VA COOPERATIVE STUDIES PROGRAM

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VA COOPERATIVE STUDIES PROGRAM

• Grant D. Huang, MPH, PhD
• VA Office of Research and Development
• Washington, DC

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OVERVIEW

• Program Overview
• Study Processes Roles
• Study Personnel Responsibilities

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VETERANS HEALTH ADMIN Office of Research
Development
Biomedical Laboratory RD
Rehabilitation RD
Clinical Science RD
Health Services RD
Cooperative Studies Program
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CSP MISSION

• To advance the health and care of Veterans
  through collaborative research studies that
  produce innovative and effective solutions to
  national healthcare problems.

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COOPERATIVE STUDY

• Facilitates accumulation of patients sufficiently
  large to provide definitive answer to a research
  question
• Characteristics include
• investigators from 2 or more sites (e.g., VAMCs)
• agreement to study a question in a uniform manner
• uses a common protocol and has central
  coordination

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VA COOPERATIVE STUDIES PROGRAM

• First Cooperative Study conducted in 1940s
  involving streptomycin for treating tuberculosis
  in WWII veterans
• Program formally established in 1972
• Over 175 clinical trials and observational
  studies completed including landmark studies in
  cardiovascular disease / cardiovascular surgery,
  infectious diseases, surgery, gastroenterology,
  mental health, oncology, and endocrinology
• National infrastructure for sponsoring,
  developing executing
• Multi-site clinical trials
• Epidemiological population research
• Genomic medicine research

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CSP STUDY FINDINGS

• Warfarin helps prevent stroke
• BP can be managed with antihypertensive drugs in
  patients with cardiovascular disease
• Aspirin helps reduce heart attacks death
• Benign prostatic hyperplasia can be relieved by
  Terazosin
• Septic shock should not be treated with steroid
  therapy (commonly used practice at the time)
• Diabetics can have ? quality of life using an
  insulin pump
• Clozapine is a cost-effective treatment for
  schizophrenia
• Shingles vaccine is effective in preventing
  shingles and reducing symptoms in patient with
  shingles
• PCI optimal medical therapy (OMT) does not
  improve coronary artery disease outcomes compared
  to OMT alone

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CSP CENTER LOCATIONS
Seattle, WA
Boston, MA
West Haven, CT
Perry Point, MD
Hines, IL
Washington, DC
Palo Alto, CA
Durham, NC
Little Rock, AR
Albuquerque, NM
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CSP ROLES

• CSP provides central coordination policies for
  conducting multi-site clinical research studies
• Biostatistical / epidemiological expertise
• Clinical expertise
• Safety and regulatory oversight
• Health economics expertise
• Pharmaceutical management
• Clinical research project fiscal management

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CSP ORGANIZATION
CSP Central Office
Located at VAMCs
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CSP CROSS FUNCTIONAL GROUPS

• Biostatistics
• Business Administration / Operations
• Informatics
• Data collection, genomics
• Organizational Quality Management
• Program Policy
• Groups serve to enhance standardization and
  interchange among research and business
  components of the national CSP Program.

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CSP STUDIES

• 30 active studies/projects
• 5 mental health/substance abuse NIDA
• 4 cancer
• 4 general and cardiac surgery
• 4 neurology
• 3 cardiovascular
• 2 renal
• Others include
• infectious disease
• diabetes
• COPD
• genetics
• spinal cord injury
• rheumatoid arthritis
• nutrition in elderly transitional care unit
  patients

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CSP 504 563 Post-Traumatic Stress Disorder
Studies

• Risperidone Treatment for Military Service
  Related Chronic Post-Traumatic Stress Disorder 
• Study chairs John Krystal, MD Robert
  Rosenheck, MD
• CSP Coordinating Center Perry Point
• To determine if risperidone will reduce symptoms
  of PTSD, relative to placebo, in veterans with
  military service related chronic PTSD who have
  been partial or non-responders to antidepressant
  medications
• 400 patients 18 sites
• Prazosin and Combat Trauma PTSD
• Study chairs Murray Raskind, MD Elaine
  Peskind, MD
• CSP Coordinating Center Palo Alto
• Goal Determine the effectiveness of prazosin vs
  placebo for PTSD trauma nightmares, sleep
  disturbance, and global clinical status.
• 326 patients 11 sites

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CSP 558 VA ROBOTICS

• Robotic Assisted Upper-Limb Neurorehabilitation
  in Stroke Patients
• Study chair Albert Lo, MD, PhD
• CSP Coordinating Center West Haven
• Goal Determine the effectiveness of robotic
  training vs usual care vs intensive comparison
  therapy for improving upper extremity function in
  stroke patients
• 4 sites 158 patients

