INTRODUCTION TO CLINICAL RESEARCH Lecture 1: Who, What, Why and Where of Clinical Research

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INTRODUCTION TO CLINICAL RESEARCHLecture 1Who,
What, Why and Where of Clinical Research

• Richard J. Barohn, M.D.
• Professor and Chairman
• Department of Neurology
• Director, General Clinical Research Center
• University of Kansas Medical School
• August 24, 2006

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What is Clinical Research?

• Types of clinical research
• Retrospective looking back at data previously
  collected
• - Case Reports
• - Case Series
• Prospective make plan for future data
  collection
• - Observational
• - Interventional
• - Device/technique
• - Drug

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Observational Research Studies

• Can involve direct participant contact
• - Measure a clinical end-point
• Obtain tissue samples from participant to study
  in the laboratory
• Can be data-mining of clinical databases
• - Never see participant
• - Example Medicare database

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Types of Clinical End-Point Measurements

• Survival (mortality)
• Physiologic parameter
• Example quantitative strength, breathing (vital
  capacity)
• Clinical scales
• Example Mini Mental Status
• Blood or other body tissue measurement
• Example - Glucose Level
• - Hormone Level

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Ann NY Acad Sci 1998
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Quantitative MG Score for disease activity
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Interventional Trials

• Open-label Trial
• Everyone receives research intervention
• Controlled Trial
• Some receive research intervention, some do not
• Control group - Ones that do not receive research
  intervention
• Control group can be getting another intervention
• Comparing new drug to older one
• Or control group can get placebo (inactive
  intervention)
• Randomized Trials
• Participants randomly allocated to active
  intervention or control group
• Blinded usually double blind
• Doctor and participant do not know which group
  subject is in
• Gold Standard Randomized Double-Blinded
  Controlled Trial

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ALS Treatment Trials at University of Kansas
Medical Center

• Most proceeded by beneficial results in
  laboratory models
• All multicenter with other ALS centers
• COX-2 inhibitor (glutamate inhibitor) (MDA)
• Celebrex trial just completed no benefit
• Creatine
• ? improves strength in athletes (NIH)
• Minocycline oral (cell death inhibitor) (NIH)
• Ceftriaxone intravenous (cell death inhibitor)
  (NIH)
• CoQ10 (antioxidant) (NIH)
• Arimoclomol (increases heat shock protein)
  (Biotech investigator initiated)
• Celebrex/creatine vs mino/creatine (ALSA)

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Drug Trials

• Pre-Clinical Animal and In Vitro Lab Studies
• Phase I Safety (normals disease)
• Phase II Preliminary Efficacy Data with
• additional safety
• usually lt 100 patients
• Phase III Pivotal efficacy trial
• Large, often multicenter
• Phase IV - Post-marketing

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Who Does Clinical Research?

• In Academic Health Centers
• Faculty MD, DO, PhD are Principal Investigators
  and Co-Investigators in Schools of Medicine,
  Nursing, Allied Health
• Trainees (students, residents, fellows) work
  under Faculty
• Outside of Academic Health Centers
• Private practice health care providers
• Industry
• Pharmaceutical companies, example Quintiles
• Biomedical device companies

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Who Does Clinical Research? Team Approach

• Investigator
• Clinical Research Coordinators
• (Example nurse, respiratory therapist, RD)
• Clinical Research Evaluator
• Research Assistant
• Biostatistician
• Data Manager
• Research Pharmacy
• If laboratory based
• Lab research personnel (students, post doctorate,
  technicians)

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Who Pays for Clinical Research?

• Federal Grants
• Example National Institutes of Health
• FDA-Orphan Drug Grant Program
• Foundations
• Example Muscular Dystrophy Association
• Industry
• Internal-funding at medical center
• Example Research Institute of KUMC
• Private Donations
• Non-Funded Research

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What Types of Grants Should a Junior Clinical
Investigator Apply For?

