Extrapolation of Adult Efficacy Data to Pediatric Systemic Lupus Erythematosus: Evaluating Similarities in Exposure-Response.

To streamline drug development, the United States Food and Drug Administration (FDA) can consider the extrapolation of adult efficacy data to children when the disease and drug effects are sufficiently similar. This study explored whether the relationship between drug exposure and response for selected drugs in systemic lupus erythematosus (SLE) was sufficiently similar to support a consideration of the extrapolation of adult efficacy data to children of ≥5 years of age. An exposure-response analysis of drugs used to treat SLE was conducted using published exposure versus response and efficacy versus time data. Statistical analyses included noncompartmental analysis of a drug's area under the effect curve and direct Imax pharmacodynamic (PD) modeling. Six drugs were included: azathioprine, belimumab, cyclophosphamide, hydroxychloroquine, mycophenolate/mycophenolic acid, and rituximab. For belimumab, the net change in responders at week 52 (the primary end point) was nearly identical between 1 adult trial and the pediatric trial. For mycophenolate, PD modeling suggested no significant differences in exposure and SLE disease activity between adults and children. For azathioprine, cyclophosphamide, hydroxychloroquine, and rituximab the data were not sufficient to quantitatively characterize the exposure-response relationship, but the clinical or pharmacologic response between children and adults was similar overall. Adult SLE data should be leveraged to guide pediatric drug development programs and identify areas with residual uncertainty regarding the effectiveness or safety of a drug in children. The degree to which efficacy extrapolation can reduce clinical trial requirements in pediatric SLE should be individualized for each new drug product, depending in part on the mechanism of action of the drug and the similarity of disease manifestations in children and adults.

Duke Scholars

Author Stephen Joseph Balevic Pediatrics, Rheumatology

Author Daniel Gonzalez Medicine, Clinical Pharmacology

Author Laura Eve Schanberg Pediatrics, Rheumatology

Author Christoph Paul Vincent Hornik Pediatrics, Critical Care Medicine