Impact of EU Directive on Clinical Development

The European Union's (EU) implementation of the Clinical Trial Directive (CTD) into laws, regulations, and administrative provisions represents one of the most demanding changes faced by pharmaceutical companies operating in Europe in the past 30 years. Although the main objective of the EU CTD was to define a more homogenous and consistent regulatory environment that offers maximum protection to participants in clinical trials (an area comprised of some 450 million people), industry experience shows that some old processes have not been decommissioned, but new ones have been added. Most disturbingly, provisions of the EU CTD are being interpreted inconsistently by the member states. Success in implementing the directive should, however, encourage transparency of information and decision making across the EU.

Benefits to industry

Interestingly, from a multinational company's perspective the EU CTD has catalyzed the overhaul of company processes and fostered a cross-departmental dialogue. For example, better communication between clinical operations/management and manufacturing because of the need to embed the qualified person (QP) in the clinical trial process has helped align the processes and procedures used in clinical trial activities, specifically between Phase II/III and Phase IV. In addition, improved collaboration and communication has been achieved through a structured training program for all staff involved in global clinical trials.

Implementation of the directive has also provided opportunities for more synergy, less duplication, and more clearly defined roles and responsibilities within cross-functional departments.

Although Roche's operations have long conformed to strict Good Manufacturing Practice (GMP), the role of the QP in the release of commercial and investigational medications has contributed to "personalizing" this procedure, making it more transparent to those involved in trial management.

Similarly, the newly created QP for pharmacovigilance supports transparency in this critical area and gives a "human face" to the demanding task of risk–benefit assessment. Although one of the goals of the EU CTD was to facilitate faster access to novel therapies through harmonization of administrative regulatory requirements and define binding timelines for the review and approval processes, evidence that this goal can be reached still needs to be produced. So far little, if any, simplification or acceleration of administrative processes has been observed.

Challenges moving forward

An improved alignment and collaboration concerning regulatory requirements is still needed at the EU level and even more so across member states. In some areas there has been a positive increase in transparency and structure. However, improvements need to be made in a number of areas, including:

Reversing additional administrative burdens. Suspected Unexpected Serious Adverse Reaction (SUSAR) "traffic" has substantially increased, and ethics committees and investigators complain of being overloaded with information of little value to help them in making an independent assessment of risk–benefit.

Changing Investigational Materials Plan (IMP) labels. Definitions of legal representatives and sponsors have been changed "mid-stream" by some member states.

Increasing transparency across the EU regarding approval criteria for trial design or protocol. More transparency has been achieved when it comes to the administrative aspects for obtaining clinical trial application (CTA) approvals.

Establishing a clear and uniform definition of what constitutes an investigational medicinal product. Because of economical considerations, definitions differ from country to country, which hampers both industry and nonindustry sponsored studies.

Creating better risk assessment algorithms to allow for tailoring of regulatory requirements in relation to the complexity of the planned research. For example, the need for a complete IMP data package for studies that explore new formulations. Failing to do so will result in such studies being placed outside the EU.

Reducing impediments surrounding administrative aspects of a trial. At present, obstacles relating to issues such as legal representation, sponsorship, and insurance can become so huge that they cause delays or render a study impossible.

Agreeing on an EU-wide "birth date" for updating national CTA dossiers. Under present rules, these deadlines are highly variable between countries, which results in a duplication of effort.

Harmonizing the timetable for CTA submissions. Currently, some CAs only allows CTA submissions on certain dates.

Easing the availability of mock-up labels. This refers to labels used for CTA submissions.

Training tactics

Training not only helps ensure people involved in clinical trials know what to do; it also lets them know why they are doing a given task. Together, communication and education help create a successful relationship between departments and clinical teams, and provides a better assurance that the EU CTD is implemented to the best practice standards and achieves the best possible results. In addition, training is the best communication tool and provides an ideal opportunity to share knowledge acquired during clinical trial experiences.

Conclusion

On the positive side, clinical trials are still being conducted in the European Union in comparable numbers and scope. One concern, however, is feedback from academic sponsors that their trial activities have been hampered,which has delayed or even made some studies impossible to launch. The "modalities about so-called noncommercially sponsored trials" will hopefully redress this situation. However, solutions still need to be found to eliminate unnecessary regulatory hurdles that do not add to improved protection of trial patients or the quality of clinical data, regardless of the affiliation of a sponsor.

Furthermore, we must find ways to improve the dialogue between stakeholders—industry, authorities, and academia. In fact, all these stakeholders share a common objective, which is to provide safer and better medicines faster to patients. There are still many unmet medical needs that must be addressed. In the clinical development and regulatory field a key factor of success will be a continuous commitment to process improvement shared by sponsors (academic and industry), investigators, and regulators.

Susanne Studer*is global head of systems and process improvement, pharma development quality (PDQ), with F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland, email: susanne.studer@roche.com Beat Widler is global head of pharma development quality (PDQ) with F. Hoffmann-La Roche Ltd., Basel, Switzerland.

*To whom all correspondence should be addressed.