Clinical Research in Ireland

The test results are back. Dr Brian Moulton, CEO of ICORG – the national cancer clinical trials organisation, spreads the word and the research team is delighted. The news is good; a groundbreaking genetic test confirms that the patient’s cancer will in all probability never recur. ICORG investigator Dr John Kennedy can give that life-affirming guarantee to his patient at their next consultation, such assurances he thought would never be possible in 2010.

It’s the science of Tomorrow’s World: a test called the Oncotype DX Breast Cancer Assay, which measures the activity of a set of genes in breast tumour tissue, can accurately forecast the risk of a patient’s cancer recurring, thus allowing clinicians to tailor treatment accordingly. And depending on the test result, high-scoring patients can steel themselves against the months of necessary chemotherapy ahead, or it can take the terrible uncertainty of recurrence out of the equation for others with low scores, who will receive a more palatable hormone treatment.

This opportunity is being made available to Irish breast cancer patients under the US coordinated TAILORx Trial. Ireland is the only country participating outside of North America.

Before the trial ends in mid 2010, the genetic test will be offered to well over 500 Irish women with early-stage breast cancer (a third of all eligible patients) by their oncologists in 14 hospitals around the country through ICORG - the All-Ireland Co-operative Oncology Research Group.

This cutting edge cancer test is one of dozens of equally exciting clinical research trials ongoing in this country in various therapeutic areas. Ireland may be a small country, but the patient ‘take up’ of these trials is higher per capita here than even the USA. In fact, it’s more than twice as high. In oncology, where the greatest cohesive research efforts are taking place across a specialty, a record 5 percent of patients with cancer in Ireland had access to a clinical trial in 2009, compared to just 2 per cent in the US.

The consultant oncologists who spoke to Scope agree that this impressive result is driven primarily by the Irish patient; his or her willingness to participate in a clinical trial, without guarantee that they will receive the new agent, appears equally rooted in the desire to serve the greater good through the development of new treatments as any personal health gain that may be achieved.

This heroic commitment, however, was not always matched by the powers that be. Less than ten years ago, the role of clinical research in the health system in Ireland had hardly registered on the Government’s radar. There was scarcely mention of fostering clinical research to be found in ministerial speeches or policy documents. When ICORG set up on a shoestring budget 13 years ago, it was because of the vision and hard work of a handful of oncologists. However, it appears that the Government – in its clamber to build Ireland’s smart economy – is throwing its hat into the ring and plans to develop health research through the island on an unprecedented level.

Late last year, the Department of Health (DoH) published its ‘Action Plan For Health Research 2009 – 2013’ together with the Health Research Board's (HRB) “Strategic Business Plan 2010 – 2014”, both championing the goal of positioning Ireland as a leading international location for health focused clinical research.

Speaking about the new HRB strategic business plan, Enda Connolly, Chief Executive, says, “Our ambition is to put health research at the heart of the health system. This will improve people's health, change how we deliver patient care, ensure evidence is applied in policy and medical practice and create opportunities for new enterprise to support our economy."

Indeed, the HRB lists the “development of excellent clinical research” as its primary strategic goal for the next five years, which represents a major departure from its previous focus on early stage biomedical research and population health studies.

A key ambition, as set out in both of these new documents, is to bring together for the first time fragmented health research activity in Ireland into an integrated and focused health research system. This would involve providing strategic leadership, setting priorities, and addressing the bottlenecks hampering clinical research, taking into account the widely unpopular changes to national regulations.

The DoH’s Action Plan has pledged to establish clinical trials networks in targeted disease areas, which it maintains would increase the volume of trials conducted in Ireland along with investment. The HRB echoes this ambition, adding that it would like to see “more clinicians and health professionals conducting top quality research”.

Scope magazine understands from well-placed sources that, as part of its five-year strategy, the HRB may soon issue calls to interested consultants to set up clinical research groups in selected therapeutic specialties.

This organised mobilisation of experts in a disease area has never proved to be a straightforward endeavour. Lack of resources and leadership, even professional jealousies, has heretofore hampered most efforts in that direction. As it stands, only ICORG has managed in a little over a decade to secure membership of more than 97 percent of oncologists working in Ireland and has trials available to patients in every hospital where cancer services are provided.

“ICORG is a fairly unique organisation in Ireland, I don’t think there is any similar group in any other disease area. As a result of ICORG’s cohesive and formal structure, patients with cancer in Ireland have benefited greatly from clinical trials over the years,” explains Consultant Medical Oncologist Dr John Kennedy, former ICORG chairman and its principle investigator at St James’s Hospital.

“We have a cohesive group of oncologists working together to make trials available to patients and that’s a real advantage. We’re able to basically provide the trials for patients, who are attracted in such numbers that we can be seen internationally as being major contributors, despite having a relatively small population by European standards.”

