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New EU legislation heralds a difficult funding environment for nonprofit research centers.
It has been well over a year since the new legislation on clinical research was introduced across the 25 states in the European Union (EU).1-7 It was indeed timely to standardize research practice in both the commercial and noncommercial sectors, but concerns have since been raised on the new administrative, legal, and financial responsibilities facing sponsors of independent noncommercial clinical trials.8-11
In this paper, we will provide a short appraisal of the need for this kind of research, describe the present environment, and discuss some perspectives for clinical researchers wishing to conduct postregistration medicinal noncommercial trials.
Typically, when pharmaceutical companies test their compounds they choose the most favorable setting (e.g., in selected populations with fewer co-existing conditions). Trials may use surrogate clinical endpoints instead of more relevant endpoints. Market pressure and the narrow agenda for development of drugs often leave many important issues unresolved, requiring further evaluation in "real life" settings more relevant to clinical practice.
Independent noncommercial research fulfills the need for large-scale, long-term, subject-focused trials, comparing viable alternative clinical strategies and addressing physiopathological issues. Data from such trials may also be useful to health policymakers and assist them in deciding on the appropriate use of limited financial resources in both resource-rich and resource-poor settings.12
For noncommercial investigators, the most challenging result of the new environment is the concept of "sponsor." Now, all interventional research (i.e., where patients are assigned to particular therapeutic strategies by a trial protocol) must be conducted with a sponsor, defined in the EU Clinical Trial Directive as "an individual, company, institution or organization which takes responsibility for the initiation, management and/or financing of a clinical trial." This means increased responsibility for all sponsors, in both commercial and noncommercial research.13
It is only since May 2004, with the obligation to register all clinical trials with Eudract, that the European and national authorities have known exactly what research is being conducted and by whom. What can be said is that most noncommercial clinical research is carried out at university (or affiliated) centers. These centers have expertise and know-how in the conduct of clinical trials because they work with both commercial and noncommercial sponsors.
Single investigators or investigator groups coordinate some multicenter, multinational noncommercial trials; although when it comes to large-scale multicenter, multinational trials, these are now often coordinated by nonprofit research organizations. In practice, this simply means that the research centers provide the study participants and data, and the research organizations offer regulatory, monitoring, and funding support. Both parties provide scientific expertise. Examples of such research organizations include CHIP (Copenhagen HIV Program) and the EORTC (European Organisation for Research and Treatment of Cancer).
It is an irony, however, that those investigators who participate in noncommercial research coordinated by research organizations are largely academics. This underlines the present day financial and structural confines of academia. Indeed, anyone reading recent European medical literature will notice the increase in discussion and debate on the problems of academic medicine and research.14-16 In essence, due to economic considerations, academia is now subject to the practical pressures of day-to-day clinical practice and budgeting, to the detriment of noncommercial clinical research.
Examples of Research Organizations
Since 2004, any idea for a noncommercial clinical trial must be tempered by very serious consideration of the new legislative environment by the investigator/sponsor. This person/organization must have resources for the scientific, ethical, regulatory, statistical, administrative, and infrastructural obligations of present day clinical trials.17
The EU health research budget for 2006–2013 will be €8.5 billion ($10 billion U.S.)—more than double the present budget—for a total EU population of 454 million. This must be divided between preclinical and clinical research, and part of the budget allocated to clinical research will be necessary to facilitate implementation of the new legislation. By comparison, the U.S. National Institutes of Health (NIH) has an annual budget of $28 billion (€23 billion) for its 300 million persons. Even with this increased budget, Europe still lags behind the United States and Japan in research spending.
So, from the perspective of the individual clinical investigator or group of investigators, what are the options for performing a clinical trial of scientific interest in the new legislative environment? They may apply for academic grants, request European or national funding, or seek research charity support—all of which impose substantial administrative and accountability constraints. An easy option would be to approach a pharmaceutical company. This would indeed be a tempting facility involving a minimum of administrative hassle, certainly much less than any grant application to national or EU authorities or even their academic institutions. Investigators, academic institution governors, and research organizations should, however, always be mindful of intellectual property protection, freedom of publication, and upholding patient/public confidence in clinical research practice.18-26
And what about the financing of the clinical centers? Indeed, the sorry situation is that because there is no system of recognition for centers in which noncommercial research is conducted, they receive no dedicated funding from any source for this specific activity.
