NINDS Workshop Translating Promising Strategies for Spinal Cord Injury Therapy

Translating Promising Strategies for Spinal Cord Injury Therapy
February 3-4, 2003
Bethesda, Maryland

• Introduction
  
• Background
  
• Discussion
  
• Recommendations/Conclusions
  
• Participants
  

Introduction

There are over a dozen spinal cord injury (SCI) / paralysis research groups in the U.S. and Canada, as well as strong concentrations of SCI investigators at other institutions. These are university based multidisciplinary research programs that focus on basic, clinical and/or translational research. Their efforts are aimed at improving treatments for paralysis caused by SCI through the application of basic science findings to clinical use, and some are formulating ideas for clinical trials. Despite numerous scientific meetings in the field, there has not been a concerted effort to identify areas of convergence of research interests and opportunities for interactions, collaborations and direct comparisons of results between the groups. The goal of this discussion-based workshop was to bring together leaders of major North American research groups that focus on SCI research, to exchange information about the scope and aims of their programs, and to increase communication and cooperation between them.

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Background

NINDS funding for SCI research has ranged from basic science studies of spinal cord function and regeneration in model systems, to clinical trials to evaluate pharmacological treatments, and rehabilitative approaches to improving outcome. In 1993, NINDS convened a workshop to evaluate "Intraspinal Transplantation and Clinical Application." Issues included our incomplete understanding of human SCI, logistics of clinical transplantation trials, and a need for better preclinical data and outcome measures (Journal of Neurotrauma, 1994, vol. 11(4):369-377). In the intervening years, safety trials of fetal spinal cord grafts have been performed, standardized models of rodent SCI and locomotor function have been established, and clinical trials in fields such as Parkinson's Disease and traumatic brain injury have set important precedents.

Also in recent years, an expanding community of SCI researchers has reported promising progress in developing interventions that limit secondary injury and enhance regeneration, functionally significant sprouting, and recovery of function. Yet, few of these new approaches are being successfully translated into therapies for SCI patients. As the lead federal agency in funding SCI research, the NINDS is ideally positioned to initiate a discussion among SCI research groups focused on the translation of basic research to clinical studies. Discussion topics were suggested by SCI researchers and by members of the International Campaign for Cures of SCI Paralysis, a group of voluntary agencies supporting SCI research in the United States, Canada, the United Kingdom and Australia.

Translation, regenerative medicine and multidisciplinary research teams are all topics of high priority for NIH, and NINDS in particular. In 2002, NINDS initiated several new program announcements in translational research. Thus, it is especially timely to bring together groups in SCI research to discuss current efforts toward translation. The goal of the workshop was to enlist these groups in targeting and accelerating research areas ready for translation. The groups were asked to discuss how, as a field, they can scientifically support the development of clinical studies. Attendance and participation by NIH Program and Review officers, and representatives from FDA, VA and NIDRR added value to the discussions for both the government and the research community.

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Discussion

1. Overview of SCI Centers and Consortia

   The first aim of this workshop was to assess and disseminate information on the breadth of the participating multidisciplinary SCI research groups. Prior to the meeting, faculty lists and interests were compiled, indicating basic-neuroprotection, basic-regeneration and clinical-rehabilitation interests at each Center. The workshop was opened by a review and brief introduction by each Center director, describing the infrastructure and resources of their group. Some SCI research groups are well established, with specialized, focused or broad research programs and experience with clinical trials. Others are relatively young, newly reorganized and/or actively growing. In all, twenty-two U.S. and Canadian Centers or consortia, representing over 250 faculty members, were described, along with some State and private funding programs.

   Some Centers have associations with the Veterans Administration, NIDRR-Model SCI Centers, and some represent regionally based consortia. Many of the Centers receive State, corporate and private funding in addition to NIH grant and contract support. All of the groups that receive funding as Facilities of Research Excellence in SCI were present, as were representatives of two European consortia that are developing novel outcome measures for human SCI trials (International Spinal Research Trust and a European Clinical Trials network).

