ORIENTATION FOR NEW CLINICAL RESEARCH PERSONNEL MODULE 3 Presented by NC TraCS Institute UNC Office of Clinical Trials UNC Network of Clinical Research Professionals Overall Agenda for Orientation Module 1: Introduction to Clinical Research, Education, and IRB Module 2: Informed Consent, Documentation, GCP and Essential Documents Module 3:

Contracting, Billing Coverage Analysis, ClinicalTrials.gov, Budgets and Accounting, Study start-up Module 4: COI, Privacy/HIPAA, Recruitment and IDS / Device Policy Module 5: From CDA to Close Out CLINICAL TRIAL CONTRACTS Aylin Regulski MS, JD Associate Director, Office of Clinical Trials Learning Objectives What are Clinical Trial Agreements (CTAs) and why do we

need them? What is inside of a CTA? Why is the CTA important to us? What does the Office of Clinical Trials (OCT) do with regards to the CTAs? Basic Definition An agreement between two or more parties outlining the responsibilities, duties, and rights of each party Sponsor agreements typically have standard, template

language for uniformity that may be difficult to change Clinical Trial Contracts Agreements Associated with Clinical Trials Clinical Trial Agreement (CTA) Sponsor-initiated Investigator-initiated Confidential Disclosure Agreement (CDA) Consortium/Network/Collaboration Agreements Material Transfer Agreement (MTA) Equipment Loan Agreement Subcontracts to sub-Sites and collaborators

All negotiated and signed by Office of Clinical Trials (OCT); important to get an early start, and involve OCT from the beginning! CTA Reviewing and Negotiating CTAs OCT, under the Vice Chancellor for Research, provides review and negotiation, if necessary, for CTAs: http://research.unc.edu/offices/clinical-trials/index.htm Location: 720 Martin Luther King Jr. Blvd, Suite 100, CB# 1651 General phone: 919-843-2698

Content of Typical CTA (not an exhaustive list) Parties to the Contract Preamble Purpose, Protocol/Statement of Work Use of CROs Conformance with Applicable laws,

Enrollment, Reporting/ Meeting Requirements Communication of results to site/subject Confidential Information Ownership & Use of Data/ Biological Specimens Intellectual Property/ Copyrights Publications Ethics Committee

Debarment Certification Access to Premises/Audits Code of Ethics (CIAs) Changes/Amendments Recordkeeping, Retention/Destruction Electronic Data/Signatures Indemnification by Sponsor Cross Indemnification by Site Subject Injury and MSP Reporting Insurance Breach, Remedies and Waivers Return/Destruction of Study Materials Purchase/Supply, Shipping, Use, Maintenance,

Risk of Loss & Disposition of Equipment HIPAA Noncompetition/ Freedom to Contract Term and Termination/ Payment in Event of Termination/ Closeout Notices and Notice Timelines Publicity/Use of Names and Personal Information, Advertising Assignment/ Delegation Survival of Obligations Choice of Law, Venue, Arbitration, Mediation Billing, Invoicing, Adjustments Budget and Payment Schedules Parties to the Contract

Parties are the sponsor and University PI is NOT a party to the agreement PI signs agreement only as acknowledging (or as read and understood) his/ her obligations outlined in the agreement (including CDA) Protocol/Statement of Work Investigator conducts study according to the protocol Need enough detail for very clear understanding of

research, conduct and deliverables (e.g., data, reports). Investigator-initiated studies: PI is sponsor Has all the regulatory and oversight obligations of a sponsor (sponsor-investigator) Make sure the protocol/statement of work (SOW) is very clear! Who, what, when, where, why, how. Protocol/Statement of Work Potential Issues: Why wont the company pay me what I expected?

Why does the company want me to do EXTRA work? Why did the company think they could use my data for their regulatory submission? WHY NOT? Communication of Results to Site/Subject SPONSOR SITE SUBJECTS Notification requirements between sponsor and site where information found during monitoring or data

collection may impact subject safety/ participation. Even after study has ended PI is required to notify subjects Such communication is subject to IRB approval Communication of Results to Site/Subject Glaxo Agrees to Pay $3 Billion in Fraud Settlement NYT 7-2-2012. In the largest settlement involving a pharmaceutical company, the British drugmaker GlaxoSmithKline agreed to plead guilty to criminal charges and pay $3 billion in fines for promoting its best-selling antidepressants for unapproved uses and failing to report safety data about a top diabetes drug [Avandia]