• Local Institutional Support
• KUMC Research Institute
• Department
• Disease-Related Foundations
• Standard Research Grants
• Career Development Grants
• NIH (NIH.gov)
• Apply to NIH for
• K23 Clinical Research
• K08 Lab/Translational
• R03 Pilot Program
• R21 Developmental/Exploratory
• Institutional Awarded Training Grants
• T32 Training
• K12 Career Development
• VA Career Development Awards
• Merit Grants
• GOAL RO-1 THE BIG ONE

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Who Monitors Clinical Research?(for science,
safety, privacy)

• Food Drug Administration (FDA)
• PI applies to get IND for drug trial
• Local Human Subjects Committee (Institutional
  Review Board)
• Local HIPPA Compliance Program
• General Clinical Research Center
• Research Subject Advocate
• Safety Monitors
• Data Safety Monitoring Boards
• Local KUMC DSMB
• National NIH DSMB

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Who Helps in Clinical Research at KUMC?

• Research Institute Clinical Trials Office
• Serve as centralized sponsor contact point for
  KUMC
• Prepares consent with PI input
• Prepares and negotiates trial budgets
• Submits protocol/consent to HSC if there is a
  sponsor
• Contact Laurie Kemble at 588-1242 or
  http//www2.kumc.edu/researchinstitute/
• Human Subjects Committee
• KUMCs Institutional Review Board
• Committed to ethical, legal and safe conduct in
  all research involving human participants
• Meets 2nd and 4th Tuesdays
• Submissions by noon Friday, 7 business days prior
  to meeting
• Submission of materials
• Contact Karen Blackwell at 588-0942 or
  http//www.kumc.edu/hipaa/
• Mentors

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Mentoring Analogy to Driving Lessons

• Focus on steering mechanism not the
• drive train or brakes, as they are
• not usually accessible to mentors.

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Keys in Finding a Mentor

• The mentor should
• Be interested
• Have experience
• Be available
• Limit number of mentees
• Commit substantial time
• Be vigilant but not intrusive

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Where is Clinical Research Done?

• In academic health centers
• Departmental clinical space
• Designated research space
• Example GCRC
• Hoglund Brian Imaging Center
• Veterans Administration Medical Centers
• Hospitals not affiliated with AHC
• NIH in Bethesda intramural
• Private health care provider offices
• Industry offices

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Why Do Individuals Want to Participate in
Research?

• Advance science/improve knowledge
• Obtain access to a potential Rx at the earliest
  possible time
• Current Rx not working
• It helps maintain hope - better than not doing
  anything
• Desire to meet and speak with researchers
• To help others
• Reimbursement to subject/patient

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Why Do Individuals not Participate?

• Painful unpleasant procedures
• Fear of going off current medication
• New treatment may not be better
• Time commitment/travel
• Side effects
• Fear of the unknown
• Fear of being assigned to placebo
• They accept the disease is their fate

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Why Do Individuals not Participate ?(More
Reasons)

• Efforts futile
• Privacy concerns publication, etc.
• Resentment of medical personnel
• Distrust of science community
• Dont want to be a guinea pig
• Dont agree with focus of research
• Long wait to get research results

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What Do Participants Want/Expect from Involvement
in Clinical Research?

• Be considered a partner in the research
• Be treated with respect / taken seriously, kept
  informed and up-to-date
• Do not want to be talked down to
• Full disclosure of side effects
• Option to stop involvement in study
• Support from research team - availability

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What Do Participants Want/Expect from Involvement
in Clinical Research? (continued)

• After study, want to know results and if they
  were on drug or placebo
• Realistic idea when results will be available
• No cost to participant
• Confidentiality
• Enough time and comfortable area
• To ask questions
• In which to do the study

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General Clinical Research Center Program
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What is a General Clinical Research Center?

