By Robert Reekie
Europe has long been an attractive location for pharmaceutical companies seeking to conduct clinical trials. With a population of 491 million, the continent offers an abundance of potential trial sites, experienced investigators, and patient populations, along with governments and local institutions eager to reap the rewards of research activity.
However, Europe presents a number of challenges to trial sponsors and CROs. While many of these challenges are well-known to the larger multinational “big pharma” companies, smaller U.S.-based companies may be less aware of them.
At first glance, the climate for conducting clinical trials in Europe may not appear to be very different from that in the United States. Since the 2004 enactment of the European Commission’s Directive 2001/20/EC, which seeks to implement “good clinical practice in the conduct of clinical trials on medicinal products for human use,” a sponsor can now theoretically submit the same clinical trial application to each EU member state, as opposed to the previous practice by which country-specific requirements resulted in major differences in content and timelines to approval. Applications can now be produced in a modular fashion, leading to greater administrative efficiencies, especially when document management is required across multiple countries. In practice, the climate is more complex. Unlike the United States, a large country with many trial sites and a relatively homogeneous culture, the EU has 27 member states with smaller populations, each with its own distinct culture, medical practices, and attitudes regarding the conduct of clinical trials. It has been said that the EU essentially watches over 27 different sets of rules governing Good Clinical Practice (GCP) in clinical trials, as well as 27 different interpretations of the directive. Consequently, there are still country-specific requirements. Moreover, although English has become the standard language for international clinical trials, and fluency would be expected at all investigational sites, some study documents may still need translation into the local language. Those issues can make assembly of an integrated, international clinical development team particularly challenging, as they require distance management, cross-cultural communication skills, and identification and application of local expertise.
In addition to standardization of clinical trials documentation, the directive has made certain things easier. For example, supplies of study drugs can now be shipped to a single distribution point in the EU, from which they can be released by a qualified person (QP). Additionally, the directive has diminished the time frame differential between historically “fast” and “slow” countries so that countries can now accrue patients and start trials more quickly and consistently. The directive also established the principles and practice of Europewide regulatory inspections of sites and sponsors. While some trial sponsors, CROs, and institutions may regard the new inspection system as burdensome, those that have undergone inspection can have a high degree of confidence in their processes and should embrace the system as an ongoing driver of continuous process improvement.
The Changing Clinical Trials Landscape
Another notable trend is largely independent of the directive: a change in the types of trials conducted in Western Europe. Ten years ago Western Europe was considered the ideal environment for conducting large-scale Phase 3 trials. In addition to the abundant talent and expertise within the region, large numbers of patients were readily available. More recently, as other regions such as Eastern Europe and Asia have emerged as attractive, cost-effective locations for Phase 3 trials, Western Europe has largely shifted its focus to “specialty” studies, such as proof-of-concept trials, or those that investigate special techniques or specialist populations such as pediatrics, the need for which is enshrined in regulatory requirements, along with postmarketing studies. Nevertheless, there still exists healthy competition within Europe for trial sites and patients. The recent implementation of clinical trial databases, which enables companies and CROs to identify ongoing trials, has assisted in the design and implementation of trials that are less vulnerable to those competitive forces.
There are conflicting opinions regarding the extent of harmonization engendered by the directive. Many observers were disappointed in the differing speed of implementation of the directive from one country to the next, as well as in areas where national special interests and differing interpretations of the directive are reflected in local regulations. Nevertheless, all national regulations comply with ICHGCP (International Conference on Harmonisation — Good Clinical Practice) guidelines for clinical trials, and the situation is significantly improved over the predirective situation. In fact, the number of clinical trials applications continues to rise, and a new directive is under active consideration in an attempt to continue the process of bringing together the 27 different sets of priorities.
There are other issues worth noting. For one, U.S.-based companies must have legal entities established in the EU in order to conduct clinical trials in any member state. The legal entity may be an affiliate company or some other construct and must be physically located in Europe. Notably, Switzerland does not belong to the EU and therefore is not an option for legal representation or drug importation. Additionally, if a comparative therapy is to be used in a trial, the sponsor must establish that the comparative therapy is registered in Europe for the indication and at the dose(s) being studied. Similarly, if an investigative therapy is to be studied in combination with — or in comparison to — the standard of care (SOC), the sponsor must be aware that the SOC in the United States may not be the SOC in Europe or that the SOC may differ from one European country to the next. That difference may have budgetary implications in that the SOC may not be paid for within certain European healthcare systems, which are not harmonized, and the sponsor may thus have to pay for the SOC in addition to the study drug. A local market presence or appropriate partnering can help companies manage these issues as well as European privacy laws, which also require appropriate processes and local knowledge.
Differing Approaches To Clinical Research
An important distinction between U.S. and European trial sites is that the former are often managed on a commercial basis, an approach much less frequently seen in Europe. While European clinicians and institutions view clinical trials as potentially good for patients and scientifically rewarding, trial activities are undertaken by staff members for whom routine patient care takes precedence (and rightly so!). Sponsors must therefore develop methodologies to support institutions that conduct trials in parallel with busy clinical practices. This can take the form of logistical support for study nurses, rapid access to sponsor- or CRO-designated staff for advice, or extensive study support documentation for patients and relatives.
Similarly, whereas IRB (internal review board) reviews may be performed appropriately in the United States on a commercial basis, the concept of a commercial-based ethical review is unheard of in Europe, where such reviews are conducted by institutional bodies on a voluntary basis. The solution is careful planning and early submission for review.
In summary, U.S.-based companies may find it both challenging and rewarding to conduct clinical trials in Europe. Although there are differences in clinical, regulatory, institutional, and cultural approaches, the challenges can be met with wellestablished solutions. Indeed, when companies take a broad and flexible world view of clinical development and when they make use of local expertise, successful Europe-based clinical trials can be well within their grasp.
About The Author
Dr. Robert Reekie is COO, late-stage development, at PharmaNet and is responsible for global operations across 40 countries. He has almost 25 years experience in drug development, having qualified in medicine from the University of Edinburgh, Scotland. He has held senior medical and regulatory positions in pharma and in a number of CROs.
Used with permission from Life Science Leader magazine.