A Primer on Clinical Trials for the Research Administrator David Lynch – Executive Director of Office of Sponsored Research, Northwestern University Mike Ritz – Research Compliance Officer, University of Rochester Tom Wilson – Senior Research Administrator and Asst. Vice President Rush University Medical Center

Contents of Chapter One “An Introduction to Clinical Research” Definitions of Clinical Trial Terms Phases of a Clinical Trial Clinical Research Requirements and Regulations Clinical Trial Requirements and Regulations

Clinical Research Requirements and Regulations – Protection of Human Subjects FDA regulations DHHS regulations The Common Rule While there are some differences, the basic requirements of an institutional assurance approved by DHHS, review of research by an IRB, the informed consent of subjects, and education and training are similar.

Clinical Research Requirements and Regulations - Protection of Human Subjects Human Subjects Protection Training Individuals who will be involved in the design or conduct of NIH-funded human subjects research must fulfill the NIH education requirement.

Clinical Trial Requirements and Regulations - Investigational New Drug (IND) Application Current federal law requires that a drug be subject of an approved marketing application before it is transported or distributed across state lines. The IND application is the means through which the sponsor obtains the exemption.

Clinical Trial Requirements and Regulations - Investigational Device Exemption (IDE) Required prior to initiation of an investigational device study Approval required from the Medicare Administrative Contractor and local carrier before Medicare can be billed for participants enrolled in a study.

Clinical Trial Requirements and Regulations - Medicare Coverage for Clinical Trials As stated in the National Coverage Determination, Medicare covers the routine costs of qualifying (as defined) clinical trials, as well as reasonable and necessary items and services used to diagnose and treat complications arising from participation in clinical trials.

Contents of Chapter Two “Preparing a Clinical Trial Budget” Key Principles for Budgeting Budgeting for Clinical Trials, other than Device Studies Budgeting for Device Studies Negotiation Tips Appendix with Templates

Clinical Trials Other Than Device Studies Prospective Reimbursement Analysis (PRA) Identify all procedures, items and tests within a clinical trial and to whom they are billable Two Steps Is it a qualifying trial (as defined)? If so, what costs can or cannot be charged to insurance?

Clinical Trials Other Than Device Studies Text provides an example of a template for documenting the PRA.

Device Studies Medicare reimbursement depends on the category the FDA assigns to the device (Category A or Category B). Costs associated with Category A devices are generally not covered by Medicare. Device and routine costs associated with Category B devices might be reimbursable if approved by the Medicare Administrative Contractor.

All Studies – Participant Costs Identify all encounters and tasks Estimate costs of clinical procedures Estimate cost of clinical team member time for tasks without billing codes

All Studies – Participant Costs Text provides an example of a template to budget these costs.

All Studies – Non-Participant Costs Text provides an example of a template to budget these costs.

All Studies – Non-Participant Costs Ideal situation is for sponsor reimbursement to include (a) a per participant reimbursement reflective of only variable costs and (b) separately invoice-able provision for fixed costs. If sponsor includes both fixed and variable costs in the per participant reimbursement, the recovery of fixed costs is then dependent on enrollment. Text provides an example to demonstrate the financial risks associated with this scenario.

Indirect Cost Rate Federal sponsor – use negotiated rate; remember there are costs excluded from the application of the rate Non-federal sponsors – best practice is to have a documented policy (i.e. standard rate)

Inflation Considerations Apply an inflation factor if the clinical study is anticipated to be active more than twelve months, considering timing of expected enrollment; and whether costs are concentrated to particular periods of the study - Text provides examples of considerations

Negotiation Tips Consistent approach to budgeting and documentation Consideration of deficits and surpluses Timing of Payments

Contents of Chapter Three “Contracting with Industry” Liability Issues Confidentiality, Publication and Use of Data/Data Ownership General Contract Terms Intellectual Property Appendix with Templates

Liability Issues Indemnification One party’s obligation to take responsibility for the legal liability of another party Insurance Adequate amounts of insurance will be maintained by the sponsor throughout the study period and for some time afterwards.

Liability Issues Insurance Text contains “Risk Assessment and Insurance Score Card”.

Liability Issues Subject Injury Define who will be responsible for providing care to treat injuries and who will pay such costs

Confidentiality Generally requires the most negotiation Openness in research and academic freedom versus secrecy and control of information Define the term “Confidential Information” and the timeframe involved

Publication PI must have freedom to publish (written and unwritten). Sponsor should never be given editorial rights, only the ability to review and comment. Case study provided in text.

Use of Data / Data Ownership Overarching principle is that the Principal Investigator may freely use the data generated by the study for future research and educational purposes.

General Contract Terms The text provides and explains the terms and conditions often included in clinical trial agreements. (Recitals, Period of Performance, Use of Name, Severability, Waiver, Notices, et cetera)

Intellectual Property (IP) Maintain the institution’s right to use the IP that may be transferred to the sponsor (consistent with the institution’s research mission and non-profit status)

Contents of Chapter Four “Financial Oversight of a Clinical Trial” Maintaining Participant-Level Information Effort of Clinical Trial Team Members Sponsor Reimbursement Close Out Appendix with Templates

Maintaining Participant-Level Information Create a grid whereby each column corresponds to tasks conducted chronologically throughout the study for which the sponsor is to pay the cost Each row is assigned to a participant enrolled in the study with respective dates the participant completes each procedure/visit. Reconcile to the clinical study’s general ledger

Maintaining Participant-Level Information Text provides an example of a grid

Effort of Clinical Trial Team Members Allocate a reasonable percentage of each clinical trial team member’s effort directly to each clinical trial account During each trial’s life, staff can account for time spent on trial activities to assist with reasonableness of allocations. Reconcile to the clinical study’s general ledger

Sponsor Reimbursement When payment is based on case report forms, ensure completeness of payments received. When payment is based on milestones and associated invoice preparation Maintain a list of invoices sent and payments received Follow-through on unpaid amounts Adopt standard payment terms

Close Out Require a thorough review of final clinical study account balances Identify reasons for deficits or residuals Text provides an example of a policy regarding usage of clinical study residuals.

Contents of Chapter Five “Other Institutional Considerations” Conflict of Interest Billing Compliance Unrelated Business Income Centralized and External IRB Review Clinical Research Administration Organization Standard Operating Procedures Appendix with List of Regulations Related to Clinical Research

Conflict of Interest Public Health Service issued regulations to provide standards to manage, reduce or eliminate financial conflicts of interest. Applies to IRB members, investigators, study coordinators, the institution, and others Real or potential conflicts

Billing Compliance Adoption of Clinical Research Billing Policy Education and training of employees Mandatory billing plan/billing grid Implement scheduling and registration controls Implement clinical trial management system that verifies correct billing Perform routine internal auditing

Unrelated Business Income Academic medical centers may be required to pay taxes on business income that is unrelated to the entity’s tax-exempt purpose. Avoid tax by establishing institutional policies interpreting its educational and research missions and strategic research operations

Unrelated Business Income Conducting research is an exempt activity if “scientific research” is carried out in the “public interest”. Best practice is a formal policy which requires, or encourages, publication of research results in a timely manner.

Organization Structure No “right way” – it depends on the culture or tradition of the institution Centralization Advantages and disadvantages Decentralization

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