Two Years Later: The Impact of the EU Directive

In the European Union, a "directive" is a type of legislation that binds Member States to specific objectives that have to be achieved within a certain time period, but allows the national government of each Member State to decide the form and means of implementation.

During the San Antonio Breast Cancer Symposium in early December 2003, a meeting took place between a small number of European investigators and clinical research managers. The single agenda item of the meeting was the impact of the EU Clinical Trials Directive (CTD) 2001/20/EC on European clinical research.

The Irish contingent was particularly concerned, as an early review of the first draft of their government's transposition of the CTD into Irish law identified a number of difficulties. For example, the first draft stated that all medications in a clinical trial must be provided free regardless of the origin of the study, be it academic or industry—which would halt the country's academic cancer clinical research in its tracks.

The Belgian contingent was equally concerned for similar reasons. Subsequently, the "Save European Research Campaign" was born. One week later a Web site was launched, and to everyone's surprise it took just six days for 1000 clinical research professionals from all over Europe to sign up in support.

Eventually this number grew to over 3000, and a press release on the subject was issued in mid- December 2003. A few days later, former Commissioner Philippe Busquin, at the time responsible for the Directorate General (DG) Research—DGs are divisions within the central European Commission government structure—gave a speech to the French medical and scientific community at the Institute National de la Santé et de la Recherche Medical (INSERM).

Reasons Behind the Research Decline

In his speech, Busquin acknowledged two key facts: first, in the 10 years from 1990 to 2000 the investment in research in Europe by European headquartered pharmaceutical companies had dropped by 10%, and second, the upcoming CTD was going to be "problematic" for European investigators, placing further pressure on already limited resources.

While those in Ireland ultimately had some success in changing the wording of the final draft of the law so as to reverse the free drug stipulation for academic studies—and some other countries had similar victories in local battles—what is the overall state of play in this campaign?

The Clinical Trials Directive

The intention of the CTD—to increase clinical trial patient protection—was honorable, but regrettably the execution has been flawed. It was hard to see how the implementation of this directive would add anything to the protection of the European patient participating in a clinical trial. Has it managed to do so? The answer is, quite simply, "No." Why? Because the vast majority of those currently involved in clinical research have for many years carefully protected their patients. Prior to the CTD, close to 100% of all patients participating in oncology clinical trials had first completed a fully informed consent process. This process always included presenting patients with a document averaging 10 pages that outlined their rights, insurance status, and alternative treatment pathways in plain language. The CTD has done nothing to change this process. In fact, it could be argued that from a patient rights' perspective, the impact of the directive has been negative.

EU Member States

The trend in the short-to-medium term has been a sharp reduction in clinical trial activity in Europe and, hence, a reduction in the opportunity for European patients to obtain access to research treatments after current best practice options have been exhausted. In cancer, the clinical trial option is particularly important.

Reduced harmonization

Before the CTD, there was broad-based, European-wide acknowledgement of and adherence to the principles of good clinical practice (GCP) in clinical research. In concert with many similar organizations based in Europe, the All Ireland Cooperative Oncology Research Group (ICORG) had ensured that all of its clinical trial work had met this standard for at least the past five years. The situation today is considerably less harmonious, and to choose a few examples of the now many differences is difficult.

Despite the absolute deadline of 1 May 2004 for the implementation of the CTD, the Netherlands took an extra 22 months to transpose the law. The requirement for academic research to provide medications for free varies from country to country. Currently, Spain and Poland demand the provision of free drugs regardless of the origin of a study. The process of ethical approval has become much more complex, with some countries moving to a single national opinion; in a number of countries, regional committees continue to demand review despite the law indicating that it is not necessary, and other countries have disbanded ethics committees with little or no warning, placing the status of prior approvals in limbo.

The key element of drug safety reporting varies as well. In some countries, ethics committees are demanding very detailed reports within days of the event. Meanwhile, other countries are refusing to accept any safety reports in protest of being overwhelmed by reams of often duplicated safety information, which has continued to grow in volume month to month since the CTD.

Impact of change

To answer the question, "Has there been an impact on clinical research activity in Europe?" let us look at the cornerstone of academic clinical research: the investigator-initiated study. This can have many formats, but the most common one is where an investigator or group of investigators approach a drug manufacturer and seek modest support to examine the activity of their compound in a niche area, a rare disease type, or a patient subgroup, or in combination with other treatments or older agents for which there is no commercial imperative to develop the compound. The barriers to overcome to successfully launch and ultimately complete this type of study today have grown exponentially.

The CTD sought to clearly identify—and some would say isolate—the "sponsor" of a study. The sponsor has been interpreted by those transposing the CTD into local Member State law as the single individual (or entity) who must take overall responsibility for the many aspects of a study. Elements of sponsorship include, to mention but a few, ensuring the following: timely SUSAR (suspected unexpected severe adverse reaction) reporting, protocol compliance by all investigators, quality standards at all collaborating centers, and drug labeling and accountability. In academic, multicenter, and multinational trials, this was traditionally a collective responsibility. Only a small minority of individual European investigators have the resources (financial and human) available to them to successfully manage all these types of responsibilities in the context of a multisite study.

Insurance woes

Also, the role of sponsor now requires the investigator to have in place specific multicenter sponsor insurance. Previously, in most Member States the standard national hospital physicians insurance included clinical trial activities if the trial protocol was followed correctly, and malpractice insurance covered sponsors when it was not. The new multicenter responsibility demanded by the CTD is not covered by standard policies, which has resulted in an expensive process. Collaborative groups such as ICORG have had to negotiate and fund separate sponsor insurance policies to enable their members to manage the liability associated with the multisite sponsor role.

