EU as Physician Rather than Police Officer

September 1, 2002

Applied Clinical Trials

Applied Clinical Trials, Applied Clinical Trials-09-01-2002,

The EU?s progress in the battle against cancer measures how effective it is as research supporter instead of regulatory enforcer.

The European Union is constantly in a legislative fervor, as this column has repeatedly demonstrated. In trying to create common pharmaceutical rules (and rules on many other areas of life and work) for 15 countriesand ensure implementation of them and compliance with themit inevitably devotes much of its energy to what is essentially police work. And with another 10 countries likely to join the EU in just over two years, the making and enforcing of rules will become even more complicated and time-consuming.

But policing is not the EUs only role in the medical and pharmaceutical arena. The EU also spends money, time, and energy backing research. This column has recently reported on the planning for the E17 billion EU research program for 20022006planning that has almost reached a conclusion in the EUs own labyrinthine system, and will pump billions of euros into clinical research over the next four years. So before that plan is finalized (and before the EU gets bogged down in another round of legislation to cope with the new eastern European and Mediterranean member states it is taking on board), perhaps it is time to look at some of what the EU has done in its role as research supporter rather than as medicines regulator. And because cancer has been repeatedly recognized as one of Europes biggest killersit is a key priority in the EUs new research programit seems apt to take the EU action on cancer as an index of how effective it is as physician rather than police officer. More than E1 billion is currently earmarked for fighting major diseases under the upcoming program, of which E400 million should go towards cancer research.

Successes at every level
The most recent example of what has been done dates from just a few weeks agothe announcement of the latest results from EU-backed trials on isotopes in the fight against cancer. Preliminary clinical trials carried out by researchers at the European Commissions Joint Research Centre in Karlsruhe, Germany, and the German Cancer Research Centre in Heidelberg show that alpha-emitting radioisotopes can kill cancer cells, offering new hope of combating cancers such as leukemia, ovarian cancer, and skin cancer. The cancer-killing mechanism works by connecting a vehicle that targets cancer cells, such as a monoclonal antibody or a peptide, to a powerful radioactive isotope. As it decays, the isotope emits particles that kill any cancer cells the vehicle encounters. In announcing the results, the Commission said the findings show that alpha-immunotherapy has the potential to develop into an effective treatment over the next few years and may lead to new methods of healing patients.

The work was funded with a E1.4 million contribution from the European Commission, under a project on the treatment of non-Hodgkins lymphoma, which began in January 1999 and ended in June 2002. More research is needed, but experts tell us that the results from preclinical and first clinical trials are promising, said European Research Commissioner Philippe Busquin. Multi-disciplinary cooperation between Europes best teams is needed to advance this innovative approach.

And in reviewing its support for cancer research earlier this summer in an article in RTDinfo, an online magazine about European research,1 the Commission congratulated itself on its contribution: after decades of research, it found progress at every levelprevention, detection, and treatmentmeaning that nearly one in two cancer patients is still alive five years after the initial diagnosis. For many pathological forms, cancer should no longer be seen as an inevitably fatal disease but as a chronic and potentially reversible one, said Shahid Baig, director of EU research programs for cancer.

Nonetheless, every year nearly four million new cancer cases are diagnosed in Europe, and with 750,000 deaths a year it is the second cause of mortality among the EU population. Although this high mortality rate is partly linked to the aging population, one in three Europeans is hit by cancer before the age of 75.

European research directions
The Commissions approach to cancer research takes account of the complexity and diversity of the disease. There are over 200 types of cancer, all with their own metabolic particularities about which we sometimes understand very little, the Commission points out in the RTDinfo article. The fight against cancer therefore requires a multi-pronged approach. The essence of the EU action is therefore to integrate research activities to create a synergy effect between the work of national governments throughout Europe and the pharmaceutical industry. So it has supported Europe-wide epidemiological studies to obtain a global view as a basis for developing and validating increasingly early and reliable methods of diagnosis. And it has supported various transnational networks set up in the fight against cancer. These guarantee the reliability and safety of scientific advances and enable all practitioners to benefit from the progress made and know-how acquired, it claims.

In addition it has focused on integration between fundamental research and clinical research, and between oncology, genetics, biochemistry, biophysics, surgery, and other disciplines involved in developing new treatments. The barriers between these disciplines must continue to be eroded, it says. The development of translational research is valuable in this respect, promoting an interdisciplinary approach and the flow of information between fundamental researchers and clinical practitioners. This rapid move from fundamental research to clinical applications has become a priority, not only because it is the patients right to have access to scientific progress but also because, in a highly competitive international environment, a heavy price is paid for any delay. And the Commission stresses the need for research to take into account patients quality of life.

The rationale behind the Commissions efforts at integration is that no single country can work in isolation and that compared with the United States, for example, where research by the National Institutes of Health is integrated nationally, European cancer research too often suffers from a duplication of research efforts.

Cancer mechanisms. Lauri Aaltonen of Helsinki University is currently coordinating research by several European teams on Peutz-Jeghers syndrome (PJS), and has identified the LKB1 gene which mutates to cause PJS. LKB1 and the protein whose synthesis it controls evidently play a key role in the appearance of a whole family of very different cancers (intestine, breast, uterus, etc.), explains Aaltonen. Sharing the same interest in the fundamental mechanisms of cancer, Jean-Marie Blanchard of the Institut de Gntique Molculaire de Montpellier in France and his team are working with EU support on assessing cancer as a cellular signaling disease. We have studied the action of a particular molecule in cellular signaling, TGFb, explains Blanchard. Cancer cells manage to escape the action of TGFb. Once we have understood how, we can seek ways of correcting this malfunctioning.

