Considerations in Demonstrating Interchangeability With a Reference Product Guidance for Industry

Description

This guidance is intended to assist sponsors in demonstrating that a proposed therapeutic protein product is interchangeable with a reference product for the purposes of submitting a marketing application or supplement under section 351(k) of the Public Health Service Act (PHS Act) (42 U.S.C. 262(k)). The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) amends the PHS Act and other statutes to create an abbreviated licensure pathway in section 351(k) of the PHS Act for biological products shown to be biosimilar to or interchangeable with an FDA-licensed biological reference product (see sections 7001 through 7003 of the Patient Protection and Affordable Care Act (Affordable Care Act) (Public Law 111-148)). Although the 351(k) pathway applies generally to biological products, this guidance focuses on therapeutic protein products and gives an overview of important scientific considerations in demonstrating interchangeability of a proposed therapeutic protein product (proposed interchangeable biosimilar or proposed interchangeable product) with a reference product.

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

8

Therapeutic protein product

Guidance focuses on these products for interchangeability demonstrations

Non-U.S.-licensed comparator product

comparator used in switching studies requiring a bridge to the U.S. reference

Reference product

single biological product licensed under section 351(a) of the PHS Act; U.S.-licensed reference product used for comparative analytical assessment; analytical studies that demonstrate that the proposed product is highly similar to the reference product

Proposed interchangeable product

product seeking licensure under section 351(k) of the PHS Act

Biosimilar product

Considered to have a new active ingredient for PREA

Interchangeable product

A biosimilar that may be substituted for the reference product

Biosimilar

Biological product shown to be highly similar to an FDA-licensed reference product; Biological product demonstrated to be highly similar to a reference product

Combination Product

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.

Stakeholders

4

Sponsor

Entity responsible for submitting applications under section 524B

Healthy subjects

Common study population for clinical DDI studies

Health care provider

Prescribing professional who does not need to intervene for interchangeable substitution

Office of Combination Products

Resource for applicants regarding combination products

Regulatory Context

Regulatory Activities

3

351(k) application

application for a proposed biosimilar product; Pathway for biosimilar licensure; submission of data derived from comparator products in support of a 351(k) application

Postmarketing Surveillance

evaluation of rare but potentially serious safety risks

Switching study

study to evaluate the impact of alternating between products

Document Types

1

Chemistry, Manufacturing, and Controls Section

section of the application providing description of the presentation

Attributes

7

Potency

Measurement of potency for biological products

PK Parameters

pharmacokinetic data collected during switching intervals

Mechanism of action

Proposed biological activity of the drug

Purity

specifications for the purity, strength, and composition of dietary supplements

Highly Similar

demonstrating that the proposed insulin product is highly similar to the reference product

AUCtau

primary study endpoint for intravenous and subcutaneous studies

Cmax

Cmax may be more informative for safety

Technical Details

Substances

2

Anti-drug antibody

ADA incidence and titer evaluation

Neutralizing antibody

NAb incidence and titer evaluation

Testing Methods

8

Switching Study

Study design to assess risk of alternating between products; design including lead-in period and switching period

Performance Testing

cybersecurity testing recommendations in Section V.C

Stability Studies

Long-term, accelerated, and forced degradation studies to ensure shelf life.; studies to be performed to demonstrate suitability

Extractable/Leachable Studies

Studies to show compatibility of delivery device with formulation.

Immunogenicity assays

must be adequately sensitive to detect ADA and NAb

Comparative Analytical Data

Highly sensitive analytics to identify molecules with different attributes

Average Equivalence Statistical Approach

statistical analysis of log-transformed AUCtau and Cmax data

Bioanalytical Method Validation

All bioanalytical methods should be validated and reported.

Processes

2

Functional Characterization

Comparative assessment of the product

Switching Study

Clinical study to determine the impact of alternating between products; prospective, controlled study to support a demonstration of interchangeability

Clinical Concepts

5

Adverse events

Safety findings including deaths and post-mortem examinations

Adverse Experience

reporting for human drug and licensed biological products

Immunogenicity

Assessment of the immune response to the biological product

Pharmacokinetics

Study of how the body interacts with administered substances

Pharmacodynamics

Study of the biochemical and physiological effects of drugs

Identified Hazards

Hazards

1

Severe Immunogenicity-Related Adverse Events

history of reference product safety concerns requiring additional data

Standards & References

Specifications

1

80% to 125%

90% confidence interval for the geometric mean ratio in average equivalence

ICH References (1)

ICH Q8(R2)

Pharmaceutical Development

Enforcement Impact

Deficiencies cited in Warning Letters referencing the same regulations

Failure to establish adequate written procedures for production and process control

2

Failure to follow appropriate written procedures to prevent objectionable microorganisms

1

Failure to establish an adequate quality control unit

1

Adulterated drug

1

Failure to have appropriate laboratory determination of satisfactory conformance to specifications for the rate of release

1

Failure to thoroughly investigate any unexplained discrepancy or failure of a batch

1

Failure to establish and follow adequate control procedures to monitor output

1

Marketing without marketing clearance or approval

1

Adulterated under section 501(f)(1)(B)

1

Failure to prevent microbiological contamination of drug products purporting to be sterile