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Pharmacogenetics and drug development: the path to safer and more effective drugs

Nature Reviews Genetics volume 5, pages 645–656 (2004)Cite this article

Key Points

  • The use of genetic analyses to predict efficacy and safety in drug discovery and development is becoming a pipeline technology. A framework for assisting in key decisions at crucial points in the pharmaceutical pipeline, using prospective pipeline pharmacogenetics, is described.

  • Although genetic and genomic technologies have been applied to target discovery, applications of prospective efficacy pharmacogenetics at the crucial proof-of-concept Phase IIA can assist in decision-making with regard to progressing an asset and can reduce attrition.

  • Prospective confirmation in larger Phase-IIB studies of efficacy predictors that were identified in Phase IIA can assist in the design of larger registration trials, potentially making clinical trial studies smaller, faster and less expensive.

  • Safety pharmacogenetics can allow the rapid identification of potential toxicity-linked human genetic profiles; an example of data obtained during the course of Phase-III clinical trials and retrospective examples are described.

  • A clear distinction needs to be made between prospective pipeline data, which can decrease attrition and diagnostic profiles, which are usually defined in retrospective studies and confirmed before clinical use.

  • Strategies for practical, post-marketing risk-management surveillance are proposed, making use of rapid high-density SNP-genotyping profiles in relatively small numbers of patients who experience adverse events.

Abstract

Pharmacogenetics provides opportunities for informed decision-making along the pharmaceutical pipeline. There is a growing literature of retrospective studies of marketed medicines that describe efficacy or safety on the basis of patient genotypes. These studies emphasize the potential prospective use of genome information to enhance success in finding new medicines. An example of a prospective efficacy pharmacogenetic Phase-IIA proof-of-concept study is described. Inserting a rapidly performed efficacy pharmacogenetic step after initial clinical data are obtained can provide confidence for a commitment to full drug development. The rapid identification of adverse events during and after drug development using genomic mapping tools is also reviewed.

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Figure 1: Efficacy pharmacogenetics for an obesity drug.
Figure 2: Bilirubin levels in patients treated with tranilast during a Phase-III clinical trial.
Figure 3: Association mapping of adverse-event susceptibility: tranilast and hyperbilirubinaemia.
Figure 4: Association as a function of the genetic load of the polymorphism.

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Acknowledgements

This research was fully supported from the sales of medicines. I especially thank my successive Presidents of Research and Development, both physician-scientists, James Niedel and Tachi Yamada, for having the foresight and commitment to support and apply strategic genetic research in 1997 when human linkage research was considered as peaked, and since 2000 when medical research investments for the future were still unfashionable for pharmaceutical R&D organizations. The ongoing pharmacogenetics work that is described in this review has been contributed to by hundreds of GlaxoSmithKline (GSK) employees over a seven year period. I also thank the Genetic Executive Teams, who have shared a vision of safer and more effective medicines, the thousands of patients who consented to participate in pharmacogenetic research protocols, Ronald Krall who provided access to all patients participating in GSK drug development, my wife, Ann Saunders, who provided intellectual, emotional and laboratory support, and my daughters — Maija, Stephanie and Joanna — who created a place to live, to work and to love.

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Authors and Affiliations

  1. Genetics Research, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, 27709, North Carolina, USA

    Allen D. Roses

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A. D. Roses is a full-time employee of GlaxoSmithKline and currently holds non-paid appointments as a clinical professor of neurology at Duke University Medical Center, and on the Science Board of the US Food and Drug Administration.

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DATABASES

Entrez

CYP2D6

UTG1A1

FURTHER INFORMATION

Food and Drug Administration Science Board meeting (22 April 2004)

Food and Drug Administration Science Board presentation (22 April 2004)

International HapMap Project

Glossary

PHASE I

Initial clinical studies usually involve small numbers of normal human volunteers and small doses to assess safety, metabolism and excretion of a drug or drug combination.

PHASE IIA

After the initial Phase-I studies, these randomized and controlled clinical studies are used to assess efficacy (proof of concept) and to continue to assess a drug or drug combination in a relatively small number of patients (tens of patients). These early studies can be non-comparative or double-blind comparisons.

PHASE IIB

After Phase-IIA studies, these randomized and controlled clinical studies are used to assess the efficacy and dose-ranging of a drug or drug combination in larger groups of patients (hundreds of patients). In some designs, there is a positive interim end point so that Phase IIB can be extended into Phase-III registration trials. Safety continues to be assessed.

PHASE III

Randomized and controlled clinical studies in patients (thousands of patients) designed to evaluate the comparative safety and efficacy of a drug or drug combination. Also includes the principal data used by regulatory agencies to approve or reject a product-licensing application.

EFFICACY PHARMACOGENETICS

The study of genetic variation that underlies variability in the efficacy of drugs for treating disease.

INTENT TO TREAT

Analysis of clinical-trial results that includes all data from patients in the groups to which they were randomized (that is, assigned through random distribution) even if they never received the treatment.

LINKAGE DISEQUILIBRIUM

The condition in which the frequency of a particular haplotype for two loci is significantly different from that expected under random mating. The expected frequency is the product of observed allelic frequencies at each locus.

TRANILAST

The name that was used for a specific anti-restenosis drug while it was being investigated by GlaxoSmithKline.

HYPERBILIRUBINAEMIA

A high level of bilirubin in the blood. This can cause yellowing of the skin (jaundice).

PERIPHERAL NEUROPATHY

A problem in peripheral nerve function (any part of the nervous system except the brain and spinal cord) that might cause pain, numbness, tingling, swelling and muscle weakness in various parts of the body. Neuropathies might be caused by physical injury, infection, toxic substances, disease (for example, cancer, diabetes, kidney failure or malnutrition) or drugs such as anti-cancer drugs.

CHARCOT–MARIE–TOOTH NEUROPATHY

A genetic disease that is characterized by progressive peripheral neuropathy and debilitating muscular weakness, particularly of the limbs. There are multiple inherited mutations of several genes that result in similar phenotypes.

ABSOLUTE D′

For specified alleles at two distinct loci, D′ is the absolute difference between the observed and expected haplotype frequencies, divided by the maximum value that the difference could possibly attain.

RESTENOSIS

A re-narrowing or blockage of an artery at the same site at which treatment, such as an angioplasty or stent procedure, has already taken place.

GILBERT'S DISEASE

A benign syndrome of increased sensitivity to external drugs that causes hyperbilirubinaemia but does not progress to severe liver impairment.

BAYES FACTOR

The ratio of the posterior odds to the prior odds.

GENETIC LOAD

The degree to which a given trait can be attributed to genetic variation by the proportion of cases that carry the allele.

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Roses, A. Pharmacogenetics and drug development: the path to safer and more effective drugs. Nat Rev Genet 5, 645–656 (2004). https://doi.org/10.1038/nrg1432

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