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NINDS is part of the
National Institutes of
Health
Emergency Neurologic Clinical Trials Network (ENCTN)
Final Report
March 17-18, 2004
Bethesda, MD
A NATIONAL INSITUTIE OF NEUROLOGICAL DISORDERS AND STROKE SYMPOSIUM
Emergency Neurologic Clinical Trials Network (ENCTN)
ContentsPreamble
Arthur M. Pancioli, M.D.
William G. Barsan, M.D.
Robin A. Conwit, M.D.
Executive Summary
Task Force Reports
How Does One Go About Doing EM Research?Arthur Pancioli, M.D., Claudia Robertson, M.D., Ian Stiell, M.D., MSC, FRCPC,
Gretchen Tietjen, M.D.
Edward Jauch, M.D., Dan Lowenstein, M.D., Stephan Mayer, M.D., John Duldner, M.D., M.S.
What Are The Topics For Research And How Will They Be Determined?
William Barsan, M.D., Guy Clifton, M.D., Judd Hollander, M.D., Donald Gilbert M.D., M.S.
Is The Research More Cost Effective If Done By The Networks?
Lewis Morgenstern, M.D., David Matchar, M.D., F.A.C.P., David Wright, M.D.
How Can Data Management Be Handled Most Efficiently?
Michael Fehlings, M.D., Roger Lewis, M.D., Ph.D., Chelsea Kidwell, M.D., Sidney Starkman, M.D.
What Are The Human Subjects Research Issues?
How Will Minority Recruitment Be Handled?
Michelle Biros, M.D., M.S., Peter Panagos, M.D., James Quinn, M.D., M.S.,
Jeff Saver, M.D.
Preamble
Arthur M. Pancioli, M.D. William G. Barsan, M.D.
Steering Committee Co-Chair Steering Committee Co-Chair
University of Cincinnati University of Michigan
Cincinnati, OH Ann Arbor, MI
Robin Conwit, M.D.
Program Director, Clinical Trials
National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda, MD
Many neurologic conditions present emergently and patient outcomes can often be determined by the care provided in the first hours after onset. Some of these conditions occur frequently (stroke, traumatic brain injury, seizures) and are associated with considerable morbidity and costs and some occur less frequently (spinal cord injury) but have very high morbidity and high costs associated with their care. Most of the clinical research in the past has focused on chronic and subacute care and there is often limited evidence to support the acute management of many of these conditions. Multicenter research networks have typically been designed to answer disease specific questions and have not been organized to address other neurological conditions that may also be present in the patient population. Each time a new clinical question is addressed, a new clinical research network is established and is usually terminated after the clinical question is answered. Significant start-up costs are associated with the establishment of these networks and are iterative in each new study.
On March 17 and 18, the National Institute of Neurological Disorders and Stroke sponsored a conference to explore the advisability of establishing a multicenter network designed to perform clinical trials in emergent neurological conditions. The Emergency Neurology Clinical Trials Network (ENCTN) concept was discussed by 25 clinicians and scientists from multiple disciplines. The goal was to improve the overall functional outcome for patients with acute neurological emergencies. The participants discussed various aspects necessary in evaluating the potential of such a network, including the organizational structure, funding, cost effectiveness and clinical conditions to be studied. A neurological emergencies network that is not disease specific would open opportunities for clinical research that would facilitate rapid effective treatment of emergent conditions and lead to improved patient outcomes. In addition, the cost savings realized through economies of scale of such a network would allow more research to be performed at a lower cost. The network would have at least 3 clinical trials selected at the time of network activation which could be either phase II or phase III clinical trials. To maintain the network and take advantage of economies of scale, new projects would be continuously developed. The conference participants identified multiple potential clinical trials which could be performed by the network and answer important clinical questions. By facilitating high priority, inter-disciplinary, multi-institutional research into the diagnosis and treatment of neurological emergencies such a network will ultimately lead to new therapies for our patients. We are grateful to the many outstanding and knowledgeable individuals from a variety of professions and medical specialties that contributed to this conference.
Executive Summary
Neurological emergencies constitute a number of serious conditions leading to significant morbidity and mortality yearly in the U.S. Many of these conditions are relatively uncommon, and there is a paucity of evidence from randomized trials to support clinical decisions, particularly in the emergency setting. Neurologists and neurosurgeons are not present during the emergency presentations of many of these disorders, and traditional neurological research has seldom addressed these conditions in the prehospital or emergency department settings.
One significant barrier to performing the necessary studies of many neurological emergencies is the low frequency of presentation to any given institution. Therefore, single institutions or small groups of institutions lack patients for adequately powered studies. A second significant barrier is the tremendous time and resources required to establish networks for multi-center trials. Prior studies of acute neurologic conditions (e.g. the NINDS study of t-PA in stroke) required the development of unique multicenter groups which disband after the study. New studies then require new investigators to construct new networks.
One solution to both of these problems is to create a large, scaleable network of institutions capable of performing research on multiple different acute neurologic emergencies. Thus, multiple relatively uncommon processes which present as acute neurological emergencies could be studied simultaneously, achieving substantial economies of scale, and allowing for adequate sample sizes. The heavy startup costs for the network would only be incurred once and support for each of the individual studies would correspondingly be decreased.
It is the intent of this manuscript to propose the concept of a large, scalable network capable of performing clinical research on acute neurological emergencies. In order to do so, a group of clinical investigators came together to evaluate this concept and generate a potential model of such a network. The following is an outline for the process of evaluation and potential design for such a network.
