Ivan Demin (1), Baldur Magnusson (1), Oliver Sander (1), Bjoern Bornkamp (1), Stephan Koehne-Voss (1), Bjoern Holzhauer (1), Michael Looby (1), Frank Bretz (1)
(1) Novartis Pharma AG, Switzerland
Objectives: Finding the best dose and regimen is a key aspect of clinical development programs and quantitative line functions, such as biostatistics, pharmacometrics (PMX), and clinical pharmacology can greatly contribute here. Questions around the design and analysis of phase 2b dose and regimen finding studies are often complex and many aspects are to be considered. Within a large pharmaceutical organization guidance for quantitative input on dose finding studies can support statisticians and pharmacometricians with their input to dose finding studies, improve collaboration of quantitative line functions, and overall increase quality of dose finding studies.
Methods: At Novartis “Guidance for design and analysis of phase 2b dose and regimen finding studies” was developed for biostatisticians and pharmacometricians. The objectives of the guidance were to 1) discuss key quantitative aspects of the design and analysis of dose-finding studies relevant for biostatistics and PMX; and 2) to highlight opportunities for collaboration between quantitative line functions such as biostatistics, PMX and clinical pharmacology. This poster presents the PMX perspective.
Results: The resulting guideline consists of five sections: 1) Scope, 2) Objectives of Phase 2b dose-finding studies, 3) Prior data to inform the design of phase 2b, 4) Designing phase 2b, and 5) Analysing phase 2b. In each section quantitative aspects of dose finding studies are discussed and different settings for dose-finding are considered. Key aspects of the analysis of phase 2b and subsequent design of phase 3 are addressed. At each stage opportunities for potential collaboration between PMX and biostatistics are highlighted.
From PMX perspective key elements of the study protocol for the dose finding study include selection of dose range, dose groups, loading and maintenance doses, duration of washout, and assessments for dose-exposure-response (D-E-R) modeling. At the analysis phase, D-E-R modelling is often performed as a secondary or exploratory analysis. Findings of primary D-R analysis and exploratory D-E-R analysis should be aligned before sharing the result with the project team.
Conclusion: Throughout design and analysis of phase 2b studies it is crucial to optimize quantitative input and to maintain close collaboration between PMX and biostatistics. This process can be facilitated by a guidance for dose-finding studies for biostatisticians and pharmacometricians.
Reference: PAGE 25 (2016) Abstr 5770 [www.page-meeting.org/?abstract=5770]
Poster: Methodology - Study Design