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CSP STUDIES

• Studies conducted across 87 VAMCs
• VA sites / study 4 to 41 Avg VAMCs/study 18
• Total budgets (VA only) 2 16 Million
• Duration 3 15 years
• Does not include non-VA sites (university
  affiliate or international sites)
• Examples
• CSP 424 (COURAGE)
• 50 sites in US and Canada ? 2,546 patients
• Data coordinated at the West Haven CSPCC
• 33.5M total budget
• 8 year study
• CSP 403 (Shingles Prevention Trial)
• 22 sites (VA university/NIH) ? over 38,500
  patients
• 30M total budget
• 7 year study

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COLLABORATIONS

• National Institutes of Health
• NIDA, NINDS, NIDDK, NCI, NIAMDS, NHLBI, NIMH,
  NIDCD
• Department of Defense
• Universities
• Industry
• International
• Canadian Institutes of Health Research
• United Kingdom Medical Research Council

Mechanisms established to facilitate
collaborations
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Recent CSP Publications

• CSP 468 A randomized controlled trial of best
  medical therapy versus bilateral deep brain
  stimulation for patients with advanced
  Parkinsons Disease (JAMA Jan 2009)
• CSP 465 (VADT) - Glucose Control and Vascular
  Complications in Veterans with Type 2 Diabetes
  (NEJM Dec 2008)
• CSP 530 (ATN) - Intensity of Renal Support in
  Critically Ill Patients with Acute Kidney Injury
  (NEJM May 2008)
• CSP 453 (HOST) - Effect of homocysteine lowering
  on mortality and vascular disease in advanced
  chronic kidney disease and end-stage renal
  disease (JAMA Sept 2007)
• CSP 424 (COURAGE) Optimal medical therapy with
  or without PCI for stable coronary disease (NEJM
  March 2007)
• CSP 410 (FeAST) Reduction in iron stores and
  cardiovascular outcomes in peripheral artery
  disease (JAMA Feb 2007)
• CSP 494 Cognitive behavioral therapy for PTSD
  in women (JAMA Feb 2007)

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CSP STUDY PROCESSES ROLES
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CSP SCIENTIFIC REVIEW PROCESS
LOI submitted to CSP CO
Planning Meetings Convened (1)
Full Study Protocol Developed
Internal Admin Review
CSSEC Face-to-Face Study Review Recommendation
Approved or Disapproved for Planning Support
Funding Decision by CSRD Director
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VAMC CONSIDERATIONS

• Investigators with an idea for changing clinical
  practice should talk with CSP
• Key elements for clinical trials research need to
  be understood
• VAMC Director and ACOS-R must approve Letter of
  Intent submission

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CSP STUDY PLANNING TEAM

• Principal Proponent
• Study Biostatistician
• Clinical Research Pharmacist
• Health Economist
• Subject matter experts
• Project manager
• CSP CC Center Director

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CSP SCIENTIFIC REVIEW PROCESS
LOI submitted to CSP CO
Planning Meetings Convened (1)
Full Study Protocol Developed
Internal Admin Review
CSSEC Face-to-Face Study Review Recommendation
Approved or Disapproved for Planning Support
Funding Decision by CSRD Director
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REVIEW CONSIDERATIONS

• Clinical relevance (to veteran population)
• Methodology
• Feasibility
• Testable hypothesis
• Sample size
• Ethics
• Resources needed
• Investigator qualifications

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CSP RESEARCH PROCESS
IRB / RD FDA Human Rts Comm Data Monitoring
Comm Scientific peer review
Scientific peer review
Scientific / Ethical review
Scientific / Ethical review
IRB / RD FDA Human Rts Comm
Human Rts Comm
Study Development
Organizational Start-up
Execution Enrollment -- Follow-up
Analyses Close-out
Study Team
Executive Committee
Study Chair Biostatistician Research
Pharmacist Health Economist
Project Manager Site investigators Nurse/Site
Coordinators Programmers
ALL are key to the success of the study
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FACTORS FOR SUCCESSFUL CSP STUDIES

• Good communication
• Adherence to protocol
• Meeting enrollment targets
• Data collection quality
• Human subjects protection
• Meeting regulatory and reporting requirements
• Commitment to completing study responsibilities

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CSP STUDY MANAGEMENT POLICIES

• Federal regulations / statutes (21 CFR)
• VA / VHA policy documents
• CSP
• VHA Directive 1205 CSP policy
• VHA Handbook 1205.01 CSP study processes
  management
• Guidelines - Policies and expectations for study
  investigators / chairs
• Staff Operations Manual - Administrative handbook
  for CSP Center staff
• Standard Operating Procedures - Program rules for
  handling CSP study and program processes
• Study Operations Manual Study protocol and
  procedures for conducting a CSP study