1. Define the mission
2. Define the scope
3. Design the governance and access
4. Design the structure
5. Describe the type of studies to be performed by this network
6. Evaluate the financial implications of such a network
7. Evaluate the potential data sharing structure of the network
8. Define the necessary human subject protection for all potential patients
Mission
The mission of the Emergency Neurology Clinical Trials Network (ENCTN) is to optimize care and improve outcomes for patients who seek care in Emergency Departments for acute neurological disorders.
The ENCTN will achieve its mission by facilitating high priority, inter-disciplinary, multi-institutional research into the diagnosis and treatment of neurological emergencies.
Scope
The ENCTN will encompass a broad range of high morbidity and mortality conditions for which treatment outcomes are poor or little rigorous evidence guides treatment decisions. This network will be built upon a "Hub and Spoke" model. This will be a Scaleable Network of multiple Hubs each responsible for multiple spokes.
ScopeGovernance And Access
The ENCTN should act in a manner similar to a public utility. It must have clearly defined governance and access. It must be designed to foster a broad range of investigations and to insure that the investigations meet the highest scientific standards. Participation in the research by both academic and private practitioners in multiple disciplines will foster acceptance of results to redefine the standard of care. The ENCTN should be open to investigator initiated proposals as well as those from industry.
ScopeEssential Elements In The Governance Of A Clinical Trial Network
Most successful clinical trials networks include a Clinical Coordinating Center and a Data Coordinating Center. An Executive or Steering Committee governs a series of Subcommittees with charges ranging from protocol review to publications.
The ENCTN Steering committee, built on this successful "Board of Directors Model," would have a chairperson, likely the Director of the Clinical Coordinating Center, and other critical members, including a predetermined number of principal investigators from the Hubs who rotate on and off the steering committee at preset intervals. Also included are the Director of the Data Coordinating Center, one or more members from NINDS, and the Chairs of each Subcommittee.
The ENCTN will require a manual of operations to guide the Steering and Subcommittees. The organization will require a geographic home. This could house the Clinical Coordinating Center or the Data Coordinating Center or both, although these may be at separate locations.
Access and Relationship to Funding (NIH and Industry)
Studies to be performed within this network can enter the network via at least two routes.
One route is for investigator-initiated studies, which would be reviewed by an Ad Hoc Review group or Study Section. This review group/study section would include members from the Executive Committee of the network. This would insure peer review from experts in the specific disease state as well as input from administrators with knowledge of the network structure and capabilities.
Studies to be funded by non-governmental entities such as industry can be proposed directly to the Executive Committee. The inclusion of NINDS staff on the Executive Committee insures the infrastructure being funded by NIH/NINDS provides the appropriate scientific return on the investment.
Who Are The People And Institutions In The Network?
Given the breadth of projects that the ENCTN could potentially conduct, a model for the ENCTN network must provide great flexibility, scalability, and institutional breadth. An essential ingredient will be Emergency Medicine and Neurology/Neurosurgery collaboration in the participating institutions. In many institutions this will represent a significant paradigm shift since there has not been a long history of close ties between these specialties. Fostering the development of collaboration between emergency and neurological specialists will be an essential task for the Clinical Coordinating Center.
To enable a scalable network, a hub and spoke model is being proposed. The hubs will be the backbone of the network and all clinical projects will be conducted at the hub centers. For studies requiring larger sample sizes, the network can be "scaled up" by the addition of spokes. Regional hubs will provide research and clinical infrastructure for the spokes, i.e. nearby collaborating hospitals with investigators but perhaps without full time research staff or advanced care capabilities. A hub is not synonymous with the coordinating center. The network will be comprised of dozens of hubs each supporting on average two to five regional spoke institutions. Hubs will likely be regional academic medical centers, the local tertiary care facilities in the region.
Spokes will vary in institutional format and will include academic centers, community hospitals with academic affiliation and community hospitals. Incorporating spokes which are not based at tertiary care centers will increase enrollment and expand patient access to studies while allowing evaluation of the study intervention in a real-world practice setting, providing an estimate of the intervention's clinical effectiveness. Depending upon the complexity of the study, spokes may either enroll and study patients locally, utilizing the hub only for general guidance, or may identify and enroll patients at the spoke prior to transfer to the hub for specialty care. Unlike many hub and spoke models, the ENCTN should also include local practice-based neurologists. These specialists would provide a referral base for potential patients and would serve as co-investigators supporting longitudinal outcome evaluations.
Participants in each spoke will vary by study. The core members at each institution will be emergency physicians with neurological collaboration. Given the existing specialty physician shortages, not all centers will have in-house access to neurologists or neurosurgeons. In these settings, access to the hub's neurologic expertise may be sufficient. In more complex therapeutic studies, lack of neurologist or neurosurgeon specialists will mandate transfer to hub institutions for continuance of the study.
Each hub and spoke will require various support staff commensurate with the studies being conducted at each institution. To some degree a research nurse or research coordinator should be identified and funded to support the ENCTN efforts at each institution. The level of training and commitment will vary by institution.
What Are The Topics For Research And How Will They Be Determined?
The Emergency Neurology Clinical Trials Network (ENCTN) should augment the efficiency and productivity of the Nation's clinical research enterprise. It should provide the capability to conduct, more rapidly and efficiently, multiple high-quality clinical studies and trials in emergency neurology. The full report contains sections addressing critical issues related to 1) the Research Agenda of the ENCTN; 2) the possible mechanisms for targeting and prioritizing specific neurologic conditions for the ENCTN; 3) possible mechanisms for submitting, soliciting, and reviewing proposals for this network, and 4) initial research questions that the ENCTN would be ideally and uniquely positioned to perform.