Outside Review of Clinical Data Finds a Spinal Treatments Benefit Overstated NYT 7-17-2013. Researchers have long argued that a heralded spinal treatment sold by the nations largest device maker, Medtronic, was no better than an older one and possibly more risky. Now with the companys help, they have the proof... Medtronics decision to release data about spinal treatment followed charges in 2011 in a medical journal that company-sponsored studies about the product had overstated its benefit and played down its risks. $650 Million to Settle Blood Thinner Lawsuits NYT 5-28-1014. The German drug maker Boehringer Ingelheim has agreed to pay $650 million to settle thousands of lawsuits involving its blood thinner Pradaxa, the company said Wednesday. The settlement will most likely resolve most of the 4,000 cases in state and federal courts filed by patients and their families who claimed that Boehringer failed to properly warn them that the drug, which is

used to prevent blood clots, caused serious and sometimes fatal bleeding that could not easily be reversed. The first case was set to go to trial in September. In a statement, the company said that it stood behind the safety and efficacy of Pradaxa and continued to believe that the lawsuits lacked merit, but that settling the case allowed the company to move on. Confidential Information The cost of bringing the average new drug to market is between $4 billion to $11 billion, taking into account failure rates. (Forbes, 2-10-2012) In such a costly and highly competitive market, the industry trial sponsor is very serious about protecting their confidential information. Control and Use of Data/ Biospecimens Important issue: Who can do what with the information

related to the study? Sponsor owns and prevents University from sharing with 3rd parties: Case Report Forms (CRFs) Study results (University carves out right to use results/data to publish) University owns and gives Sponsor limited right to use:

Subject medical records Research notebooks Control and Use of Data/ Biospecimens For industry-initiated studies, University gets to use results/data for: - Own internal research, educational, and patient care purposes -Publication, in accordance with terms of the contract For investigator-initiated studies, important to know: - Who owns the data or how can we use it?

- Can PI use the data to seek funding for future studies? If Biospecimens are collected: - Can we use them for other research? - Can we put samples in a repository? Let OCT know If you want to use the data or bio-specimens collected under the study/ protocol for future funded research (RRF). Intellectual Property (IP) Protected by patents

Industry-initiated studies Important goal is to protect PIs background IP Investigator-initiated studies OCT may seek input from PI. PI may have rights. Please make sure OCT is aware if you have additional funding for your study from other sources (e.g., Federal, Industry, Foundation) because the other funders may have study-related IP rights! Intellectual Property (IP) Gatorade

Head football coach of U. Florida Gators, Ray Graves- Practical need UFL researcher/ nephrologist, Robert Cade- Developer Stokely - Van Camp - Funder Federal Government- Funder? University of Florida- Institution Intellectual Property (IP) Minoxidil- late 1950s, Upjohn Company developed a chemical compound in pursuit of a new ulcer treatment. In trials using dogs, the compound did not help ulcers, but it did lower blood pressure. In ulcer trials, Dr. Chidsey (UC consultant) noted hair growth in unusual places, requested feedback from UC head of dermatology, Guinter Kahn.

In 1986, after 15 years of back-and-forth between Guinter Kahn and his medical assistant, Dr. Paul Grant, against Upjohn Co. (now Pfizer), the U.S. Patent and Trademark Office added Kahns name to the first patent granted for a baldness remedy, minoxidil, to be sold under the name Rogaine. 2013/ UPenn -A research team led by stem cell biologist George Cotsarelis identified a key protein that may be able to help people grow new hair follicles; Study results were published in Nature Medicine. The UPenn spinoff company, Follica, claims to have used its technology in a procedure that successfully grew new hair follicles in humans in a clinical trial Publications Importance of publication to University: Closely linked to academic freedom/tax exempt mission

Sponsor cannot have editorial control (academic freedom) Registry requirement must be met in order to preserve ability to publish Clinicaltrials.gov Publications Importance to PI: Helps to establish PIs expertise in field and build connections Recordkeeping, Retention/Destruction Contract specifies: How long records must be kept How they will be stored

When they can be given to sponsor or destroyed Sponsors typically want long retention and storage obligations. Ask for funding for it in your budget! Indemnification by Sponsor Protects Institution and employees from study- related claims/ lawsuits BUT You must give Notice as required in the contract. You must follow the Protocol. You must properly report adverse events.

You must comply with applicable laws and regulations for the study. You must keep good study records. Subject Injury in Industry-Initiated Trials Sponsor covers cost of care and treatment of research-related injuries to subjects Covers Injuries directly related to use of investigational product or protocol procedures Subject injury payment wording in CTA and informed consent must be consistent! Subject Injury Medicare Secondary Payor (MSP) Requirements

Reporting Medicare Reporting: Medicare Secondary Payer (MSP): Medicare is secondary to sponsor obligation to pay for injuries in a clinical trial contract. Sponsors obligations to verify Medicare status and report subject- identifiable information (e.g., social security number [SSN]) to CMS are only triggered when: Sponsor has agreed to be responsible for medical expenses Research subject is injured; and Claim is made for payment of expenses relating to injury