There have been thoughtful papers in recent medical literature on the need for financial means and the political will for the support of noncommercial research and for the creation of a central European agency that would promote, coordinate, and allocate funding.27,28 We can only endorse the appeals of these authors.
Our emphasis for the future will be on investigators and research centers. It is they who are at the center of this type of research. There is no doubt about it: Noncommercial research in Europe is in a difficult situation. Academics and clinical researchers were not adequately consulted on the 2004 legislation, and did not therefore work toward more facilities for this type of research. Clearly, the days of a "soft" approach to noncommercial research in Europe are gone. We are now in a highly professional, single system on par with the pharmaceutical industry.
Noncommercial research is little known and undervalued. In our view, it is primarily the responsibility of clinical investigators—who are, after all, the primary advocates for this type of work—to use the popular press (in all its forms) to inform and shore up support from a largely ignorant public and their political representatives.
And within the investigative centers, there must be awareness and training of personnel at all levels to permit growth and survival of 21st century noncommercial clinical research.
At national levels, positive acknowledgment should be given to recognized centers conducting this type of research through the provision of dedicated funding, with periodic evaluation of the quality of research practice and the quantity of scientific production of such centers.
It has been suggested that investigators organize themselves into networks of centers of research for each pathology.29 Indeed, some dynamic networks already exist for the major pathologies (i.e., HIV, cancer, cardiology). These networks would be investigator-driven and, with adequate funding, free from political and commercial influence.
Ongoing intensive research into the clinical applications of proteomic and genomic advances in medicine will have benefits in the long term for all clinical research. These are still in the early stages of evaluation, but the potential for individualizing patient therapy is enormous.30,31 A more targeted selection of participants for clinical trials will mean that in the future there will not be a need for such large numbers, as seen in some of today's mega-sized trials, thus lowering infrastructural and operational costs.32 This, however, is some time in the future. In the meantime, researchers must invest commitment and energy in adapting to their present environment.
Wider access should be granted to the Eudract database. At present, this is only accessible to each sponsor for information on their own trials—done in order to protect the interests of the commercial sponsors. Those noncommercial trials using approved medications have only scientific or participant welfare considerations, so access to Eudract would avoid duplication and waste of scarce financial resources.
Noncommercial research is in a weak situation in Europe. It is clearly dependent on the dynamism of the clinical investigators themselves in a setting that will need heavy financial and infrastructural support in times to come.
Elizabeth O'Doherty ,* RN, is a research nurse and site coordinator and Nathan Clumeck, MD, PhD, is the head of department, The Department of Infectious Diseases (PL5), St. Pierre University Hospital, 290, Rue Haute, 1000 Brussels, Belgium, +32 2 535 41 31, fax +32 2 539 36 14, email: email@example.com
*To whom all correspondence should be sent.
1. Guidelines for Good Clinical Practice, www.ich.org/MediaServer.jser?@_ID=482&@_MODE=GLB.
2. Directive 2001/20/EC of the European Parliament and the Council of 4 April 2001 on the 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, Official J Eur Commun, 121, 33–44 (2001).
3. Detailed guidance on the European Clinical Trials Database (Eudract Database), http://pharmacos.eudra.org/F2/pharmacos/dir200120ec.htm (April 2003).
4. Detailed guidance on the European Database of Suspected Unexpected Serious Adverse Reactions (Eudravigilance–Clinical Trial Module), http://pharmacos.eudra.org/F2/pharmacos/dir200120ec.htm.
5. Detailed guidance on the application format and documentation to be submitted in an application for an Ethics Committee opinion on the clinical trial of medicinal products for human use, http://pharmacos.eudra.org/F2/pharmacos/dir200120ec.htm.
6. Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human use to the competent authorities, notification of substantial amendments, and declaration of the end of the trial, http://pharmacos.eudra.org/F2/pharmacos/dir200120ec.htm (April 2003).
7. Detailed guidance on the collection, verification, and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use, http://pharmacos.eudra.org/F2/pharmacos/dir200120ec.htm (April 2003).
