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A guide to drug discovery

Making Better Drugs: Decision Gates in Non-Clinical Drug Development

Nature Reviews Drug Discovery volume 2, pages 542–553 (2003)Cite this article

Key Points

  • It is estimated that only 1 out of 5,000 screened compounds is approved as a new medicine. Success or failure in drug development often depends on selecting one or two molecules for development from many choices offered by the engines of high-throughput discovery.

  • Drug development is a process that proceeds through several key go/no-go 'decision gates', from the identification of a potential therapeutic candidate through to marketing a drug product.

  • Success rests not only in the intrinsic qualities of the molecule but also in how the drug's development is planned and executed, and in the effective management of key resources: effort, time and cost.

  • Non-clinical studies form the basis for confidence in the safe and efficient progression of a new chemical entity into clinical testing. New in vitro methodologies that predict human response, coupled with time-tested protocols for drug testing in live animals and the emergence of sensitive analytical instrumentation and molecular genetics, play important roles in bringing safe and efficacious new drug candidates to market.

  • This review discusses how to strategically identify which non-clinical studies should be performed to provide the required guidance and comfort to stakeholders involved in clinical drug testing.

Abstract

Drug development is a risky business. Success or failure often depends on selecting one or two molecules for development from many choices offered by the engines of high-throughput discovery. A lead candidate needs to possess adequate bioactivity, appropriate physical–chemical properties to enable formulation development, the ability to cross crucial membranes, reasonable metabolic stability and appropriate safety and efficacy in humans. Predicting how a drug will behave in humans before clinical testing requires a battery of sophisticated in vitro tests that complement traditional in vivo animal safety assessments. This review discusses how to strategically identify which non-clinical studies should be performed to provide the required guidance and comfort to stakeholders involved in clinical drug testing.

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Figure 1: Key decision gates in drug development.
Figure 2: Potential flowchart for assessing whether a small-molecule new drug candidate is developable.
Figure 3

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Author information

Authors and Affiliations

  1. MDS Pharma Services, 3504 Proprietor Way, Raleigh, 27612, North Carolina, USA

    J. Fred Pritchard

  2. MDS Pharma Services, 2350 Cohen Street, St. Laurent, Montreal, Quebec, Canada

    Malle Jurima-Romet, Mark L. J. Reimer & Brenda Rolfe

  3. MDS Pharma Services, Les Oncins, BP118, 69593 l'Arbresle, Cedex, France

    Elisabeth Mortimer

  4. Cayen Pharmaceutical Consulting, 98 Autumn Ridge Road, Bedminster, 07921, New Jersey, USA

    Mitchell N. Cayen

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Corresponding author

Correspondence to J. Fred Pritchard.

Related links

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DATABASES

LocusLink

CYP1A2

CYP2C9

CYP2C19

CYP2D6

CYP3A4

CYP3A5

P-glycoprotein

FURTHER INFORMATION

National Center for Toxicogenomics

US Food and Drug Administration

International Conference on Harmonization

Indiana University School of Medicine Cytochrome P450 Drug Interaction Table

Glossary

TORSADES DE POINTES

This is a form of polymorphic ventricular tachycardia that is preceded by a prolongation of the QT interval. Although this condition is found in many clinical settings, it is mostly induced by drugs and drug interactions that prompt a long QT syndrome.

MINI-PIG

A small species of pig weighing about 20–45kg.

GAMMA SCINTIGRAPHY

Gamma scintigraphy is a non-invasive method of examining the deposition of a compound in the test subject's body using standard radiolabelling techniques. A computerized image of γ-emissions displays overall product deposition, including differentiation of test article concentration.

POSITRON EMISSION TOMOGRAPHY

(PET). A method for imaging that measures changes in blood flow associated with brain function by detecting positrons emitted by radioactively labelled substances that have been injected into the body.

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Pritchard, J., Jurima-Romet, M., Reimer, M. et al. Making Better Drugs: Decision Gates in Non-Clinical Drug Development. Nat Rev Drug Discov 2, 542–553 (2003). https://doi.org/10.1038/nrd1131

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