• A NIH-supported multidisciplinary research unit
  which facilitates investigator-initiated clinical
  studies and trials conducted by full-time faculty
  of the AHC.
• Provides clinical research infrastructure to
  investigators who receive funding from federal
  agencies, private foundations, other
  peer-reviewed sources.
• Also, can include investigator initiated unfunded
  pilot studies and industry sponsored studies.
• This is at no cost to the PIs for
  Investigator-Initiated Trials

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General Clinical Research Center (GCRC) at KU
Medical CenterGoals established in 2002

• Provide clinical investigators from the SOM, SON,
  and SOAH with a modern, state-of-the-art facility
  in which clinical research could be conducted
• Enhance multidisciplinary research across
  departments and the three schools
• Enable and train junior faculty and trainees to
  become more involved in clinical research
• Apply for federal funding to support the GCRC

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Typical GCRC Organizational Structure
Principal Investigator (PI) (Usually Dean
of School of Medicine)
GCRC Advisory Committee (30 Members) (GAC)
Program Director (Senior Faculty/Investigator)
Facilities

• Outpatient Unit
• Inpatient Unit
• Scatter Beds
• Core Lab
• Metabolic Kitchen
• Informatics Core

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GCRC Advisory Committee (GAC) Members - June
2006Matthew Mayo, PhD Jared Grantham, MD
(Co-Chairs)

• VOTING MEMBERS
• Matthew Mayo, PhD
• Jared Grantham, MD
• Marge Bott, RN, PhD
• Richard McCallum, MD
• Stephen Williamson, MD
• Richard Dubinsky, MD
• Barbara Lukert, MD
• Kevin Latinis, MD, PhD
• Debra Sullivan, PhD, RD, LD
• Patrick Moriarty, MD
• Jo Ann Harris, MD
• John Ferraro, PhD
• Andrea Charbonneau, MD
• Kathryn Ellerbeck, MD

• Ossama Tawfik, PhD, MD
• Barbara Quaney, PT, PhD
• Kathleen Gustafson, PhD
• NON-VOTING EX OFFICIO MEMBERS
• Barbara Atkinson, MD Executive Dean SOM
• Richard J. Barohn, MD Program Director
• Curt Hagedorn, MD Associate Director
• Jeff Burns, MD Assistant Director
• Patricia Kluding, PT, PhD Assistant Director
• Paul Terranova, PhD
• Susan Schmitz, BA, CCRC Administrative Director
• Judy Otey, RN, BSN Nurse Manager
• Ed Ellerbeck, MD, MPH
• Jon Jackson
• Jo Denton, MSN
• Laurie Kemble, BS, CRT

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What The GCRC Can Do

• For GAC approved studies
• Space to see patients
• Biostat support study design
• Data management
• Nurse support
• Administrative support
• Specimen collection/storage
• Common equipment
• Some labs
• No cost for above services to PIs on
  investigator initiated studies
• Industry sponsored with charges for
  space/resources

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What The GCRC Cannot Do

• Space/resources for industry studies
• Permanent space for research coordinators
• Overnight stay on GCRC unit

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A Visit to the GCRC
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KUMC - GCRC Time-line/Progress

• GCRC Planning Committee formed 2002
• Construction/Remodeling began June 1, 2004
• Completed October 2004
• 6, 000 square feet in Delp
• Announce GAC will accept research applications
  from investigators, September 2004
• Began doing studies on GCRC January 2005
• Approval of 53 on-going studies by GAC as of June
  2006
• GCRC NIH grant submitted June 1, 2006
• 2 million (direct costs) per year for 3 years

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To Find Out More Information About the GCRC

• Contact Judy Otey, RN, BSN
• GCRC Administrative Director
• 913-588-0984 alt. 2460
• jotey_at_kumc.edu
• Nicole Ladesich, BS
• GCRC Senior Coordinator
• 913-588-0976 alt. 2294
• nladesich_at_kumc.edu
• Visit Website http//gcrc.kumc.edu

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How to access the GCRC websitewww.gcrc.kumc.edu
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Current Challenges for Clinical Researchas
perceived by Dr. Zerhouni in May 2005 and NEJM
October 2005

• Recruiting and retaining researchers
• Explosion in clinical demands, reduced financial
  margins ? limit time, diluted value
• Regulatory burden
• Fragmented training
• Complexity of training
• No real HOME for clinical researchers
• Limitations / barriers due to NIH funding
  mechanisms, review, program structures

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Definitions per Dr. Zerhouni / NIH

