Description
The purpose of this document is to recommend international standards for, and promote harmonisation of, the nonclinical safety assessments to support the development of pharmaceuticals intended for pediatric use. Harmonisation of the guidance for nonclinical safety studies will define the current recommendations and reduce the likelihood that substantial differences will exist among regions. It should facilitate the timely conduct of pediatric clinical trials and reduce the use of animals in accordance with the 3R (replace/reduce/refine) principles.
Key Topics
Terms and concepts identified from this document
Scope & Applicability
Product Classes
10Scope of the ICH S11 guidance
Products combining drug, device, or biological constituents; Generally recommended for Enhanced Documentation; Requires 14971-based framework incorporating ICH Q9; A drug-device combination where the device constituent part detects ingestion.
dose selection principles described in ICH S6
Regulatory considerations for products containing multiple active ingredients
Within the scope of ICH S11
Scope of carcinogenicity testing for specific product types
Excluded from the scope of ICH S11
Excluded from the scope of ICH S11
Products for which batch/lot information is particularly important
Assessed in pharmacologically relevant species; When studies in juvenile animals are warranted for biopharmaceuticals
Stakeholders
9FDA's role within the ICH organization.
Maternal transfer of immunity and maternal care
Entity responsible for submitting NDINs
NHP used in ePPND studies
animal in any postnatal stage not fully matured in terms of organ or system morphology
Known to have a lower risk of GVHD than adults; population with response profiles differing from adults; Pediatric patients may have response profiles that differ from adults; Population: ≥12 years old or ≥ 2 years old
starts with a First in Human (FIH) study in healthy adult volunteers
Entity responsible for submitting applications under section 524B
children and adolescents included in clinical trials with specific safeguards
Regulatory Context
Regulatory Activities
5Clinical development supported by nonclinical safety assessments
development for treatment exclusively in pediatric ages
development for treatment of pediatric patients before any development for an adult indication
starts with a First in Human (FIH) study in healthy adult volunteers; FIH abbreviation
JAS supporting initial clinical trials in children
Document Types
2Chromatogram integration should be described in a study plan
allocation methods should be clearly described in the study plan/protocol and report
Attributes
10Weight of Evidence factor for clinical context; Key factor in the WoE evaluation
Clinical treatment duration factor in WoE analysis
Clinical treatment duration factor in WoE analysis
Criteria for selecting an animal model for highly targeted therapies
Developmental milestone used to compare species
deviation from isometric growth where properties change according to an exponential function of body mass
important variable to consider for stratification; Factor related to systemic exposure and renal excretion
Efficiency in study design is critical to reduce animal use as per the 3R principles
measured by systemic availability of pharmaceutical-related substances
Factor in determining if additional nonclinical studies are warranted
Technical Details
Substances
8Differences in excipients may affect product stability
Serum IgG providing passive immunity in infants
Maternal transfer of immunoglobulin in NHP and humans
NHP models often used for biopharmaceuticals
Case studies involving small molecules with known or novel pharmacology
Specific milk composition to be considered in PK
variations in the pharmacokinetics of a drug over time due to anti-drug antibodies
Considered for hazard identification in juvenile rodents
Testing Methods
10Nonclinical studies to support pediatric age groups.
Use of rabbits and NHP in reproductive toxicology
Adult general toxicology studies
Endpoint included in compressed development species like rats
Endpoint difficult to perform in large animals
DRF studies mentioned in abbreviations
abbreviation for Juvenile Animal Study
nonclinical safety study to provide an assessment of the toxicity profile of a pharmaceutical
qualitative histologic assessment of spermatogenesis
Functional assays should be performed at appropriate stages of development, e.g., for TDAR; TDAR abbreviation
Processes
9Testing in support of development of pediatric pharmaceuticals
Nonclinical safety testing in support of pediatric drug development; Extensive juvenile study to cover developmental phases
study design based on biopharmaceutical experience, often in NHP
Nonclinical safety assessment in young animals; nonclinical safety testing in support of pediatric pharmaceuticals; A definitive JAS can become large and complex
PPND study used to address safety concerns
Juvenile Animal Study used to assess nonclinical safety
Pre- and postnatal development studies; Pre- and postnatal development.
Enhanced Pre- and Postnatal Development study design for Cynomolgus Monkey
Dose Range-Finding study in juvenile animals
Clinical Concepts
10Safety findings including deaths and post-mortem examinations
Pediatric population that may be included in adult clinical trials.; inclusion in adult clinical trials recommended when disease is similar
The target population (persons not more than 12 months old)
Target population for long-term neurodevelopmental safety studies
Reproductive milestone in humans and non-human primates
preterm neonates and infants are at particularly high risk
assessments for immunotoxicity should be considered
timing of the treatment and assessments in relation to that of sexual maturation
Reported outcomes following the use of a drug or drug class.; provide information to predict potential adverse effects in the target species
physical indicators of onset of puberty like vaginal opening; period of intense endocrine activity with structural and functional maturation; Developmental milestone in humans and animals
Identified Hazards
Hazards
4Safety concern for pediatric patients
Risk of malformations from exposure
ovarian histology can identify many developmental reproductive hazards
Potential age-related differences in efficacy and toxicity; high dose should not result in marked toxicity
Standards & References
Specifications
2Standard measurements in juvenile animal studies including growth and clinical pathology
Used in calculating the margin of safety
ICH References (8)
Nonclinical Safety Testing in Support of Development of Pediatric Pharmaceuticals.
Immunotoxicity Studies for Human Pharmaceuticals; guidance regarding nonclinical immunotoxicity assessment of small molecule drugs; Describes WoE integration for immunotoxicity evaluation.
Guidance for industry on Toxicokinetics and systemic exposure in toxicity studies.
Clinical Investigation of Medicinal Products in the Pediatric Population.
Nonclinical Safety Studies for the Conduct of Human Clinical Trials
Detection of Toxicity to Reproduction for Medicinal Products; Standard pre- and postnatal development (PPND) study and alternative assays
Nonclinical Evaluation for Anticancer Pharmaceuticals; Guideline regarding pharmaceuticals for advanced cancer.
Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals
Related MFDS Guidelines
Korean regulatory guidelines covering similar topics
See Also (8)
- E11A Pediatric Extrapolation
- M15 General Principles for Model-Informed Drug Development
- Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product
- Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances
- Rare Diseases: Considerations for the Development of Drugs and Biological Products
- Q3C Impurities: Residual Solvents_2011
- Providing Regulatory Submissions in Electronic Format --Content of the Risk Evaluation and Mitigation Strategies Document Using Structured Product Labeling: Guidance for Industry
- Q4B Annex 5: Disintegration Test General Chapter