A US-based clinical trial for a new treatment for Parkinson's disease was abruptly stopped recently due to the appearance of serious unexpected side effects. Such a sudden decision to stop a trial, which was otherwise producing good results, highlights the issue of using people as guinea pigs for new drugs.
Surprisingly, some of those on the trial who experienced the worst side effects (violent and uncontrollable movements known as dyskinesia) were the ones who were most disappointed that the trial had to be halted. The trial involved the transplantation of foetal brain cells to replace the disintegrated dopamine-producing cells in sufferers from Parkinson's disease.
John Cerullo (49) was one of the 5 per cent in the study group who experienced the alarming side-effects. "I knew there were drawbacks. I did feel like a guinea pig," Cerullo told the London Times.
But, like many others on the trial, his desire for a treatment which would improve his speech and mobility surpassed his fears of the unforeseen consequences of participating in a clinical trial.
Internationally, medical researchers claim that patients who participate in clinical trials do better than those who don't. This can sometimes even be the case for patients receiving a placebo (an inert substance used as a control to compare the effects of the drug with no treatment). The improvement of such patients is usually attributed to the fact that they are receiving more individual monitoring and care while participating in the clinical trial. In some cases, symptoms for other conditions are picked up and treated during such monitoring.
In the Republic, the history of clinical trials has been mixed. In the 1980s, the high-profile Institute of Clinical Pharmacology Institute, headed by Prof Austin Darragh, ran clinical trials using paid healthy volunteers.
The death in 1984 of an unemployed man, Niall Rush, from the interaction of two drugs while participating in the trial for a new heart drug, cast a dark shadow over its activities. Subsequent financial difficulties for the CPI led to its closure in 1990.
Perhaps as an indirect consequence of these events, the Irish government introduced legislation to control clinical trials. The Control of Clinical Trials Acts 1987 and 1990 are now deemed to have created the legislative backdrop for high standards in clinical research in this country.
There are about 30 pharmaceutical companies who conduct clinical trials in Ireland. The annual spend on clinical research for many of these companies is about £1 million, according to Leonie Clarke, medical and regulatory affairs manager of the Irish Pharmaceutical Healthcare Association.
When a pharmaceutical company wants to test a drug on humans - after the selection of a specific compound in the laboratory and animal testing - it must submit what's called a protocol to the Irish Medicines Board for approval. The IMB gave the go-ahead for 160 clinical trials last year.
The drug company must then have its trial passed by an ethics committee. These committees are formed from both medical and lay people. Their brief is to ensure that the patients' safety and well-being will be attended to throughout the trial. Once the drug company receives approval from both the IMB and the chosen ethics committee (for example, the Irish College of General Practitioners and the Federated Dublin Voluntary Hospitals have ethics committees), their trial can begin.
There are, however, strict guidelines to be followed throughout the trial. For example, a trial must be halted if unexpectedly good or bad results are forthcoming.
"This can cause problems if limits of statistical significance are set too finely. If the trial is too small, you might miss the clinical effect of the treatment; if the trial is too large, a trivial clinical effect might become a massive statistical significance. It's important to balance statistical significance against clinical significance," explains Prof Ian Graham, professor of cardiology at the Adelaide and Meath Hospital, who has acted as an investigator on drug trials.
Hospital-based consultants and/or general practitioners act as investigators for drug trials. While they work independently on the trial, the drugs company owns the data and results from the trial. There is an independent data review committee which oversees the interpretation of the results.
Research nurses are funded by the pharmaceutical company, as is any specific equipment required for monitoring. The trial drugs are provided free. Neither patients nor investigators are paid directly but expenses incurred during the trial are covered.
Clinical trials fall into three categories: phase one, which uses healthy volunteers, phase two, which uses a small group of patients and phase three, which is a multi-centre study of a large number of patients.
Further trials take place once the drug is on the market. These trials often test new properties or the use of the drug in a different treatment. All participants must give their "informed consent" before entering a clinical trial.
The majority of clinical trials in the Republic fall into the phase three category. So, how enthusiastic are Irish patients in participating in clinical trials?
"In Ireland, less than 2 per cent of oncology patients participate in clinical trials and I'd say less than 1 per cent of all hospital patients take part in clinical trials here," says Brian Moulton, senior clinical research coordinator of the Irish Clinical Oncology Research Group (which is part-funded by the Irish Cancer Society).
These figures compare to about 10 per cent of all patients in the US and up to 30 per cent of US patients suffering from some cancers with high mortality risks, according to Moulton.
Moulton says that the low participation rates may be linked to delays which sometimes prevent hospital trials from being set up in time in order to meet the pharmaceutical companies' international deadlines for initiating multicentre trials.
Ashley Smyth, clinical research nurse in the Department of Cardiology at the Adelaide and Meath Hospital in Tallaght, believes that it is getting more difficult to recruit patients into trials. "It depends on how time-consuming the study is for patients - especially if they work," she says. Eastern European countries and Russia are now competing more and more with countries such as Ireland to attract clinical research.
The number of clinical trials carried out in the Republic has fallen from 243 in 1997 to 160 last year. Dr Joan Gilvarry, medical director at the Irish Medicines Board, says this is a "Northern European problem".
"There are a lot of new sites opening up for clinical research in Eastern Europe and there is a perception that they are cheaper. Also, there has been a number of mergers in pharmaceutical companies which means fewer drugs are being tested. The EU Clinical Trials directive has taken time to finalise and some companies believe it is safer to take trials out of Northern Europe until it comes on stream."
Moulton believes that if the number of trials continue to drop, Irish patients - particularly in the area of oncology - are losing out.
"It is very important for oncology patients to have access to clinical research. It means they can have access to drugs five years earlier than they would through the licensing process. Clinical research is crucial for good medicine.
"Despite having no statutory funding for research, all the top cancer-treating consultants appreciate its importance and are therefore involved in clinical research. It is the responsibility of everyone in this area to make sure Ireland can be at the leading edge of such work."
See also www.clinicaltrials.gov