Research Agenda of the ENCTN
In general terms, the mission of the ENCTN is to optimize care and improve outcomes of patients who seek care in Emergency Departments for acute events affecting the nervous system. The ultimate measure of success for clinical trials is the reduction of mortality and disability in persons who present to the Emergency Department after suffering acute neurologic events.
In specific terms, the research agenda of the ENCTN will involve two categories of diagnoses. The first category comprises high prevalence neurologic diagnoses like ischemic stroke. Despite the high prevalence of these neurologic diagnoses, many diagnostic and therapeutic questions are unanswered. Treatment protocols vary widely among Emergency Departments, and little evidence supports current diagnostic and therapeutic practices. Clinical trials demonstrating even modest treatment effects for these high prevalence diagnoses would result in large absolute benefit in reduction of human suffering and economic losses. Accurately estimating critical, though small, treatment effects requires large absolute numbers of study participants. The ENCTN would have the large number of centers required to perform this research. The involvement of a large number of centers should also greatly enhance dissemination of research findings into the community, accelerating the pace at which new, effective treatments improve outcomes nationally.
The second category is low prevalence but high morbidity and mortality neurologic diagnoses. These diagnoses are not seen at single centers in sufficient numbers to allow adequately powered clinical trials. Yet, from a standpoint of human suffering and societal burden, they merit careful clinical trials. Much clinical research to date on these problems has been piecemeal and inconclusive. For these lower prevalence diagnoses, even multi-center trials can fall short of necessary sample sizes. Thus the ENCTN would be ideally suited to involve the large number of hospitals, both university and community based, required to enroll sufficient numbers of patients.
Examples of high and low prevalence neurologic diagnoses are found in table 1.
|
High prevalence neurologic diagnoses |
Low prevalence, high morbidity/mortality neurologic diagnoses |
|
Stroke Intracerebral hemorrhage Subarachnoid hemorrhage Traumatic Brain Injury Seizure/ Status epilepticus |
Global Brain Ischemia Venous Sinus Thrombosis Spinal Cord Injury Meningitis/encephalitis |
Criteria for targeting and prioritizing specific neurologic conditions for ENCTN study
Proposals for clinical trials through the ENCTN should be evaluated for significance to human health and scientific merit. With regard to significance to human health, we propose these factors be considered in prioritizing clinical studies and trials:
1. Prevalence of the condition.
2. Mortality.
3. Morbidity, including lost Quality Adjusted Life Years (QALYs).
4. Economic impact.
5. Relevance to the NIH Roadmap goals and appropriateness for ENCTN.
Other Research Considerations
While the main thrust of the ENCTN will be interventional studies, there will be an excellent opportunity to incorporate observational studies into the larger context of these interventional trials. The ability of the Network to collect observational data will be of critical importance in evaluating new areas for interventional studies and providing data regarding numbers of patients and outcomes with conventional therapy prior to designing interventional studies.
The ENCTN will be best utilized if there are multiple simultaneous studies in different disease areas. The simultaneous conduct of multiple studies will enable greater economies of scale and the projects can be phased in such a way that there is no "idling time" present in the network.
Is The Research More Cost Effective If Done By The Networks?
The cost analysis in the full report is organized into three subsections. In the first subsection, a simplified theoretical framework for identifying and calculating the major components of cost is described. In the second subsection, we consider the factors that may make a network a more efficient strategy for setting up new multicenter clinical trials. In the final section, we use this framework to create an approximate estimate of the relative steady state costs of the ENCTN.
The task force determined that beyond the potential value of developing the ENCTN in promoting the social welfare, we estimate that developing such a network would make economic sense. Specifically, for a fixed portfolio of three large clinical trials, we estimate that for an initial investment of approximately $1.5 million, a network would result in a net savings of nearly $8 million. This savings would result primarily from efficiencies in the operation of trials, since modest decreases in per subject costs is multiplied over a large number of subjects. In order to more precisely predict the cost impact of research performed in the ENCTN, it would be essential to specify the projects in some detail. Despite the highly speculative nature of the current estimates, they do suggest that the ENCTN could be economically feasible.
How Can Data Management Be Handled Most Efficiently?
In order to facilitate multi-center clinical trials in emergency neurological conditions, it is critical that data be collected in an efficient, cost effective, and readily accessible manner that facilitates merging data from a variety of sources and takes into consideration current HIPAA compliance issues. The full report of this task force addresses critical issues related to 1) the type of data entry forms; 2) enrolling and tracking patients; 3) merging data from a variety of sources; 4) centralized data safety monitoring; 5) protocol compliance; 6) the need to generate regular (e.g. monthly) data reports; 7) compliance with current HIPAA regulations. Based on current advances in web-based technologies, electronic data forms and availability and access to the internet, it is apparent that the management of the ENCTN would be greatly facilitated by an efficient web-based data management system.
To maximize the efficiency of the ENCTN and the quality of collected data, a centralized electronic data collection strategy is required. The use of web-based approaches has several advantages over non-web-based systems. Capability to incorporate complex data from a variety of sources will need to be built in. This approach could facilitate the activities of a Data Safety Monitoring Board. HIPAA compliance issues are important to consider when designing the centralized data collection strategy. Several examples of successful application of web-based strategies to run clinical trials have been reported in the literature and attest to the utility and practicality of this approach.
What Are The Human Subjects Research Issues?
While there are many ethical aspects to research, the Emergency Neurology Clinical Trials Network as a whole will most likely be concerned with those related to the rights of human subjects in research, especially those made vulnerable by a devastating disease or injury. These include, but are not limited to, the issues of meaningful consent for research participation, privacy of medical records, and the adequate recruitment of minority patients into clinical trials. There are also unique aspects of clinical trials research and out of hospital research that pose special challenges for emergency neurology researchers.