The most troublesome aspect of the process of obtaining this insurance has in many cases been the demand by the insurance companies to show a track record of trial management prior to receiving a quote for coverage. Many investigators and some collaborative groups do not have formal records of clinical research management experience. This is a new insurance market, and one hopes that the conditions of entry will change. However, to comply with the conditions, the insured collaborative group or investigator must have sufficient resources in place to ensure that an adequate quality standard is maintained throughout all parts of the study.

It has also recently emerged that the conditions of these insurance policies vary widely from country to country. In Germany and Ireland, for example, insurers have issued policies that cover all of the academic unit's activities across the range of studies it has opened at any one time—which is a reasonable position. If a research group has sponsor activities associated with enrolling 200 patients into research protocols in 2006 and plans on a similar workload in 2007, then in reality the risk involved is constant, regardless of the studies that are opened by the group. In other countries such as the United Kingdom, the insurance environment is much more difficult.

Many insurers in the United Kingdom have issued policies that cover the units at a basic level but require those units to purchase extra insurance for each new study it takes on and in some cases for each site that participates in the group study. This has proven to be a new and unexpected challenge in cross border or pan-European research. For example, in our company's case, a recent request to join a worthy multicenter, academic, UK-based study was turned down on the basis of the coordinating groups inability to fund the extra insurance costs. Those that have been involved in the difficult process of trying to turn around an ailing or slow-recruiting study by trying to enlist international collaborators will understand how painful it was for this group to have to reject willing suitors.

These are substantial barriers that many academic groups and investigators have struggled to negotiate. The result has been a dramatic fall off in investigator initiated studies.

Recent figures

New clinical trial initiation is an obvious and widely accepted barometer of clinical trial activity. In Sweden the number of submissions are down by 25% since the May 2004 CTD transposition date. In Ireland that figure is 40%, with the academic submission rate estimated to be down by at least 60%.

In May 2005 at a meeting of the European Forum for Good Clinical Practice (EFGCP) in Brussels, the European Organization for the Research and Treatment of Cancer (EORTC) confirmed that its new study start-up rate was significantly down. At the same meeting, the single largest financial supporter of academic-based cancer clinical research in Europe, Cancer Research UK (CRUK), confirmed that their new study start-up rate was down by approximately 50%.

At the same time, pharmaceutical giant F. Hoffman-La Roche indicated that it had accrued approximately 50% fewer patients into its European studies in 2004 than in 2003. While it was explained that this was due to factors other than the CTD—such as the completion of some large European studies in 2003—it does beg the question: How easy will it be to correct this overall trend in the more complex post-CTD environment? Roche at the Brussels meeting and GlaxoSmithKline a few days later in the American newspaper USA Today both announced their successful expansion or movement of research programs into Asia.

In March 2006 at an international cancer research managers meeting in Nice, France, CRUK confirmed that the 50% reduction in new study start-ups had not improved. During the meeting the Polish contingent indicated that the stipulation in Polish law that all medications be provided for free had caused a reduction in academic-led research activity by 90%. Spain confirmed that they also were legally bound to provide all medications for free. In this situation, the only way that an academic group can realistically complete a study is with the financial help of the pharmaceutical industry. But, in time, will this dependence result in undue influence on what research does or does not happen in those countries?

The early figures indicate that Europe has suffered as a region as a result of the implementation of Clinical Trials Directive 2001/20/EC. The downward trend is obvious. The lack of a clear response from those who formulated this directive is troublesome. At the EFGCP meeting in May 2005 it was apparent that both the unit in charge of the CTD's implementation (DG Enterprise) and the unit most effected by changes in the European research environment (DG Research) were neither mapping the changes in activity nor seeking to act quickly to bring together stakeholders to agree on a corrective action plan.

Conclusion

Europe has always been at a disadvantage in the medical research arena, protected time for European investigators is not commonplace, and clinical research infrastructure is well down the list of priorities for European hospital managers. Despite these challenges, however, European investigators have contributed much to the development of medical science, especially in recent years.

The CTD has undoubtedly reduced the enthusiasm and commitment of the middle-ground investigators, who make up approximately 60% of the research community. Because they are essential to the future of clinical investigation in Europe, the difficulties of the CTD need to be addressed before this disenchanted group walks away.

The solutions may not be difficult to put in place. In brief, I suggest that the EU Commission mandate that all Member States take out national academic clinical research insurance policies under which any recognized research body within that Member State can work, providing they comply with basic conditions. The obvious second part of this suggestion is that each Member State put into place a competitive grant funding program for those involved in clinical research so that these groups can employ the extra clinical research management personnel required to comply with the CTD.

The problem is the old enemy: time. Traditionally the time frame for the EU Commission to achieve such an initiative has been measured in years rather than months; and every new research program opened in Asia is a missed opportunity for Europe—a trend that is not easy to reverse.

The first step is for those responsible for monitoring the impact of the CTD at the European Commission and Member State level to acknowledge that the problem exists. Then, they need to act quickly and initiate a process of repair. I believe that they will find many in the academic community willing to help them with this important task.

References

1. J. Schmit, "Costs, Regulations Move More Drug Tests Outside USA," USA Today (18 May 2005).

Brian Moulton, PhD, is chief executive officer of ICORG, 120 Pembroke Road, Ballsbridge, Dublin 4, Ireland, +353 1 6697869, www.icorg.ie.