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A new, standard-based approach minimizes the delays between discovery of innovative agents and identification of their therapeutic benefit for patients-critical in cancer research.
The European Organization for Research and Treatment of Cancer (EORTC), created in 1962, is an international nonprofit association dedicated mainly to clinical cancer research in Europe. The aims of the EORTC are to conduct, develop, and coordinate academic and pivotal Phase I, II, and III clinical trials, with the ultimate goal of improving survival of all patients with cancer.1
The EORTC operates with a European network of about 2000 collaborators in 350 institutions to perform high-quality cancer-related studies. Over the years, the EORTC Data Center has progressively adapted its structure to respond to today's requirements. To enable its network of investigators to perform clinical trials in full compliance with good clinical practice (GCP), the EORTC Data Center provides the support of all its specialized units including: protocol development; contract, data, and project management; statistics; regulatory affairs; safety desk; quality assurance; quality of life; and health economics.2,3
In 1999, the EORTC created the "New Drug Development Programme" (NDDP), dedicated to the development of innovative anticancer agents. The NDDP has become a primary partner for the pharmaceutical industry in all fields of cancer research leading to state-of-the-art treatments.4
Recently, multicenter clinical trials have become substantially more complex to initiate, with a major increase in administrative and regulatory requirements following the new Directive 2001/20/EC of the European Parliament and Council, an "Approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of Good Clinical Practice in the conduct of clinical trials on medicinal products for human use."5
Table 1. EORTC facts & figures
Timelines have become more difficult to respect, and it is not clear whether real harmonization will result from the implementation of this directive in the various national laws. Thorough drug development planning and monitoring until trial closure, as well as data publication, are necessary to successfully manage the multiple steps of study activation and conduct.6 More recently, in 2001, the NDDP developed a new strategy with the creation of the "project management platform," which provides a centralized process within the EORTC. Within this framework, a project manager is dedicated to each pharmaceutical industry clinical trial and coordinates the activities of the study team members, assures timelines, and assumes responsibility for harmonization of procedures, quality, efficacy, and cost control.
Providing the liaison among the sponsor, the investigators, the EORTC units, and eventually an external contract research organization (CRO) for specific tasks, the project manager needs to communicate in an optimal way, ensuring that specific milestones are met and deliveries are successfully achieved.
This article analyzes the two-year experience of the EORTC project management platform, pointing out the successes and achievements, the new challenges emerging, and the areas for improvement.
Over the last five years, more than 1600 patients have been included in EORTC Phase I, II, and III trials conducted in cooperation with the pharmaceutical industry through the investigators of the New Drug Development Group (NDDG) and the Clinical Research Division Group (CRDG). This total includes more than 900 patients who have been entered into Phase III trials (56%), 564 patients into Phase II trials (35%), and 137 patients into Phase I trials (9%), with a targeted accrual of at least 1500 patients in ongoing Phase III trials. Eleven studies will be activated in 2004 within the project management platform. These include Phase I (5), Phase II (4), and Phase III (2) trials.
Table 2. Responsibilities of the project manager
The strategy of EORTC Drug Development is founded on basic principles: quality of the clinical data, speed of patients' accrual, rapid communication with investigators and sponsors, and the respecting of agreed study timelines.7 With the creation of its project management platform, providing the support of a coordinating person, the EORTC is now able to handle the specific requirements of company-sponsored and company-monitored clinical trials, and ensure a consistent approach to the management of new projects.
The project management platform is currently composed of four project managers, who have been previously working as clinical monitors at the EORTC. They are operating under the supervision of the assistant director, who is head of the New Drug Development Programme.
For each individual project, the EORTC Study Team consists of the coordinating physician, data manager, statistician, regulatory affairs manager, safety desk manager, and the project manager. Specific functions and responsibilities are clearly described for the various team members, from protocol preparation through to the final publication. In this study team, the project manager will play the role of coordinator between the internal parties (EORTC) and the external parties (investigators, sponsor, CRO).
The scientific aspects of the projects developed by disease-oriented groups are led by the coordinating physician and the group statistician. On the other hand, the project manager is responsible for the daily operational and logistics aspects of the projects.
Figure 1. NDDP interactions with internal and external partners.
In large Phase II and III sponsored studies with extensive monitoring, the EORTC may delegate the day-to-day monitoring activities to a CRO acting as a partner, based on its experience in oncology trials. In such studies, the project manager is responsible for interacting with and supervising the daily activities of the clinical research associates (CRAs). Evaluation of the contract research organization's CRAs is carried out using the routine monitoring reports, the co-monitoring visits, and the resolution of any data queries generated by the data manager.
Before study initiation, the project manager will perform a training session for all of the CRAs involved in the trial. This session is organized with the support of the coordinating physician and the data manager, and it focuses both on the specific and the practical requirements of the study protocol, on-site monitoring procedures, CRF completion, pharmacokinetics handling, drug handling, source document verification, as well as data/queries flow.
From study initiation to closure, the project manager will be the exclusive contact person for the CRO. With the help of the EORTC study team, he/she will be responsible for resolving any pending issues observed on-site. After each site visit, the project manager will summarize the monitoring report issues in the "Site Visit Summary Report," which will be entered into the EORTC monitoring database.