Issues associated with informed consent and privacy will be common for all centers participating in the network. The goals of the Emergency Neurology Clinical Trials Network will be to inform and educate patients and to protect patient privacy. Site investigators will need to be aware of local and state regulations. The ENCTN will work with local sites to enhance patient protections as well has patient recruitment and enrollment. An expert panel, developed from within and outside of the ENCTN, will advise investigators on ethical, privacy and access issues.
SUMMARY
The NINDS conference brought together a diverse group of clinician/scientists to evaluate the advisability and feasibility of establishing a network to conduct clinical trials in emergent neurologic conditions. The attendees developed a structural framework for the network and identified potential clinical trials to be performed in the network. The network would be built on a hub and spoke model and would incorporate academic as well as community hospitals, leading to better generalizability of the research findings to the community at large. The conduct of multiple simultaneous clinical trials in the network should lead to economies of scale and reduced costs in performing clinical research. Establishment of a clinical research network has the potential to significantly impact the morbidity and mortality from acute neurological disorders and lead to improved outcomes and cost savings in the future.
TASK FORCE REPORT
How Does One Go About Doing Emergency Neurological Research?
Arthur Pancioli, M.D.
Associate Professor and Vice Chairman
University of Cincinnati
Department of Emergency Medicine
Cincinnati
Claudia Robertson, M.D.
Professor
Baylor College of Medicine
Department of Neurology
Houston
Ian Stiell, M.D., MSC, FRCPC
Professor
Ottawa Health Research Institute
Department of Emergency Medicine
Ottowa
Gretchen Tietjen, M.D.
Professor and Chair
Medical College of Ohio
Department of Neurology
Toledo
Neurological emergencies constitute a number of serious conditions leading to significant morbidity and mortality yearly in the U.S. Many of these conditions are relatively uncommon and there is a paucity of evidence from randomized trials to support clinical decisions, particularly in the emergency setting. Neurologists and neurosurgeons are not present during the emergency presentations of many of these disorders, and traditional neurological research has seldom addressed these conditions in the prehospital or emergency department settings.
One significant barrier to performing the necessary studies of many neurological emergencies is the low frequency of presentation to any given institution. Therefore, single institutions or small groups of institutions lack patients for adequately powered studies. A second significant barrier is the tremendous time and resources required to establish networks for multi-center trials. Prior studies of acute neurologic conditions (e.g. the NINDS study of t-PA in stroke) required the development of a unique multicenter groups which disband after the study. New studies then require new investigators to construct new networks.
One solution to both of these problems is to create a large, scaleable network of institutions capable of performing research on multiple different acute neurologic emergencies. Thus, multiple relatively uncommon processes which present as acute neurological emergencies could be studied simultaneously, achieving substantial economies of scale, and allowing for adequate sample sizes. The heavy startup costs for the network would only be incurred once and support for each of the individual studies would correspondingly be decreased.
It is the intent of this manuscript to propose the concept of a large, scaleable network capable of performing clinical research on acute neurological emergencies. In order to do so, a group of clinical investigators have come together (see list of participants) to evaluate this concept and generate a potential model of such a network. The following is an outline for the process of evaluation and potential design for such a network.
1. Define the mission
2. Define the scope
3. Design the governance and access
4. Design the structure
5. Describe the type of studies to be performed by this network
6. Evaluate the financial implications of such a network
7. Evaluate the potential data sharing structure of the network
8. Define the necessary human subject protection for all potential patients
Mission
The mission of the Emergency Neurology Clinical Trials Network (ENCTN) is to optimize care and improve outcomes of patients who seek care in Emergency Departments for acute events affecting the nervous system.
The ENCTN will achieve its mission by facilitating high priority, inter-disciplinary, multi-institutional research into the diagnosis and treatment of neurological emergencies
Scope
The ENCTN will encompass a broad range of high morbidity and mortality conditions for which treatment outcomes are poor or little rigorous evidence guides treatment decisions. This network will be built upon a "Hub and Spoke" model. This will be a Scaleable Network of multiple Hubs each responsible for multiple spokes.
Governance And Access
The ENCTN should act in a manner similar to a public utility. It must have both governance and access that are clearly defined. It must be designed to foster a broad range of investigations and to insure that the investigations meet the highest scientific standards. Participation in the research by both academic and private practitioners in multiple disciplines will foster acceptance of results to redefine the standard of care.
In order to facilitate discussion of the potential governing structure of the ENCTN, our group has reviewed and summarized the organizational structure of a series of representative successful clinical trial networks, as well as the organization of one intervention-specific large-scale multicenter trial.
Examples
The Pediatric Emergency Care Applied Research Network (PECARN)
The goal of this network is to conduct high priority multi-institutional research into the prevention and management of acute illnesses and injuries in children and youth of all ages. The PECARN network structure features four regional multi-institutional "Nodes" and a coordinating data center. Each "Node" has 25 affiliated Hospital Emergency Department Affiliates (HEDAs). Each Node works with the funding agencies (MCHB/HRSA) to initiate, implement, and administer network research. The PCARN network is governed by a Steering Committee that formulates and monitors policies and procedures guiding all research activities, and reviews and approves research proposals. All major scientific and operational decisions are made by majority vote. Five subcommittees carry out specific tasks identified by the Steering Committee.
