News - drugs fail in human clinical trials.

Drugs fail in human clinical trials.

"many compounds tested in rodents raise hopes of their becoming potential cures, and almost as many go on to fail in human clinical trials."

Nature, Volume: 465, Pages: 267–268, 20 May 2010, DOI:10.1038/465267b



In 2007, a paper in the journal Cancer Cell announced that the compound dichloroacetate (DCA) had been found to shrink tumours in rats (S. Bonnet et al. Cancer Cell 11, 37–51; 2007). That news by itself would not have created much of a stir: many compounds tested in rodents raise hopes of their becoming potential cures, and almost as many go on to fail in human clinical trials. But DCA had already been tested in humans against a condition called lactic acidosis, and so seemed to be relatively safe. Indeed, the authors of the paper argued that DCA could swiftly find its way into late-stage clinical trials against cancer — except for one problem. The drug was no longer protected by patents, and no pharmaceutical company would invest the millions of dollars needed to fund clinical trials.

Since then, the researchers have managed to pull together enough funding for preliminary trials, the first of which was published last week (E. D. Michelakis et al. Science Transl. Med. 2, 31ra34; 2010). Supported by a mix of Canadian federal grants and donations from philanthropic organizations and individuals, the study showed promising results when DCA was used against a form of brain cancer. But the team was able to test the drug in only five patients. And although the researchers have gathered enough funding for additional small studies, they admit that the prospect of moving into the final phase of clinical testing — which typically involves a much larger trial — is daunting.


Over the past few years, as observers have lamented the declining productivity of the pharmaceutical industry, there have been many calls to speed up the process by 'repurposing' or 'repositioning' existing drugs. Unfortunately, that suggestion runs up against the same stumbling block faced by DCA: when drugs have gone off patent, it is difficult for a company to recoup the substantial investment required to test the drug in a new population of patients. Large pharmaceutical companies have expressed little interest in repurposing drugs — and at least two of the small companies that have tried have gone bankrupt.


The fundamental difficulty is that patent systems generally reward innovation, not development. Although it is possible to file a new 'method of use' patent to cover a repurposed drug, such patents are difficult, if not impossible, to enforce if a generic copy of the drug is already on the market.

Several solutions have been proposed, none of them perfect. One would be for the federal government to pay for clinical trials of repurposed drugs that — like DCA — lack intellectual-property protection. This is an expensive proposition, however, and taxpayers might chafe at the notion of paying for trials that were previously the responsibility of the private sector.


Another possibility is to follow the path taken by the European Union, which allows an extra year of patent exclusivity if new uses are found for an approved drug. In the United States, a similar approach is already being used to encourage the testing of drugs for treating children: drug manufacturers get an extra six months of protection if they find a new paediatric use for their product. But this programme, although successful, comes with a trade-off: the drugs will remain free from generic competition, and therefore more expensive, for longer.


It is a difficult conundrum, but one that warrants serious thought and creativity from researchers, agencies and policy-makers alike. This is especially true as the US National Institutes of Health designs its Cures Acceleration Network, which was mandated in the recent health-care reform bill. Funds permitting, the network will try to repurpose drugs that pharmaceutical companies have abandoned. Such an initiative could cut down the time and expense needed to find new therapies, and those who would take up the effort deserve support.