How human biology can prevent drug deaths

Thousands of people die from adverse effects of medicines that have been tested on animals. There is a better way, say geneticist Kathy Archibald and pharmacologist Robert Coleman

ADVERSE drug reactions are a major cause of death, killing 197,000 people annually in the European Union and upwards of 100,000 in the US. Little coverage is given to such grim statistics by governments or pharmaceutical companies, so patients and their doctors are not primed to be as vigilant as they should be, and adverse drug reactions (ADRs) remain seriously under-recognised and under-reported.

The ?5.88-million EU-ADR project, which published its final report in October, showed that it is possible to spot these reactions earlier by applying data-mining techniques to electronic health records. These techniques could, for example, have detected the cardiovascular risk signals of arthritis drug Vioxx three years before the drug was withdrawn in 2004 - saving many tens of thousands of lives. But invaluable as such systems are, it would be even better to detect risk signals before a drug reaches humans, thus saving even more lives.

Currently, 92 per cent of new drugs fail clinical trials, even though they have successfully passed animal tests. This is mostly because of toxicity, which can be serious and even fatal for the people taking part in the trials. For example, in 2006, six people enrolled in a UK trial of the drug TGN1412 were hospitalised after developing multiple organ failure. Many clinical trials are now conducted in India, where, according to India's Tribune newspaper, at least 1725 people died in drug trials between 2007 and 2011. Clearly, there is an urgent need for better methods to predict the safety of medicines for patients as well as volunteers in clinical trials.

At the patient safety charity, Safer Medicines, we believe this goal is most likely to be achieved through a greatly increased focus on human, rather than animal, biology in preclinical drugs tests. New tests based on human biology can predict many adverse reactions that animal tests fail to do, and could, for example, have detected the risk signals produced by Vioxx, which in animal studies appeared to be safe, and even beneficial to the heart.

These techniques include: human tissue created by reprogramming cells from people with the relevant disease (dubbed "patient in a dish"); "body on a chip" devices, where human tissue samples on a silicon chip are linked by a circulating blood substitute; many computer modelling approaches, such as virtual organs, virtual patients and virtual clinical trials; and microdosing studies, where tiny doses of drugs given to volunteers allow scientists to study their metabolism in humans, safely and with unsurpassed accuracy. Then there are the more humble but no less valuable studies in ethically donated "waste" tissue.

These innovations promise precious insights into the functioning of the integrated human system. Many are already commercially available, but they are not being embraced with the enthusiasm they merit.

Pharmaceutical companies would make much greater use of them if governments encouraged it, but inflexible requirements for animal tests is a major deterrent. Ever since the thalidomide birth-defects tragedy, animal testing has been enshrined in law worldwide, despite the irony that more animal testing would not have prevented the release of thalidomide, because the drug harms very few species.

So how well have animal tests protected us? Many studies have calculated the ability of animal tests to predict adverse reactions to be at or below 50 per cent. In 2008, a study in Theriogenology (vol 69, p 2) concluded: "On average, the extrapolated results from studies using tens of millions of animals fail to accurately predict human responses." And a recent study in Regulatory Toxicology and Pharmacology (vol 64, p 345) shows that animal tests missed 81 per cent of the serious side effects of 43 drugs that went on to harm patients.

It is hard to understand why governments defend a system with such a poor record, or why they are dismissive of new technologies that promise increased patient safety while decreasing the time and cost of drug development, not to mention the savings to healthcare systems from fewer adverse drug reactions. Proposals to compare human-based tests with animal-based approaches have been strongly supported by members of the UK parliament. The Early Day Motions they signed were among the most-signed of all parliamentary motions between 2005 and 2006, 2008 and 2009, and 2010 and 2012.

Safer Medicines has put these concerns to the UK Department of Health and the prime minister - to be told that "human biology-based tests are not better able to predict adverse drug reactions in humans than animal tests".

It is a tragedy that so many suffer or die through the use of inadequately tested drugs when tests based on human biology are readily available. Yet governments continue to mandate animal tests, despite the lack of a formal demonstration of fitness for purpose, and a growing global realisation among scientists that animal toxicity tests are inadequate and must be replaced.

In its 2007 report, Toxicity Testing in the 21st Century: A Vision and a Strategy, the US National Research Council called for the replacement of animal tests: "The vision for toxicity testing in the 21st century articulated here represents a paradigm shift from the use of experimental animals... toward the use of more efficient in vitro tests and computational techniques." To its credit, the US government is at least working on initiatives to hasten this. The UK government, however, still denies there is a problem. How many must die before it listens?

Kathy Archibald is director of the Safer Medicines Trust. She is a geneticist who worked in the pharmaceutical industry.

Robert Coleman is a pharmacologist with pharmaceutical industry experience. He is now a drug discovery consultant and adviser to the trust

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