The Asthma Clinical Research Network (ACRN)
This network was established in 1993 by the Division of Lung Diseases (DLD) and the National Heart, Lung and Blood Institute (NHLBI). The objectives of this multi-center program are to conduct multiple well designed clinical trials for rapid evaluation of new and existing therapeutic approaches to asthma and to disseminate laboratory and clinical findings to the health care community.
Administratively, the main governing body of the ACRN is its Steering Committee. The Steering Committee consists of the Principal Investigator from each Clinical Center (there are now 10 Centers), the Principal Investigator from the Data Coordinating Center (DCC), a Chairman who is not an Investigator, and a Project Scientist from the NHLBI.
Access to the network follows a standard protocol. Prior to implementation, an ACRN protocol must be approved by its' Protocol Review Committee (PRC). The PRC consists of clinical scientists, basic scientists, and biostatisticians who are not associated with any other ACRN activity. After a protocol has been approved, patients are recruited, enrolled, and monitored at the Clinical Centers. The Data Coordinating Center provides overall scientific, data management, and administrative coordination during the progress of the trial.
The Parkinson's Study Group (PSG)
The PSG has carried out cooperative therapeutic research since 1986, beginning with the NIH-sponsored DATATOP (Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism) clinical trial. This group has carried out more than 34 multi-center trials examining the symptomatic and neuroprotective effects of experimental interventions in Parkinson's disease. The PSG has partnered with numerous pharmaceutical companies and The National Institutes of Health (NIH) in bringing five new drugs for Parkinson's disease to the market. The PSG now includes more than 350 active investigators, coordinators and scientists from approximately 85 PSG sites located throughout the United States and Canada.
The PSG is governed by a constitution and bylaws and an elected executive committee that is primarily responsible for the direction and oversight of its' research projects and activities. The PSG has a Clinical Trials Coordination Center (CTCC) that is responsible for the overall coordination of the research activities, including data management for PSG clinical trials. About 70 staff members, including postdoctoral fellows in experimental therapeutics, are involved in the implementation of study protocols, site communications, and data management. The Biostatistics Center of the PSG is comprised of three principal biostatisticians, an 11-member faculty, and three postdoctoral fellows. A group of 12 programmers and research associates are responsible for the analysis of all PSG databases.
Emergency Medicine Cardiac Research and Education Group (EMCREG)
The Emergency Medicine Cardiac Research and Education Group (EMCREG™) was founded in 1989 to conduct multi-center clinical research trials on serum markers for the early diagnosis of acute myocardial infarction (AMI). The EMCREG mission has promoted the collaboration between emergency medicine and other specialties in the arenas of both academic research and clinical practice. Structurally, EMCREG is a collective group of emergency physicians with expertise in cardiovascular and neurovascular emergencies that design and implement multicenter trials as well as coordinate seminars on advances in cardiovascular and neurovascular emergencies. Thus it is an inter-disciplinary group which seeks to advance care at the intersection of multiple disciplines including emergency medicine, cardiology, and neurology.
The group has a president as well as executive committee and a series of subcommittees. Access to the research infrastructure comes from member sponsorship and is primarily industry supported. The group currently performs multiple diagnostic studies, runs the largest chest pain registry in existence, and has a strong educational and CME reputation.
American Brain Injury Consortium (ABIC)
The ABIC was established in April 1993 as a non-profit, academic, research based organization with the primary mission of designing, implementing and evaluating the results of clinical trials directed toward improving outcome of brain injury patients.
The concept was to have a group of experienced clinical traumatic brain injury (TBI) centers who are willing and capable of contributing patients to a drug trial continuously available and a central data coordinating center. The individual centers would have a trained nurse coordinator who has experience in collecting the core data set. The centers would also have an interested primary investigator, a large TBI population, and clinicians who are willing to follow the head injury management guidelines. The central data coordinating center would have available accurate information on patient characteristics and patient volume of each individual center, which could be used to design an optimal clinical trial. This organization of continuously available clinical centers was intended to facilitate the conduct of drug trials funded by pharmaceutical companies or by NIH through a partnership. ABIC would provide the expertise for designing and conducting clinical trials in TBI patients, and the pharmaceutical companies would provide the drugs for testing and the financial support.
The group has two co-directors, the ABIC chairman who leads the clinical centers, and the technical director who runs the central data coordinating center located at Medical College of Virginia. The group has an executive committee, consisting of 13 senior investigators from the clinical centers. The group has additional working sub-committees.
Organizational Structure of the NIH Renal Artery Stent Trial (CORAL)
The Renal Artery Stent Trial (CORAL) is a multi-center (65 sites to start, expansion to 85 sites) NIH-sponsored trial (NHLBI) comparing medical therapy to interventional + medical therapy. The trialists include nephrologists, cardiologists, interventional radiologists, and hypertension specialists. It was submitted as a "cluster" application rather than the traditional single R01 (with one PI) with multiple subcontracts. A cluster application is composed of a cluster of interdependent R01s, each with a separate key function, funding and PI. Advantages of the cluster over the R01 include: 1) each R01 has its own direct and indirect costs, 2) Each PI has a 25 page limit, rather than 25 page limit for the entire grant, 3) This arrangement fosters innovation. Disadvantages are that the grant score is that of the weakest link and the coordination is complex and challenging.
The Study has a Chair and Co-Chair who report to the Project Officer and Deputy Project Officer at the NHLBI. The Executive Committee is composed of the Study Chairmen, the PIs of the separate RO1s, the Core lab PIs, and key members (2 interventionalists and 2 clinical trialists). This committee has the responsibility for running the study, the monthly conference-call, and yearly meeting. Committees reporting to them include:
1) The Study Committees: Interventional Committee, Hypertension/Renal Failure Committee, Statistics Committee, Site Selection Committee.