8. A. Hemminki, P. Kellokumpu-Lehtinen, "Harmful Impact of EU Clinical Trials Directive," BMJ, 332, 501–502 (2006).
9. A.H. Morice, "The Death of Academic Clinical Trials," The Lancet, 361, 1568 (2003).
10. Editorial, "Who's Afraid of the European Clinical Trials Directive?" The Lancet, 361, 2167 (2003).
11. F. Meunier and D. Lacombe, "European Organisation for Research and Treatment of Cancer's Point of View," The Lancet, 362, 663 (2003).
12. S.R. Tunis, D.B. Stryer, C.M. Clancy, "Practical Clinical Trials. Increasing the Value of Clinical Research for Decision Making in Clinical and Health Policy," JAMA, 290, (12) 1624–1632 (2003).
13. E. O'Doherty and N. Clumeck, "The EU Directive: Practical Implications for Clinical Research Teams," Applied Clinical Trials, 42–48 (May 2004).
14. P. Tugwell, "Campaign to Revitalise Academic Medicine Kicks Off," BMJ 328, 597 (2004).
15. Editorial, "Who Cares About Academic Medicine?" BMJ, 329, 751–752 (2004).
16. S. Lindahl, "Academic Medicine Sets Focus on Clinical Research," The Lancet, 356, Suppl s54 (Dec. 2000).
17. E. O'Doherty, S. Dewit, N. Clumeck, "Standardising EU Investigative Sites," Applied Clinical Trials, 38–42 (July 2005).
18. M. Angell, "Is Academic Medicine for Sale?" N Engl J Med, 342, 1516–1518 (2000).
19. T. Bodenheimer, "Uneasy Alliance: Clinical Investigators and the Pharmaceutical Industry," N Engl J Med, 342, 1539–1544 (2000).
20. D.F. Thompson, "Understanding Financial Conflicts of Interest," N Engl J Med, 329, 573–576 (1993).
21. Editorial, "The influence of Big Pharma," BMJ, 330, 855–856 (2005).
22. R. Steinbrook, "Gag Clauses in Clinical Trial Agreements," N Engl J Med, 352, (21) 2160–2162 (2005).
23. M.M. Mello, B.R. Clarridge, D.M. Studdert, "Academic Medical Centers' Standards for Clinical Trial Agreements with Industry," N Engl J Med, 352 (21) 2202–2210 (2005).
24. H. Melander, J. Ahlqvist-Rastad, G. Meijer, B. Beermann, "Evidence Biased Medicine—Selective Reporting from Studies Sponsored by Pharmaceutical Industry: Review of Studies for New Drug Applications," BMJ, 326, 1171–1173 (2003).
25. J. Lexchin, L.A. Bero, B. Djulbegovic, O. Clark. "Pharmaceutical Industry Sponsorship and Research Outcome and Quality: Systematic Review," BMJ, 326 (7400) 1167–1170 (2003).
26. F. Davidoff, C.D. DeAngelis, J.M. Drazen et al., "Sponsorship, Authorship, and Accountability." N Engl J Med, 345, 825–827 (2001).
27. J.P. Bassand, J. Martin, L. Ryden, M. Simoons, "The Need for Resources for Clinical Research: Proceedings of a Policy Conference Held at the European Heart House 27–28 June 2002, Executive Summary," Eur Heart J, 24 (12) 1171–1173 (2003).
28. G. Remuzzi, A. Schieppati, J.P. Boissel, S. Garattini, R. Horton, "Independent Clinical Research in Europe," The Lancet 364, (9446) 1723–1726 (2004).
29. N. Clumeck and C. Katlama, "Call for Network of Centres of Excellence in Clinical Research in Europe," The Lancet, 363, 901 (2004).
30. W.E. Evans and H.L. McLeod, "Pharmacogenomics—Drug Disposition, Drug Targets, and Side Effects," N Engl J Med, 348, 538–549 (2003).
31. M.J. Khoury, Q. Yang, M. Gwinn, J. Little, W.D. Flanders, "An Epidemiologic Assessment of Genomic Profiling for Measuring Susceptibility to Common Diseases and Targeting Interventions," Genet Med, 6, 38–47 (2004).
32. B.A. Silver, "Molecular and Genomic Research: Assessing the Impact," Applied Clinical Trials, Electronic Pressroom, 2 April 2005.