Antivivisection groups are still claiming that the clinical trial tragedy at Northwick Park Hospital was caused by a failure of animal studies. For example, a recent post by a previously unknown Marius Maxwell on the website of the antivivisection group VERO claims that ’imprecise animal-based research‘, including on TG1412 ’is reflected in tens of thousands of unnecessary human deaths‘. This Maxwell, who writes very imprecisely (we assume he means TGN1412), leaves strangely little information about where he works, his expertise or experience. Although he claims to be a neurosurgeon, how he is qualified to make such sweeping statements is left entirely open.
If it was true that animal research was to blame at Northwick Park, then that would imply that the thousands of other phase I clinical trials which have been run successfully over recent years were a shining testament to the success of animal research. A failure rate of less than 0.1 per cent can’t be bad.
But as ever, it’s not that simple. We can now turn to the genuinely expert views found in the so-called Duff Report, published in December 2006 by the Expert Scientific Group (ESG) that was set up to investigate the very serious adverse reactions that occurred in the first-in-man clinical trial of TGN1412.
The central conclusion of the report is that ’none of the pre-clinical development studies that were performed with TGN1412 predicted a safe dose for use in humans, even though current regulatory requirements were met‘. This included all the ‘alternative’ methods which antivivisection groups like to promote. For example, it was noted as a ’striking observation‘ that TGN1412 was ineffective when simply incubated with whole human blood or in other tests.
The Expert Scientific Group looked in great detail at the role of animal experiments in pre-clinical testing. They were rightly honest about both the benefits, and the limitations, of such studies. But their conclusions could not be more clear-cut. The group state that:
Most, if not all, new medicines arise from biological insights gained from well-designed animal studies. Important information can be learned about the intended pharmacological response of a new medicine, and its potential for adverse reactions, from studies in animal models.
Animal studies taking due regard of the three ‘Rs’ remain necessary for many aspects of pre-clinical development of novel agents including testing of ‘off-target’ and ‘on-target’ toxicity and understanding the fundamental biology relevant to a new medicine and its target molecules in the human. The key point we want to make is the importance of deciding what can be learned from animal studies in the pre-clinical development of a new medicine, and what limitations there might be when it comes to predicting the response, and dose-response relationship, in humans.
It is clear from the report that there remains much work to be done to elucidate the predictive value of the animal model for responses in humans. For example, the Expert Scientific Group sees possible value in using genetically modified animal cells, tissues or whole animal models, or cellular chimeras, to evaluate responses to human-specific agents. It is likely that we are only at the start of a whole new understanding of the relevance of animal models to these new biological agents. But to rule out animal studies now, as the antivivisectionists wish, would be a disaster.
Some of the other interesting findings in this report relate to ’a number of discrepancies‘ identified in the conduct of the clinical trial. For example, the company involved (Parexel) failed to complete the full medical background of a trial subject in writing. It is strange that when occasionally animal studies are found to be poorly designed or conducted, the whole relevance of animal research is questioned by some commentators (see for example our earlier blog on the Guardian article and BMJ paper claiming that many animal tests are ‘badly flawed’). But when clinical trials are poorly conducted, it’s obvious that they simply need to be improved.
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