BACKGROUND

Over the past two decades, MS researchers have been fairly successful in establishing informative trial paradigms, validating and refining clinical and imaging endpoints, and contributing to the development of 6 FDA approved disease modifying agents and a variety of symptomatic therapies. While these successes have improved our ability to care for MS patients, they have also created a need for even more effective treatment strategies and research methods. Addressing these challenges requires increasingly complex interactions between clinical researchers, biostatisticians, radiologists, basic and translational researchers, industry representatives, and others. Clinicians can play a central role because they have more intimate contact with patients and their families, providing insight into the most pressing therapeutic issues and optimal assessment techniques.

Through institutions such as the NMSS Advisory Committee on Clinical Trials of New Drugs in MS and the Sylvia Lawry Centre for MS Research, clinicians have already been attempting to deal with selected research issues by utilizing existing data and seeking consensus, such as the new diagnostic criteria for MS,¹ clinical course characterizations,² paradigms for combination therapy studies,³ suggested interactions between clinical researchers and the pharmaceutical industry,⁴ ethics of placebo controlled studies in MS,⁵ optimizing clinical outcome measures for clinical trials,^6-10 and guidelines for the use of MRI in clinical trials.^11,12 While these are clearly important activities, the groups involved have limited ability to generate new data addressing research issues.

Most investigator-initiated clinical research is done in single center projects. This is most appropriate at the discovery stage, in which disease mechanisms and therapeutic effects are initially explored. Once hypotheses are honed through these preliminary studies, however, multicenter studies are needed to address research questions in larger, more broadly representative patient groups. If done well, these multicenter studies not only provide definitive answers for the main research questions, but also establish additional hypotheses for both basic and clinical studies.¹³ Yet because of the complexity and costs of performing multicenter studies, they are rarely initiated and performed by investigators. Instead, it is more common that multicenter studies have been sponsored and essentially run by the pharmaceutical industry, with key investigators serving as advisors. As a result, studies largely focus on corporate strategies and regulatory requirements while important scientific questions are often left unanswered. More flexibility in study design is needed to address the broader needs of the MS community, including longer follow-up, combination therapies, secondary endpoints, and mechanistic assays.

Empowering clinicians to perform more multicenter investigator-initiated research projects would have several benefits. It would allow us to promote a research agenda driven by the most relevant clinical issues rather than commercial interests. It would provide the ability to incorporate clinical insight and expertise into every aspect of trial design, implementation, and analysis, maximizing the yield from trials over and above regulatory requirements. It would provide more opportunity to improve the science of MS experimental therapeutics by evaluating meaningful secondary aims, fully validating endpoints, and thoroughly assessing secondary treatment effects on cognition, affective symptoms, fatigue, quality of life, and biomarkers.

With these issues in mind we obtained competitive funding from the National MS Society in 2003 to create a new pathway for MS clinical research – the Multiple Sclerosis Cooperative Research Group (MS-CORE) that would specifically foster multicenter investigator-initiated projects.

References:
1. McDonald WI. Compston A. Edan G. Goodkin D. Hartung HP. Lublin FD. McFarland HF. Paty DW. Polman CH. Reingold SC. Sandberg-Wollheim M. Sibley W. Thompson A. van den Noort S. Weinshenker BY. Wolinsky JS. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50:121-7.
2. Lublin FD. Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 1996; 46:907-11.
3. Lublin FD. Reingold SC. Combination therapy for treatment of multiple sclerosis. Ann Neurol 1998; 44:7-9.
4. Lublin FD. Reingold SC. Guidelines for clinical trials of new therapeutic agents in multiple sclerosis: relations between study investigators, advisors, and sponsors. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 1997; 48:572-4.
5. Lublin FD. Reingold SC. Placebo-controlled clinical trials in multiple sclerosis: ethical considerations. National Multiple Sclerosis Society (USA) Task Force on Placebo-Controlled Clinical Trials in MS. Ann Neurol 2001; 49:677-81
6. Whitaker JN. McFarland HF. Rudge P. Reingold SC. Outcomes assessment in multiple sclerosis clinical trials: a critical analysis. Multiple Sclerosis 1995; 1:37-47.
7. Rudick R. Antel J. Confavreux C. Cutter G. Ellison G. Fischer J. Lublin F. Miller A. Petkau J. Rao S. Reingold S. Syndulko K. Thompson A. Wallenberg J. Weinshenker B. Willoughby E. Clinical outcomes assessment in multiple sclerosis. Ann Neurol 1996; 40:469-79.
8. Rudick R. Antel J. Confavreux C. Cutter G. Ellison G. Fischer J. Lublin F. Miller A. Petkau J. Rao S. Reingold S. Syndulko K. Thompson A. Wallenberg J. Weinshenker B. Willoughby E. Recommendations from the National Multiple Sclerosis Society Clinical Outcomes Assessment Task Force. Ann Neurol 1997; 42:379-82.
9. Fischer JS. Rudick RA. Cutter GR. Reingold SC. The Multiple Sclerosis Functional Composite Measure (MSFC): an integrated approach to MS clinical outcome assessment. National MS Society Clinical Outcomes Assessment Task Force. Multiple Sclerosis 1999; 5:244-50.
10. Cutter GR. Baier ML. Rudick RA. Cookfair DL. Fischer JS. Petkau J. Syndulko K. Weinshenker BG. Antel JP. Confavreux C. Ellison GW. Lublin F. Miller AE. Rao SM. Reingold S. Thompson A. Willoughby E. Development of a multiple sclerosis functional composite as a clinical trial outcome measure. Brain 1999; 122:871-82.
11. Miller DH. Albert PS. Barkhof F. Francis G. Frank JA. Hodgkinson S. Lublin FD. Paty DW. Reingold SC. Simon J. Guidelines for the use of magnetic resonance techniques in monitoring the treatment of multiple sclerosis. US National MS Society Task Force. Ann Neurol 1996; 39:6-16.
12. Miller DH. Grossman RI. Reingold SC. McFarland HF. The role of magnetic resonance techniques in understanding and managing multiple sclerosis. Brain 1998; 121:3-24.
13. Schwid SR, Noseworthy JH. Targeting immunotherapy for multiple sclerosis: a near hit and a clear miss. Neurology 1999; 53: 444-445.