Sponsor must then collect subjects SSN for reporting purposes Term and Termination/Payment in Event of Termination Term: How long is the agreement in effect? Fixed with provisions for extension Open, based on duration of study Termination: Who can quit and under what conditions? Termination rights may not always be mutual Payment in the event of early termination Nonrefundable start-up costs

Expenses incurred Non-cancellable obligations Notices and Notice Timelines Even though you notify sponsor of important events, it may not legally count as notice under your contract The contract language matters! Notices: Who to notify, who to copy, how to notify Throughout contract: When to notify Events trigger timelines (e.g., you become aware of a study related

legal claim, subject is injured, someone working on the study is debarred, you find out you are going to be audited, there is a breach of a confidentiality obligation, you have a discovery or invention). You may work through UNC to notify in some cases. Final Helpful Hints About Clinical Trial Contracts Get your Review Request Form (RRF)/submission to OCT as soon as possible to begin the reviewing and negotiating process: https://apps.research.unc.edu/crms/ (Contact Arielle Wright with questions: email: [email protected] phone: (919)843.2698)

Work with OCT to provide important information as necessary for your study Before signing, read, paying close attention to: Final budget to ensure it is the one you agreed to! Any study specific revisions you may have requested of OCT Your obligations under the agreement Dont Forget READ THE CONTRACT before signing!

Call OCT if you have questions! 919-843-2698 General Number PLEASE VISIT TRACS.UNC.EDU / RESEARCH CENTRAL FOR A COPY OF THIS PRESENTATION & ADDITIONAL HELPFUL INFORMATION BILLING COVERAGE ANALYSIS (BCA) Monica Coudurier Office of Clinical Trials The Billing Coverage Analysis should:

Lead budget development process: to allow negotiators to identify what items and services can appropriately be billed to third party payers, Be completed: before negotiating budget to ensure the sponsor adequately covers study costs, and prior to enrolling study subjects and performing clinical research procedures, Be communicated: to the charge capture and billing systems (Epic) in order to prevent inappropriate Medicare billing. Protocol Evaluation Protocol

Do we have the correct patient population? Do we have the staff and resources? Does it require a Billing Coverage Analysis (BCA)? If you have answered yes to the above questions then you are ready to take the next steps. BCA Definition Billing Coverage Analysis (BCA): A systematic review of research-related documents to determine the (Medicare) billing status of both the study itself and the items and services provided to the research subjects over the course of the

study. A.K.A. Medicare Coverage Analysis Medicare ?#$%&*/!?? Primary BCA objective -- to ensure that all clinical trial costs are billed to the appropriate payer (i.e., Sponsor, a third-party payer (including Medicare), or the patient. Almost every study has the potential to enroll Medicare patients as participants. Medicare rules tend to set the trend for the payor industry. Which studies require BCA?

A billing coverage analysis is required for ALL trials involving any kind of Hospital billingeven those studies wherein the sponsor pays for everything. Drug trials Device trials Otherwise, any trial (e.g., behavioral) that included hospital billed charges of any kind Which studies require BCA? (cont) Who will pay for procedures and services listed in the protocol of your research study? Payer Definition Bill to sponsor only

Procedures/Services are being done for BCA Fee Not Reqd research purposes only and all will be paid for by the research sponsor. Required BCA Worksheets Instructions, Coverage Analysis, Billing Calendar, and Integrated Billing Tabs. [Deemed & Qualifying is optional] Bill to sponsor and patients insurance BCA Fee is Required except for Federally funded trials Procedures/Services are being done for a mix

of research and routine care* purposes only. This may include procedures/services which are done for research purposes or for routine purposes that are paid for by the sponsor or the patients insurance. Instructions, Deemed & Qualifying , Coverage Analysis, Billing Calendar, Integrated Billing Tabs. Bill to patients insurance only BCA Fee Not Reqd All procedures/services are routine care and would be done whether or not the participant

was in the trial. Instructions, and Deemed & Qualifying Tabs There is nothing to bill BCA Fee Not Reqd Study team effort only, no billable procedures/services. BCA Worksheet completion is not required. Current Medicare Clinical Trial Policy National Coverage Determination (NCD) 310.1

Medicare covers the routine costs of qualifying clinical trials, as well as reasonable and necessary items and services used to diagnose and treat complications arising from participation in all clinical trials. All other Medicare rules apply. Pre-Study Financial Workflow Performing BCA Gather necessary items: Final Protocol; Draft contract + budget; Informed Consent (Sponsors model is fine);

Investigational brochure; Lab manual; FDA correspondence; Miscellaneous: IND/IDE number, NCT number. Completing the BCA workbook Download BCA workbook template from CRMS CRMS Step 1: Research Coordinator Saved Initial Budget Instructions tab and other various tabs as applicable (see Billing Coverage Analysis Instructions document at http:// researchcentral.tracs.unc.edu ) Deemed & Qualifying tab Assess trial type: Drug, Device, other (e.g., service) Apply criteria to qualify & determine trials billing status ([NCD 310.1]

