Clinical Immunogenicity Considerations for Biosimilar and Interchangeable Insulin Products | Guideline Explorer

Description

The purpose of this guidance is to provide recommendations to applicants regarding whether and when comparative clinical immunogenicity studies may be needed to support licensure of proposed biosimilar and interchangeable recombinant human insulins, recombinant human insulin mix products, and recombinant insulin analog products that are intended for the treatment of patients with Type 1 or Type 2 diabetes mellitus (collectively described as “insulin products”). The recommendations in this guidance are applicable only to proposed biosimilar and interchangeable insulin products seeking licensure under section 351(k) of the Public Health Service Act (PHS Act) in biologics license applications (BLAs).

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

3

Interchangeable insulin product

licensure of a proposed interchangeable insulin product

Interchangeable

Biological product shown to be interchangeable with a 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

Regulatory Context

Regulatory Activities

6

Licensure

Requirement for biological products under the PHS Act

BPD Meeting

applicant should request a Biosimilar Biological Product Development meeting; request a Biosimilar User Fee Act (BsUFA) development program meeting

351(k) BLA

Biologics license application submitted under section 351(k) of the PHS Act

NDA

New Drug Application

Rule does not apply to products marketed under an NDA

Biologics License Application

BLA for biological products

Document Types

1

Orange Book

Approved Drug Products With Therapeutic Equivalence Evaluations

Attributes

1

Highly Similar

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

Technical Details

Substances

5

Novel excipients

novel excipients giving rise to questions or residual uncertainty

Impurities

Components which may be expected to be present alongside the analyte.

Insulin

A manufacturer of insulin develops a mobile app intended for use with their insulin product.

Recombinant insulin analog

Proposed biosimilar and interchangeable recombinant insulin analog products

Recombinant human insulin

Proposed biosimilar and interchangeable recombinant human insulins

Testing Methods

5

Euglycemic Clamp Procedure

used for glucose response testing

Comparative Clinical Pharmacology Study

provides a time-concentration profile and a time-action profile

Comparative Clinical Immunogenicity Study

generally would be unnecessary to support a demonstration of biosimilarity; needed to support a demonstration of biosimilarity or interchangeability

Pharmacodynamics

assessment of PD in animals and clinical testing

Pharmacokinetics

Proof-of-concept studies may evaluate tolerability, pharmacokinetics, and preliminary clinical efficacy.

Processes

1

Comparative Analytical Assessment

Assessment used to detect differences between two products at a structural and functional level

Clinical Concepts

3

Type 1 Diabetes

insulin products are used by patients with type 1 and type 2 diabetes

Type 2 diabetes mellitus

Insulin products intended for the treatment of patients with Type 2 diabetes

Type 1 diabetes mellitus

Insulin products intended for the treatment of patients with Type 1 diabetes

ICH References (2)

ICH Q11

Development and Manufacture of Drug Substances; General principles for selection of starting materials

ICH Q7

Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients; Reworking needs more evaluation and testing according to ICH Q7; Good manufacturing practice for API starting materials; Referenced regarding the definition of intermediates.

Related CFR Sections (1)

21CFR601.2§ 601.2 Applications for biologics licenses; procedures for filing.
(a) General. To obtain a biologics license under section 351 of the Public Health Service Act for any biological product, the manufacturer shall submit an application to the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research (see mailing aRead full regulation →

Enforcement Impact

Deficiencies cited in Warning Letters referencing the same regulations

Quality control unit failed to exercise its responsibility

101

Failure to conduct at least one test to verify the identity of each component

95

Failure to establish adequate written procedures for production and process control

88

Failure to have appropriate laboratory determination of satisfactory conformance to final specifications

56

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

56

Failure to establish an adequate quality control unit

49

Failure to test samples of each component for identity and conformity

47

Failure to establish laboratory controls

35

Failure to thoroughly investigate any unexplained discrepancy

28

Failure to test samples of each component for identity

25

Recent Cases

Related Warning Letters (10)

Related MFDS Guidelines

Korean regulatory guidelines covering similar topics