1. What Are the Essentials to Run a Large Research Organization?
CRT 2017, Washington, DC. February 2017
What Are the Essentials to Run a Large Research Organization?
A. Michael Lincoff, M.D.
Director, C5Research
(Cleveland Clinic Coordinating Center for Clinical Research)
Director, Center for Clinical Research
Lerner Research Institute
Vice Chairman of Cardiovascular Medicine
Professor of Medicine
Heart and Vascular Institute

2. Speaker Disclosure – A. Michael Lincoff, MD
Relationships with Industry
Research Funding:
AstraZeneca, CSL Behring, Eli Lilly, Esperion, Pfizer, Roche
Consultant:
Abbott, Amgen, Sarepta, Sermonix, St. Jude Medical
Supervisory – C5Research Director:
Amgen, Atricure, Cardiovascular Systems, Centocor, Covidien, Edwards Lifesciences, Early Sense, Ethicon, Janssen, Juventas, Medicines Company, Medtronic, Novartis, Orexigen, Stemedica, Takeda 2

3. The Clinical Research Complex
Compliance
Legal
IRB
COI
Finance
Industry
NIH
DARPA
Foundations
Other Grantors
FDA
NIH
OHRP
CMS
OIG
Physician
Investigators
Nurses and Coordinators
Patients
Human Subjects

4. Clinical Research Challenges
Regulatory Compliance
protocol adherence and deviations
consent issues
adverse event reporting
case report form completion, data queries

5. Clinical Research – Regulatory Compliance
Public skepticism and caution regarding clinical research, conflict of interest , leading to more stringent regulations and increased oversight of violations by OHRP and FDA.
FDA Will Move Faster To Ban Bad Actors From Clinical Trials
By Jessica Bylander
Recent changes will speed FDA’s process for barring non-compliant clinical trial investigators from future product research, agency staffers say.
. . . “Members of Congress have expressed concern that the FDA has not adequately used its debarment and disqualification authorities,”.. .
. . . Current law allows FDA to disqualify researchers from conducting clinical testing when the agency determines that they have not followed human subject protection rules or have inaccurately reported study findings. . .”
Clinical Trials Advisor. Aug. 20, | Vol. 14 No. 16

6. Clinical Research Challenges
Regulatory Compliance
protocol adherence and deviations
consent issues
adverse event reporting
case report form completion, data queries
Financial
budget performance
billing compliance

7. Financial – Research Budgeting
What Goes Wrong?
Inadequate enrollment – do not reach “break even point”
Underestimated difficulty and complexity of screening
Trial more complex and requires more resources than anticipated
Incorrect allocation of medical costs to “Standard of Care” (SOC) vs Research
Budget did not consider all costs
Contractual terms and conditions
Failure to invoice

8. Financial Audits Major Settlements Public and Legislative Demands
University of Minnesota Misuse federal funds $32 million
New York University Medical Center Inflated research grant costs $15.5 million
Johns Hopkins University
Effort Certification $2.7 million
Palm Beach Imaging
Anti-kickback
$7 million
Scripps Memorial Hospital
Medicare Fraud
charged experimental cardiac devices not reimbursable
$29 million
Public and
Legislative Demands
East Carolina University
Questioned Costs HHS/OIG Audit
$2.4 million
Cornell Medical Clinical Research Issues $4.4 million
Harvard/Beth Israel
Costing Issues Self-Reported $3.25 million
University of Alabama Effort Cert & Double Billing
$3.4 million
Northwestern University
Committed Time/Effort
$5 million

9. Clinical Research Challenges
Regulatory Compliance
protocol adherence and deviations
consent issues
adverse event reporting
case report form completion, data queries
Financial
budget performance
billing compliance
Trial performance
enrollment
data quality
retention, follow-up

10. Recruitment Challenges
Trial Recruitment
Recruitment Challenges
Recruitment
% of Target
Review of 114 trials funded by UK Medical Research Council and Health Technology Assessment Program from :
McDonald et al. Trials 2006;7:8

11. Trial Recruitment – Common Barriers
“We don’t see the population here” - tertiary care center (disease too advanced, patients come specifically for certain therapies, etc). ?suitable for regional practices
Patients from outside of geographic area - follow-up not feasible, arrive with inadequate time for consenting or screening, etc.
Competing trials with overlapping patient populations
Investigators too busy to advocate to patients. Colleague physicians not interested, won’t participate
Requires collaboration with other departments (e.g. endovascular therapy for resistant hypertension – heart and renal)
Onerous procedural or follow-up requirements for patients

12. Clinical Research Challenges
Regulatory Compliance
protocol adherence and deviations
consent issues
adverse event reporting
case report form completion, data queries
Financial
budget performance
billing compliance
Trial performance
enrollment
data quality
retention, follow-up
Physician investigator participation, protected time, incentives

