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Investigational Enzyme Replacement Therapy Products: Nonclinical Assessment: Guidance for Industry

FinalCenter for Drug Evaluation and Research10/03/2019
Good Laboratory PracticePOC

Description

The purpose of this guidance is to help sponsors design and conduct nonclinical studies during development of investigational enzyme replacement therapy (ERT) products. Specifically, this guidance describes the Food and Drug Administration’s (FDA’s) current thinking about the substance and scope of nonclinical information needed to support initiation of clinical trials, ongoing clinical development, and marketing approval for investigational ERT products.

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

2
Enzyme Replacement Therapy

Therapy type requiring CRIM status assessment.

Investigational ERT product

Enzyme Replacement Therapy products under development

Stakeholders

1
Sponsor

Entity responsible for submitting applications under section 524B

Regulatory Context

Regulatory Activities

6
First-in-human clinical trial

Initial clinical testing supported by POC and toxicology data

Marketing approval

may provide adequate support for a marketing approval

Clinical trials

Development program for drugs intended for sGERD treatment

IND

Investigational New Drug submissions

Marketing application

Submission for drug approval

Pre-IND meeting

discuss these considerations with OTP prior to the IND submission as part of a pre-IND meeting

Document Types

2
Study protocol

Should include biological rationale for subgroups

Nonclinical study report

Report summarizing deviations and study integrity

Attributes

1
Antidrug Antibodies

Assessment of ADA effect on drug exposure and toxicology findings

Technical Details

Substances

3
Pancreatic enzyme products

Guidance specifically does not apply to these products

Excipients

Differences in excipients may affect product stability

Chemically modified ERT products

Recombinant human enzyme conjugated with a chemical linker

Testing Methods

6
Juvenile Animal Studies

Nonclinical studies to support pediatric age groups.

Proof of Concept Studies

Studies in animal models to demonstrate biological effect and identify effective doses

Toxicity studies of 3 months' duration

Sufficient to support a marketing application for ERT

Reproductive toxicity studies

Battery of studies recommended per ICH S5(R2)

Genotoxicity studies

Standard battery of tests to evaluate genetic toxicity

Carcinogenic potential evaluation

Generally not needed unless product is chemically modified

Processes

3
Toxicology Studies

Pivotal toxicology studies considering disease biology and pharmacology

Pharmacodynamic characterizations

Includes proof-of-concept studies to demonstrate functional enzyme replacement

Bridging studies

In vitro and/or in vivo studies to bridge products after manufacturing changes

Clinical Concepts

9
Lysosomal storage diseases

Diseases for which ERT products are indicated

Inborn errors of metabolism

medical condition requiring exempt infant formula

Gaucher disease

Example of an inborn error of metabolism treated by ERT

Fabry disease

Example of an inborn error of metabolism treated by ERT

Pompe disease

Example of an inborn error of metabolism treated by ERT

Mucopolysaccharidoses

Example of an inborn error of metabolism treated by ERT

Pediatric Patients

Target population for efficacy extrapolation

Biomarkers

may be considered when validated

Patient population

including inputs, outputs, limitations on patient population.

Standards & References

Specifications

2
No Observed Adverse Effect Level

Used in calculating the margin of safety

Minimum Efficacious Dose

Predicted by animal disease models to select starting dose

ICH References (3)

ICH M3(R2)

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

ICH S6(R1)

Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals; guidance regarding nonclinical immunotoxicity assessment of biopharmaceuticals

ICH S5(R2)

Detection of Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility

View on FDA.govDownload PDF

Related CFR Sections (1)

Enforcement Impact

Deficiencies cited in Warning Letters referencing the same regulations

Failure of the study director to assure protocol compliance and accurate data recording
1
Failure of the study director to assure experimental data are accurately recorded and verified
1
Failure to properly identify specimens
1
Failure to assure experimental data were accurately recorded and verified
1
Failure to authorize and document deviations from standard operating procedures
1
QAU failed to assure reported results accurately reflect raw data
1
Failure to maintain a Quality Assurance Unit
1
Study director failed to assure protocol compliance and data accuracy
1
Fabrication of animal weight data
1
Failure to establish procedures for handling test and control articles
1

Recent Cases

Related Warning Letters (9)

Related MFDS Guidelines

Korean regulatory guidelines covering similar topics

See Also (8)