VA COOPERATIVE STUDIES VA COOPERATIVE STUDIES PROGRAMPROGRAM

Grant D. Huang, MPH, PhD

VA Office of Research and Development

Washington, DC

OVERVIEWOVERVIEW

• Program Overview

• Study Processes & Roles

• Study Personnel & Responsibilities

VETERANS HEALTH ADMINVETERANS HEALTH ADMINOffice of Research &Office of Research &

DevelopmentDevelopment

VETERANS HEALTH ADMINVETERANS HEALTH ADMINOffice of Research &Office of Research &

DevelopmentDevelopment

BiomedicalLaboratory

R&D

RehabilitationR&D

Clinical Science

R&D

Health Services

R&D

Cooperative Studies Program

CSP MISSIONCSP MISSION

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

COOPERATIVE STUDYCOOPERATIVE 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

VA COOPERATIVE STUDIES PROGRAMVA 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

CSP STUDY FINDINGSCSP 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

CSP CENTER LOCATIONSCSP CENTER LOCATIONS

West Haven, CT

Seattle, WA

Palo Alto, CA

Albuquerque, NM

Durham, NC

Hines, IL

Washington, DC

Perry Point, MD

Boston, MA

Little Rock, AR

CSP ROLESCSP 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

CSP ORGANIZATIONCSP ORGANIZATION

Grant D. Huang, MPH, Ph.D.CSP Deputy Director

Mark Holodniy, MDActing DirectorPalo Alto CSPCC

Michael Gaziano, MDDirector, Boston ERIC (MAVERIC)

Louis Fiore, MD, MPHDirector, Boston CSPCC (MAVERIC)

Dawn Provenzale, MDDirector, Durham ERIC

Domenic J. Reda, Ph.D.Director, Hines CSPCC

Nick Smith, PhDDirector, Seattle ERIC

Joseph F. Collins, Sc.D.Director, Perry Point CSPCC

John Concato, MD, MPHDirector, West Haven CERC

Timothy J. O’Leary, MD, PHD

CSRD Director

Paul G. Barnett, Ph.D.Director, HERC

Mike R. Sather, Ph.D.Director, Albuquerque Clinical Research Pharmacy CC

Peter Peduzzi, Ph.D.Director, West Haven CSPCC

David BurnaskaCSP Program Mgr

Bridgett BaerAdministrative Officer

Kelli PotterCSP Program Spec

CSP Central Office

Located at VAMCs

CSP CROSS FUNCTIONAL GROUPSCSP 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.

CSP STUDIESCSP 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

CSP 504 & 563 CSP 504 & 563 Post-Traumatic Stress Disorder StudiesPost-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

CSP 558 – VA ROBOTICSCSP 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

CSP STUDIESCSP 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

COLLABORATIONSCOLLABORATIONS

• 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

Recent CSP PublicationsRecent CSP Publications

• CSP 468 – A randomized controlled trial of best medical therapy versus bilateral deep brain stimulation for patients with advanced Parkinson’s 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)

CSP STUDY PROCESSES & CSP STUDY PROCESSES & ROLESROLES

CSP SCIENTIFIC REVIEW PROCESSCSP SCIENTIFIC REVIEW PROCESSCSP SCIENTIFIC REVIEW PROCESSCSP SCIENTIFIC REVIEW PROCESS

LOI submitted to CSP CO

External ReviewExternal Review

External ReviewExternal Review

Internal – Admin Review

Approved or Disapproved for

Planning Support

Planning Meetings Convened (1+)

Full Study Protocol Developed

External CSSEC Review Clinical CSSEC

Review Biostat CSSEC Review

CSSEC Face-to-Face Study Review & Recommendation

Funding Decision by CSRD Director

VAMC CONSIDERATIONSVAMC 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

CSP STUDY PLANNING TEAMCSP STUDY PLANNING TEAM

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

CSP SCIENTIFIC REVIEW PROCESSCSP SCIENTIFIC REVIEW PROCESSCSP SCIENTIFIC REVIEW PROCESSCSP SCIENTIFIC REVIEW PROCESS

LOI submitted to CSP CO

External ReviewExternal Review

External ReviewExternal Review

Internal – Admin Review

Approved or Disapproved for

Planning Support

Planning Meetings Convened (1+)

Full Study Protocol Developed

External CSSEC Review Clinical CSSEC

Review Biostat CSSEC Review

CSSEC Face-to-Face Study Review & Recommendation

Funding Decision by CSRD Director

REVIEW CONSIDERATIONSREVIEW CONSIDERATIONS

• Clinical relevance (to veteran population)• Methodology• Feasibility

– Testable hypothesis– Sample size

• Ethics• Resources needed• Investigator qualifications

CSP RESEARCH PROCESSCSP RESEARCH PROCESS

ALL are key to the success of the study

Study TeamStudy Team

StudyStudy DevelopmentDevelopment

Organizational Organizational & Start-up& Start-up

ExecutionExecution

EnrollmentEnrollment -- -- Follow-upFollow-up

Analyses & Analyses & Close-outClose-out

Study Chair

Biostatistician

Research Pharmacist

Health Economist

Project Manager

Site investigators

Nurse/Site Coordinators

Programmers

Executive Committee

Scientific / Scientific / EthicalEthicalreviewreview

Scientific Scientific peerpeer

reviewreview

Scientific / Scientific / EthicalEthicalreviewreview

IRB / R&D

FDA

Human Rts Comm

IRB / R&D

FDA

Human Rts Comm

Data Monitoring Comm

Scientific peer review

Human Rts Comm

FACTORS FOR SUCCESSFUL CSP STUDIESFACTORS 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

CSP STUDY MANAGEMENT & POLICIESCSP 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

CSP TRAININGCSP 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

CSP CENTRAL OFFICECSP 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

CSP COORDINATING CENTERSCSP 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

CSP PHARMACY COORDINATING CENTERCSP 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

CSP STUDY EXECUTIVE COMMITTEECSP 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 sitesAll subject to approval of Director, CSRD

DATA MONITORING COMMITTEESDATA 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

CSP HUMAN RIGHTS COMMITTEESCSP 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

CSP STUDY SITESCSP 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)

VAMC CONSIDERATIONSVAMC 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

ADVERSE & SERIOUS ADVERSE EVENTSADVERSE & 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 study’s kick-off meeting– Personnel need to understand how to work with CSP

Coordinating Center

CONCLUSIONCONCLUSION

• 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

Contact Information

Grant D. Huang, MPH, Ph.D.Deputy DirectorCooperative Studies Program (125)810 Vermont Ave, NWWashington, DC 20420

Phone: (202) 461-1661Fax: (202) 254-0471E-mail: grant.huang@va.gov Website: http://www.csp.research.va.gov

QUESTIONS?QUESTIONS?