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CSP TRAINING

• CSP requires GCP training for site investigators
  and coordinators at Kick-off meetings
• Formal commitments made on study conduct,
  reporting, records maintenance, management
  oversight of study personnel
• Proof of VA research training collected by CSP
  Coordinating Centers
• HIPAA
• Privacy
• Human Subjects Protection
• Research Data security
• VA Cyber Security
• Boston CSPCC only

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CSP CENTRAL OFFICE

• Director, CSRD is responsible for CSP studies and
  related activities
• All centers are managed by and report to CSPCO
• Provides approvals on major activities related
  to
• Funding
• Protocol changes
• Investigators / sites
• Program policies
• Other key responsibilities include
• Scientific review
• Budgetary / fiscal management reporting
• Program / center coordination
• Reporting to VA/VHA leadership
• Interactions with non-VA collaborators /
  stakeholders
• Program communications

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CSP COORDINATING CENTERS

• Provides statistical and administrative
  leadership for designing and conducting CSP
  studies
• Each study assigned a biostatistician and project
  manager
• Responsible for central management of CSP studies
• Data collection / verification
• Maintaining study records copies of some site
  records
• Managing study budgets / finances
• Monitoring site adherence to protocol
• Communicating with key parties
• Providing statistical analyses/reports

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CSP PHARMACY COORDINATING CENTER

• Coordinate the acquisition of study drugs
• Package and ship study drugs
• Liaison with the FDA
• Prepare and maintain Investigational New Drug
  Applications (IND) with the FDA
• Monitor studies for safety and regulatory
  purposes
• Visits may be unannounced
• Prepare AE and SAE reports for DMC and FDA
  reports
• May send aggregate SAE reports to IRB if needed
• Sends safety reports to site PIs with submission
  instructions to IRB
• If SAE is serious, unexpected and reasonably
  attributable to the study intervention

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CSP STUDY EXECUTIVE COMMITTEE

• Comprised of 6-10 members
• Study Chair, biostatistician, research
  pharmacist, national study coordinator, project
  manager, site investigators
• Responsible for reviewing / approving
• Protocol changes
• Subprotocols
• Use of study data / publications
• Monitoring site progress / adherence to protocol
• Actions on participating sites
• All subject to approval of Director, CSRD

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DATA MONITORING COMMITTEES

• Comprised of 5-8 members
• Major responsibilities
• Considers if study should continue
• Progress, safety, treatment efficacy
• Review of biostatistical monitoring procedures
• Performance of sites
• Review / recommend protocol changes
• Decisions presented as recommendations to
  Director, CSRD

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CSP HUMAN RIGHTS COMMITTEES

• Comprised of individuals from VHA and community
• 2 members must be non-VA
• 1 physician
• 1 non-physician scientist
• May include clergy, attorney, veteran and/or
  minority
• Reviews protocol prior to submission to CSSEC
  (JIT may apply)
• Meets with DMC at least once/year
• Conducts site visits to participating study sites

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CSP STUDY SITES

• PI responsible for all study activities
• Reporting submitting all documents to IRB
• VA Central IRB used for CSP studies
• Files Serious Adverse Events (PCC may help
  prepare Safety Report)
• Timely reporting to CSP Coordinating Center
• Maintaining up-to-date and accurate study records
• Facility director reports to ORO if needed (VHA
  Handbook 1058.1)

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VAMC CONSIDERATIONS

• Site investigators (PIs) assume ultimate
  responsibility for study conduct at their site
• Study PIs and coordinators form an essential team
  to the success of studies
• Administrative and clinical/scientific support
  from VAMC is also key

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ADVERSE SERIOUS ADVERSE EVENTS

• Adverse events serious adverse events collected
  by all studies
• Executive Committee and Study Management Team
  determines how adverse events (AE) and serious
  adverse events (SAE) are collected and monitored
  in a study
• Site personnel are trained in the reporting
  procedures at the studys kick-off meeting
• Personnel need to understand how to work with CSP
  Coordinating Center

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CONCLUSION

• CSP is a unique VA infrastructure for conducting
  multi-site clinical research
• Established scientific, operational, and
  management processes have contributed to key
  findings aimed at enhancing veteran health and
  care
• Collaborative spirit and approach have been
  essential for enabling success
• Site PIs and VAMC leadership play important roles

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• Contact Information
• Grant D. Huang, MPH, Ph.D.
• Deputy Director
• Cooperative Studies Program (125)
• 810 Vermont Ave, NW
• Washington, DC 20420
• Phone [phone]
• Fax [phone]
• E-mail grant.huang_at_va.gov
• Website http//www.csp.research.va.gov

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QUESTIONS?