   A key component of these Centers is their multidisciplinary faculties. Many foster the interaction of basic and translational scientists with clinicians in neurosurgery, neurology and rehabilitation medicine. The Centers offer some training in translation, though they agree there is a need for additional training opportunities in clinical trials development, conduct and interpretation. Other resources include core facilities, registries of SCI persons, and collections of human SCI tissue available at a few Centers. The stated goal of most groups is to apply basic science findings to developing strategies for clinical studies in SCI. Issues under consideration include which level of injury to target, how much regeneration is possible or needed, what outcome measures will detect changes due to the treatment, and what would most improve quality of life after SCI. The need for delayed interventions and studies that define the nature and reparability of chronic injuries was a recurring theme here and throughout the meeting.

   In addition to the Centers represented, SCI funding by California, New Jersey and New York was described. These are a subset of the states that now fund SCI and TBI research through either peer-review or designated support mechanisms. In addition to initiating a competitive grants program, N.Y. State has contracted with the Institute of Medicine to assess the current state of SCI research over the next two years.

2. Development of SCI Clinical Trials

   The discussion of clinical trials included brief mention of several ongoing clinical studies and highlighted the long history of SCI trials, lessons from drug company studies and those in related fields such as TBI. It was clear, however, that many SCI researchers lack knowledge or access to details about this history, and its importance in developing future trials. General issues discussed included patient selection and availability of sufficient study participants, the apparent lack of rigor or equipoise in some clinical applications of novel therapies, and issues of informed consent and understanding of the nature of clinical trials on the part of the patients.

   Despite, or because of the enthusiasm often expressed in press coverage of SCI research and the promise of new therapeutic strategies in animal studies, it was considered important to assess these results with great care. This includes the need to directly associate evidence of regeneration with behavioral changes, and to consider that very complex models tested in rodents will not easily translate into clinical applications. The question of what and how much preclinical evidence is needed to warrant a trial in humans led to questions of regulation of trials, and how the decision to initiate a trial is made. The need for researchers in the field to address these questions was raised throughout the workshop. While "advice" on these topics from a group of leaders in the field was seen as valuable, development of further roadblocks or regulations was not supported. It was agreed, however, that training in trials design, mentorship from those experienced with trials and analysis of trial data, and possibly a registry of clinical trial experiences would accelerate the field in a productive direction.

   The decision of when to initiate a trial is made by researchers and their sponsors, often with encouragement from patient groups. Trials using investigational drugs, biologics and devices are subject to FDA regulation, and human subject protection is reviewed by local IRBs in accordance with applicable federal regulations. FDA/CBER representatives clarified their role by pointing out that they assess the safety, not efficacy of the treatment or the rationale for going to a trial. FDA representatives strongly encourage researchers to confer with them early in the planning process, as does the NINDS Clinical Trials group, which also advises on pre-phase III studies (pilot studies and planning grants). FDA/CDRH pointed out some differences between device, cell and drug regulations of which applicants should be aware.

3. Acute, Neuroprotection

   The experience of the NASCIS trials of methylprednisolone and other neuroprotection drug candidates was discussed in relation to recent controversies over use of high-dose steroids as a standard-of-care. There is little consensus on standard of acute care in SCI, as illustrated by recently published Guidelines by the American Association of / Congress of Neurological Surgeons (Neurosurgery, supplement to March 2002, volume 50, no. 3). In addition to a lack of evidence-based practice guidelines, medico-legal issues will affect treatment and trial design.

   Many issues of trial design were raised for which there were no ready answers. A key issue is how big an effect size to expect and what outcome measures can detect this in large-scale trials. In relatively "safe" areas, such as thoracic injuries, even measures that are sensitive enough to detect reliable changes in function attributable to an intervention will not likely yield a functional improvement to patients, or improve their quality of life. Setting the bar too high for trials is also not productive. SCI trial designs will be complicated by naturally occurring recovery in some patients and our limited ability to predict such recovery reliably. Yet placebo controlled trials of complex invasive therapies were considered unlikely to be attempted.

   The question of how much benefit justifies a trial depends in large part on the potential risk of the therapy to the patients. It was suggested that acute neuroprotective studies might offer relatively more potential benefit than currently available regenerative strategies. Before experimental therapies are tested, it was suggested that some surgical issues (decompression, realignment, stabilization) be addressed in randomized controlled studies. For new therapies, more information is needed about the window of therapeutic opportunity, which depends in part on the mechanism of action of a particular intervention.