A number of European laboratoriesin particular those working on the EU-backed inducible melanoma model projectare trying to develop transgenic mice expressing human tumors to study their characteristics. Medical imaging is also benefiting from research on breast cancer carried out by five European laboratories with EU support. We have developed a method of surgery guided by magnetic resonance imaging, according to project coordinator Sylvia Heywang-Kobriunner of Halle University in Germany. This method offers many benefits: less damage is done to the breast, there are cleaner margins around the tumor, and the risk of residual tumors is avoided. In January, a team from the European Molecular Biology Laboratory in Heidelberg, Germany, headed by Giulio Superti-Furga, announced the discovery of a molecular mechanism which is the cause of several types of lethal leukemias.

Clinical trials. And a sizable wedge of EU money goes into supporting the European Organisation for Research and Treatment of Cancer (EORTC). With 2500 voluntary practitioners in some 200 hospitals, it is described by the European Commission as a major spearhead in the global fight against cancer . . . By organizing rigorous clinical trials on a vast scale it has permitted major progress in the treatment of the most varied forms of the disease. As Franoise Meunier, the organizations director general, was quoted in the RTDinfo article, At first it was no more than a meeting of a select group of eminent and visionary oncologists without any mandate. But given the urgency of the fight against cancer they were aware that one country alone would never be able to cope and that it was crucial to make the most of the potential offered by European coordination of clinical research.

Still a police officer
Nevertheless, despite all its activities in direct support of treatment, policing remains the European Unions principal role. Among the latest examples of this are two further draft guidelines which have appeared as the continuing follow-up to the 2001 clinical trials rules in the EU ( pharmacos/docs/Doc2002/june/ ins_gcp_06_2002. pdf). One relates to the qualifications of inspectors who are to verify compliance in clinical trials with the provisions of good clinical practice for an investigational medicinal product. The other concerns inspection procedures themselves for the verification of GCP compliance.

The guideline on inspectors demonstrates one of the curious aspects of the EU acting as a police officer: it will obtain a successful result indirectly rather than directly. The guideline requires member states to appoint inspectors to inspect the sites concerned by any clinical trial conducted, and with sufficient resources at all levels to meet, effectively and efficiently, the requirements of verifying compliance with GCP and GMP of investigational medicinal products used in clinical trials. The inspectors are to be officials of the national authorities, or appointed by them, and competent to carry out their assigned duties. They also have to receive appropriate training, and each member state has to act to maintain and improve inspection skills. Inspectors necessary qualifications include high personal integrity, maturity, be open-minded, understanding of complexity, possess sound judgment, assertiveness, analytical skills and tenacity and have the ability to perceive situations in a realistic way.

In fact, the minimum requirements set out hardly seem arduous:
The inspector should preferably have completed education at university level, or equivalent, in medicine, pharmacy, pharmacology, toxicology or other relevant fields. The level of education should allow good communication with all persons concerned with the clinical trial from sponsor, investigator or ethics committee. The inspector should have demonstrated competence in clearly and fluently expressing concepts and ideas orally and in writing in their officially recognized language. The inspector should have knowledge of the principles for development of drugs and clinical research procedures as well as requirements for clinical trials. This includes knowing the role of pharmaceutical, preclinical and clinical documentation. The inspector should have knowledge of the national legislation as well as systems, national and within EU, for conducting clinical trials and applications for marketing and control of marketed drugs. Basic medical terminology should be known and the inspector should be familiar with medical procedures and systems for recording clinical data, as well as member state regulations for the work and procedures of health care personnel and organizations providing care to patients. When applicable the inspector should also understand the patient care and regulatory systems of other countries. To be able to act as lead inspector [in EU-level inspections] and to participate in the ongoing cooperation and harmonization of procedures within EU, the inspector should also be able to write and speak English.

The relatively low level of requirements does not, however, suggest that the EU is not able to discharge its role as a police officer. The guidelines set out minimum requirements for inspectors on education, training, independence, seniority, and so on, and none of them are anything more than would have been expected for such a job. The fact that the minimum qualifications are not explicitly high is not surprising, because they result from a European-level process. Each member state will have to provide inspectors for clinical trials from its nationally available pool of talent. For large countries such as the UK or Germany, this presents no problem. For smaller countriesand plenty of EU member states have only a few million citizens (Luxembourg has only 300,000)the problem is more acute.

Because guidelines of this sort have to be agreed upon by all member states, the explicit barriers are not set impossibly high. To have insisted on a more rigorous list of minimum requirements would have run into difficultiessome member states might not have been able to back them. That would not have raised the standards of inspection, and would have held up the installation of a slightly more standardized European system. What counts, however, is the implementationand because (for instance) few clinical trials are conducted in Luxembourg, it will need few inspectors, while in the United Kingdom, where many are conducted, it will be possible to find plenty of adequate inspectors. The real arbiter will be peer pressure in practicewhich will ensure that where inspectors are nominated and active, they operate at levels judged acceptable across Europe. In true European style, this will emerge from pragmatic experience, rather than from a list of minimum academic requirements.

1. Cancer: A European Priority, RTDinfo, April 2002, comm/research/news-centre/en/ med/02-03-med01.html.