Orientation for New Clinical Research PERSONNEL Module 2

1. Orientation for New Clinical Research PERSONNELModule 2 Presented by NC TraCS Institute UNC Office of Clinical Trials UNC Network of Clinical Research Professionals

2. Overall Agenda for Orientation • Module 1: September 12, 2012 - Introduction to Clinical Research, Education, and IRB • Module 2: September 19, 2012 - Study Implementation, Documentation, and GCPs • Module 3: September 26, 2012 - Contracting and Hospital Administrative Elements • Module 4: October 3, 2012 - Clinical Trial Management, Budgeting, Hospital and Research Accounting

3. Overall Agenda for Orientation • Module 1: Introduction to Clinical Research, Education, and IRB • Module 2: Study Implementation, Documentation, and GCPs • Module 3: Contracting, COI, and Hospital Administrative Elements • Module 4: Clinical Trial Management, Budgeting, Hospital and Research Accounting

4. Study Team Responsibilities Michelle Duclos, NCRP

5. 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

6. 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. • PI’s nine responsibilities (or commitments) as stated in FDA regulations are detailed on Form 1572 for Drug Trials.

7. 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 investigator’s 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.

8. 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.

9. Should Sub-investigator be listed in Section #6 of FDA 1572? • FDA’s 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. “Sub-investigator” 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. • See Information Sheet Guidance for Sponsors, Clinical Investigators, and IRBS – FAQs – Statement of Investigator (Form FDA 1572) • http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm214282.pdf

10. 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. • A research pharmacist may prepare test articles and maintain drug accountability for many clinical studies that are ongoing concurrently at an institution. Because the pharmacist would not be making a direct and significant contribution to the data for a particular study, it would not be necessary to list the pharmacist as a subinvestigator in Section #6, but he/she should be listed in the investigator’s study records. • A research coordinator has a greater role in performing critical study functions and making direct and significant contributions to the data. For example, a research coordinator often recruits subjects, collects and evaluates study data, and maintains study records. Therefore, the research coordinator should usually be listed in Section #6 of the 1572. • Excerpt from FDA Guidance document #33

11. 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

12. 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 Instructor • Others?

13. 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 sponsor1.” • Role has evolved over the years as the clinical research industry has evolved

14. Shared Responsibilities Many PI responsibilities are delegated and become the CRC’s 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/GuidanceComplianceRegulatoryInformation/Guidances/UCM187772.pdf

15. FDA Final Guidance • Guidance provides an overview of the responsibilities of a person who conducts a clinical investigation of a drug, biological product, or medical device (an investigator as defined in 21 CFR 312.3(b) and 21 CFR 812.3 (i)) • Guidance and information sheets represent the Agency’s current guidance and EXPECTATIONS on good clinical practice and conduct of clinical trials. • Goal of this guidance is to help investigators better meet their responsibilities with respect to protecting human subjects and ensuring the integrity of the data from clinical investigations. • Guidance intended to clarify for investigators and sponsors FDAs expectation concerning the investigator’s responsibility. • To supervise a clinical study in which some study tasks are delegated to employees or colleagues of the investigator or other third parties, and • To protect the rights, safety, and welfare of study subjects

16. General CRC ResponsibilitiesProtocol Evaluation • Subject availability • Personnel requirement • Equipment & facility availability • Develop timelines • Propose & negotiate alternatives to improve implementation

17. General ResponsibilitiesAdministrative • Interact with IRB, lab staff, clinic staff, pharmacy, nursing homes, assist living, churches, community centers, etc • Prepare IRB documents including ICF • Prepare Study Budget • Assure 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 • Resolve data queries • Facilitate inspections/audits • Document study progress

18. General CRC ResponsibilitiesStudy Subjects • Recruit study subjects • Assess subjects for eligibility • Discuss study with subject • Obtain informed consent • Schedule subject visits/assessments • Assure all study tests and visits are done at appropriate time intervals

19. General CRC ResponsibilitiesStudy 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 PI’s recommendation • Maintain follow-up until reconciliation • Communication with sponsor