   Promising strategies for neuroprotection are evolving, including hypothermia, blockers of secondary injury, and cellular therapies. Therapies with differing mechanisms may have different optimal times of application. To ensure the robustness of preclinical findings, these strategies need to be tested in more than one laboratory, model of injury or in larger animal models; the results of these studies, positive or negative should be published. Additional considerations discussed included gender differences, genetic diversity and the use of relatively young rodents versus trials on mature patients. The need for primate studies was conditional, depending on the model, intervention and functional analysis being studied. Improving outcome measures in animal studies would involve use of physiological measures, biomarkers, and indicators of cell survival where appropriate. In addition, longer studies to assess the persistence of any functional advantage to a protective therapy were called for.

4. Chronic, Regeneration

   A number of strategies to promote regeneration have been identified, including growth factors, stem cells, Schwann cells and olfactory ensheathing cells, myelin neutralization, extracellular matrix inhibition, and guidance channels. Some also promote remyelination. The timeframe for application of a therapy will depend on its effects on the spinal cord; some strategies could be advantageous in both acute and chronic injuries. A common component of effective therapies, including activity-based therapies, may be altering function by stimulating endogenous plasticity. The question of how much of the mechanism needs to be clearly defined before a strategy is tested clinically was a topic of some discussion.

   While trials should be designed to apply a therapy at a time that is appropriate to its mechanism of action, calling for more mechanistic studies can also lead to a perpetual "we need to know more" research mode. One advantage of proving a therapy successful in a number of models in the preclinical stage is to assess its robustness, despite a lack of clear understanding of its mechanism of action. In this respect, rehabilitation studies are an example of studies that can be safe and productive, and inform future trials in defining functional outcomes that can be assessed, without full understanding of their physiological consequences.

   The issue of understanding what a truly chronic injury is in animal models was raised several times. Relating animal findings to human studies requires better information about continuing damage in the cord, and the potential for plasticity and regeneration. A resource for housing chronically injured animals was suggested to accelerate translational studies.

   Assessing the "window of opportunity," for maximal effectiveness of a therapy has not been accomplished preclinically for most, if any, strategies. The NASCIS neuroprotection trials defined the useful therapeutic window during the clinical trials. It is also not known when there may be no hope for effect, or what the optimal duration of most treatments are. Relying on anatomical changes seen in animal studies is not sufficient, as behavioral recovery can be measured over many weeks, while lesion size may be expanding in experimental models. Attention to these questions with further research is needed.

5. Translation

   Regardless of the intervention being targeted, common issues arose relating to translation and preclinical testing. These include assessment of potential adverse effects, and developing a hierarchy of interventions to be translated, based in part on risk. In Phase I trials that assess safety of cellular grafts, it was pointed out that measuring adverse events is not enough; proof that the cells survived is needed to truly assess safety, and therefore better imaging or biomarkers are needed. Because the criteria needed to initiate any given trial are so dependent on the specifics of the chosen patient population, intervention, and follow-up measures, many of the workshop participants felt that it was essential to seek agreement based on considerations of animal models, replications, safety and mechanism of action. It was agreed that a fair evaluation of evidence would require access (preferably in reviewed publications) to both positive and negative findings relating to the strategies being tested. Development of an informatics structure to make such findings available was suggested.

   Many topics of clinical relevance were discussed for which no simple guidelines are available from animal studies: testing for side effects such as pain, determination of appropriate patient inclusion and exclusion criteria, best outcome measures, consideration of normal functional recovery, length of trial, coordination of multi-center sites to ensure compliance, marketing of eventual treatment, definition of trial success. Clinical experience shows that the accuracy of prognosis after SCI increases over the first hours and days after the injury. Neuroprotection trials may be initiated before a clear prognosis can be established, and so may require blinded, controlled trials for assessment, whereas trials in complete subjects initiated several days or a week after injury may strongly suggest efficacy without placebo controls.

