IQ consortium – CPLG Pediatric Working Group: S. Y. Amy Cheung1, Ashley Strougo2, Sebastian Haertter3, Jing Liu4, Steven J. Kovacs5, Solange Corriol-Rohou6, Christina Bucci-Rechtweg7, Jeffrey S. Barrett8, Raafat Bishai9, Angela James10, Dennis Potempa2 and Konstantina Vaneski11
1. Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Cambridge, UK. 2. Translational Medicine, Pharmacokinetics, Dynamics and Metabolism, M&S, Sanofi, Frankfurt, Germany. 3. Translational Med & Clinical Pharmacology, Boehringer-Ingelheim Pharma, Ingelheim, Germany 4. Clinical Pharmacology, Pfizer, Groton, Connecticut, USA. 5. Translational Medicine, Novartis Institutes for BioMedical Research, East Hanover, New Jersey, USA. 6. GRAPSQA, Global Medicines Development, AstraZeneca, Paris, France. 7. Global Health Policy, Regulatory Affairs, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA. 8. Translational Medicine, Translational Informatics, Sanofi, Bridgewater, New Jersey, USA. 9. Clinical Development, Cardiovascular Renal Metabolism, Global Medicines Development, AstraZeneca, Gaithersburg, USA. 10. Clinical Pharmacology and Exploratory Department, Astellas Pharma, Northbrook, Illinois, USA. 11. Global Clinical Development, Bayer HealthCare, Basel, Switzerland.
Objectives: Children deserve medical therapies that have been properly evaluated for safety and efficacy and formulated specifically to meet their needs. With the release of paediatric regulations in the European Union (EU) and the United States (US), there are new opportunities for strategies that can provide robust evidence for use of medicinal products in children [1, 2]. Use of innovative approaches such as extrapolation from a reference population is now being applied to paediatric drug development – expediting articulation of dose rationales and/or replacing RCTs in children. The IQ consortium – CPLG Pediatrics Working Group’s objective is to improve drug development in children by sharing knowledge amongst industry and regulators regarding their experiences related to paediatric product development process.
Methods: We reviewed and evaluated the challenges and opportunities in paediatric drug development and the role of extrapolation [3] in 4 parts, including (1) the current regulatory framework for the use of extrapolation in paediatric drug development; (2) recent discussions for potential enhancements to this regulatory framework; (3) a quantitative toolbox (i.e., model-based/informed drug discovery and development (MID3) [4] with a focus on tools and methods to support extrapolation) to advance efficiency and science in the development of new medical therapies for paediatric populations; and (4) examples of diseases/indications where extrapolation has been used and accepted by regulators are presented to identify gaps and opportunities for improvement.
Results: Part 1 provides background on paediatric regulatory policies and how modelling and simulation and extrapolation were incorporated in the recently published ICH-E11 (R1) and EMA Paediatric Extrapolation Reflection Paper. Part 2 identifies current gaps and proposes points to consider for future regulatory policy. This includes the need for disease-specific regulatory guidelines, context-specific considerations of the source data available for extrapolation, limitations of partial extrapolation, knowledge gaps and special provisions regarding therapies targeting the special needs of neonates and extrapolation for safety. Part 3 details how the application of MID3 can benefit the paediatric extrapolation framework (e.g. assumption setting/evaluation and assessment of disease similarity between adults and children). Recommendations on the use of various types of modelling including systems pharmacology modelling, empirical modelling and meta-analysis and the value and importance of read-world evidence (RWE) are also addressed. Part 4 provides case studies covering 5 disease areas (partial-onset seizures, pain, gastroesophageal reflux disease, type 2 diabetes mellitus and cancer) with application of extrapolation for 3 situations with a focus on prior knowledge, assumptions, extrapolation rationale and impact: 1) Similar disease and similar exposure-responses (ER) relationship 2) Similar disease by diagnostic criteria and different ER relationship 3) Different disease and ER relationship to compare the strength and limitation.
Conclusions: There is growing experience with quantitative approaches and data to guide the appropriate use of extrapolation in the development of new therapies for paediatric populations. However, better alignment of regulatory authorities on the definition of extrapolation and agreement on acceptable uses is still warranted. The successful application of extrapolation for paediatric patients with partial-onset seizures highlights the importance of quantitative approaches and knowledge-sharing/collaboration among stakeholders (sponsors, investigators, and regulators) to reach a mutual understanding about similarities in pathophysiology and responses to therapy. Educating others about what paediatric extrapolation and quantitative approaches are may inspire more trust, improve care, and promote collaborations or partnerships to improve the way the needs of paediatric patients are addressed in the future.
References:
[1] Frattarelli, D.A. et al. Off-label use of drugs in children. Pediatrics 133, 563–567 (2014)
[2] Turner, M.A., Catapano, M., Hirschfeld, S., Giaquinto, C. & Global Research in, P. Paediatric drug development: the impact of evolving regulations. Adv Drug Deliv Rev 73, 2–13 (2014).
[3] Barrett JS, Bishai R, Bucci-Rechtweg C, Cheung SYA, Corriol-Rohou S, Haertter S, James A, Kovacs SJ, Liu J, Potempa D, Strougo A, Vanevski K; IQ consortium – CPLG Pediatric Working Group. Challenges and Opportunities in the Development of Medical Therapies for Pediatric Populations and the Role of Extrapolation. Clin Pharmacol Ther 100(3), 419-433 (2018).
[4] EFPIA MID3 Workgroup, Marshall SF, Burghaus R, Cosson V, Cheung SYA, Chenel M, DellaPasqua O, Frey N, Hamrén B, Harnisch L, Ivanow F, Kerbusch T, Lippert J, Milligan PA, Rohou S, Staab A, Steimer JL, Tornøe C, Visser SA.
Reference: PAGE 27 (2018) Abstr 8586 [www.page-meeting.org/?abstract=8586]
Poster: Drug/Disease Modelling - Paediatrics