Description
This guidance is intended to assist the pharmaceutical industry and other investigators engaged in new drug development in evaluating how variations in the human genome, specifically DNA sequence variants, could affect a drug’s pharmacokinetics (PK), pharmacodynamics (PD), efficacy, or safety. The guidance provides recommendations on when and how genomic information should be considered to address questions arising during drug development and regulatory review.
Key Topics
Terms and concepts identified from this document
Scope & Applicability
Product Classes
4development program for drug and biological products
Devices used to identify patients eligible for specific drug treatments
validate the companion diagnostic across cancer types
An in vitro PGx test would be considered a companion diagnostic device
Stakeholders
1Target audience for recommendations on assessment of overall survival
Regulatory Context
Regulatory Activities
5process of evaluating genomic variations
therapeutic products under review for approval
required for tests used to select patients or dosing regimens
Trials conducted to support approval of drugs
A medical device submission type (IDE).
Document Types
7Cybersecurity information should be included in device labeling
Section containing detail about drug interaction studies.
Clinically significant increases in blood pressure should be described in sections like BOXED WARNING
Changes made to add a package type term to labeling and prescribing information; Document where package type terms must be consistent with labeling
Must conform to requirements of 21 CFR 107.10-107.30.
the terms informed consent form and informed consent document are used interchangeably; Document used to provide information to prospective subjects; The entire document used to obtain subject participation agreement
Document describing procedures followed and samples retained
Attributes
8Assessment for both mother and child
information for a patient used for dosing
ultrarapid, extensive, intermediate, and poor phenotypes for CYP2C19
covariate associated with sex affecting device performance
Cmax may be more informative for safety
AUC or Cmin may correlate with efficacy
genetically defined subgroup for comparative PK
genetically defined subgroup for comparative PK
Technical Details
Substances
10reacting with DNA bases
ABC (bid)+ 3TC + EFV
genetic variant affecting warfarin response; genotype information used for dosing
enzyme induced via activation of the PXR; Cytochrome P450 enzyme
Examples of GT products can include purified nucleic acid such as RNA.
Example drug with multiple serious drug interactions.
KRAS mutations with cetuximab and panitumumab indicated for colon cancer
KRAS mutations with cetuximab and panitumumab indicated for colon cancer
enzyme induced via activation of the PXR; Cytochrome P450 enzyme
enzyme generally considered not inducible by drugs; Specific enzyme used for extrapolation of DDI results.; Cytochrome P450 enzyme
Testing Methods
9collection of samples for genomic analysis
International Normalized Ratio used for warfarin dose modification
prospective screening to avoid abacavir-induced HSR
method to filter genetic markers
method to control for multiplicity in genomic data
Models that may aid in assessing the effect of CYP3A modulators.
investigate the causes of lack of efficacy using exploratory genome-wide association investigations
data generated from higher-throughput technologies; technology platform for characterizing allelic variations
high-throughput platform for uncharacterized pharmacology
Processes
3evaluation in early-phase clinical studies
Dosing considerations for pregnant women in trials; Study of drug movement in the body, which may change during pregnancy.
Study of drug effects, which may be impacted by physiological changes in pregnancy.
Clinical Concepts
10critical consideration in phase 1 oncology studies
gene encoding vitamin K epoxide reductase affected by polymorphisms
polymorphic enzyme affecting clopidogrel metabolism
genetic allele associated with hypersensitivity reactions
adverse reaction observed in clinical trial patients
Information to be included in labeling for the neonate.
subjects with polymorphic enzymes who should not be enrolled in certain drug-drug interaction studies
Increased risk when daily wear lenses are worn overnight
indicated for colon cancer
Potential safety concern/adverse effect of some antiemetic drugs.
Identified Hazards
Hazards
2risk associated with genetically mediated alteration in metabolism
risk increased in carriers of LOF CYP2C19 alleles
ICH References (1)
Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding Categories
Related CFR Sections (1)
- 21CFR312.21§ 312.21 Phases of an investigation.
An IND may be submitted for one or more phases of an investigation. The clinical investigation of a previously untested drug is generally divided into three phases. Although in general the phases are conducted sequentially, they may overlap. These three phases of an investigation are a follows:Read full regulation →
Related MFDS Guidelines
Korean regulatory guidelines covering similar topics
See Also (8)
- Diversity Action Plans to Improve Enrollment of Participants from Underrepresented Populations in Clinical Studies: Draft Guidance for Industry (Status: Draft)
- Frequently Asked Questions – Statement of Investigator (Form FDA 1572): Guidance for Sponsors, Clinical Investigators, and IRBs (Status: Final)
- General Principles for the Development of Vaccines to Protect Against Global Infectious Diseases: Guidance for Industry (Status: Final)
- Questions and Answers on Informed Consent Elements, 21 CFR § 50.25(c): Guidance for Sponsors, Investigators, and Institutional Review Boards (Status: Final)
- Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products: Guidance for Industry (Status: Final)
- Adaptive Design Clinical Trials for Drugs and Biologics Guidance for Industry (Status: Final)
- Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research Guidance for Industry: Guidance for Industry (Status: Final)
- Standardized Format for Electronic Submission for Marketing Applications Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for Center of Biologics Evaluation and Research Submissions (Status: Draft)