PII-191 - PEDIATRIC CLINICAL TRIAL DESIGNS FOR TESTOSTERONE REPLACEMENT THERAPY.

H. Seo¹, K. Shimy², Y. Lu³, G. Buckart⁴, J. Yu⁵, Y. Wang⁶, S. Kaul⁷, C. Yu⁸; ¹Department of Chemistry and Biochemistry, University of California San Diego, ²Division of Diabetes, Lipid Disorders, and Obesity, Office of New Drugs, US Food and Drug Administration (FDA), ³Division of Cardiometabolic and Endocrine Pharmacology, Office of Clinical Pharmacology, US Food and Drug Administration (FDA), ⁴U.S. Food and Drug Administration, ⁵Division of Pharmacometrics, Office of Clinical Pharmacology, US Food and Drug Administration (FDA), ⁶Division of Pharmacometrics, Office of Clinical Pharmacology, U.S. Food and Drug Administration, ⁷Division of Urology, Obstetrics and Gynecology, Office of New Drugs, US Food and Drug Administration (FDA), ⁸Division of Cardiometabolic and Endocrine Pharmacology, Office of Clinical Pharmacology, U.S. Food and Drug Administration.

Background: Testosterone replacement therapy (TRT) is indicated for deficiency or absence of endogenous testosterone (T). Pediatric studies are required under the Pediatric Research Equity Act in certain circumstances. Challenges in designing pediatric TRT trials include:
• Lack of formal clinical practice guidelines
• Variable clinical parameters for assessing pubertal development
• Published standards for growth/pubertal development derived from healthy children
• Complex assessment of pubertal stage in hypogonadal boys
• Wide and overlapping range for T concentrations during puberty
• Lack of standardization for target normal T concentrations for each Tanner stage
This research was done to provide clinical pharmacology insight for designing pediatric TRT trials.

Methods: Essential clinical pharmacology information in designing pediatric TRT clinical trials was collected from publicly available sources (e.g., Drugs@FDA). Dose selection, inclusion/exclusion criteria, reference T ranges, and efficacy endpoints were summarized. Clinical outcomes such as height velocity, Tanner staging, stretched penile length, bone age, bone mineral density (BMD), and body composition (e.g., lean body mass) were investigated to identify appropriate response parameters for exposure-response (E-R) analysis.

Results: Important clinical pharmacology considerations included selection of an appropriate dosage regimen, a dose titration scheme (for products that can be titrated) using an adequate pharmacokinetic (PK) parameter, and when the PK-based primary efficacy endpoint should be assessed relative to the assessment of other clinical endpoints. We identified clinical outcomes including Tanner staging, stretched penile length, height velocity, bone age, BMD, and body composition as potential response parameters for E-R analysis.

Conclusion: Unlike in adults, different normal T concentration ranges should be targeted depending on the targeted Tanner stage. Modeling and simulation could aid in dose selection and establishing dose titration schemes in the pediatric population. This analysis establishes potential key clinical pharmacology considerations in designing pediatric safety and efficacy trials for TRT and has identified knowledge gaps that warrant further investigation.