Platform trial design for neurofibromatosis type 1, NF2-related schwannomatosis and non-NF2-related schwannomatosis: A potential model for rare diseases.

Background: Neurofibromatosis type 1, -related schwannomatosis and non--related schwannomatosis (grouped under the abbreviation "NF") are rare hereditary tumor predisposition syndromes. Due to the low prevalence, variability in the range, and severity of manifestations, as well as limited treatment options, these conditions require innovative trial designs to accelerate the development of new treatments.

Methods: Within European Patient-Centric Clinical Trial Platforms (EU-PEARL), we designed 2 platform-basket trials in NF.

Exposure-response modeling for extrapolation from adult to pediatric patients who differ with respect to prognostic factors: Application to everolimus.

Pediatric extrapolation is essential for bringing treatments to the pediatric population, especially for indications where the recruitment of pediatric patients into clinical trials is difficult and where fully powered trials are impossible. Often a similar exposure-response relationship between adult and pediatric patients can be assumed, but just matching exposures can be misleading when some prognostic factors for efficacy differ between those two patient populations. We present an example in liver transplantation where different study designs led to different (time-dependent) hazards between populations.

Identifying challenges in neurofibromatosis: a modified Delphi procedure.

Neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SWN) are rare conditions with pronounced variability of clinical expression. We aimed to reach consensus on the most important manifestations meriting the development of drug trials. The five-staged modified Delphi procedure consisted of two questionnaires and a consensus meeting for 40 NF experts, a survey for 63 patient representatives, and a final workshop.

Cardiac risk assessment based on early Phase I data and PK-QTc analysis is concordant with the outcome of thorough QTc trials: an assessment based on eleven drug candidates.

Cardiac safety assessment is a key regulatory requirement for almost all new drugs. Until recently, one evaluation aspect was via a specifically designated, expensive, and resource intensive thorough QTc study, and a by-time-point analysis using an intersection-union test (IUT). ICH E14 Q&A (R3) (http://www.