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Translation of pharmacogenomics and pharmacogenetics: a regulatory perspective

Nature Reviews Drug Discovery volume 3, pages 763–769 (2004)Cite this article

Abstract

Pharmacogenomics and pharmacogenetics provide methodologies that can lead to DNA-based tests to improve drug selection, identify optimal dosing, maximize drug efficacy or minimize the risk of toxicity. Rapid advances in basic research have identified many opportunities for the development of 'personalized' treatments for individuals and/or subsets of patients defined by genetic and/or genomic tests. However, the integration of these tests into routine clinical practice remains a major multidisciplinary challenge, and even for well-established biomarkers there has been little progress. Here, we consider this challenge from a regulatory perspective, highlighting recent initiatives from the FDA that aim to facilitate the integration of pharmacogenetics and pharmacogenomics into drug development and clinical practice.

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Figure 1: Ten-year trends in major drug and biological product submissions to the FDA.
Figure 2: Ten-year trends in biomedical research spending.
Figure 3: An example of a decision tree for submitting pharmacogenomic data during the IND period as a required submission or as a voluntary genomic data submission.

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Acknowledgements

We would like to acknowledge the helpful comments of our FDA colleagues F. Frueh, S.-M. Huang and A. Rudman.

Author information

Authors and Affiliations

  1. Director of the Office of Clinical Pharmacology and Biopharmaceutics, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland, USA

    Lawrence J. Lesko

  2. Acting Deputy Commissioner of Operations, Food and Drug Administration, 5,600 Fishers Lane, Rockville, 20857, Maryland, USA

    Janet Woodcock

Authors
  1. Lawrence J. Lesko
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  2. Janet Woodcock
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Corresponding author

Correspondence to Lawrence J. Lesko.

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The authors declare no competing financial interests.

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DATABASES

Entrez Gene

CYP2D6

EGFR

TPMT

UGT1A1

National Cancer Institute Cancer Topics

ALL

NSCLC

Online Mendelian Inheritance in Man

Alzheimer's disease

FURTHER INFORMATION

Center for Drug Evaluation and Research

Draft Guidance for Industry Pharmacogenomic Data Submission

Food and Drug Administration

National Institutes of Health

Glossary

ALLELES

Different or alternative forms of the same gene that can occupy a particular locus on a specific chromosome. Humans have two alleles at that location, one on each chromosome of a homologous pair.

AREA-UNDER-CURVE

(AUC). A metric that summarizes serum or plasma drug concentrations measured over time (for example, 24 hours) in a given individual following the administration of a drug. The AUC is interpreted as the total systemic exposure and is an index of how much of a drug reaches the bloodstream in a set period of time. AUC is also a means to compare the bioavailability of drug from a drug product.

BAYESIAN STATISTICS

A statistical method of analysis that incorporates prior knowledge (for example, on safety and efficacy parameters), specifications of prior distributions and accumulated clinical data experience into making probability calculations and designing future clinical trials.

BIOLOGIC LICENSE APPLICATION

A formal application analogous to a New Drug Application, but for biotechnology-derived pharmaceuticals (for example, complex, large molecules).

BIOMARKER

A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention.

HAPLOTYPE

A set or combination of alleles or linked genetic markers found on a single chromosome, which tend to be inherited together in a given individual.

INVESTIGATIONAL NEW DRUG APPLICATION

Before initiating any clinical trials of a new drug in humans, a drug sponsor must submit an Investigational New Drug application (IND) to the FDA. The IND contains three broad categories of information: data from animal pharmacology and toxicology studies, manufacturing information, and clinical protocols and investigator information.

NEW DRUG APPLICATION

A formal application that serves as a vehicle through which sponsors propose that the FDA approve a new pharmaceutical (for example, traditional small molecules) for sale and marketing in the United States. When the investigational phase of a drug is completed, the manufacturer submits the results of all the studies to the FDA in a New Drug Application (NDA) for review by FDA officials. The purpose of the NDA is for the FDA to decide if the drug meets the statutory standards for safety, effectiveness and benefit/risk for its intended use, and labelling and manufacturing quality.

NEUTROPENIA

An abnormal decrease in the number of white blood cells in the blood (as measured by an absolute neutrophil count), which increases the risk of infection and fever. It usually occurs as a result of chemotherapy.

SINGLE-NUCLEOTIDE POLYMORPHISM MAPS

A diagram or overview of a stretch of DNA containing single-nucleotide polymorphisms (SNPs). SNPs are DNA sequence variations that occur when a single nucleotide (A, T, C or G) in the genome sequence is altered in different individuals. A map of SNPs across the genome allows genetic traits to be localized by statistical association with the specific region of the genome that is marked by the SNP or multiple nearby SNPs.

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Lesko, L., Woodcock, J. Translation of pharmacogenomics and pharmacogenetics: a regulatory perspective. Nat Rev Drug Discov 3, 763–769 (2004). https://doi.org/10.1038/nrd1499

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