• Clinical Research covers all studies of diseases
  and trials of
• treatments in human subjects
• Translational Research describes the steps
  between a
• fundamental discovery and its application in
  clinical
• medicine. For example
• Testing a new anti-cancer drug in humans for the
  first time
• Identifying best practices in the diagnosis,
  prevention, or management of a disease and
  enhancing their adoption by the community

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Current Clinical Science Infrastructure as
perceived by Dr. Zerhouni
Disease X Center
GCRC
Disease Y Center
Training Programs
K30 Curriculum
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Dr. Zerhounis ModelSystems Biology Approach
to Creating a Home for Clinical and Translational
Sciences

Disease X Center
Upgraded Biostatistics
IRB
Upgraded Regulatory Advice
???
NECTAR NCRA
Degree Granting
Training Programs
Clinical Research Design Incubator
Disease Y Center
K30 Curriculum
Translational Cores
GCRC
Upgraded Informatics
???
NIH RAID
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Institutional Clinical and Translational Science
Award (CTSA)RFA announcement Oct. 12, 2005

• Purpose Forge a transformative and integrative
  academic home for clinical and translational
  science
• The home must be a Center, Department, or
  Institute.
• Encompass all components of clinical research
  (education, career development, clinical research
  infrastructure)
• Promote multidisciplinary research teams
• Create an incubator for innovative research tools
• Catalyze the application of new knowledge to
  clinical practice
• Degree granting capabilities in Clinical Research
  
• Masters and/or PhD

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KUMC Strengths and Weaknesses for CTSA Application

• Weaknesses
• No current GCRC funding
• No T32
• Current K12 applicability?
• Small pool of clinical mentors, current clinical
  R01s
• Limited culture for CR

• Strengths
• K30
• GCRC infrastructure
• Institutional support
• Research Institute
• SOM / SON / SOAH
• Bioinformatics Center (Mayo)
• K-BRIN (Hunt)
• KU Lawrence (Georg and others)
• Intro to CR Course

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KUMC Strengths and Weaknesses for CTSA Application

• Strengths
• K30 (MSCR program)
• GCRC infrastructure
• Institutional support
• Research Institute
• SOM / SON / SOAH
• Bioinformatics Center (Mayo)
• K-BRIN (Hunt)
• KU Lawrence
• Life Span Institute
• Drug Development
• Introduction to CR Course

• Weaknesses
• No current GCRC funding
• No Clinical T32
• Small pool of clinical mentors, current clinical
  R01s
• Limited culture for CR

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CTSA Application Funding and Timeline

• Letter of Intent February 27, 2006
• Grant Application March 27, 2006
• Planning grant 150,000 for 1 year
• Full CTSA up to 6 million with pediatrics
• 4 million without pediatrics
• Existing K30, T32, and GCRC are in addition
• 5 year award RFA offered annually
• Goal 60 CTSAs to be awarded by 2012
• Will replace all GCRCs and NCRR / Roadmap K12s

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CTSA Planning Process at KUMCEstablished CTSA
Planning Committees and Sub-Committees in
October 2005

• Planning Steering Committee
• Chairs
• Barbara Atkinson, MD
• Richard J. Barohn, MD
• Governance Planning Sub-Committee
• Chairs
• Richard J. Barohn, MD
• Barbara Atkinson, MD
• Grant Writing Planning Sub-Committee
• Chairs
• Richard J. Barohn, MD
• Lauren Aaronson, PhD, RN
• Education Planning Committee
• Chair Ed Ellerbeck, MD, MPH
• Clinical Research Resources Planning Committee

• Regulatory Planning Committee
• Chairs
• Jim Voogt, PhD
• John Finley, JD, MPH
• Novel Methods Translational Technologies
  Planning Committee
• Chairs
• Curt Hagedorn, MD
• Paul Terranova, PhD
• Health Disparities Research Planning Committee
• Chairs
• Patricia Thomas, MD
• Kirby Randolph, PhD
• Community Participant Planning Committee
• Chairs
• Joshua Freeman, MD
• Lauren Aaronson, PhD, RN

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