20. General CRC ResponsibilitiesStudy Subjects • Provide information for treatment and reactions • Administer or dispense investigational agent, as outlined in the protocol, under the investigator’s supervision • Investigational Drug Accountability • Order, store, dispense, retrieve, log • Randomization codes • Unblindingprocedures • Promote subject compliance by providing patient support and education • Prepare lab specimens; ship biological samples and radiologic films • Arrange for study subject compensation • Comply with FDA regulations for conducting clinical trials

21. Study Implementation Michelle Duclos, NCRP

22. Protocol Implementation

23. Protocol Implementation • Research Site – 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 • Pre-identification of potential subjects – • Once IRB approval received, contacting potential subjects regarding participation in research protocol • Development of a recruitment plan • Organization of study materials • Creation of source documents

24. Protocol Implementation • Organization of study materials • Regulatory binder • IRB binder • Correspondence binder • Protocol binder • Investigator brochure binder • IVRS information • Supply Order forms • Investigational Drug • Study Manual

25. Is this how your office looks? Patient Research Charts

26. Protocol Implementation • Creation of source documents • Helpful hints: • review your study visit schedule • review the Case Report Forms or eCRFs to ensure you collect all information that will be documented on CRF • Develop standard forms for department that can be used across studies. • Examples • Physical Exam form • Medical history form • General Research Record or SOAP note • Documentation of Informed Consent Template

27. Depending on study development of a study start up checklist may be helpful

28. Recruitment • A recruitment plan should be developed as soon as you have begun work on the protocol, whether investigator initiated, industry sponsored, or NIH (IRB approval of all recruitment materials is required) • Advertising campaign • TV, Radio, Print, Website • Dear Doctor Letters –fax or email local providers, recommend follow-up with a meeting if you want practice to help • Direct to Patient from databases • Posters, Pamphlets, Mailings (letters, post cards) • Determine if Carolina Data Warehouse can be utilized • Develop a phone screen/script as necessary for phone calls • Social networking opportunities • Community events (fairs, flea markets, senior centers) • Develop a UNC mass email • Communicate internally with departmental doctors for referrals, develop a system in department for identification of potential subjects • Communicate with NC TraCS

29. Good Clinical Practices &Study Documentation Marie Rape, RN, BSN NC TraCS Institute

30. Good Clinical Practice GCP defined as “…international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects.” E6 Good Clinical Practice: Consolidated Guidance

31. E6 Good Clinical Practice: Consolidated Guidance • 1996: In an attempt to provide consistency among clinical trials, US, European Union, and Japan established a unified standard, called the International Conference on Harmonisation’s “Good Clinical Practice: Consolidated Guideline,” (ICH-GCP). • Objective of “guidance is to provide a unified standard to facilitate mutual acceptance of clinical data by the regulatory authorities in these jurisdictions.” • E6 Good Clinical Practice: Consolidated Guidance recognized by industry sponsors as the gold standard for conduct of ethically and scientifically sound human subject research. From the Introduction of Guidance for Industry, E6 Good Clinical Practice

32. Topics Covered in ICH GCP

33. Why is Adherence to GCP Important? Main tenets of GCP: research involves good science, is verifiable, monitored, well-documented, and study complies with the highest ethical standards. Adherence to GCPs: • Protect the rights and well-being of human subjects • Ensure accuracy and credibility of the data and reported results • Ensure conduct of the trial is in compliance with: • the protocol/amendment(s) currently approved by the IRB • applicable regulatory requirements • institutional policies • all applicable rules and regulations

34. Who Should Adhere to GCP? • The general concept of GCP is essential for any research study involving human subjects. • Whether conducting research involving a new drug or device, a behavioral intervention, or an interview/survey, Good Clinical Practice (GCP) provides investigators and study teams with the tools to protect human subjects and collect quality data. • Following the ICH-GCP is one of the best ways to substantiate the quality of any research study and its resulting data.

35. Documentation • Once a scientifically valid research idea has been proposed and approved, the key to successful implementation of the study lies in the documentation. • “If you didn’t document it, it didn’t happen.” • Validity of research data rests in the documentation • Resources, such as checklists and templates assist investigators & study staff in implementing, and documenting that they followed GCP and the protocol.