2) The Operations Committee, which is responsible for the day-to-day operations, the
members of whom are also on the Executive Committee, has a conference call on a weekly
basis. The committees which report to it include: Clinical Coordinating Center (coordinates
the investigative sites and deals with the drug and device sponsors) and the Data
Coordinating Center (to whom the investigative sites report).
Essential Elements In The Governance Of A Clinical Trial Network
These successful clinical trials networks include a Clinical Coordinating Center and a Data Coordinating Center. An Executive or Steering Committee governs a series of Subcommittees with charges ranging from protocol review to publications.
The ENCTN Steering committee, built on this successful "Board of Directors Model," would have a chairperson, likely the Director of the Clinical Coordinating Center, and other critical members, including a predetermined number of principal investigators from the Hubs who rotate on and off the steering committee at preset intervals. Also included are the Director of the Data Coordinating Center, one or more members from NINDS, and the Chairs of each Subcommittee.
Sub-Committees include:
Protocol Subcommittee
Publications Subcommittee
Data Management and Analysis Subcommittee
Safety and Regulatory Subcommittee
Quality Assurance Subcommittee
Budget, Finance and Funding Subcommittee
Human Subjects/ Ethics Subcommittee
The ENCTN will require a constitution and bylaws to drive the organization and to guide the Steering and Subcommittees. The organization will require a geographic home. This could house the Clinical Coordinating Center or the Data Coordinating Center or both although these may be at separate locations.
Access and Relationship to Funding (NIH and Industry)
Studies to be performed within this network can enter the network via at least two routes.
One route is for investigator-initiated studies, which would be reviewed by an Ad Hoc Review group or Study Section. This review group/study section would include members from the Executive Committee of the network. This would insure peer review from experts in the specific disease state as well as input from the administrators with knowledge of the network structure and capabilities.
Studies to be funded by non-governmental entities such as industry can be proposed directly to the Executive Committee. The inclusion of NINDS staff on the Executive Committee insures the infrastructure being funded by NIH/NINDS provides the appropriate scientific return on the investment.
Note that there is a considerable span of access among current research networks. Some networks run trials exclusively designed by members of the network, others facilitate studies brought to the network from investigators outside of the network or from industry.
TASK FORCE REPORT
Who Are The People And Institutions In The Network?
Edward Jauch, M.D.
Assistant Professor
University of Cincinnati
Department of Emergency Medicine
Cincinnati
Dan Lowenstein, M.D.
Professor of Neurology
University of California - San Francisco
Department of Neurology
San Francisco
Stephan Mayer, M.D.
Associate Professor
Columbia University
Department of Neurology
New York
John Duldner, M.D., M.S.
Research Director and Assistant Professor
Akron General Medical Center
Department of Emergency Medicine
Akron
Introduction
Given the breadth of projects that the ENCTN could potentially conduct, a model for the ENCTN network must provide great flexibility, scalability, and institutional breadth. Key to these features is to encourage Emergency Medicine and Neurology/Neurosurgery collaboration in the participating institutions. In many institutions this will represent a significant paradigm shift. In order for this to occur, visionary physician leaders in these specialties must lead and move the process forward within their institutions. Additional leadership can come from the regional "hubs" where such collaboration already exists.
The breadth of potential studies will likely require a hub and spoke model for the ENCTN. Regional hubs will provide research and clinical infrastructure for the spokes, i.e. nearby collaborating hospitals with investigators but perhaps without full time research staff or advanced care capabilities. The network will be comprised of dozens of hubs each supporting from two to perhaps twenty regional spoke institutions. Hubs will likely be regional academic medical centers, the local tertiary care facilities in the region.
Spokes will vary in institutional format and will include academic centers, community hospitals with academic affiliation, community hospitals, and to some degree practice-based settings (neurology clinics). Incorporating spokes which are not based at tertiary care centers will not only increase enrollment and expand patient access to studies but will allow evaluation of the study intervention in a real-world practice setting, providing an estimate of the intervention's clinical effectiveness. Depending upon the complexity of the study, spokes may either enroll and study patients locally, utilizing the hub only for general guidance, or may identify and enroll patients at the spoke prior to transfer to the hub for specialty care. Unlike many hub and spoke models, the ENCTN should also include local practice-based neurologists. These specialists would provide a referral base for potential patients and serve as co-investigators for low-risk intervention studies and for longitudinal outcome evaluations.
Figure 1. Potential Network Components
Participants in each center will vary by study. The core members at each institution will be emergency physicians. At most centers, neurologists and neurosurgeons will participate equally. Given the existing specialty physician shortages, not all centers will have in-house access to neurologists or neurosurgeons. In these settings access to the hub's neurologic expertise may be sufficient. In more complex therapeutic studies, lack of neurologist or neurosurgeon specialists will mandate transfer to hub institutions for continuance of the study.
Each hub and spoke will require various support staff commensurate with the studies being conducted at each institution. To some degree a research nurse or research coordinator should be identified and funded to support the ENCTN efforts at each institution. The level of training and commitment will vary by institution.
Additional resources at hub and spoke institutions will include:
Table 2 Network resources
|
Hub Components |
Spoke Components |
|
Physicians Emergency Medicine Neurology Neurosurgery Neurointensivists / Intensivists Neuroradiology Support Clinical nurse coordinator Site (spoke) monitors Central pharmacy IRB / Centralized IRB for spokes Blood / biologic sample repository |
Physicians Emergency Medicine Neurology (hospital and practice based) Neurosurgery
Support Clinical nurse coordinator IRB Pharmacy |
Examples of Hub / Spoke networks by study type
1) Management of Hypertension in Subarachnoid Hemorrhage
Background
At present, evidence-based management of blood pressure in the hyperacute setting of subarachnoid hemorrhage does not exist. A prospective, randomized trial is needed to guide care provided by emergency professionals. The proposed trial would be randomized treatment of patients with SAH in the Emergency Department with nicardipine to achieve target blood pressure reduction. Treatment would begin within 4 hours of ictus.
