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

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

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

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

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 (j.bylander@elsevier.com) 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, 2009 | Vol. 14 No. 16

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

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

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

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

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 1994-2002: McDonald et al. Trials 2006;7:8

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

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

Principal Investigator

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

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

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)

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

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

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

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

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

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

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

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

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

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

Heart and Vascular Institute