Tightening regulations on new drug trials may not be good news for Irish patients, writes David Labanyi
The multimillion pharmaceutical research sector in Ireland has been struck by a series of difficulties following the introduction of EU-wide legislation governing studies on humans.
Researchers, industry and patients' groups agree that while the Clinical Trials Directive is a laudable attempt to harmonise rules across Europe, all are predicting a negative impact on research into a range of potentially life-saving studies if problems with the new laws are not resolved.
The industry fears the new rules will increase the cost of research and development to the extent that R&D funding will migrate outside the EU, leading to a loss of research expertise and later access for patients to next-generation medicines.
The impact of the new legislation can be seen in figures from the clinical trial regulator, the Irish Medicines Board (IMB).
Last year 162 clinical drug trials were approved, with the majority, 113, approved in the first four. However, only 49 were approved in the eight months following the directive's introduction on May 1st.
Brian Moulton, chief executive of the Irish Clinical Oncology Research Group (ICORG), says the new laws started out as an attempt to harmonise standards but ended up stifling research.
"We're looking at an almost 50 per cent drop off in the number of proposals going forward to the IMB over the last eight months of 2004 which is very significant. The directive started as a good idea. But they brought it in without proper consultation with researchers.
"In Ireland they brought in a new system of ethics committees overnight, and only three or four have now been approved. I have heard from people in the industry that companies are reducing their clinical research spend in Europe," Moulton says.
ICORG, which represents oncology experts involved in cancer research in Ireland, believes the new laws also place independent researchers at a disadvantage.
"The directive places such huge administrative demands on independent researchers that it will become almost impossible for them. Previously pharmaceutical companies could give grants to independent researchers but that is no longer possible under the directive," he says.
A spokeswoman for the Irish Pharmaceutical Healthcare Association (IPHA) admitted there was serious concern at the drop in the number of trials being approved. The IMB and an ethics committee must approve all trials.
"Clinical research is an area where Ireland does very well. Irish investigators are very well regarded as they tend to be very highly trained. But now a back log has built up as only three ethics committees have been approved.
"If a trial is delayed because of difficulties getting it approved here, that one may still go ahead but next time the company is running high quality clinical trials they may skip Ireland."
The directive dissolved the 50- odd old ethics committees and requires stringent requirements for applicants to join the 10 new committees. Only one ethics committee opinion is now required for a study in Ireland, whereas previously every hospital or centre participating had an opportunity to examine the proposals.
The migration of research funding has already started with GlaxoSmithKline's announcement late last year that it plans to move one-third of all clinical trials to low- cost countries.
The impact of research moving from Ireland would be a loss of clinical expertise and pharmaceutical research funding. The IPHA estimates more than €100 million is spent on clinical research annually, a figure it says is growing quickly. According to the Central Statistics Office (CSO), more than 21,000 people work in the pharmaceutical industry generating over €13.3 billion for the economy.
Patients groups are also concerned at the prospect of a drop off in pharmaceutical research. Stephen McMahon, chairman of the Irish Patients' Association, says "the delays threaten the availability of the most up-to-date drugs for Irish patients".
"If Ireland becomes an unattractive place for clinical trials then Irish patients are looking at having to wait an extra five or 10 years before these trial drugs are on the market coupled with a gradual loss of research expertise. Many patients want and need the opportunity to be involved in a trial."
The changes wrought by the directive come at a time of rising costs for the industry. Developing a new drug now costs more than €860 million, according to the European Federation of Pharmaceutical Industries and Associations, a three-fold increase since 1987.
An example of the clinical research being carried out in Ireland was the five-year study of Arimidex, which concluded successfully in December. Dr Caroline Waldon, head of research at Astra Zenca Ireland, was involved the running of this trial, which was the world's largest breast cancer study. "Every single thing in a trial is very strictly controlled because the directive is now law."
Researching a new drug takes about 12 years and starts with laboratory studies in which a new drug is tested to determine whether it is safe for humans. Known as the pre-clinical stage, these tests can last from one to five years and during this time a company will also apply for a patent to protect its research. Patents usually last for 20 years, creating an incentive for testing to be carried out swiftly. If a product successfully completes these pre-clinical tests, the next stage are clinical trials involving humans.
Dr Waldon says Ireland was one of a number of countries participating in large international clinical trials. In the Arimidex trial, more than 9,000 women in 21 countries took part, including 42 women from Ireland.
The majority of trials run in Ireland are "phase 3 trials". This is the last stage in the process where researchers compare a new product with the accepted "gold standard", she explains.
Before this there are phase 1 and phase 2 studies designed to determine safe dosages and side effects associated with the new drug. If these results are positive, a phase 3 trial is carried out.
The lead clinical investigator for the Irish trials of Arimidex was Prof Tom Gorey, consultant surgeon at the Mater Hospital in Dublin. When approaching patients about taking part in the trial Prof Gorey says he explained how the drug worked and what it was for. "There was no placebo element to this trial so the patient was getting an active compound although they did not know until the end whether they were on Arimidex or Tamoxafin, the current 'gold standard'.
"I would also tell them they could withdraw at any time. If there was any problem I have to follow it up. Everything, even if the patient got flu, was tabulated at the start as a serious adverse event [SAE] and it was considered due to the drug until proven otherwise. Patients are not paid for participating in trials and have to give their informed consent before participating. For many, the opportunity of receiving the next generation of pharmaceutical drugs is enough. In certain cases, where, for example, a participant faces significant travel expenses, the researchers will pay for these."
Patients involved in the Arimidex will be followed up in the future to monitor the development of any side effects or adverse reactions even though they are no longer being treated with the product.
Stephen McMahon of IPA says this type of long-term follow up is essential. "It is important that we keep tracking the safety of all medicines even once the trials have ended. I also welcome the fact, for example, that GlaxoSmithKline is going to publish all research data. Up to now there has been too much cloak and secrecy about clinical trials."
This view was echoed recently by 11 of the leading medical journals. In a shared editorial in November the editors agreed not to publish trial results from studies not registered straight away. The group,which included the British Medical Journal, said the move was to stop trial results being distorted by companies not releasing unflattering or unclear results.