Evaluation proposal

The recent clinical trial disaster at Northwick Park Hospital and the withdrawal of Vioxx from the market have highlighted the need for an urgent review of how new medicines are developed and tested. Adverse drug reactions (ADRs) now constitute the fourth biggest killer in the Western world, epitomised by the Vioxx catastrophe, which is estimated to have caused 320,000 heart attacks and strokes worldwide – almost half of them fatal.

Sweeping regulatory changes were made in the wake of the thalidomide tragedy forty years ago in order to try to prevent such a disaster from recurring. In light of Vioxx and TGN1412, it is imperative that the scientific basis of current regulatory requirements is re-examined.

Whilst there is no doubt that pharmaceuticals improve the quality of life for millions of people, the scale of ADRs and the fact that they are escalating at a pace twice that of prescriptions gives great cause for concern. This trend must be halted by addressing the root of the problem and critically assessing pre-clinical safety screening methods.

The recent Health Select Committee inquiry into the influence of the pharmaceutical industry recommended that there should be a public inquiry every time a drug is withdrawn due to adverse effects, to determine whether adequate testing took place before marketing. The US Food and Drug Administration (FDA) is seeking to apply gene-based methods of drug evaluation as outlined in their 2004 “Critical Path” (Innovation or Stagnation) white paper. This approach is projected to cut drug development times from 15 years to five, saving nearly $500 billion. Reducing adverse drug reactions could save the NHS up to £466 million a year, according to the British Medical Association.

The FDA laments; “We’re using 20th century methods to develop 21st century drugs.” Meanwhile, British and international companies such as SimuGen, Xceleron and Biopta amongst many others have developed a range of new tests which outperform those currently required by regulators, including the UK Medicines and Healthcare products Regulatory Agency. It is clearly time to rationalise toxicity testing of new drugs along the same lines as the vision outlined by the US National Research Council in their report “Toxicity Testing in the Twenty-first Century: A Vision and a Strategy,” recently commissioned by the US Environmental Protection Agency (http://safermedicines.org/reports/toxicitytesting.shtml). This report calls for the replacement of animal toxicity tests with superior human based tests, saying: “The vision for toxicity testing in the 21st century articulated here represents a paradigm shift from the use of experimental animals and apical end points toward the use of more efficient in vitro tests and computational techniques.”

We propose an independent scientific evaluation to establish, by directly comparing the current regime of animal tests with a battery of newer human-based tests, which suite of tests would best predict safety in humans.

Pilot study
A sample of ten or more drugs which are, or have been, on the market (for which we therefore already have both clinical and animal data) should be put through a battery of the newer tests offered by a range of companies, which could be selected by tender. A statistical review of all the available data: human, animal and new test-derived, should then be conducted. The battery should be flexible, to take account of the varying worth of different tests depending on the type of disease or drug under investigation, but should include the following as a minimum:

Tissue Cultures
Tissue culture-based tests have considerable advantages in terms of speed, cost and ease of performance. There are many tests & many providers in the UK employing human tissue cultures in order to assess drug effects. A 10 year international multi-centre study, the results of which have been published in the scientific journal Alternatives to Laboratory Animals, found that a battery of such tests out-performed animal tests in predicting acute toxicity in humans (www.cctoxconsulting.a.se/meic.htm). Similar tests can also be performed in order to assess the cancer causing potential of new drugs. An example of a fast new test with improved specificity and sensitivity is Gentronix’s GeneScreen HC (www.gentronix.co.uk). It is vital that we use tests that accurately detect which  drugs (or indeed any chemicals) will harm humans, and the new tests have been shown to be both sensitive- picking up known dangerous chemicals- and specific- i.e. they don’t cause false alarms over safe & useful chemicals.

Human Tissues
Human tissues, both diseased and healthy, can be used to assess the effects of a new drug on every organ in the body. Results can be analysed to take into account factors such as age, health, sex, etc, to investigate whether a drug should be targeted to certain people (moving towards more personalised medicine) or to reflect patients more realistically. There are a number of companies offering human tissue services in the UK, such as Asterand Plc (http://asterand.com/Asterand/) and Biopta Ltd (http://www.biopta.com/). The need to assess new drugs whilst keeping in mind the variability of individual patients’ responses leads onto another test in the proposed suite:

DNA chips
DNA chips can be used in conjunction with tissue samples or tissue cultures to study the effects of drugs at the genetic level in order to predict how a patient will respond. These chips can also be used to profile patients in order to find out which drugs are likely to help them. Genetic screening is now carried out before certain drugs are prescribed for breast cancer (Herceptin) and AIDS (Abacavir), for example. This technology could also be used to follow up volunteers or patients who have already suffered side-effects from a drug in order to compare them with patients who have been helped by it, to find out the reasons for the difference. Again, there is a variety of companies specialising in providing such technology, e.g. Cambridge-based SimuGen (http://simugen.co.uk/index.htm).

Computer modelling
Computer models can take many forms, ranging from models of individual organs (www.physiome.org/), such as the virtual heart developed successfully by Professor Denis Noble at Oxford University in conjunction with colleagues around the world, to virtual patients (http://www.entelos.com//mhra_index), and even virtual clinical trials (www.pharsight.com/main.php).

Testing for birth defects
Three methods of testing for drugs dangerous to unborn babies that do not use whole animals have already been validated. A review (http://safermedicines.org/reports/teratology.pdf) found that these methods predicted what happens in humans better than the usual animal tests. Their accuracy would probably be improved even further if human embryonic tissue were used.

Microdosing
Ultra-sensitive scanners enable volunteers to take minuscule, safe doses of new drugs to reveal how they are broken down by the body. Xceleron, based in York, estimates that microdosing could reduce preclinical studies from 18 to 6 months and from £1.6-2.7m to £0.18m (http://xceleron.co.uk/). The European Medicines Agency (EMEA) and the US FDA have already endorsed its use. 90% of pharmaceutical companies say they will use microdosing by 2010. Microdosing would naturally represent one of the final tests before conventional clinical trials but the other technologies described above could be used much earlier in the drug development pipeline.

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