ICH S11 Step 5 on nonclinical safety testing in support of ...

31 March 2020 EMA/CHMP/ICH/616110/2018 Committee for Medicinal Products for Human Use

ICH guideline S11 on nonclinical safety testing in support of development of paediatric pharmaceuticals

Step 5

Transmission to CHMP Adoption by CHMP for release for consultation Start of consultation End of consultation (deadline for comments) Final adoption by CHMP Date for coming into effect

20 September 2018 20 September 2018 24 September 2018 24 March 2019 26 March 2020 26 September 2020

Official address Domenico Scarlattilaan 6 1083 HS Amsterdam The Netherlands Address for visits and deliveries Refer to ema.europa.eu/how-to-find-us Send us a question Go to ema.europa.eu/contact Telephone +31 (0)88 781 6000

An agency of the European Union

? European Medicines Agency, 2020. Reproduction is authorised provided the source is acknowledged.

Document History

Code S11

History

Adopted by the Regulatory Members of the ICH Assembly under Step 4 .

Date N/A

ICH guideline S11 on nonclinical safety testing in support of development of paediatric pharmaceuticals EMA/CHMP/ICH/616110/2018

Page 2/45

ICH guideline S11 on nonclinical safety testing in support of development of paediatric pharmaceuticals

Table of contents

1. Introduction ............................................................................................ 6

1.1. Objectives of the guideline ....................................................................................6 1.2. Background .........................................................................................................6 1.3. Scope .................................................................................................................6 1.4. General principles.................................................................................................6

2. Considerations for additional nonclinical safety investigations ............... 7

2.1. Clinical context ....................................................................................................7 2.2. Weight of evidence approach .................................................................................7 2.3. Considerations to inform the weight of evidence evaluation .......................................9 2.3.1. Clinical information (WoE factors: youngest intended patient age; amount/type of existing data; clinical treatment duration) ......................................................................9 2.3.2. Pharmacological properties (WoE factors: effects on developing organ systems; pharmacological target has role in organ development; selectivity and specificity of pharmaceutical)........................................................................................................ 10 2.3.3. Pharmacokinetic data (WoE factors: amount/type of existing data) ........................ 10 2.3.4. Nonclinical safety data (WoE factors: effects on developing organ systems; amount/type of existing data) .................................................................................... 11 2.3.5. Feasibility ....................................................................................................... 11 2.4. Application and outcome of the weight of evidence evaluation ................................. 12

3. Design of nonclinical juvenile animal studies ........................................ 12

3.1. General considerations/study objectives ................................................................ 12 3.2. Dose range-finding studies .................................................................................. 12 3.3. Animal test system selection................................................................................ 13 3.4. Age of Animals, Dosing Period, and Dosing Regimen ............................................... 14 3.5. Post-treatment period assessments ...................................................................... 15 3.6. Route of Administration....................................................................................... 15 3.7. Dose selection ................................................................................................... 16 3.8. Endpoints .......................................................................................................... 16 3.8.1. Core endpoints ................................................................................................ 16 3.8.2. Additional endpoints to address identified concerns.............................................. 17 3.9. Allocation of animals to study groups and endpoint subsets ..................................... 20 3.9.1. Preweaning allocation ...................................................................................... 20 3.9.2. Postweaning allocation ..................................................................................... 21 3.9.3. Animal numbers and sex .................................................................................. 21

4. Considerations for paediatric-first/only development ........................... 21

5. Data interpretation ................................................................................ 22

5.1. Considerations for endpoint interpretation ............................................................. 22 5.2. Overall interpretation .......................................................................................... 23

6. Other considerations ............................................................................. 23

6.1. Excipients.......................................................................................................... 23

ICH guideline S11 on nonclinical safety testing in support of development of paediatric pharmaceuticals EMA/CHMP/ICH/616110/2018

Page 3/45

6.2. Combination pharmaceuticals .............................................................................. 23

Glossary .................................................................................................... 24 References ................................................................................................ 25 Appendix A: overview of age-dependent development of organ systems by species ...................................................................................................... 26 Appendix B: case studies applying the weight of evidence approach........ 39 Appendix C: Approaches to Preweaning Litter Allocation in the Rodent .... 43

ICH guideline S11 on nonclinical safety testing in support of development of paediatric pharmaceuticals EMA/CHMP/ICH/616110/2018

Page 4/45

List of abbreviations

ADME Absorption, Distribution, Metabolism, and Excretion

CNS Central Nervous System

CYP Cytochromes P450

DRF Dose Range-Finding

ePPND Enhanced Pre- and Postnatal Development

FIH First in Human

FOB Functional Observational Battery

GABA Gamma Aminobutyric Acid

GFR Glomerular Filtration Rate

GI

Gastrointestinal

HPG Human Pituitary Gonadotropin

ICH International Council on Harmonisation

JAS Juvenile Animal Study

NHP Non-Human Primate

NOAEL No Observed Adverse Effect Level

PND Postnatal Day

PPND Pre- and Postnatal Development

PK

Pharmacokinetics

PD

Pharmacodynamics

TDAR T-Cell-Dependent Antibody Response

TK

Toxicokinetic

WoE Weight of Evidence

ICH guideline S11 on nonclinical safety testing in support of development of paediatric pharmaceuticals EMA/CHMP/ICH/616110/2018

Page 5/45

 ................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download