He adds: “ICORG has forged links with the large North American academic centres and the leading research groups and has done so very successfully. ICORG is seen by a number of these groups as being a real asset in terms of access to Europe and access to European investigators and institutions.”

It would appear to the observer that ICORG’s success on the international stage must have contributed to at least some of this extraordinary and coordinated shift towards realising Ireland’s bright future in the clinical research arena. As an internationally recognised and respected high quality clinical trials group, ICORG has opened well over 100 trials and made a research option available to more than 4000 Irish cancer patients since its establishment in 1996.

“Investment in oncology research is on the up,” observes Dr Brian Moulton, the founding CEO of ICORG. “The actual statistics are that five years ago one in five research dollars in the world were spent in the area of oncology, which was quite an impressive statistic historically, but now it’s one in three. It’s a huge move, and it’s because of the early successes of a number of exciting new treatments such as the tyrosine kinase inhibitors and monoclonal antibodies that has brought this increasing investment.

“Next year, we will have available through trials between 6 and 10 of the most exciting, lead candidate drugs in cancer from the world’s top pharmaceutical companies - the best cancer drugs that are in development in the world - available in Ireland through clinical trials, and part of the reason that this is happening is the partnership and attitude of Irish patients who in the past participated in ICORG trials.”

At present, ICORG is coordinating 44 cancer trials throughout the country. The Group will this month announce a record-breaking enrollment of more than 1,000 patients participating in its trials in 2009, which is a tremendous achievement when you consider the research group’s modest beginnings.

Dr Moulton has met with many hospital consultants in various specialties over the years, offering advice on how to set up a clinical research group. His dominant message has always been for them to unify as a community; without a majority membership in their specialty, there is little chance of success.

“We’re just too small a country for fragmentation within the specialty. If you want to go out into the world and bring the best research to Ireland you need a critical mass. And the critical mass in most areas, probably in all areas, would require everybody in the country to be on the same team, in the same group,” he maintains.

Dr Kennedy adds that there is “very substantial enthusiasm” among most Irish consultants with regard to participating in clinical trials. “The problem is that some of them work in institutions that are so significantly under resourced they just don’t have the time to do it. We still have a situation in some hospitals where there is only one medical oncologist – the idea that someone in a single-handed practice could conduct clinical trials is just not tenable.”

Dr Moulton concurs that funding is too often an insurmountable barrier for many trying to set up research groups, especially in the current regulatory environment, which is far more onerous than when ICORG set up in the 1990s.

“Back in those days the regulatory pressure wasn’t as high, now if an organisation was to set up in cardiology for example about 50 percent of the first six people they employ to help organise them  - my guess is six is about the minimum – would have to be employed in the regulatory compliance area. In the early days for us, only one of our first 6 employees was in regulatory compliance,” he says.

In 2004, Dr John Crown from ICORG and Dr Martine Piccart from the Brussels based Breast International Group spearheaded a major campaign by thousands of academics and scientists across Europe, seeking to repeal a new European Directive on Clinical trials, due to come into effect on 1 May that year.

They warned that this new legislation would seriously hamper, if not bring to a halt, the performance of academic clinical trials in Europe. It was claimed that the bureaucracy and additional costs associated with the new rules would make it almost impossible to sustain most publicly funded clinical research.

The 2,000-strong lobby proved unsuccessful and the revised EU-wide legislation was introduced as planned. In Ireland, the HRB, which was monitoring the implementation of this new directive, expressed its concern in 2005 to the Department of Health about the difficulties these regulations were causing for clinical trial activity in Ireland.

“Before the Clinical Trials Directive came into place in 2004 there were 300 clinical trials a year being submitted to the IMB. In 2003, about 75 of these were by academic bodies, about 25 of which were ICORG. Two years later there were less than 100 clinical trials in total, including the pharmaceutical sector.  So it has dropped substantially,” reflects Dr Moulton.

A Galway consultant working outside of oncology contacted by Scope, who preferred not to be named, confided that the regulatory obligations were defeating her attempts to get patients onto clinical trials: “It’s extraordinarily difficult to get on clinical trials in Ireland. Our regulation is through the Irish Medicines Board and they are very strict. It’s just very, very hard to get patients in the trials in Ireland.”

But Mr Pat O’Mahony, Chief Executive of the IMB, told Scope that the regulatory requirements for the approval of clinical trials in Ireland are in line with other European countries. “These requirements are reviewed on a regular basis and the IMB actively participates in the Clinical Trials Facilitation Group and the EU Commission working groups established to assess the implementation and impact of the legislation,” he comments.

Mr O’Mahony stresses that while fees for clinical trials are on a par with those for other Member States, academic (non-commercial) investigators can apply for a fee waiver and these are generally approved.

“A voluntary harmonisation procedure was recently introduced to facilitate the authorisation of multi-centre trials in the EU. The IMB is highly supportive of this procedure and no additional fee for participation in this procedure is proposed at present,” he adds.