   Comparing the realities of clinical testing to expectations from animal studies highlighted issues of functional outcome assessment. The usefulness and sensitivity of existing outcome measures to assess regeneration strategies was questioned. While these strategies may not restore "useful" function, early studies will need to assess any improvement. Motor and sensory function assessed by the ASIA scale does not take pain, autonomic or sexual function into account, and may not be sensitive enough to detect even several spinal levels of regeneration in thoracic injuries. The basic scientists were reminded that acute SCI patients are not stable, and risks of surgeries can be high. Long-term studies, that require rehabilitation and continued follow-up may not be practical for patients, especially when long distance travel is involved. The financial implications of such studies were also discussed

   There is general agreement among basic scientists that some combination of strategies will be needed to restore function. Developing these combinations clinically will present challenges, and incremental tests of therapies will need to aim at detecting incremental benefits. Many rehabilitation therapies being discussed are not, themselves, evidence-based standards of care, and so multiple experimental therapies would, by necessity, be tested simultaneously. It is not clear whether patients that have participated in one trial should be excluded from other trials, but this is an additional "risk" to the patient that must be considered. It was pointed out that every patient experiences a "combination" therapy, and examples from other fields, such as cancer therapy should be sought. FDA representatives pointed out that in combination therapies, each component must be shown to be effective and required, whereas approved devices (e.g., drug pumps) are approved for their function, not specific applications.

   One of the largest hurdles may lie in overcoming patient expectations. Patients must be made aware that there is always "something to lose" as well as gain. Obtaining informed consent in trauma cases is a difficult issue (especially in very acute interventions), but precedents have been set in brain injury and other SCI trials. Subjective reports are subject to large placebo effects in SCI patients, and objective outcome measures are needed. Basic scientists need to be better educated about available tools for behavioral analysis as well, and their limitations. It was agreed that improved outcome measures for both animal and human studies need to be addressed, and some new measures are being developed. Finally, given the initiation of several Phase I trials in recent years, it is not clear what outcome is being sought to justify planning for further clinical studies. Without the possibility in clinical studies of assessing evidence of cell survival, clear assignment of clinical prognosis, markers of cell or drug activity, or even clearly defined mechanisms of action, many participants remained skeptical of taking any of the existing strategies to trial.

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Recommendations/Conclusions

Discussion throughout the meeting was active, and important concerns emerged. While agreement was not reached on solutions for many of these concerns, the discussion was viewed as useful and productive for further consideration at the Centers. Participants expressed enthusiasm for continuing the discussion next year. While specific therapies were not identified or prioritized within the context of this meeting, working groups were initiated to work in the coming year on several documents, including a summary paper from this meeting, a historical look at SCI trials and lessons learned from them, and a position paper providing advice on translation in SCI. The following issues were identified as important to accelerating translation:

• Improving outcome measures (animal and human) sensitive to regeneration/plasticity
• Training of SCI trial specialists, or information about and access to available training
• Definition/study of chronic injury, relationship between animal and human injuries
  • Need for chronic animal resource to accelerate initiation of studies, study of human tissue samples after SCI
• Replication of promising studies, publication of results positive or negative
  • FORE-SCI contract is initiating acute and chronic replication studies
• Trials in larger animals in some interventions
• Continued discussion across disciplines, international groups
  • Participants valued present workshop/style and endorse meeting again next year
• Increased awareness/training of trial design and history among basic/translational labs;
  • Decision: to draft a paper reviewing SCI trials experience, past to present; participants will follow up
• Need for an advisory group within the field for anticipating trials, planning translation
  • Decision: participants will follow up

The NINDS would like to acknowledge additional support for this workshop provided by the Christopher Reeve Paralysis Foundation.