Deemed & Qualifying; CMS coverage website) Completing the BCA workbook (cont) Coverage Analysis tab List all billable procedures Match visit headings to protocol Identify items/services provided free by Sponsor Indicate billing category type (Routine, Study, Effort) for each visit at which the procedure is performed Provide audit-worthy justification for procedures designated as Routine Care

Completing/Routing the BCA workbook Integrated Billing (IB) tab Specify location(s) where each procedure will be performed Include any other details to help identify correct procedure code Enter CPT code (if known) Route BCA to OCT within CRMS CRMS Step 2: OCT Coverage Analysis Review Upload Informed Consent and Protocol into CRMS OCT performs QA review then routes [CRMS Step 3] to Integrated Billing Integrated Billing enters codes and pricing information (except Hospital Pharmacy

Completing/Routing the BCA workbook (cont) BCA workbook Returned to Originator in CRMS CRMS Step 4: Research Coordinator Budget Finalization BCA creator receives email from CRMS Check proposed budget/contract to determine if offer covers items and services that are not billable Negotiate with sponsor to finalize budget terms CRMS Step 5: Lead Principal Investigator BCA Certification Finalize Will it cost you anything to be in this study?

Completing/Routing the BCA workbook (cont) Route final BCA (in CRMS) along with final negotiated budget (in RAMSeS) to OCT for inclusion in final contractual agreement CRMS Step 6: OCT Budget Review and Contract Finalization Process can languish if contract is not being negotiated by OCT BCAs for agreements negotiated outside OCT still need Calendarthis step must be completed Finalize Will it cost you anything to be in this study? section of Informed Consent Qualifying Clinical Trials Determined by 2-step process:

Step 1: Determine if trial is one that CMS has deemed to meet the desirable characteristics NIH, CDC, AHRQ, CMS, DOD, or VA Funded by Supported by center or cooperative group funded by OR Conducted under an IND application Determined IND-exempt according to FDA regulations Step 2: Confirm that trial meets all 3 of the following criteria

1. Evaluates an item or service that falls within a benefit category 2. Study designed with therapeutic intent 3. Enrolls patients with diagnosed disease Qualifying Clinical Trials (cont) If the study is a qualifying clinical trial, then routine costs in the trial can be billed to Medicare, provided the item or service is otherwise covered by Medicare. In simple terms, a routine cost is one of the following: Conventional care Administration of the investigational item Detection, prevention, and treatment of side effects or complications Routine costs do not include items like data collection,

quality of life assessments, or tests done more often than routinely outside the trial. Qualifying Clinical Trials (cont) If trial fails either part of the two-part test, it is not a qualifying clinical trial and none of the protocol-required items and services is billable to Medicare, even if it would be covered outside the trial. Qualifying Clinical Trials (cont) Determining the qualifying status is done by answering a series of questions as shown below: 1.

Does the investigational item/service fall into a Medicare benefit category? 2. 3. Does the study have therapeutic intent? Does the study enroll patients with diagnosed disease? 4. Is the study a deemed trial? Qualifying Clinical Trials (cont) A service or item that is NOT covered outside a clinical

trial will not be covered when performed or given as part of a qualifying trial, even if the item or service is standard of care. Most self-administered drugs are such non-covered items. Example: P.O. or orally administered Exclusions from Medicare Coverage Medicare will not pay routine costs that are: paid for by the sponsor, promised free in the informed consent document, not ordinarily covered by Medicare, or performed solely to determine trial eligibility, data collection, or

analysis. In other words.. If the sponsor pays for an item or service; or an item or service is provided free of charge to an enrollee, then Medicare cannot be billed for that service Practical Implications If a deal (i.e., free service) is given to an enrollee in a research study, then Medicare must receive the same deal (i.e., a free service) and cant charge Medicare. Non-Compliance Failure to comply with applicable laws, regulations, and Informed Consent documents

Intentional or unintentional Serious and continuing non-compliance is reportable to federal funding agencies and FDA (for studies subject to their authority) Why does this happen? Decentralization Unfamiliar with the rules Not paying attention Lack of coordination, collaboration, and communication False Claims Act (31 USC 3729-33) Enacts liability against a person or entity who knowingly

ignores CMS regulations (as demonstrated by reckless disregard or deliberate ignorance) by: Submitting a false claim, Using a false record or statement to get a claim paid or approved, Causing a 3rd party to do either of the above Civil penalties: $5K-$11K per submitted claim plus up to 3x damages incurred by government Possible exclusion from participation in federal health care programs Risks of Non-Compliance Properly performed BCA is necessary to protect researchers and the institution against violations of the False Claims Act and other

regulations. Inappropriate Medicare billing is considered fraud and can lead to large fines. The rules do not allow billing for services: that are part of a non-qualifying clinical trial promised free in the informed consent already paid by the sponsor (double-dipping) performed for research-purposes only without providing the NCT number to Part C (Medicare Advantage Plans) rather than the Medicare Administrative Contractor (MAC) DEVICES: without MAC approval letter in-hand Systems & processes are needed to apply proper billing and diligence to ensure charges go to the correct party and are not billed incorrectly or to multiple payers. Role of Informed Consent Form

