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First dose of potential new medicines to humans: how animals help

Key Points

  • The aim of a first study of a new drug in humans is to explore in a safe and ethical manner the dose and exposure range that is well tolerated, and, if possible, to identify any dose-limiting adverse events. Achievement of these aims represents a major leap from the laboratory bench to humans. It requires a substantial body of information characterizing the test substance, which can only be derived from animal studies.

  • Despite these activites being regulated by many national and international guidelines, the approach to preclinical studies remains largely empirical. There is a paucity of evidence about the performance of the widely employed preclinical tests in prediction of toxicity in humans. There is a need for much better performance data in this area.

  • The available limited, retrospective evidence indicates that the conventional approach using experimental pharmacology alongside toxicity studies of one month's duration reasonably predicts adverse events in the first human studies. The conventional methods identify more than 90% of toxicities that can be detected in animals.

  • If toxicity studies are shorter than one month, there is a risk of certain organ toxicities being overlooked. However, single studies seem to have the capacity to detect many of the most important potential adverse effects.

  • Data obtained from dog studies are frequently better predictors than data from rodent experiments.

  • Although uncommon, serious idiosyncratic drug reactions involving skin, liver and haemopoiesis — which conventional animal studies usually fail to predict — are major problems in drug development.


The need for careful testing of new drugs in animal models before study in humans has been recognised by physicians since the First World War. Now, first human studies on new drugs are subject to detailed government guidelines, which in the European Union are presently being reinforced through the wide-ranging Clinical Trials Directive. However, despite their long history and widespread application, these guidelines are empirical and have been formulated with a paucity of critical scientific evidence. Here, we review the principles and the available, albeit limited, evidence that support the design and conduct of preclinical studies in a way that permits effective and safe first-dose studies of potential new medicines in humans.

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Figure 1: Animal and human toxicities of 45 drugs assessed by the Committee on Safety of Medicines in the United Kingdom during the eight or nine months prior to publication in 1978 (Ref. 11).
Figure 2: The dog as a predictor of organ-specific toxicity (n = 25)16.
Figure 3: The monkey as a predictor of organ-specific toxicity (n = 23)16.
Figure 4: Percentage concordance between animal and human toxicities, grouped by organ.
Figure 5: Time to first detection of animal toxicity.
Figure 6: Correlation of lethal dose 10% (LD10) in BDF1 mice with the human maximum tolerated dose for anticancer drugs18.
Figure 7: Prediction by species.


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Correspondence to Peter Greaves.

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Competing interests

Drs Greaves and Eve presently act as consultants for Marix Drug Development Ltd. Dr Greaves receives a pension from AstraZeneca, and has recently consulted for Shire Pharmaceutical Development Ltd, Experimental Pathology Laboratories Inc. and Aventis.

Related links

Related links


European Union Clinical Trials Directive (2001/20/EC)

Guidance Documents, Center for Drugs Evaluation and Research, US Food and Drug Administration

Guidelines from the European Union including those of the International Conference on Harmonisation

Japanese Pharmaceutical Manufacturers Association



An old antimicrobial drug that is still occasionally used therapeutically.


(GLP). This defines a set of rules and criteria for the organizational processes and the conditions under which preclinical safety studies are planned, performed, monitored, recorded, reported and archived.


(GMP). This defines an assurance process that is similar to GLP. It ensures that products are consistently manufactured and controlled to the quality standards that are appropriate to their intended use.


A detailed post-mortem examination. Also referred to as autopsy.


Increase in the total time of ventricular polarization as measured from the onset of the Q wave to the end of the T wave on the electrocardiogram of the heart.


Infrequent adverse responses to drugs that differ from predictable, dose-dependent toxicities. They are characterized by a variable delay or latency period and might cause severe injury and death.


A cellular change characterized by an increase in lipid, usually seen as cytoplasmic droplets.

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Greaves, P., Williams, A. & Eve, M. First dose of potential new medicines to humans: how animals help. Nat Rev Drug Discov 3, 226–236 (2004).

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