13. Principal Investigator

14. Clinical Research Challenges
Meeting the Challenges with a Research Organization
Education
Financial
Infrastructure
Project selection
Trial performance monitoring

15. Clinical Research Challenges
Meeting the Challenges with a Research Organization
Education
for all levels of research personnel, including MDs
standardized policies and expectations
core competencies linked to standardized job descriptions
Financial
Infrastructure
Project selection
Trial performance monitoring

16. Cleveland Clinic Research Education
Multifaceted Layered Approach
Physician / Scientist Education Course (mandatory - 4 hr CME credit)
Nurse / Coordinator Education Workshops
Requirements based on standardized job descriptions and core competencies
Research Webpage – tools, templates (trial protocol, case report forms, informed consent), feasibility checklists, etc.
Monthly newsletter – methodology, compliance
Individual investigator / nurse / administrator education and mentoring (IND/IDE trials, other compliance or methodologic issues)

17. Physician-Investigator Education Track
Mandatory 4 Hour Course to Perform Clinical Research
Human Subjects Research Process
Advanced Trial Design / Protocol Development
Conflict of Interest
Databases and Clinical Data Management
Legal Agreements
Trial Budgeting and Billing Compliance
IRB Submission, Application, and Review Criteria
Informed Consent Document and Process
Unanticipated Problems and Deviations
Serious Adverse Events and Adverse Events
FDA Inspection and Response to Audit Findings

18. Cleveland Clinic Research Education
Mandatory Topics for Non-Physician Personnel
Intro to Clinical Research at CC
CC Research Policy
Basics of Trial Design
Introduction to Databases
21 CFR Part 11 Compliance
Protocol Writing, Editing, Review
CRU Collaboration
IRB Submission
Webkit Troubleshooting
Regulatory Binder Essentials
Informed Consent Document
Informed Consent Process
Adverse Event Reporting
Unanticipated Problems
Clinical Data Management
Monitoring
IND Regulations
IND Application and Reporting
Medical Device Regulations
IDE Application and Reporting
Ethics of Regulations
Preparing and Hosting an FDA Inspection
Response to FDA or external audits
Publications – common errors
Budget Development
Budget Negotiations
Research Billing Compliance

19. Clinical Research Challenges
Meeting the Challenges with a Research Organization
Education
Financial
budgets and negotiation by finance personnel, not physicians
account for all research costs
Infrastructure
Project selection
Trial performance monitoring

20. Clinical Research Finances
General Principles
Industry-sponsored research should not lose money; the not-for-profit academic medical centers should not “subsidize” medical industry.
Unfunded investigator-initiated research should be financed through “profits” (residuals) from sponsored research or philanthropic funds.
Research spending must be accountable and transparent – costs for research-related activities and personnel should not be mixed with clinical operating expenses

21. Clinical Research Budget
What Must Be Considered?
Total Research Costs
Research personnel time
Patient tests and procedures
Subject assessments (history, examinations, etc)
Budget prep / negotation
Training, meetings
Adverse event reporting
CRF completion, source documents
FDA or sponsor visits, monitoring
Supplies, storage and shipping
Fees (IRB, Pharmacy, Lab, etc.)
Difficult consent for controversial or complex studies
Excessive screening, restrictive
Protocol amendments
Complex reporting / CRFs
Unscheduled visits
Unexpected excessive AE’s, reporting burden
Institutional indirect overhead charges
Direct Costs
“Hidden” Costs

22. Clinical Research Challenges
Meeting the Challenges with a Research Organization
Education
Financial
Infrastructure
research personnel report to administration, not individual MD’s
centralized, de-centralized, or hybrid administration
research nurse / coordinator pools
Project selection
Trial performance monitoring

23. Clinical Research Challenges
Meeting the Challenges with a Research Organization
Education
Financial
Infrastructure
Project selection
departmental review and approval
feasibility assessment – enrollment, resources
Trial performance monitoring

24. Protocol Feasibility Checklist - 1
CTN Best Practices - ctnbestpractices.org
Enrollment – time, population, competing studies
Required collaboration with other departments
Equipment or resources
Complexity, prolonged follow-up times
Workload vs resources
Investigator time commitment
Compliance issues

25. Clinical Research Challenges
Meeting the Challenges with a Research Organization
Education
Financial
Infrastructure
Project selection
Trial performance monitoring
enrollment
variance to budgets
modify or close underperforming trials

26. Clinical Trial Management System
ClickTM CTMS
Management of participants, progress, results and budgets allowing for transparency to the status and financial health of clinical trials
Track patients enrolled in research across the enterprise
Integrate financial systems and EMR
Reporting of:
Enrollment – expected, actual, last patient enrolled
Finances – expenses, revenue, receivables
Schedules and linking to patient registration

27. Heart and Vascular Institute