Every research study must have a section in the Informed Consent Document that discloses added costs the subject may incur while participating in the trial. EXAMPLE: You or your health plan must provide payment for hospital, clinic, and other medical costs that are considered routine care for patients with your disease. The sponsor of the study XYZ Company will provide the study drugs at no cost to you. Those procedures done solely for the purposes of the study will also be provided to you by XYZ Company at no charge. Make sure the Sponsor budget and Informed Consent

Document match for items billed to insurance or covered by Sponsor BCA Training Training needed to properly complete the Billing Coverage Analysis process. UNC is making BCA training a priority and will be bringing in experts to help with training. TRIAL REGISTRATION AT CLINICALTRIALS.GOV: FDA, ICMJE, NIH, AND CMS Monica Coudurier

Office of Clinical Trials What is ClinicalTrials.gov? Web based registry that provides regularly updated information about federally and privately supported clinical trials First version publicly available February 29, 2000 Some information provided in ClinicalTrials.gov records includes the following: Disease or condition and experimental treatments studied Title, description, and design of study Requirements for participation Location(s) where the study is available Overall study status Recruitment contact information

Links to relevant information at other health Web sites, such MedlinePlus and PubMed What Trials Must be Registered? There are 4 independent reasons requiring trial registry: ICMJE (International Committee of Medical Journal Editors) FDA - FDAAA Section 801/Code of Federal Regulations NIH (National Institutes of Health) CMS (Centers for Medicare & Medicaid Services) The International Committee of

Medical Journal Editors (ICMJE) Policy Per the ICMJE, any trial meeting the following definition of clinical trial must be registered to be considered for publication: any research study that prospectively assigns human participants or groups of humans to one or more health related interventions to evaluate the effects on health outcomes. Health-related interventions include any intervention used to modify a biomedical or health-related outcome (e.g., drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and process-of-care changes). Health outcomes include any biomedical or health-related measures obtained in patients or participants, including pharmacokinetic measures and adverse events. Purely observational studies (those in which the assignment of the medical intervention is not at the discretion of the investigator) will not require registration.

PHS Act/Code of Federal Regulations (CFRs) Trials that must be registered are called Applicable Clinical Trials (ACTs), these trials generally include: Trials of Drugs and Biologics: Controlled, clinical investigations, (other than Phase 1 investigations), of a product subject to FDA regulation (If efficacy is an endpoint of Phase I study, it must be registered). Trials of Devices: Controlled trial with health outcomes, other than small feasibility studies, and pediatric postmarket surveillance.

National Institutes of Health (NIH) NIH requires registration of trials meeting FDA requirement; encourages registration of ALL trials whether required under the law or not. NIH encourages results reporting for all NIH supported clinical trials registered in ClinicalTrials.gov, regardless of whether or not they are required to do so under FDAAA Centers for Medicare and Medicaid Services (CMS) Effective January 1, 2014 CMS began requiring the NCT number on claims submitted to Medicare

Interim stage (NCT99999999) from 1/1/2014 thru 1/1/2015 Dummy numbers no longer optional (since Jan 1, 2015) What Studies Require Data Results? FDAAA 801 (effective Sept. 27, 2008) expanded registry and added results database: to include reporting of results for those trials that meet the definition of Applicable Clinical Trial or ACT (regardless of whether the study has an IND or IDE) Serious Adverse Event reporting (effective Sept. 27, 2009)

Federally funded trials? Who is Responsible for Registering Trials? Clinicaltrials.gov registration is the responsibility of the trial sponsor: UNC Investigator initiates and sponsors trial PI registers Trial in which PI obtains industry funds NIH or other grant funded trial (external or internal grants) UNC PI holds an IND or IDE

Industry initiated/sponsored trial Industry sponsor registers Getting Started CT.gov User Account Set-Up If UNC PI must register on CT.gov: CT.gov user account set-up and record assistance available through the UNC Office of Clinical Trialscontact Monica Coudurier at 843-2333 or [email protected] Mary ODwyer for LCCC/Oncology studies [email protected]

Deadlines for Registering Trials ICMJE Policy Study must be registered prior to enrollment of first subject. If an investigator would like to publish the data actice should be followed PHS Act, CFRs: FDAAA, Section 801 Study must be registered no later than 21 days after enrollment of the first subject. This is required by US Public Law and must be done NIH Unspecified