Although it was suggested to Scope that the roll of the IMB should include “a strong collaborative arm” with regard to clinical trials, Mr O’Mahony points out that the IMB is the independent regulator and is not a collaborator in clinical trials but does aim to facilitate a positive research environment in Ireland.

With this fresh, concerted national drive to expand and harmonise clinical research in Ireland kicking off in 2010, perhaps the future is bright for both consultants and patients interested in participating in trials.

“I hope so,” says Dr Moulton. “What I know is that clinical research is now a recognised priority. What I don’t know is that the money will be there to do it.

“I’m nervous about our situation; I’m nervous that some people will take ICORG as big enough and strong enough, that we’re already there. The truth is we’ve reached the end of the beginning of our development, if you know what I mean. We have a fantastic platform now to grow from. But we already know we have less funding for 2010 and that we can therefore open fewer new trials in 2010, but if that trend continues for the next three years, frustratingly, we could even end up back where we started.”

In 2008, the cancer initiative cost the Government about €4.5 million. In the same year ICORG, through its research trials, brought into the country more than € 4 million worth of free drugs as part of these trials.

Dr Moulton suggests: “If you made an investment in 2010 of €6 million in oncology clinical research, for example, not only would you have a high chance of bringing in €6 million worth of extra benefit in the form of free drug and diagnostic tests etc and also add value to the research system and increase options for Irish cancer patients but you also would have an opportunity to expand this area and create more jobs. Let’s hope those with the power and the purse strings embrace this opportunity.”

A Win Win Scenario

Saying yes to a clinical trial may be very good for your health. That’s the message from UK researchers who found that patients with chronic heart failure, who agreed to take part in clinical trials, had a better prognosis than those who do not.

Publishing their findings in recently in the European Journal of Heart Failure, the authors remarked that this positive outcome may even call into question the commonplace ethical requirement of most clinical trials that by choosing not to take part in the study a patient will not be disadvantaged.

The study involved 2,332 consecutive patients diagnosed with chronic heart failure at Castle Hill Hospital in Hull, UK. After a median follow-up of 55.7 months, analysis of the full cohort showed that 792 (34 percent) had died. However, survival was significantly associated with a willingness to take part in clinical trials, which more than halved the risk of death.

The authors note that outcomes for patients with chronic heart failure are generally very poor; epidemiological studies show that around 40 percent of patients diagnosed with chronic heart failure die within a year of diagnosis.

"However," says investigator Dr Andrew Clark from Castle Hill Hospital, "two-year mortality rate in recent trials of chronic heart failure trials has been in the order of 20 percent. And even in studies of very sick patients, mortality has only been 30 percent."

Irish hospital consultants agree that the overall patients benefit from enrolling in clinical trials. Volunteering for research studies can give patients access to promising new drugs long before they are available to the general public, but even for those not on the active arm of a research trial, there are well-documented benefits to their health.

“There is some evidence that patients who participate in clinical trials do better in general than people who don’t participate in clinical trials. That’s just a fact,” says Dr John Kennedy, Consultant Medical Oncologist in St James’s Hospital.

“Secondly, the treatment must be delivered in exactly the same way as all over the world for the scientific validity of the trial, so the patients are very closely monitored and scans happen on time, all of the things that you’d wish was the same for every patients happens for research patients.”

Colon Cancer Trial

Ten percent of all cancer diagnosed in Ireland is colon cancer, far too often presenting in a more advanced and harder to treat phase. So when Dr Seamus O’Reilly had the opportunity to enrol some of his patients in a promising international research trial combining Vectibix - a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR) - and chemotherapy, he signed up as one of the lead investigators in Ireland.

“We were approached by Amgen (a leading human therapeutics company in the biotechnology industry) to see if we were interested in getting involved in the study. It seemed interesting, with a newer, second generation of a drug that we have been using, but had the potential for less allergic reactions because it was more humanised,” explains Dr O’Reilly, a consultant medical oncologist in Cork University Hospital.

In fact, the trial demonstrated significantly improved median progression-free survival, and Vectibix was found to be very well tolerated.  

“What was particularly interesting about this study was the opportunity to identify those patients who would benefit most from the drug by testing for the KRAS wild-type tumours. Just over 90 percent of the patients will have this gene, whether it’s wild or mutated.

“We now routinely test for tumour KRAS status; we send the samples to the UK for testing and we’ve been doing that for about 18 months. It means that instead of treating everybody and hoping you’ll get a benefit, you’ll test everyone and approximately 50 percent of the patients will have the wild type and 50 percent will have the mutated form of KRAS. If it’s the latter then you don’t treat them. In this way the patients are spared unnecessary treatment and it also reduces the expense of treatment as well.

“In fact, it has resulted in significant resource savings for our day wards, but also there is nothing worse for a patient than to go through a treatment and find after all that, it hasn’t worked. There’s benefit all-round,” Dr O’Reilly adds.