One has only to look at the multitude of adverse events that have been linked to medicines over the years to recognise that using animals to predict drug safety in humans has its shortcomings. Vioxx (rofecoxib), the arthritis drug linked to the deaths of many thousands of people after being "proven safe" in mice, rats, rabbits, dogs and monkeys, is a notable example of how animal trials might fail to spot potential human safety issues. CD28-SuperMAB (TGN1412), the agent that was being developed to treat B cell chronic lymphocytic leukaemia and rheumatoid arthritis but which caused near-fatal side effects in its first human trial in 2006, is another. Of course, not all adverse events in humans can be blamed entirely on the inadequacy of animal trials: pharmacists, prescribers and patients also have a role to play in ensuring that medicines are used properly.
But are animals the best models we have today to screen for safety problems during the development of human medicines? A UK bill, introduced in the House of Commons on 26 January, is aiming to find out just that.
As we report in this issue of RAJ Pharma, the Safety of Medicines (Evaluation) Bill 2009 calls for an assessment to be carried out to see whether advances in human biology-based tests outperform animal tests in evaluating the safety of drugs before they are tested in conventional clinical trials. Human biology-based tests include in vitro, in silico (computer simulation) and microdosing methods. They have been available for some time and there has been something of an explosion recently in novel techniques. The bill proposes to determine whether the tests in aggregate are more predictive than the animal tests currently required.
The chief architect of the bill, the Safer Medicines Campaign, claims that such an assessment would be the first to measure how well animal trials can predict drug safety and to test whether the newer human-based technologies are superior. The campaigners - a group of scientists and doctors - believe there are strong scientific grounds for switching to the human biology-based approach.
The human-based tests are also expected to speed up drug development for manufacturers. A report by the US Food and Drug Administration in 2004 found that as much as 92% of new drugs fail in clinical trials following success in animal tests. The Safer Medicines campaigners accept that these failures are not all due to safety concerns, but believe the rate of attrition could be improved by relying more on human biology-focused assays. In addition, they say, substances that could save many lives are not approved because they are harmful to animals.
Regulators have to some degree already acknowledged the value of human in vitro tests. In a move to protect animal welfare, the European Union adopted Directive 86/609 (now under review), which mandates the replacement of animal tests with in vitro alternatives where they are available. In the US, a report in 2007 concluded that animal testing for environmental toxicity should largely be replaced by in vitro and in silico methods within a decade and suggested that advances in technologies for medical toxicity testing ought to be adopted for this purpose. Three US federal agencies have now embarked on a major collaboration to bring about the use of the newer technologies for environmental toxicity testing purposes.
But despite the growing acceptance of in vitro techniques, it will still be a challenge to get regulators and manufacturers of human medicines to drop animal trials in favour of a human-based approach. Animal testing for drug safety has been a legal requirement worldwide for decades, and the practice is deeply ingrained in the toxicological testing environment. Overcoming resistance to novel approaches from scientists keen to maintain the status quo will not be easy.
Critics of the human biology approach say that even humans are not a perfect model for each other because of genetic variations. Adverse events, they note, can be missed even when drugs have been tested in many thousands of human subjects. They also point to the limitations of working in vitro, when what is needed is information relating to the whole body (ie in vivo). They do not believe that in silico methods are sufficiently advanced to predict in vivo parameters such as absorption, distribution, metabolism and excretion. They also fear that in vitro tests will not be able to address a number of the regulatory questions that must be answered.
Given the conservative nature of the toxicological testing community, these arguments come as no surprise to the Safer Medicines Campaign. "Frankly, it is only through a study such as that proposed by the Safety of Medicines bill that the real strengths and weaknesses of human biology-based testing will become apparent," says Dr Bob Coleman, the campaign's science advisor. "Having said this, I truly believe that with our present level of knowledge and technological strengths, if all animal testing was banned next week, all brains would be directed to how best to exploit human biology -in vitro, in vivo and in silico- and a more reliable testing paradigm would emerge."
The campaigners also question whether the time has come to review the regulatory questions that are asked of companies and to question their validity. "Are we asking the right questions at the right time?" asks the campaign's science consultant, Dr Margaret Clotworthy.
The campaigners believe that animal tests themselves have never been properly validated. They suggest that we may have simply become very familiar with something very imperfect and not fit for purpose.
Dr Coleman acknowledges that perhaps human-based tests are still at too early a stage and are not sufficiently worked up. This may be so. We won't know until we put them to the test. As Dr Coleman says, until we address this issue properly, serious work on developing tests to the necessary level will not happen.