CMS Prior to claims submission Record Upkeep: Following Registration Ensure the information is complete, accurate, and updated every 6 months or as changes occur Review the record and update as necessary Active trials (Not yet recruiting; Recruiting; Enrolling by Invitation; Active, not recruiting) Update status when enrollment ceases Provide Results within 1 year of Actual Primary Completion Date

i.e., date that the last primary outcome measure data was collected Registration Overview Other Registration Phase Phase Interventiontimeline Posting of Results I II-IV al Trials NIH YES

YES YES Unspecified Encourages results reporting for all NIH supported clinical trials registered in ClinicalTrials.gov, regardless of whether or not they are required to do so

under FDAAA ICMJE YES YES YES Prior to enrollment of 1st subject NO

Applicable Clinical Trial (ACT) per CFRs: FDAMA, FDAAA, Public Law 110-85 NO YES NO Within 21 days of 1st subjects enrollment

YES CMS YES YES YES Prior to claims submission NO

Monetary Penalties What are the penalties for failing to register an Applicable Clinical Trial? Penalties for responsible parties who fail to register, or provide false or misleading information in connection with, applicable clinical trials are significant and may include civil monetary penalties (up to $10,000 per day) and, for federally-funded trials, the withholding or recovery of grant funds. See PL 110-85, Sections 801(a), (b), (adding new 42 U.S.C. 282(j), and new 21 U.S.C. 331(jj). BUDGETING AND ACCOUNTING OF

RESEARCH FUNDS Jillyan Cunnup Administrator, Division of Endocrinology The Financial Struggle Process of Building a Budget Review most recent protocol and study activity listings (Protocol Feasibility) Review

Contract and current budget (if provided) List all other fees, direct and indirect Identify procedures required and determine cost Budget Development Clinical Trial Agreement

Start up and Advance payment When and How much? Payment Cycle How often will they pay? Withholding % How much are they going to hold back? Length of Storage 10-20-30 years? Final Payment Timing of Payment? External Budget Direct Costs Labs EKG

CT Scans Effort Costs Informed Consent- Creation of CF as well as consenting subject Physical Exams, Vitals and History Coordinator and PI Time Drug Dispensing Review of Labs Coordinator and PI Time Scheduling of Patients How long does it take to transport that patient for a CT Scan etc? Recruitment Monitor Visits Effort Based Costs

Effort Based Procedures Informed Consent Physical Exams Vitals and History Drug Dispensing PI and CRC Time Review of Labs, Scheduling of patients, recruitment of patients monitor visits etc. F&A Ensure correct University F&A rate is being applied Invoiced Items Start Up Fee Advertising Document Storage

Rent IRB Renewal IDS Screen Fails Adverse Events Dry Ice Protocol Amendment FDA/Sponsor Audits IRB Fee Facilities and Administration Rate

Activity On-Campus Off-Campus (10-mile radius) Off-Campus (Remote) Organized Research 52%

28.00% 26.00% Instruction 50% 28.00% 26.00% Other Sponsored Activities

36.% 28.00% 26.00% Clinical Trials (Federal)** 52.00% 28.00% 26.00%

Clinical Trials (Non-Federal)*** 28.00% 28.00% 26.00% Successful Negotiation What is negotiation? Negotiation is the process of two parties or individuals reaching an agreement and actively participating in making decisions

Successful Negotiation? Succeeding means that you work with the other party to reach a solution to the issue you are all happy with it does not mean viewing negotiation as a battle to be won! Federally Funded Budgets RFA-Request for Application All Federal Funded applications are linked to a RFA which details the requirements for the application. SF424 Common packet used for NIH submissions will include budget, bio

sketches, research plans, science of grant etc. Salary Cap/Cost Share The current NIH Salary Cap is 179,700 anyone being paid from the grant making over that amount must have a cost shared effort. Cost Sharing is the portion of the project that is contributed by the University for example if you have a salary of 200,000 and are going to spend 10% of your efforts (20,000) you are only allowed to charge the grant for 10% of 179,700 (17,970) the difference must be charged to a University account and paid for by the University. Using this example you would need approval to cost share $2,030. Modular Budget Vs. Detailed Budget

Modular Budget Used only in certain types of NIH applications provides a less detailed budget with a maximum of 25,000 per module (250,000 per project) Does NOT list out salary and fringe benefit rates though the salary cap does still apply Detailed Budgets Effort must be shown in Calendar months not % of effort (10% effort =1.20 calendar months) Fringe Benefits Senior/Key Personnel

Equipment Travel Publication Other costs related to project Maximum depends on the information in the RFA Accounting of Research Funds The tracking of research funds can make or break a research project. This is often done by various people in the department but is crucial to success Visits Payment

