Pediatric Drug Development Under the Pediatric Research Equity Act and the Best Pharmaceuticals for Children Act: Scientific Considerations

Description

The purpose of this guidance is to assist industry in developing data and obtaining information needed to support approval of drug products in pediatric populations. This guidance addresses selected clinical, scientific, and ethical issues regarding the development of drugs for pediatric use when such drugs are subject to the Pediatric Research Equity Act (PREA) and/or the Best Pharmaceuticals for Children Act (BPCA). In 2010, the Biologics Price Competition and Innovation Act of 2009 extended provisions of the BPCA to biological products.

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

5

Biological products

development program for drug and biological products

Oncology Drug

Pediatric studies may begin as early as adult phase 1

Biological Product

Regulated under section 351(i) of the PHS Act; Virus, therapeutic serum, toxin, vaccine, or protein applicable to prevention or treatment; Alternative regulation category for products meeting device definition

Oncology drugs

Development of cancer drugs for use in novel combinations

Gene Therapy

A type of ATMP involving recombinant nucleic acids or viral vectors.

Stakeholders

2

Sponsor

Entity responsible for submitting applications under section 524B

Institutional Review Board

Governs top dose in clinical studies

Regulatory Context

Regulatory Activities

7

Molecularly targeted pediatric cancer investigation

Requirement under Section 505B(a)(1)(B) of the FD&C Act

End-of-phase 1 Meeting

Early discussion with Agency on development plans

Pre-investigational New Drug Application

Early meeting with FDA for drug development planning

Initial Pediatric Study Plan

Sponsors are encouraged to submit as soon as practicable

Written Request

FDA document issued under BPCA to request pediatric studies for exclusivity

New Drug Application

Rule does not apply to products marketed under an NDA

Biologics License Application

BLA for biological products

Document Types

3

Pediatric Assessments

Required under Section 505B(a)(1)(A) of the FD&C Act

Pediatric Assessment

Required report on pediatric studies

Proposed Pediatric Study Request

Submission by an applicant proposing studies to obtain a Written Request

Attributes

3

Palatability

Characteristic of orally administered dosage forms for children

Molecular targets

Substantially relevant to the growth or progression of a pediatric cancer

Age-appropriate pediatric formulation

Requirement for assessments to use formulations suitable for the age group

Technical Details

Substances

1

Excipients

Differences in excipients may affect product stability

Testing Methods

3

Dissolution Testing

Failure to meet specification for certain dosage forms

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.

Population Pharmacokinetics

guidance for industry on data analysis

Processes

2

Formulation Development

Scientific considerations for pediatric drug development; Developing appropriate formulations for each age group under PREA

Pediatric Extrapolation

The process of using existing data to support pediatric drug development.; used to assess similarity of disease and response to treatment

Clinical Concepts

7

Neonatal Population

Drug development specifically for neonates; Birth through 27 days corrected gestational age

Surrogate Endpoint

Clinical data used in HCEI analyses to predict clinical benefit.

Pediatric Extrapolation

Approach to increase efficiency of pediatric drug development

Adverse reactions

Increased risk when daily wear lenses are worn overnight

Pediatric Cancer

Condition for which molecularly targeted investigations may be required

Pharmacodynamics

Study of the biochemical and physiological effects of drugs

Pharmacokinetics

Study of how the body interacts with administered substances

Identified Hazards

Hazards

2

Neurotoxicity

Reason for limiting Class 2 solvents

Neurocognitive Effects

Potential developmental risks in the neonatal population

Standards & References

External Standards

1

Public Health Service Act

Licensing of biological products

ICH References (2)

ICH E11A

Pediatric Extrapolation Guidance for Industry; Pediatric Extrapolation guideline; The primary document being analyzed regarding pediatric extrapolation.

ICH M3(R2)

Guidance on when particular studies can be abbreviated or deferred for life-threatening diseases

Related CFR Sections (4)

21CFR50.51§ 50.51 Clinical investigations not involving greater than minimal risk.
Any clinical investigation within the scope described in §§ 50.1 and 56.101 of this chapter in which no greater than minimal risk to children is presented may involve children as subjects only if the IRB finds that:Read full regulation →
21CFR600.3§ 600.3 Definitions.
As used in this subchapter:Read full regulation →
21CFR50.52§ 50.52 Clinical investigations involving greater than minimal risk but presenting the prospect of direct benefit to individual subjects.
Any clinical investigation within the scope described in §§ 50.1 and 56.101 of this chapter in which more than minimal risk to children is presented by an intervention or procedure that holds out the prospect of direct benefit for the individual subject, or by a monitoring procedure that is likely tRead full regulation →
21CFR50.53§ 50.53 Clinical investigations involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subjects' disorder or condition.
Any clinical investigation within the scope described in §§ 50.1 and 56.101 of this chapter in which more than minimal risk to children is presented by an intervention or procedure that does not hold out the prospect of direct benefit for the individual subject, or by a monitoring procedure that is Read full regulation →

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