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Participants

Douglas K. Anderson, Ph.D.
Deputy Director of Medical Research
Department of Veterans Affairs Medical Research Service
Washington, DC

Beth Ansel, Ph.D.
Director, Clinical Practices Research
National Center for Medical Rehabilitation Research
National Institute of Child Health and Human Development
Bethesda, MD

Maureen J. Beanan, Ph.D.
Program Analyst, Repair and Plasticity
National Institute of Neurological Disorders and Stroke
Bethesda, MD

Michael S. Beattie, Ph.D.
Chairman, Department of Neuroscience
The Ohio State University
Columbus, OH

William C. Benzing, Ph.D.
Scientific Review Administrator
Brain Disorders and Clinical Neurosciences IRG (BDCN-2)
NIH Center for Scientific Review
Bethesda, MD

Barbara S. Bregman, Ph.D.
Professor and Chair, Department of Neuroscience
Georgetown University Medical Center
Washington, DC

John F. Cavanagh, M.Sc.
Head of Research, International Spinal Research Trust
Guildford, United Kingdom

Daofen Chen, Ph.D.
Program Director, Channels, Synapses and Circuits
National Institute of Neurological Disorders and Stroke
Bethesda, MD

Arlene Y. Chiu, Ph.D.
Program Director, Repair and Plasticity
National Institute of Neurological Disorders and Stroke
Bethesda, MD

Guy L. Clifton, M.D.
Professor and Chairman, Department of Neurosurgery
The University of Texas
Medical School at Houston
Houston, TX

W. Dalton Dietrich, III, Ph.D.
Kinetic Concepts Distinguished Chair in Neurosurgery
Scientific Director, The Miami Project to Cure Paralysis
University of Miami School of Medicine
Miami, FL

Volker Dietz, FRCP, Professor, Dr.
Visiting Professor at The Miami Project to Cure Paralysis and
Director of the Paraplegic Center
Institute for Rehabilitation and Research
University Hospital Balgrist
Zurich, Switzerland

Bruce H. Dobkin, M.D.
Professor, Department of Neurology
University of California, Los Angeles
David Geffen School of Medicine
Los Angeles, CA

Marian Emr, B.A.
Director, Office of Communications and Public Liaison
National Institute of Neurological Disorders and Stroke
Bethesda, MD

Rebecca M. Farkas, Ph.D.
AAAS Science Policy Fellow
Office of Science Policy and Planning
National Institute of Neurological Disorders and Stroke
Bethesda, MD

James W. Fawcett, Ph.D.
Centre for Brain Repair, Cambridge University
Cambridge, United Kingdom

Michael G. Fehlings, M.D., Ph.D.
Professor of Surgery
Director, Neural and Sensory Science Program
Krembil Chair in Neural Repair and Regeneration
Head, Spinal Program, University Health Network
Toronto Western Hospital
Toronto, Ontario, Canada

Donald W. Fink, Ph.D.
Biologist/Regulatory Review Scientist
Office of Cellular, Tissue and Gene Therapies Division of Cellular and Gene Therapy
Center for Biologics Evaluation and Research
U.S. Food and Drug Administration
Rockville, MD

Robert C. Grossman, M.D.
Professor and Chairman, Department of Neurosurgery
Baylor College of Medicine
Houston, TX

Edward D. Hall, Ph.D.
Director, Spinal Cord & Brain Injury Research Center (SCoBIRC)
University of Kentucky, Chandler Medical Center
Lexington, KY

John W. Hick, B.A.
Trustee, International Spinal Research Trust
Guildford, United Kingdom

John D. Houle, Ph.D.
Professor, Department of Anatomy and Neurobiology
University of Arkansas for Medical Science
Little Rock, AR

Susan P. Howley
Director of Research, Christopher Reeve Paralysis Foundation
Springfield, NJ

Naomi Kleitman, Ph.D.
Program Director, Repair and Plasticity
National Institute of Neurological Disorders and Stroke
Bethesda, MD

Anne K. Krey, M.S.
Scientific Review Administrator, Division of Scientific Review
National Institute of Child Health and Human Development
Bethesda, MD

Daniel P. Lammertse, M.D.
Medical Director, Craig Hospital
Department of Rehabilitation Medicine
CNS Medical Group PC/Craig Hospital
Englewood, CO

Laura A. Mamounas, Ph.D.
Program Director, Repair and Plasticity
National Institute of Neurological Disorders and Stroke
Bethesda, MD

Nancy S. Markovitz, Ph.D.
Senior Staff Fellow, Division of Cellular and Gene Therapy
Center for Biologics Evaluation and Research
U.S. Food and Drug Administration
Rockville, MD

John W. McDonald, III, M.D., Ph.D.
Department of Neurology
Washington University School of Medicine
St. Louis, MO

