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Safety & Testing

New medicines or chemicals which may affect the health of humans are required by law to be tested on animals. These safety tests, which providecrucial information for planning human trials, represent a very small proportion of the development process for a new medicine. While animal tests cannot predict all of the reactions a human may have to a given substance, broader questions about effects on the heart, liver, lungs or skin are answered through animal studies so that its relative toxicity is known. Acute toxicity tests, where a single, high dose of a substance is given to animals, are performed early on in development. The results are used to design studies which examine the compound in more detail.

Safety testing begins early in the exploratory development of a potential drug, with acute toxicity tests. These are usually carried out on a rodent species, and a non-rodent mammalian species, as this gives the minimum data necessary for making comparisons between effects on different species.

Studies are designed so that the maximum information is obtained from the smallest number of animals. In the past, large numbers of animals were used to determine the lethal dose of a compound (the LD 50 test). This test is no longer used, and toxicity studies are carried out on small groups of around 3-5 animals of each sex per dose. The non-rodent species groups are often smaller.

Acute toxicity testing

Safety tests begin with acute toxicity testing, where the animals are given a single dose of the test compound. The aim of the tests is to determine the range between the dose that causes no adverse effect and the dose that is life-threatening. Legislative guidance suggests that the effects on test animals should be compared with the effects on control groups of animals which have not received the compound.

The test compound is given to the animals by a single IV injection. If it is intended to be taken by humans though any other route, such as a tablet, it must also be tested this way in animals. The way that a drug is taken affects the amount of the compound which reaches the blood stream, and how it is distributed around the body.

Animals are observed for 14 days after they have received the compound, and detailed records are made of any toxic effects, including when the first signs of toxicity occur and whether there is any recovery. These studies can also provide more general data about a potential drug, such as the dose-response relationship. When day 14 is reached all the surviving animals are all killed by a humane method, and dissected to look for any further signs of toxicity.

The results of these tests allow further studies to be planned, as they give information about the dosage that should be used, and how toxicity may occur. For example, a study may test whether the compound damages the liver or whether it interacts with DNA. Compounds that are found to be toxic are not necessarily abandoned, as the degree of allowable toxicity will depend on the intended medical application. If the drug is intended for the treatment of life-threatening diseases, toxicity is less of a concern than in a drug intended for use in healthy individuals.

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Repeat-dose toxicity testing

A compound which survives these early tests can be considered for repeat-dose studies in animals. These studies give most of the basic information about how the compound acts on the body. The relationship between the dose and the animal's response to the compound is studied in more detail, and the organs that may suffer toxic effects are examined. General aspects of the relationship between exposure and toxicity and the potential reversibility of the drug's effects are also important principles of safety testing. This information is essential for estimating the safe starting dose for human clinical trials.

After initial pilot studies, safety and toxicity tests are based on the clinical plan, so that the structure and duration of the animal testsare directly linked to the clinical trial protocol. This, in turn, will be based on proposals for the target human population, the human dose, the treatment regime, route of administration (tablet / injection etc.) and how long the doses will be given for. The target population is particularly important, as this takes account of the effects of disease or age on the action of a potential drug.

From the clinical plan a toxicological plan can be drawn up, showing the number of studies the compound must undergo before it can reasonably be given to a human volunteer. Enough data must be gained from the animal studies to make useful decisions about a compound, and any potential build up that might occur in the body. The minimum duration of repeated-dose toxicity studies in animals, before testing can move to single dose trials in humans, is recommended to be 2 weeks in the EU and US, and 4 weeks in Japan. These studies must be carried out in both a rodent and a non-rodent species. Animal studies to support longer trials in humans usually match the length of the human trial

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Long-term toxicity testing

Longer toxicity studies are used to support and inform long term clinical studies, with the registration requirement of the drug in mind. These are usually 30 day studies, followed by six month toxicity studies in rodent and non-rodent species. The results of these studies allow the researchers to review the suitability of species used, and ensuring that the compounds are tested in the most appropriate species increases the validity of the study. The right animal is one that reacts to the test compound in the same way as humans, and gives an accurate idea of what can be expected when the drug is given to humans.

Once a drug has been studied for long term toxicity in animals, and to determine whether it interacts with DNA to cause mutations, it can be tested on humans in phase I clinical trials.

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Late-stage toxicity testing

Drug candidate compounds continue to be tested on animals throughout the clinical trial process, and the results of the human studies are used to inform and refine the animal studies so that they reveal more useful and accurate data. Later stage animal testing includes fertility studies, chronic studies and tests to see whether the substance is carcinogenic. These tests will determine how the drug can be used, and to determine the design of phase II and III clinical trials.

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New developments

A recent review has shown that fewer animals can now be used in the early stages of drug development, with alternative methods replacing acute toxicity tests. The findings of the report by the NC3Rs and EFPIA will inform a review of the international guidelines on toxicity testing. However, changes to safety requirements for environmental toxicology and general chemical testing within the EU (REACH)will mean that the number of animals used in safety testing will increase overall in the coming years.

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