Harmful impact of EU clinical trials directive

Innovative clinical and translational research, instigated and conducted by motivated physician-scientists, has had an important part in the development of modern oncology. For example, adjuvant treatments for breast and colorectal cancer, shown in randomised trials to be effective in preventing recurrence, have been developed and tested through research performed largely by academic clinicians.1^–3 Similarly, such clinicians have been responsible for researching, developing, and introducing sentinel node biopsy and breast conserving surgery, which have reduced morbidity for many hundreds of thousands of women.4 5 Yet investigator initiated academic clinical research is under threat—ironically, from a European Union directive that is aimed at protecting patients and improving research standards.

The official goals of the EU clinical trials directive, implemented in 2004,6 were to improve the protection of patients and the reliability of research reporting and to harmonise and increase the competitiveness of European clinical research. The responsibilities of the research sponsor were increased significantly, and at the outset many investigators were worried that that the labour intensive, bureaucratic, and expensive endeavour of running a clinical trial would become worse.7 In particular, academic researchers funded by grants, who have so far performed most oncology trials, were worried that their resources might no longer suffice to meet the requirements of the new directive. A recent analysis of research since the directive suggests that many of those fears have been realised.

The European Organization for Research and Treatment of Cancer (EORTC), the largest independent cancer research ne in Europe, recently analysed the effect of the directive its trials (P Therasse, European Cancer Conference, Paris, Nov 2005). The number of new trials fell from 19 in 2004 to seven in 2005 (63%), and a third fewer patients were enrolled. Simultaneously, trial costs increased by 85% and insurance costs from 70m to 140m euros. Trial initiation was about five months slower than in 2004, mostly the result of the increased workload of ethics committees. Paperwork and documentation increased “a lot.”

Instead of benefiting patients, the EORTC thought that the directive had hindered their access to new treatments. Moreover, the organisation reported significant variations in the way the directive was interpreted in different countries, suggesting unsuccessful harmonisation. On the positive side, the employment of EU officials and contract research organisations (to do the work that clinicians don't have the time to do) was thought to be improved.

Our own experiences are in accordance with EORTC findings. For example, we are taking part in multinational randomised studies of an antiangiogenesis agent, given in combination with standard therapy. Many participating patients have advanced disease and are very ill. Yet the directive requires reporting of all suspected serious adverse events, regardless of whether they are caused by the underlying disease, chemotherapy, or by the investigational drug. Information on each such adverse event needs to be distributed globally to all investigators working on the molecule. The Finnish coordinating investigator has already received 219 faxes, each consisting of 2-36 pages. The directive also requires that each event is reported to local ethics committees, together with an ethical evaluation; so far these have been discussed in 14 sessions of the Tampere ethics committee.

In the ethics committee that reviews surgery and oncology trials in Helsinki, the number of approved applications has steadily decreased from 120 in 2002 to 70 in 2005 (42% decrease). These numbers include both academic and company sponsored trials and also permits for the use of clinical specimens (A Keskinen, personal communication). Academic drug trials decreased from 20 to five between 2003 and 2005 (75% decrease). Nevertheless, the workload of the committee increased, because protocol amendments increased from 18 to 69 (283%) and reports of serious suspected adverse events from 16 to 138 (763%).

These numbers seem to confirm the initial worries about the future of investigator initiated clinical cancer research. Current and future patients with metastatic cancer should be worried. If clinical and translational research is thwarted the newest or most effective therapies may not become available rapidly. The rational development of cancer treatments may be at risk if enrolling patients into trials requires insurmountable efforts from the practising physician. In the era of evidence based medicine, it is noteworthy that these increased requirements are not based on evidence of benefit to patients.

If the current situation is increasingly difficult for industry supported research, academic translational research aimed at testing novel therapies is in particularly dire straits. Academic translational research has yielded many of the great medical discoveries (such as antibiotics and vaccines) but is now practically impossible without drug company support. The directive requires that even phase I trials fulfil pharmaceutical industry grade good manufacturing practice standards, comprehensive preclinical biodistribution and toxicity experiments, and qualified person status for importing experimental drugs between countries. Taken together, these requirements make conducting trials too expensive for investigators supported exclusively by grants.

The development of unconventional approaches such as cancer vaccines and cell and gene therapy has suffered the most, because such approaches have not been attractive to pharmaceutical companies owing to complexities in intellectual property and manufacturing. Moreover, in many European countries drug development is considered an activity conducted only by pharmaceutical companies, which has resulted in inadequate financial support to academic groups. Consequently clinical researchers have had little impact in the decision making process on new treatment strategies. The directives and rules for European clinical research are designed by the Enterprise and Industry Directorate General and not by branches responsible for health care or research (http://europa.eu.int/comm/dgs_en.htm). This may explain why rapid development of new strategies for severely ill patients seems to have received little priority.

New directives on clinical research are in preparation (http://pharmacos.eudra.org/F2/). Therefore, now is the time for action by physicians, patients, universities, and politicians to ensure that academic, investigator initiated translational research can continue in Europe. It is in no one's interest if only commercial corporations have the resources to plan and carry out clinical trials.