Mary Ellen Michel, Ph.D.
Program Director, Repair and Plasticity
National Institute of Neurological Disorders and Stroke
Bethesda, MD

Marion Murray, Ph.D.
Professor, Department of Neurobiology and Anatomy
Drexel University, College of Medicine
Philadelphia, PA

Carlos Pena, Ph.D.
Division of General, Restorative and Neurological Devices
Office of Device Evaluation
Center for Devices and Radiological Health
U.S. Food and Drug Administration
Rockville, MD

Miriam C. Provost, Ph.D.
Deputy Director, Division of General, Restorative and Neurological Devices
Office of Device Evaluation
Center for Devices and Radiological Health
U.S. Food and Drug Administration
Rockville, MD

Louis A. Quatrano, Ph.D.
Program Director, Behavioral Science and Rehabilitation Engineering
National Center for Medical Rehabilitation Research
National Institute of Child Health and Human Development
Bethesda, MD

Cynthia A. Rask, M.D.
Acting Division Director, Office of Cellular, Tissue and Gene Therapies
Division of Clinical Evaluation and Pharmacology/Toxicology Review
Center for Biologics Evaluation and Research
U.S. Food and Drug Administration
Rockville, MD

Paul J. Reier, Ph.D.
Mark F. Overstreet Professor, Department of Neuroscience
McKnight Brain Institute
University of Florida College of Medicine
Gainesville, FL

Theresa B. San Agustin, M.D.
Program Coordinator, Spinal Cord Injury and Burn
Co-chair, ICDR Subcommittee on Medical Rehabilitation
National Institute on Disability and Rehabilitation Research
U.S. Department of Education
Washington D.C.

Mercedes Serabian, M.S., DABT
Expert Toxicologist, Office of Cellular, Tissue and Gene Therapies/PTB
Division of Clinical Evaluation and Pharmacology/Toxicology Review
Center for Biologics Evaluation and Research
U.S. Food and Drug Administration
Rockville, MD

Nancy L. Shinowara, Ph.D.
Health Scientist Administrator, National Center for Medical Rehabilitation Research
National Institute of Child Health and Human Development
Bethesda, MD

Kathy Smith
President, Kent Waldrep National Paralysis Foundation
Addison, TX

John D. Steeves, Ph.D.
Director, International Collaboration on Repair Discoveries
University of British Columbia
Vancouver, British Columbia, Canada

Oswald Steward, Ph.D.
Director, Reeve-Irvine Research Center Professor
Departments of Anatomy & Neurobiology, and Neurobiology & Behavior
University of California, Irvine, College of Medicine
Irvine, CA

Michaela Thallmair, Ph.D.
Laboratory of Genetics
The Salk Institute
La Jolla, CA

Mark H. Tuszynski, M.D., Ph.D.
Professor of Neurosciences, Department of Neurosciences - 0626
University of California, San Diego
La Jolla, CA

Stephen G. Waxman, M.D., Ph.D.
Professor and Chairman, Department of Neurology
Yale University School of Medicine
New Haven, CT

Michael Weinrich, M.D.
Director, National Center for Medical Rehabilitation Research
National Institute of Child Health and Human Development
Bethesda, MD

Scott R. Whittemore, Ph.D.
Henry Garretson Eudowed Chair
Scientific Director, Kentucky Spinal Cord Injury Research Center
Department of Neurological Surgery
University of Louisville
Louisville KY

Barbara J. Wilcox, Ph.D.
Regulatory Scientist, Center for Biologics Evaluation and Research
U.S. Food and Drug Administration
Rockville, MD

Jonathan R. Wolpaw, M.D.
Lab Chief, Laboratory of Nervous System Disorders
Division of Genetic Disorders
Wadsworth Center
New York State Department of Health and State University of New York
Albany, NY

Wise Young, M.D., Ph.D.
Chair and Professor, Department of Cell Biology and Neuroscience
WM Keck Center for Collaborative Neuroscience
Rutgers, The State University of New Jersey
Piscataway, NJ

Robert Zalutsky, Ph.D.
Senior Science Advisor, Office of Science Policy and Planning
National Institute of Neurological Disorders and Stroke
Bethesda, MD

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