General Clinical Pharmacology Considerations for Neonatal Studies for Drugs and Biological Products Guidance for Industry

Description

This guidance is intended to assist sponsors of investigational new drug applications (INDs) and applicants of new drug applications (NDAs), biologics license applications (BLAs), and supplements to such applications who are planning to conduct clinical studies in neonatal populations. This guidance provides recommendations for neonatal clinical pharmacology studies, whether the studies are conducted pursuant to section 505A of the Federal Food, Drug, and Cosmetic Act (FD&C Act), section 505B of the FD&C Act, or neither. Effectiveness, safety, or dose-finding studies in neonates involve assessing clinical pharmacology information, such as information regarding a product’s pharmacokinetics (PK) and pharmacodynamics (PD) to inform dose selection and individualization. As such, the general considerations described in this guidance apply to any neonatal studies which incorporate clinical pharmacology assessments. This guidance does not discuss the timing to initiate neonatal studies. Questions regarding the appropriate timing for the initiation of neonatal studies should be discussed with the relevant FDA review division.

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

5

Drugs

Clinical investigations of drugs, including human drugs and biological products

Therapeutic proteins

Generally have lower risk of pharmacokinetic DDIs compared to small molecules.

Biological Products

Requires analytical comparability per ICH Q5E

Preterm neonates

neonatal subpopulation categorized by gestational age

Term neonate

neonates born between 37 to <42 weeks GA

Stakeholders

3

Sponsor

Entity responsible for submitting applications under section 524B

Institutional Review Board

Governs top dose in clinical studies

Data and Safety Monitoring Board

Independent board to oversee neonatal trials

Regulatory Context

Regulatory Activities

5

IND

Investigational New Drug submissions

First-in-human studies

Sponsors should conduct first-in-human studies in healthy volunteers to characterize safety

NDA

New Drug Application

BLA

Biologics License Application

PREA requirements

Pediatric Research Equity Act requirements for pediatric study plans

Document Types

2

initial pediatric study plan

Required document for supplements subject to PREA

Clinical Study Report

CSR supported by ADaM datasets; Contains analysis results and animal listings

Attributes

10

Dose Selection

inform dose selection and individualization

PNA

Postnatal age, a key covariate for neonatal subgroups.

PMA

Postmenstrual age, a key covariate for neonatal subgroups.

ADME factors

Absorption, distribution, metabolism, and excretion factors that must be considered in models.

Hemoglobin

Hemoglobin used for CR response

Total blood volume

Limits for neonatal studies typically range between 1 to 5 percent for a single draw.

Bioavailability

Biological property that may be altered by manufacturing changes; safety narrative should address bioavailability of the ingredients

Postmenstrual Age

Factor related to systemic exposure and renal excretion

Gestational age

Factor related to neurodevelopmental vulnerability

Postnatal age

important variable to consider for stratification; Factor related to systemic exposure and renal excretion

Technical Details

Substances

7

CYP3A7

metabolizing enzyme with higher expression in neonates

DNA samples

Sponsors are encouraged to collect these for pharmacogenetic analysis.

Benzyl alcohol

Excipient to be considered for toxicity

Propylene glycol

Ingredient in e-liquids often abbreviated as PG

Ethanol

Total Margin of Exposure of Ethanol and Acetaldehyde

Excipients

Differences in excipients may affect product stability

CYP3A4

metabolizing enzyme with lower expression in neonates compared to adults

Testing Methods

10

Bioanalytical Methods

Study design considerations for neonates

PBPK modeling

Physiologically based pharmacokinetics modeling for breast milk levels

Adaptive study designs

Flexible clinical trial design option.

Modeling and Simulation

Approaches used in pediatric extrapolation plan; M&S strategies should be applied to support the initial dose selection; Used to summarize reference data or inform the choice of analysis strategy.

Clinical trial simulations

Used to integrate PK/PD aspects to aid in design with feasible sample sizes.

Dried blood spots

Minimally invasive sampling technique requiring low blood volume.

Sparse sampling

Practical approach for obtaining pharmacokinetic data in neonatal studies due to blood volume limits.

Non-compartmental pharmacokinetic approach

Standard approach for performing PK analyses.

Population pharmacokinetic approach

One of two basic approaches for performing PK analyses in pediatric participants.

Pharmacokinetic analysis

Characterization of drug exposure in neonates.

Processes

3

ADME

Absorption, distribution, metabolism, and excretion properties evaluated for extrapolation.

Dose selection

The process of determining the appropriate drug dose for neonates.

Bioanalytical validation

Essential for quantifying drugs and metabolites in small volume neonatal samples.

Clinical Concepts

7

Neonatal populations

planning to conduct clinical studies in neonatal populations

Adverse events

Safety findings including deaths and post-mortem examinations

Neonates

Target population for long-term neurodevelopmental safety studies

Neonatal population

Target population for long-term safety evaluations

Immunogenicity

Assessment of the immune response to the biological product

Glomerular Filtration Rate

Low in neonates and increases rapidly after birth

Intrauterine growth restriction

A complication of pregnancy to be assessed.

Identified Hazards

Hazards

3

hyperbilirubinemia

risk in neonates involving displacement of bilirubin from albumin

Toxicity

Assessment of toxicity required in a 351(k) BLA

Drug toxicity

Risk factor necessitating therapeutic drug monitoring

Standards & References

Specifications

1

95 percent confidence interval

Statistical criteria for the observed response rate in single-arm trials

ICH References (1)

ICH E11(R1)

Addendum: Clinical Investigation of Medicinal Products in the Pediatric Population

Enforcement Impact

Deficiencies cited in Warning Letters referencing the same regulations

Failure to obtain informed consent

5

Failure to ensure that the investigation was conducted according to the investigational plan

3

Failure to submit an Investigational New Drug application (IND)

2

Failure to ensure proper monitoring of the investigation

1

Failure to submit an IDE application and obtain FDA approval

1

Failure to secure clinical investigator's compliance

1

Failure to immediately conduct an evaluation of unanticipated adverse device effects

1

Failure to obtain permission from the subjects' parent or guardian

1

Failure to review proposed research at convened meetings with a majority of members present

1

Failure to prepare and maintain adequate documentation of IRB activities, including minutes of IRB meetings