NONCLINICAL SAFETY TESTING IN SUPPORT OF EVELOPMENT OF ...

INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICAL REQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USE ICH HARMONISED GUIDELINE

NONCLINICAL SAFETY TESTING IN SUPPORT OF DEVELOPMENT OF PAEDIATRIC PHARMACEUTICALS

S11

Final version Adopted on 14 April 2020

This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of ICH regions.

Code S11

S11

S11 Document History

History

Endorsement by the Members of the ICH Assembly under Step 2 and release for public consultation (document dated 9 July 2018). Adopted by the Regulatory Members of the ICH Assembly under Step 4 (document dated 10 March 2020).

Date 18 September 2018

14 April 2020

Legal notice: This document is protected by copyright and may, with the exception of the ICH logo, be used, reproduced, incorporated into other works, adapted, modified, translated or distributed under a public license provided that ICH's copyright in the document is acknowledged at all times. In case of any adaption, modification or translation of the document, reasonable steps must be taken to clearly label, demarcate or otherwise identify that changes were made to or based on the original document. Any impression that the adaption, modification or translation of the original document is endorsed or sponsored by the ICH must be avoided. The document is provided "as is" without warranty of any kind. In no event shall the ICH or the authors of the original document be liable for any claim, damages or other liability arising from the use of the document. The above-mentioned permissions do not apply to content supplied by third parties. Therefore, for documents where the copyright vests in a third party, permission for reproduction must be obtained from this copyright holder.

ICH HARMONISED GUIDELINE

NONCLINICAL SAFETY TESTING IN SUPPORT OF DEVELOPMENT OF PAEDIATRIC PHARMACEUTICALS

S11

ICH Consensus Guideline

TABLE OF CONTENTS

1. INTRODUCTION .............................................................................................................. 2 1.1 Objectives of the Guideline .......................................................................................... 2 1.2 Background ................................................................................................................... 2 1.3 Scope ......................................................................................................................... 2 1.4 General Principles......................................................................................................... 2

2. CONSIDERATIONS FOR ADDITIONAL NONCLINICAL SAFETY INVESTIGATIONS ................................................................................................................. 3

2.1 Clinical Context ............................................................................................................ 3 2.2 Weight of Evidence Approach...................................................................................... 3 2.3 Considerations to Inform the Weight of Evidence Evaluation ..................................... 5

2.3.1 Clinical Information (WoE Factors: Youngest Intended Patient Age; Amount/Type of Existing Data; Clinical Treatment Duration) ........................ 5

2.3.2 Pharmacological Properties (WoE Factors: Effects on Developing Organ Systems; Pharmacological Target has Role in Organ Development; Selectivity and Specificity of Pharmaceutical) ................................................................... 5

2.3.3 Pharmacokinetic Data (WoE Factors: Amount/Type of Existing Data)........... 6 2.3.4 Nonclinical Safety Data (WoE Factors: Effects on Developing Organ

Systems; Amount/Type of Existing Data) ........................................................ 6 2.3.5 Feasibility ......................................................................................................... 7 2.4 Application and Outcome of the Weight of Evidence Evaluation................................ 7 3. DESIGN OF NONCLINICAL JUVENILE ANIMAL STUDIES ................................. 7 3.1 General Considerations/Study Objectives .................................................................... 7 3.2 Dose Range-Finding Studies ........................................................................................ 8 3.3 Animal Test System Selection ...................................................................................... 8 3.4 Age of Animals, Dosing Period, and Dosing Regimen ................................................ 9 3.5 Post-Treatment Period Assessments ........................................................................... 10 3.6 Route of Administration ............................................................................................. 11 3.7 Dose Selection ............................................................................................................ 11 3.8 Endpoints .................................................................................................................... 12

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3.8.1 Core Endpoints ............................................................................................... 12 3.8.1.1 Mortality and Clinical Observations............................................................... 12 3.8.1.2 Growth ............................................................................................................ 12 3.8.1.3 Food Consumption.......................................................................................... 12 3.8.1.4 Sexual Development ....................................................................................... 12 3.8.1.5 Clinical Pathology .......................................................................................... 12 3.8.1.6 Anatomic Pathology ....................................................................................... 13 3.8.1.7 Toxicokinetics................................................................................................. 13 3.8.2 Additional Endpoints to Address Identified Concerns ................................... 13 3.8.2.1 Other Growth Endpoints ................................................................................. 13 3.8.2.2 Bone Assessments .......................................................................................... 13 3.8.2.3 Clinical Pathology .......................................................................................... 13 3.8.2.4 Anatomic Pathology ....................................................................................... 14 3.8.2.5 Ophthalmologic Examinations ....................................................................... 14 3.8.2.6 CNS Assessments ........................................................................................... 14 3.8.2.7 Reproductive Assessments ............................................................................. 15 3.8.2.8 Immunologic Assessments ............................................................................. 16 3.9 Allocation of Animals to Study Groups and Endpoint Subsets ................................... 16 3.9.1 Preweaning Allocation....................................................................................... 16 3.9.2 Postweaning Allocation ..................................................................................... 17 3.10 Animal Numbers and Sex ........................................................................................... 17 4 CONSIDERATIONS FOR PAEDIATRIC-FIRST/ONLY DEVELOPMENT.......... 17 5. Data Interpretation .......................................................................................................... 18 5.1 Considerations for Endpoint Interpretation ................................................................ 18 5.2 Overall Interpretation.................................................................................................. 19 6. OTHER CONSIDERATIONS ........................................................................................ 19 6.1 Excipients.................................................................................................................... 19 6.2 Combination Pharmaceuticals .................................................................................... 19 Glossary................................................................................................................................... 20 References ............................................................................................................................... 21 Appendix A: Overview Of Age-dependent Development Of Organ Systems By Species 22 Appendix B: Case Studies Applying the Weight of Evidence Approach ....................... 33 Appendix C: Approaches to Preweaning Litter Allocation in the Rodent .................... 37

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ICH S11 Guideline

LIST OF ABBREVIATIONS

ADME CNS CYP DRF ePPND FIH FOB GABA GFR GI HPG ICH JAS NHP NOAEL PND PPND PK PD TDAR TK WoE

Absorption, Distribution, Metabolism, and Excretion Central Nervous System Cytochromes P450 Dose Range-Finding Enhanced Pre- and Postnatal Development First in Human Functional Observational Battery Gamma Aminobutyric Acid Glomerular Filtration Rate Gastrointestinal Human Pituitary Gonadotropin International Council for Harmonisation Juvenile Animal Study Non-Human Primate No Observed Adverse Effect Level Postnatal Day Pre- and Postnatal Development Pharmacokinetics Pharmacodynamics T-Cell-Dependent Antibody Response Toxicokinetic Weight of Evidence

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