Expenses Visit Tracking Industry Sponsored Trials Log of completed, skipped or incomplete visits Track when data entry is completed per visit Keep a log of each visit completed by the subject and make note if certain parts of the visit were not completed or if a visit was skipped. Federal Funded Tracking subject visits is equally important on a federal funded studies. Depending on how the study is set you up may have already received a set amount based on the number of patients. If you fail to recruit or skip a visit you

could end up paying back money at the end of the grant. Patient Data Invoicing- Why and How? Why should we invoice? To ensure ACCURATE payment of completed work. To ensure TIMELY payment of completed work To ensure QUALITY reconciliation can occur How do we invoice? Send invoice to the sponsor with visit data Send invoice to managers with visit data Payment and Expenses Checks Ensure checks are sent in a timely manner based upon contract Always verify that the amount of money received matched the

amount of work completed. Expenses Track procedure, patient payments, salary, supplies as well as other study related costs. Financial Compliance Effort Certification and Reporting Technology Effort is the portion of time spent on a given professional activity and expressed as a percentage of the total 100% professional activity for which an individual is employed by UNC. Important points: The government recognized that it is a reasonable estimate Total effort must equal 100%

Effort is not based on a standard (e.g 40-hour) work week, instead based on whatever was worked 100% effort considers all professional activities related to the individual UNC appointment. Effort does not include outside activities (external consulting etc) Certifying Effort Effort is certified on a regular basis via ecrt.unc.edu All employees paid from sponsored activities are required to certify the effort spent Effort is calculated based on the information in the payroll system The investigational item or service itself, unless otherwise covered outside the clinical trial Closing of Account

All money received? Make sure all visits, invoiced items, Always verify that the amount of money received matched the amount of work completed as well as the amount on the contract. Expenses Verify IRB, IDS and other University expense have been paid. Often with UNC bills are delayed and it is your responsibility to check this before closing a study. Residual Funds If you have money leftover you will be allowed to transfer the funds into a residual. Residual accounts are managed at the Department/Division level. You will need to be aware of what the policy is on spending and accountability. Federal funded grants will require written communication and

approval from the NIH for carryover or no-cost extensions. STUDY TEAM RESPONSIBILITIES Laura Tuttle, MA, CCRP Hypertension Research Program Manager Chair, NCRP Principal Investigator Ultimate administrative and fiscal responsibility for the team performance of the study subject to IRB/Institution review and oversight: The science The integrity The business operations

Understanding and following the protocol as approved by the IRB is the first and most critical obligation of the investigator in human subjects research. Legal Commitments in Drug & Device Research When PI signs FDA form 1572 (for IND studies - Drugs) or "Statement of the Investigator (for IDE studies - Devices), signing a legally binding document committing themselves to conduct study according to protocol and FDA regulations. Form 1572 is a written agreement (signed) between PI and federal government. PIs nine responsibilities (or commitments) as stated in FDA

regulations are detailed on Form 1572 for Drug Trials. Form FDA 1572 (excerpts) I agree to conduct the study(ies) in accordance with the relevant, current protocol(s) and will only make changes in a protocol after notifying the sponsor, except when necessary to protect the safety, rights, or welfare of subjects I agree to inform any patients, or any persons used as controls, that the drugs are being used for investigational purposes and I will ensure that the requirements relating to obtaining informed consent in 21 CFR Part 50 and institutional review board (IRB) review and approval in 21 CFR Part 56 are met

I agree to report to the sponsor adverse experiences that occur in the course of the investigation(s) in accordance with 21 CFR 312.64. I have read and understand the information in the investigators brochure, including the potential risks and side effects of the drug. I will ensure that an IRB that complies with the requirements of 21 CFR Part 56 will be responsible for the initial and continuing review and approval of the clinical investigation. I also agree to promptly report to the IRB all changes in the research activity and all unanticipated problems involving risks to human subjects or others. Additionally, I will not make any changes in the research

without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects. Form FDA 1572 Oversight of Staff I agree to personally conduct or supervise the described investigation(s). I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the study(ies) are informed about their obligations in meeting the above commitments. You failed to personally conduct or supervise the clinical investigation your lack of supervision resulted in significant findings as detailed below, and raises significant concerns with respect to data integrity and how you protected rights, safety and welfare of study subjects

Should Sub-investigator be listed in Section #6 of FDA 1572? FDAs regulation at 21 CFR 312.3(b) states In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. Subinvestigator includes ANY other individual member of the team. Purpose of Section #6 is to capture information about individuals who will assist the investigator and make a direct and significant contribution to the data. Should coordinator be listed on FDA 1572? The decision about whether to list a pharmacist or research coordinator on the 1572 is a matter of judgment, dependent upon the contribution that the individual makes to the study.

