Description
The Food and Drug Administration (FDA) is announcing the availability of a guidance for industry entitled “Nonclinical Safety Evaluation of Pediatric Drug Products.” This document provides guidance on the role and timing of animal studies in the nonclinical safety evaluation of therapeutics intended for the treatment of pediatric patients. The guidance discusses some conditions under which juvenile animals can be meaningful predictors of toxicity in pediatric patients and makes recommendations on nonclinical testing.
Key Topics
Terms and concepts identified from this document
Scope & Applicability
Product Classes
5The primary subject of the nonclinical safety evaluation guidance; Nonclinical Safety Evaluation of Pediatric Drug Products; Nonclinical safety evaluation of these products
Class Labeling for Intranasal and Oral Inhaled Corticosteroids Containing Drug Products
found to decrease growth velocity in children
associated with chondrotoxicity in immature animals
Typically, at least two adequate and well-controlled trials are needed to support approval of a new molecular entity.
Stakeholders
4Assist sponsors in the nonclinical evaluation
Entity responsible for submitting applications under section 524B
Youngest pediatric group requiring cautious bridging
Population group through 12 months of age; Population group for specific labeling rules (through 12 months).
Regulatory Context
Regulatory Activities
3Clinical testing phase where certain safety effects cannot be ethically assessed; supported by data generated from juvenile animal studies
Legislation made permanent under FDASIA
PMCs agreed upon in writing; Studies or clinical trials agreed upon in writing by FDA and the applicant
Document Types
3Source cited for lack of pediatric safety and efficacy information in drug listings
Class Labeling for Intranasal and Oral Inhaled Corticosteroids
Required documentation for review including mechanism of action statements
Attributes
5PK data used to evaluate drug pharmacology.
Hemodynamic parameter
Accurate dose-response information is important for maximizing desirable effects.
PD data used to evaluate drug pharmacology.
Property used to determine maintenance dose intervals and safety monitoring
Technical Details
Substances
10Known or potential interferent for blood glucose measurement.; Listed as an example interferent in the recommended summary table format.
Low-Dose Vigabatrin (gamma-vinyl GABA)-Induced Damage
Rats Treated with Fluoxetine During Early Juvenile Life
Fatal Benzyl Alcohol Poisoning in Neonatal Intensive Care Units
metabolizing enzyme with lower expression in neonates compared to adults
enzyme generally considered not inducible by drugs; Specific enzyme used for extrapolation of DDI results.; Cytochrome P450 enzyme
Nervous system developmental event
Requests related to inactive ingredients in generic drugs
Positive control example in Reference Compound List; CAS No.: 99-66-1 (sodium valproate: 1069-66-5)
Drug substance mentioned in veterinary context; Drug substance subject to specific regulatory policy; CPG 654.300 regarding chloramphenicol
Testing Methods
5Nonclinical studies to support pediatric age groups.
Methods used to evaluate the safety of nanomaterials
Cardiac parameter maturation
measurement of organ weights, gross and microscopic examinations, and neurobehavioral testing
histopathologic examinations and effects on specific growth parameters
Processes
7tissues that undergo significant postnatal development in pediatric patients
Metabolic process of lamotrigine induced by CHCs
Used to identify specific age groups or unsafe parameters of exposure
Required before initiating long-term clinical studies
Assessments that may not adequately identify postnatal developmental toxicities
can be modified to include juvenile animals
Developmental stage evaluated in combined FEED/EFD studies; Critical period for dosing in developmental toxicity
Clinical Concepts
10Target population for efficacy extrapolation
clinical studies planned in pediatric populations
Potential for Growth Suppression in Children
Renal system anatomical development
Pulmonary system developmental event
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
Associated with adverse effects in nonclinical studies
Reported outcomes following the use of a drug or drug class.; provide information to predict potential adverse effects in the target species
Toxicities that juvenile animal studies may assist in identifying
Reporting adverse events when engaging with patients.; changes may be related to benefits, tolerability, and/or unintended effects
Identified Hazards
Hazards
5Safety effects of particular concern that cannot be safely assessed in clinical trials
Identified through juvenile animal studies
Adverse effects such as dysmorphogenesis or fetal mortality
Reason for limiting Class 2 solvents
risk identified in immature animals with fluoroquinolones
Standards & References
Specifications
1No observed adverse effect level used to calculate ADI and margin of safety.
ICH References (4)
Nonclinical Safety Studies for the Conduct of Human Clinical Trials
Clinical Investigation of Medicinal Products in the Pediatric Population.
Detection of Toxicity to Reproduction for Medicinal Products
Guidance for industry on Toxicokinetics and systemic exposure in toxicity studies.
Related MFDS Guidelines
Korean regulatory guidelines covering similar topics
See Also (8)
- DSCSA Implementation: Product Tracing Requirements — Compliance Policy
- E6(R3) Good Clinical Practice: Annex 2
- Consumer Antiseptic Rub Final Rule Questions and Answers Guidance for Industry: Guidance for Industry
- Best Practices for Communication Between IND Sponsors and FDA During Drug Development
- Botanical Drug Development: Guidance for Industry
- Prescription Requirement Under Section 503A of the Federal Food, Drug, and Cosmetic Act Guidance for Industry
- Reformulating Drug Products That Contain Carbomers Manufactured With Benzene
- ANDA Submissions -- Refuse-to-Receive Standards Rev.2