Process
Treatment of subarachnoid hemorrhage requires a comprehensive care continuum. The primary centers (hubs) that will provide definitive management are those centers that have the resources to provide a comprehensive approach.
The network is activated based on the type of hospital to which the patient presents as the first medical contact. If a patient presents to a community hospital emergency department (spoke), then transfer to a tertiary center (hub) is mandated. In the event that a patient presents as the first medical contact to a "hub", no additional measures are necessary.
The key to the network (for this and for similar trials) lies in the level or degree of involvement of the community hospital. Two options for the spoke hospitals exist, they are (1) to rapidly evaluate, screen and transfer patients .jpg who satisfy inclusion & exclusion criteria, or (2) to evaluate, screen, enroll, initiate therapy and then transfer patients. In either scenario, this would require prearranged cooperation between hub and spoke hospitals. The role a particular spoke hospital will define for itself will be dictated by willingness and resources present at the spoke hospitals. It is conceivable that depending on the nature of the intervention, the spoke hospital may be able to enroll and initiate treatment prior to transfer to the hub. In trials where a time-to-intervention element is critical any efforts by the spoke hospitals would optimize enrollment. Key personnel resources for this type of study will include Emergency Medicine, Neurology / Neurocritical Care, Interventional Neuroradiology, Neurosurgery, and Critical Care Transport Services (aeromedical or ground).
Issues
A potential limitation in the hub and spoke model is the link between these two elements. The primary means of transport between these elements in subarachnoid hemorrhage is rotorcraft. Dedicated services providing inter-hospital transport between the hub and spoke will also need to agree to provide the link under the auspices of the protocol.
Summary
Applying the model of acute management of hypertension in SAH to the hub and spoke model is feasible. Presentation to a hub would be the most direct route of entry into a trial. Because of the temporal requirements in the time to treatment (4 hours), presentation to a spoke would afford either mechanism (screen and transfer, or screen, enroll and transfer). Moreover, the protocol care continuum could be employed in the transport link.
2) New Protocols for the Treatment of Status Epilepticus in the Emergency Department
Background
Generalized, convulsive status epilepticus (defined, for practical purposes, as seizures lasting more than 5 minutes) remains a common and important neurological emergency seen in the emergency department setting. New approaches for the treatment of status epilepticus have been advocated in recent years, including greater reliance on longer-acting benzodiazepines such as lorazepam, rapid sequencing of therapy to propofol, midazolam or pentobarbital if seizures do not respond to front-line agents, and the use of new intravenous agents such as valproate. Nonetheless, there have been no large-scale clinical trials looking at the relative risks and benefits of these various, newer strategies. The ENCTN would be an obvious system for carrying out such studies.
Process
Patients will arrive at tertiary care facility. Transfer may not be eligible depending upon allowed medication use prior to enrollment. What exactly does this mean? Early notification of research team, primarily neurology investigators, will facilitate early EEG. This will likely be required for enrollment and monitoring. The study will transition to the ICU possibly involving the intensivist (neuro-intensivist). This study will also be fairly labor intensive.
Resources
The logistical issues would be relatively complex compared to the studies described above. Personnel necessary for such a study would include Emergency Medicine, Neurology, Intensive Care, Clinical Nurse, EEG technician, and pharmacy. First, given that the response to therapy and outcome of status epilepticus are closely linked to etiology, careful diagnostic assessment would be required at all enrollment sites. Second, the study would almost certainly require real-time EEG monitoring, so all emergency departments would need to be equipped with EEG machines, technicians and personnel qualified to interpret the EEG as a guide to treatment (all of which, of course, would need to be available 24 hours a day). It is likely that a neurologist would need to be closely involved with all patient enrollments, both at the time of emergency room management and for subsequent follow-up in-hospital and after discharge. Also, given how difficult it is to follow the clinical course of these patients (in terms of adherence to protocols, response to treatment, hospital course, etc.); an on-site study coordinator would probably be required at each of the participating centers.
3) Emergency Department Evaluation of New Diagnostic Biomarkers for Stroke
Background
Similar to the use of biomarkers for myocardial injury in acute coronary syndromes, biomarkers of brain jury, especially in the setting of acute stroke, are coming closer to fruition. The Emergency Department has vast experience utilizing biomarkers. Additionally, there has been a recent a growth of markers for various conditions, including B-type naturetic protein for congestive heart failure and more accurate d-dimer tests for venous thromboembolism. An important feature of these new tests is the point-of-care (POC) setting. These ELISA based test platforms allows for the test results to be available to the treating physician within 15 minutes. Several companies are in final stages of refining and producing POC stroke marker tests. They will logically be evaluated by Emergency Department staff but Neurology awareness and involvement in the evaluation of these news diagnostics will be critical to building a consensus on if and how these tests will be used in routine practice.
Ideally the setting for evaluating this technology would be in a hospital with a commitment to acute stroke treatment. This will facilitate not only the evaluation of the test performance but also its impact on stroke care (time to CT, time to MD, time to treatment, etc.). Of the several possible studies this hypothetical study will focus on acute stroke (within 4-6 hours of symptom onset), evaluating the markers as a diagnostic aid. The mechanics of the study will likely require serial blood draws to evaluate the acute temporal change in markers in the first 24 hours.
