based on all available safety information about the class of drugs, the disease characteristics of the target patient population, safety issues that patients and healthcare providers have identified as important to them, and early input from payors about desirable safety profiles of GLP-1s in the new population.  In addition to clinical trial data, sponsors must proactively plan their post-marketing surveillance program and other real-world data assessments. Comprehensive strategies to fully assess safety in the pre- and post-market settings provide reassurance to regulators and other stakeholders that sponsors have (1) not made assumptions about the safety of GLP-1s in the new population and (2) have appropriately established a positive benefit-risk profile for the drug in the new population.

Resources

1. FDA’s Concerns with Unapproved GLP-1 Drugs Used for Weight Loss, Postmarket Drug Safety Information for Patients and Providers (Accessed April 17, 2025).
2. Obesity and Overweight: Developing Drugs and Biological Products for Weight Reduction, FDA Draft Guidance (January, 2025).
3. NDA Approval Letter for Ozempic, Drugs@FDA.gov (December 5, 2017).
4. European Medicines Agency decision (October 29, 2021).
5. Global, regional, and national prevalence of child and adolescent overweight and obesity, 1990–2021, with forecasts to 2050: a forecasting study for the Global Burden of Disease Study 2021, The Lancet (March 8, 2025).
6. Noncirrhotic Nonalcoholic Steatohepatitis With Liver Fibrosis: Developing Drugs for Treatment, FDA Draft Guidance (December 2018).
7. E1A The Extent of Population Exposure to Assess Clinical Safety: For Drugs Intended for Long-term Treatment of Non-Life-Threatening Conditions, FDA Guidance Document (March 1995).
    

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