Pediatric Drug Products Session 5: Safety Qualification of - PowerPoint PPT Presentation

Challenges and Strategies to Facilitate Formulation Development of Pediatric Drug Products Session 5: Safety Qualification of Excipients Session Chairs: Darren Fegley (FDA) Lorrene Buckley (Eli Lilly & Co) Jacqueline Carleer (FAGG-AFMPS) Gerri Baer (FDA) 6/6/2016 Pediatric Excipients Workshop - Session 5 1

Darren Fegley* Anthony Nunn Pharmacologist Honorary Fellow USFDA/CDER/OND/DPP Dept Women’s & Children’s Health Gerri Baer* University of Liverpool Lead Medical Officer Smita Salunke USFDA/OC/OPT Sr Scientific Manager EuPFI UCL School of Pharmacy Lorrene Buckley Organizing Sr Research Fellow Committee Toxicology & Pathology Brian Aylward Lilly Research Laboratories EU Irish HPRA Karen Thompson Regulatory PDCO, Member Sr Principal Scientist, Oral Expert Chair, Formulations WG Formulation Science & Technology Jacqueline Carleer Merck Research Laboratories Belgian FAM Mark Turner PDCO, Alternate Member SL / Consultant Chair, Nonclinical WG Dept Women’s & Children’s Health University of Liverpool * Disclaimer: Opinions expressed do not necessarily reflect those of the FDA or its policy 6/6/2016 Pediatric Excipients Workshop - Session 5 2

Excipients: Not always inert, Use must be justified • FDA 2005: New excipients- inactive ingredients intentionally added USFDA Guidance: Nonclinical Studies for the Safety Evaluation of Pharmaceutical – Not intended to exert therapeutic effects at intended dose; may improve product delivery (e.g., enhance absorption or control release of drug) Excipients 2005 – Not fully qualified by existing safety data with respect to currently proposed level of exposure, duration of exposure, or route of administration package leaflet of medicinal products for EU Guideline: Excipients in the label and – May not be inert • EU 2003: Excipients are generally considered to be ‘inert’ – Desirable that excipients should have little or no pharmacological action, however, some have a recognized human use 2003 action or effect in certain circumstances • EU 2013: Need comprehensive development rationale considering relative benefits and risks of possible alternatives EU Guideline on pharmaceutical development of medicines for – Avoid excipients with a potential cause for concern (pending more research) paediatric use 2013 – Justify added value of a novel excipient 6/6/2016 Pediatric Excipients Workshop - Session 5 3

Risk: Exposure and Toxicity Excipient Characterizing Functionality Toxicity/Hazard & Exposure in a dynamic system of physiological development ? Dose/Exposure x Response Relationship 6/6/2016 Pediatric Excipients Workshop - Session 5 4

Risk : Benefit Assessments Hazard Exposure Identification Characterization What do we know? What don’t we know? Dose/Exposure - Response Analysis What do we need to know, given particular clinical scenarios Risk:Benefit Assessment Understanding risk in the context of benefits Risk Management Minimize / mitigate risk to patients Heightened Safety Monitoring 6/6/2016 Pediatric Excipients Workshop - Session 5 5

Risk:Benefit Assessments – All agree on the Need EU Guideline: Guideline on pharmaceutical development of medicines for paediatric use 2013 Risk Considerations Linked to Use and Function HOWEVER - Target age group  Perform risk-benefit Not Everyone Agrees on the “How” or the “What” - Pharmaceutical form and assessments on use? … information sources should proposed new excipients - Excipient function? be consulted in order to in drug products to - Route of administration assess the safety profile of establish permissible & - Excipient proportion in each excipient in a paediatric safe limits medicinal product? formulation resulting in an  Existing human data can - Daily intake? overall conclusion as to substitute for certain - Composition? whether or not additional nonclinical safety data data are needed 6/6/2016 Pediatric Excipients Workshop - Session 5 6

Juvenile toxicology studies: Performed ‘for cause’ • Toxicology studies may be necessary if the use of an existing excipient in a paediatric medicine can not be justified based on information sources (EU 2013) • Consider all relevant information first Image source: http://users.unimi.it/gazzalab/wordpress/wp • Avoid routine , “box - ticking” conduct of content/uploads/2014/11/FINAL_PreclinicalFormulation_05NOV204-ALL-Monzani- Colombo.pdf standard juvenile animal tox studies Consider relevance / value to inform clinical practice • If warranted, a juvenile toxicology study with the active drug can be used to assess the safety of excipients at the same time • Interspecies extrapolation further confounded by translational complexities across postnatal development stages 6/6/2016 Pediatric Excipients Workshop - Session 5 7

Safety Qualification of Excipients in Paediatrics • Limited availability of and access to safety data, esp for paediatric use FDA IID => Gaps in Paediatrics?? Current • Extrapolation uncertainties in exposure & effect Paradigms • Lack of standardization with regard to what is adequate / necessary to sufficiently characterize risk:benefit for excipient use in (various) pediatric patients and disease states Risk: Benefit Assessment Framework NEED • Knowledge-based, standardized approach 6/6/2016 Pediatric Excipients Workshop - Session 5 8

Session 5: Case Scenarios & Questions to Inform Development of a Risk Assessment Framework Two Breakout discussion groups: GROUP 1 GROUP 2 incomplete information (eg, New/Novel Excipients Established / a new use, dose, duration, Standard Excipients route, disease • “Inactive” vs • Clarify what is known severity, age biologically active (experience) as it relates group, etc) agents (e.g. SNAC) to the proposed setting • European vs. US • Identify information gaps approaches • Identify alternative sources of information & the appropriateness thereof

Breakout session discussion How to justify excipient use (novel, established) in paediatrics? What are the hurdles? Risk assessment & Information needs Information sharing platform • Can a common template or approach • Where to find the existing information? (framework) be developed for implementing • Platform to share information? risk assessments for individual excipients? (eg, STEP database) • What minimum information is required? • extending the FDA inactive ingredient What additional data is required? database to paediatrics • What circumstances and factors should be considered regarding the justification for Proposed Framework – juvenile tox studies ? Your opinion matters!! • Should toxicology studies with the final • Would the proposed framework help formulation be conducted? If so, when & address the issues of use of excipients in which studies ? • What alternative options are available if no paediatrics? • What are the pros and cons of the additional information is available? • What clinical trial design factors can be presented framework ? • What additional elements would you incorporated to provide information on the consider in the framework? safety of excipients? • Where are the knowledge gaps and how would • Can we evaluate data on excipients & you prioritize studies needed to approach the present in a format which will satisfy evaluation of excipients for paediatrics? regulators? 6/6/2016 Pediatric Excipients Workshop - Session 5 10