For general issues regarding overall performance of the CRO, the project management platform will provide its recommendations. Regular meetings involving all project managers will address these issues.
During the first year, the project management platform has established standard documents to be used by all project managers, in order to simplify and harmonize the procedures.
The project management plan is set up by the project manager at the beginning of the study. It provides an overview of the timelines for all of the activities including contract, protocol preparation, CRF development, regulatory affairs approvals, drug preparation and supply, and monitoring training. This plan allows for anticipation of a start date for patient accrual and provides for the follow-up of agreed study timelines.
With the help of the task allocation list, the project manager is responsible for coordinating and following all of the steps within the specialized units, including the safety desk, regulatory affairs, and contract management.
The cooperation document describes in detail the protocol procedures and the responsibilities of the CRO and EORTC study team within the specific protocol.
Figure 2. Structure and interconnections of the study team.
The CRO management plan is set up by the project manager before the start of the study in order to assess the performance, commitment, and adherence to timelines by the CRO.
This plan specifies the criteria and methods by which the CRO's performance should be evaluated:
The results of the CRO's CRA assessment are centralized in a common database available to all EORTC project managers. This avoids any duplication of CRA evaluation.
The main responsibility of the project manager is to coordinate the interaction and foster communication within the entire study team (EORTC study team, EORTC study coordinator and investigators, CRO, sponsoring company) by acting as the liaison person between these various parties. The project manager ensures this by organizing regular meetings and phone conferences. All communications are channeled through the project manager.
Before and after study activation, much data needs to be transmitted as rapidly as possible to the various collaborators. For this purpose, the project manager uses a password-protected, Web-based database called the trial status database. This database is updated on an ongoing basis and represents the current status of a trial site at the time, including the status of regulatory affairs, drug supplies, and initiation site visit.
1. centralization and simplification of communication between the EORTC and external parties: investigators, data managers, sponsor, and CRO
2. improved definition of task coordination, and enhanced respect of the responsibilities of each member of the EORTC Study Team
3. creation and maintenance of specific study databases accessible to all parties
4. prediction of costs and time-phased budgets using estimating methods
5. harmonization of the procedure
6. performance assessment
7. adherence to pre-agreed and optimal timelines for study activation.
Knowing the large number of steps preceding study activation, the planning of timelines over a period of six months is essential to ensure successful study management.
Figure 3. Timelines for study activation.
Since its creation in 1999, the New Drug Development Programme has successfully conducted 22 sponsored and monitored clinical trials, addressing a panel of 14 investigational drugs, in 11 different tumor types, leading to 18 abstracts and seven peer-reviewed publications. Two years after the creation of the Project Management platform, the first results appear very promising in terms of the conduct and management of EORTC-sponsored and -monitored clinical trials.
The project management platform has demonstrated that coordination and planning are the key functions in clinical trials, and that the use of standards does simplify work procedures and shorten timelines. This approach minimizes delays between the discovery of innovative agents and identification of their therapeutic benefit for patients, which is extremely important in cancer research. Based on this experience, the EORTC is now extending the project management concept to nonsponsored academic Phase II and III trials.
With its large network of investigators around Europe and its single database, the EORTC will continue providing and enhancing high-quality support for the development of new anticancer agents from Phase I to Phase III clinical trials, establishing optimal therapeutic strategies and state-of-the-art treatments.
1. F. Meunier and A.T. van Oosterom, "40 Years of the EORTC: The Evolution Towards a Unique Network to Develop New Standards of Cancer Care. European Organisation for Research and Treatment of Cancer,"
European Journal of Cancer
, 38 (4) 3-13 (March 2002).
2. A. Debbaudt, L. Roche, D. Lacombe, A.-J. Baeyens, "EORTC's Regulatory Affairs Unit," Applied Clinical Trials, September 2002, 61-66.
3. N. Dubois and D. Lacombe, "SAE Report Handling in a Multinational Academic Research Environment," Applied Clinical Trials, April 2000, 38-44.
4. D. Lacombe, A. Butler-Smith, P. Therasse, P. Fumoleau, S. Burtles, H. Calvert, S. Marsoni, C. Sessa, J. Verweij, "Cancer Drug Development in Europe: A Selection of New Agents Under Development at the European Drug Development Network," Cancer Investigation, 21 (1) 137-147 (2003).
5. Editorial "Who's afraid of the European Clinical Trials Directive?", Lancet, 361 (9376) (28 June, 2003).
6. A. Verny and I. Klingmann, "A 6-Month Process for Planning Multinational Clinical Trials," Applied Clinical Trials, February 2003, 58-61.
7. D. Lacombe, P. Fumoleau, H. Zwierzina, C. Twelves, L. Hakansson, G. Jayson, F. Lehmann, J. Verweij on behalf of the EORTC New Drug Development Group and New Drug Development Programme, "EORTC and drug development,"European Journal of Cancer, 38 (4) 19-23 (2002).
Christine de Balincourt,* PhD, Sandrine Marreaud, MD, Mauro Placchi, MS, Bart Vandael, MS, and Denis Lacombe, MD, are with the EORTC, Avenue E. Mourier 83, 1200 Brussels, Belgium, (+32) 2 774 1684, fax (+32) 2 772 6701, email: email@example.com.
*To whom correspondence should be addressed.