Process
Following the elements of the Stroke Chain of Recovery, prehospital care personnel would notify the receiving hospital of a potential stroke patient arrival. This would facilitate both emergent evaluation of the patients and timely CT but would also mobilize the research infrastructure to evaluate the patient for study enrollment. Due to potential cognitive or language impairment in study subjects, informed consent would frequently be obtained from next of kin. The blood samples would be collected and processed locally on the manufacturer's platform. The study may require additional samples to be shipped to the sponsor or to a core lab for validation. A research nurse or assistant could perform sample collection and case-report-form completion.
Resources
The study would have a local emergency medicine principal investigator and ideally, but not necessary, a neurology co-investigator. The study would likely require research nurse or assistant (10-20% FTE); ideally in center with an existing research infrastructure that could be utilized. No additional personnel would be required and clinical data would be obtained from standard of care evaluation of stroke patients. Data processing and analyses would be performed by the core facilities. No outpatient followup would be required.
Issues
Industry sponsorship an issue related to data management and analysis and would be an issue for the network governance. Given the relative simplicity of such a study it is suitable for a broad spectrum of Emergency Department settings. Given ongoing biomarker research into other diseases there is potential for follow-up trials utilizing same technology (traumatic brain injury, subarachnoid hemorrhage, etc.).
What Are The Topics For Research And How Will They Be Determined?
William Barsan, M.D.
Professor and Chair
University of Michigan
Department of Emergency Medicine
Ann Arbor
Guy Clifton, M.D.
Professor and Chairman
The University of Texas Medical School at Houston
Department of Neuosurgery
Houston
Judd Hollander, M.D.
Professor of Emergency Medicine
University of Pennsylvania
Department of Emergency Medicine
Philadelphia
Donald Gilbert M.D., M.S.
Associate Professor
Children's Hospital of Cincinnati
Division of Neurology
Cincinnati
Purpose
The primary goal of this meeting is to define the critical issues related to clinical trials in emergency neurology, and to determine priorities for future clinical and basic research.
Introduction
The Emergency Neurology Clinical Trials Network (ENCTN) should augment the efficiency and productivity of the Nation's clinical research enterprise. It should provide the capability to conduct, more rapidly and efficiently, multiple high-quality clinical studies and trials in emergency neurology. This section will address critical issues related to 1) the Research Agenda of the ENCTN; 2) the possible mechanisms for targeting and prioritizing specific neurologic conditions for the ENCTN; 3) possible mechanisms for submitting, soliciting, and reviewing proposals for this network, and 4) initial research questions that the ENCTN would be ideally and uniquely positioned to perform.
Research Agenda of the ENCTN
In general terms, the mission of the ENCTN is to optimize care and improve outcomes of patients who seek care in Emergency Departments for acute events affecting the nervous system. The ultimate measure of success for clinical trials is the reduction of mortality and disability in persons who present to the Emergency Department after suffering acute neurologic events.
In specific terms, the research agenda of the ENCTN will involve two categories of diagnoses. The first category is high prevalence neurologic diagnoses like ischemic stroke. Despite the high prevalence of these neurologic diagnoses, many diagnostic and therapeutic questions are unanswered. Treatment protocols vary widely among Emergency Departments, and little evidence supports many current diagnostic and therapeutic practices. These high prevalence neurologic diagnoses are associated with irreversible damage to the central nervous system, and thus, the extent to which practice variations result in worse outcomes has devastating results for patients, families, and the healthcare system. Clinical trials demonstrating even modest treatment effects for these high prevalence diagnoses would result in large absolute benefit in reduction of human suffering and economic losses. Accurately estimating critical, though small, treatment effects requires large absolute numbers of study participants. The ENCTN would have the large number of centers required to perform this research. The involvement of a large number of centers should also greatly enhance dissemination of research findings into the community, accelerating the pace at which new, effective treatments improve outcomes nationally.
The second category is low prevalence but high morbidity and mortality neurologic diagnoses. These diagnoses are not seen at single centers in high enough volume to enable efficient clinical trials. Yet, from a standpoint of human suffering and societal burden, they merit careful clinical trials. Much clinical research to date on these problems has been piecemeal and inconclusive. For these lower prevalence diagnoses, even multi-center trials can fall short of necessary sample sizes. Thus the ENCTN would be ideally suited to involve the large number of hospitals, both university and community based, required to produce sufficient numbers of patients, whereas more traditional, investigator initiated studies may lack sufficient subjects.
Examples of high and low prevalence neurologic diagnoses are found in table 1.
|
High prevalence neurologic diagnoses |
Low prevalence, high morbidity/mortality neurologic diagnoses |
|
Stroke Intracerebral hemorrhage Subarachnoid hemorrhage Traumatic Brain Injury Seizure/ Status epilepticus |
Global Brain Ischemia Venous Sinus Thrombosis Spinal Cord Injury Meningitis/encephalitis |
Criteria for targeting and prioritizing specific neurologic conditions for ENCTN study
Proposals for clinical trials through the ENCTN should be evaluated for significance to human health and scientific merit. With regard to significance to human health, we propose these factors be considered in prioritizing clinical studies and trials:
1. The prevalence of the condition, which can be estimated superficially, although not always accurately, through identifying ED ICD-9 billing codes.
2. Mortality.
3. Morbidity, including lost Quality Adjusted Life Years (QALYs) when this can be calculated. These factors will in some cases be critical for prioritizing lower prevalence neurologic conditions.
4. The economic impact of these diagnoses, when known.
5. Relevance to