36. FDA Regulations Require Investigator to Maintain Study Files For FDA Drug studies(21 CFR 312.62) • prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the (drug) investigation on each individual administered the investigational drug or employed as a control in the investigation • case histories include the case report forms and supporting data (source documents). For FDA Device Studies (21 CFR 812.140) • Maintain accurate, complete, and current records relating to participation in (device) investigation

37. Source Documents • Source Documents: All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstructionand evaluationof the trial. International Conference on Harmonization E6 • The first place something is recorded is considered the source document for that clinical trial activity • A “trail for the trial”: Source documents should create a “trail” so that anyone can verify and follow what happened throughout a clinical trial and where the data came from (an audit trail)

38. Types of Source Documents • Medical history • Hospital records • Clinic & office charts • Progress notes • Lab notes • Memoranda • Meeting minutes • Notes to file • Phone records • Subject diaries • Questionnaires • Subject files or records • Drug dispensing records • Recorded data from automated instruments (DynaMap, ECG, EEG, ) • X-rays, scans, MRIs

39. Example of a source document? Subject 105-0001 ABC 3/1/06

40. Case Report Forms (CRFs) • CRFs are paper or electronic documents/forms designed to record all information required by the study protocol for a participant (provided by Sponsors). • All information entered on CRF must be supported by source documents • If data recorded directly on CRF, there should be an entry in subject's medical record or subject file that records date information was obtained, how and by whom. • CRFs may be used as a source document IF data elements are newly created and not transcribed from other sources. • FDA opinion that copies of CRF used as a source document are not a replacement for original source documentation.

41. Important Events to Document • The Consent Process (more than just signed consent form) • Documentation of subject eligibility (inclusion/exclusion criteria) • Study randomization, study drug adherence or non-adherence • Completion of all protocol-required tests, procedures • Missed visits, subject contacts, procedures, or examinations • Protocol deviations & violations (notifications to IRB / sponsor and corrective actions) • All subject contact – either via phone or in person (include date/time and reason for contact) • Unanticipated problems or adverse effects and relationship to study intervention, severity, action taken and reporting to IRB • Subject termination (withdraw of consent, lost to follow up, PI removal)

42. Templates Improve Source Documentation • Some research data collected on Hospital based forms as part of medical care: • Vital signs on clinic record sheet • Medication administration on MAR for inpatients, • Laboratory tests • History and physical exam • Other research data only collected by study staff and not maintained in Medical Record or on any other form. • Use of templates to document research data helps study team collect required data and have a place to record it. • Other data can be written on progress notes.

44. I / E Criteria Checklists • Good practice for study teams to incorporate an eligibility checklist into each subject’s study record so that study staff can document on a form how each of the inclusion and exclusion criteria have been met. • Create a template that is study specific, listing all the inclusion and exclusion criteria for the study and check off that subject meets each and every criteria Documentation of Eligibility Important! • Keep supporting documentation that demonstrates that subject meets criteria (e.g., colonoscopy results to demonstrate normal colon)

45. Sample Inclusion/Exclusion Criteria Checklist

46. Signature by PI that Subject is Eligible If the responses to all the inclusion criteria are YES and all the exclusion criteria are NO, the subject is eligible to participate in the trial. Is the subject eligible to participate in the trial? YES NO If NO, discontinue the subject and complete the study termination form. If YES, I have reviewed the inclusion and exclusion criteria and have determined that the subject is eligible for participation in the trial. Investigator ___________________________ Date ___________

47. Eligibility Criteria • IRB approval of protocol includes approval of inclusion & exclusion criteria as written. These eligibility criteria are NOT guidelines, but are requirements that must be followed. • The “inclusion/exclusion criteria” define the study population, and ensure the safety and the integrity of the data • Investigator may wish to enroll a subject who does not precisely fit the eligibility criteria • PI must obtain IRB approval for the change in eligibility criteria • May make an exception for a single subject (not change criteria in protocol) • After the amendment or exception is approved by IRB, the subject can be then be enrolled

48. Enrollment Note Template Study IRB #: Principal Investigator: Subject Name: ___________________ ID#: ___________ Yes No Investigator’s Signature ____________________ Date ________

49. Note to File Template From Office of Clinical Trials

50. Template for Progress Notes or PE PROGRESS NOTES IRB # Study Title: Subject ID#: _________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________ Signature______________ Date __________