The role of a research pharmacist may be: Prepare test articles Maintain drug accountability The role of a research coordinator may be: Recruit subjects Collect and evaluate study data Maintain study records Claudia Christy and Laura Cowen of UNC TraCS recently published a column in the ACRP journal advocating for coordinators to be included in 1572. Investigator Obligation at UNC-CH With or Without FDA Involvement

Obtain IRB approval before performing the protocol and before performing any changes or additions from what the IRB has approved for the project. Perform the protocol AS APPROVED by the IRB Provide the IRB with accurate and complete information and updates as the information changes Notify the IRB of all unanticipated or serious adverse events involving risk to human subjects Provide all reports required by the IRB on the timeline

required by the IRB Clinical Research Coordinator (CRC) What is your title? Social/Clinical Research Assistant Social/Clinical Research Associate Social/Clinical Research Specialist Research Nurse Clinical Nurse Project Manager Research Manager Research Instructor Others?

Primary Responsibility Per UNC OCT, role of the CRC is to . . . ensure smooth, accurate progress of the project from the planning stage through study end (and often beyond) by acting as liaison to the investigator, the subject, the institution, and the company or government sponsor. Role has evolved over the years as the clinical research industry has evolved Requires: Attention to detail Good communication Flexibility Ability to work independently Organization

Continuing education Primary Responsibility The Invisible Hand in Clinical Research: The study coordinators critical role in human subjects protection (Davis et al., 2002) Metaphors for 3 primary roles: Mother patient welfare / patient advocate Lawyer participant rights and welfare / providing neutral information Teacher / Policeman understand value of protocol and defend it Conducting Clinical Research, Judy Stone, MD Coordinators manage the logistics of everything!!!

Shared Responsibilities Many PI responsibilities are delegated and become the CRCs operational responsibility Know what responsibilities belong only to PI and what roles you are capable of performing FDA Guidance Document: Investigator Responsibilities protecting the rights, safety, and welfare of study subjects http:// www.fda.gov/downloads/Drugs/GuidanceComplianceRegulat oryInformation/Guidances/UCM187772.pdf General CRC Responsibilities: Protocol Evaluation Subject availability Personnel requirement

Equipment & facility availability Testing capabilities Develop timelines Propose & negotiate alternatives to improve implementation General CRC Responsibilities: Administrative Interact with IRB, lab staff, clinic staff, pharmacy, nursing

homes, assisted living, churches, community centers, etc. Prepare IRB documents including ICF Prepare Study Budget Ensure all documentation is maintained Interact with Sponsor Interact with PIs and sub-investigators Coordinate and participate in monitoring visits with sponsor Complete CRFs and submit to sponsor Facilitate inspections/audits Document study progress

General CRC Responsibilities: Study Subjects Recruit study subjects Determine subject eligibility Discuss study with subject Obtain informed consent Schedule subject visits/assessments Ensure all study tests and visits are done at appropriate time intervals General CRC Responsibilities: Study Subjects Evaluate study subjects at appropriate intervals

Assess laboratory data and clinical signs for potential adverse events Adverse Events (AEs) Assist PI with gathering information to help PI determine classification, and causality Observe and document AEs Act on PIs recommendation Maintain follow-up until reconciliation Communication with sponsor General CRC Responsibilities:

Study Subjects Provide information for treatment and reactions Administer or dispense investigational agent, as outlined in the protocol, under the investigators supervision Promote subject compliance by providing patient support and education Arrange for study subject compensation General CRC Responsibilities: Data Management Investigational Drug Accountability

Order, store, dispense, retrieve, log Randomization codes Unblinding procedures Prepare lab specimens; ship biological samples and radiologic films Ensure data is collected in accordance with the protocol Complete data collection forms Enter data into database

Maintain data security Check data for validity Respond to data queries STUDY START-UP AND IMPLEMENTATION Laura Tuttle, MA, CCRP Hypertension Research Program Manager Chair, NCRP Protocol Implementation Protocol Implementation Before your study starts, some things to consider: Study start up meeting

Documentation of training of all individuals listed on delegation log Notification to providers, nurses, clinic staff, and other team members of upcoming research protocol Once IRB approval received, contacting potential subjects regarding participation in research protocol Development of a recruitment plan and materials Creation of source documents Organization of study materials Protocol Implementation Organization of study materials: Regulatory binder Randomization information Supply order forms

Investigational drug Standard operating procedures (SOPs) Case report forms (CRFs) Visit checklists Is this how your office looks? Patient Research Charts Protocol Implementation Creation of source documents:

Review your study visit schedule Review the case report forms to ensure you collect all information that will be documented on CRF Develop standard forms for department that can be used across studies. Physical Exam form Medical history form General Research Record Documentation of Informed Consent Template Depending on study development of a study start up checklist may be helpful PLEASE VISIT


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