Unanswered questions on Cork trial

(This originally appeared in the Irish Examiner, 4 Sept. 2010, but it has not been available online up to now.)

The most urgent question to arise out of last week's ill-fated clinical trial at the Shandon Clinic is why the drug, rimcazole, was given to twelve healthy volunteers when it was previously linked with at least one seizure. The journal Psychopharmacology published a paper in 1984 on a Canadian trial of the drug in sixteen patients, during which one participant suffered a grand-mal seizure, while another experienced what the report described as "an episode of loss of consciousness of unknown origin".

Modern Biosciences, a London-based drug development firm, was responsible for designing the trial, which the Irish Medicines Board (IMB) approved on 11 June and which the Shandon Clinic subsequently conducted in Cork. Modern Biosciences now states that the seizures which three of the twelve volunteers suffered last week occurred "at doses predicted to be safe". Assuming that they actually received the correct doses - and an IMB investigation into the study will need to confirm this - it is clear that the data on which Modern Biosciences based its predictions were inadequate, to put it mildly. Another key question is whether the effects seen were due to the expected actions of the drug - it acts via a protein called the sigma receptor - or due to some unknown 'off-target' activity.

It would not be the first time that the scientific assumptions underlying a clinical trial have been proven to be false. The notorious trial of the TeGenero drug TGN1412 in London in 2006, in which six volunteers suffered life-threatening immune reactions and, potentially, longterm damage to their immune systems, is the most blatant example. One of the most immediate and obvious lessons learned from that case was the need to stagger the administration of new drugs being tested in man for the first time. It is not yet clear whether - or to what extent - this precaution was followed in the rimcazole trial. As the drug, unlike TGN1412, has a history of previous clinical research, it may not have been considered necessary.

Burroughs Wellcome (now part of GlaxoSmithKline) had originally tested rimcazole as a potential treatment for schizophrenia, but it wasn't effective enough to gain approval. It recently gained a second lease of life as a potential cancer drug on the strength of research conducted by Barbara Spruce of Ninewells Hospital University of Dundee, in Scotland. She showed that rimcazole has an unusual quality, which makes it particularly promising in cancer. It selectively triggers a biological process called apoptosis - or programmed cell death - in tumor cells, while not interfering with that process in normal, healthy cells. Apoptosis is switched off in many different types of cancer, which allows the tumor to grow uncontrollably. Switching it back on is one of the key overarching goals of cancer drug development.

Modern Biosciences licensed the University of Dundee's patents in 2007. The company is led by two prominent figures in the UK's biotechnology industry. Its CEO, Sam Williams, was previously a stock analyst at Lehman Brothers. Its chairman, Clive Dix, previously led a vaccines firm called PowderMed, which Pfizer acquired in 2006, and is also a former chairman of the UK BioIndustry Association. The extent to which it is responsible for the problems seen in the rimcazole trial should be established by the IMB investigation. It not uncommon for small firms with limited cash to move drugs into clinical trials prematurely. Promising clinical trial data are a form of currency in the pharmaceutical sector, allowing companies to drum up interest from investors and large pharmaceutical firms.

But there are additional reasons why the rimcazole trial is unlikely to be the last that leads to unexpected drug reactions. No less an authority than the U.S. Food & Drug Administration has highlighted the failure of the applied science of drug development to keep pace with the rapid advance of basic biomedical research: "Not enough applied scientific work has been done to create new tools to get fundamentally better answers about how the safety and effectiveness of new products can be demonstrated, in faster time frames, with more certainty, and at lower costs." Industry-wide efforts to address these issues are underway in both Europe and the U.S., but it will take some time for these to produce any useful results.

Meanwhile, the three volunteers who suffered the most severe reactions to rimcazole appear, thankfully, to have made a full recovery, and their future health will hopefully not be adversely affected by their experiences. But their experience illustrates yet again the risks clinical trial participants undertake when they sign up for studies that, by their very nature, have unpredictable outcomes.

There is an economic dimension underlying all of this. Indeed, a Shandon Clinic executive recently commented in this newspaper that the current recession had made the task of recruiting volunteers much easier. It's one of the pharmaceutical industry's most uncomfortable truths. Most new drugs need to be tested in healthy volunteers, before they can be tested in patients. But how many senior industry executives would like to see their own sons or daughters sign up for these trials ?