Objectives

1. Session III: (Breakout A) - Nuts and Bolts of Clinical Trials Participation for Investigators and Sub-Investigators Clinical Research Documentation and Review Tuesday, February 2, 2010 Lindsey J. Klane

2. Objectives • GCP And Training Requirements (GCP, GMP And GLP) • Role And Responsibilities • Sponsor • Monitor • IRB/ERB • Clinical Research Site Staff • Documentation • Site Binder • Subject Binder • Central Image Binder • Reporting And Training

3. Good Clinical Practice is… … an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well being of trial subjects are protected…. The guidance was developed with consideration of the current good clinical practices of the European Union, Japan, and the United States, as well as those of Australia, Canada, the Nordic countries and the World Health Organization (WHO). April 2006 CFR & ICH Guidelines

4. Good Clinical Practice (continued) & Additional Regulations • All Research Staff Must Receive Documented Training • Investigator Meetings • Online Training • CRO Monitor On-Site • Refresher Training (annual) • Good Manufacturing Practices • Manufacturing radiopharmaceuticals • Good Lab Practices • Handling/analyzing study specific lab samples

5. Sponsor Responsibilities Prepare the IB (Investigational Brochure) Design medically & scientifically sound clinical protocols Obtain regulatory approvals Select clinical investigators (CRO) Supply the investigators with all the necessary technical & safety data to treat patients Define the compensation to the investigator & subjects (if applicable) Manage proper monitoring & quality assurance procedures Handle and manage adverse events Process clinical data (Outsource) Prepare and report safety findings Prepare clinical study reports Establish & maintain company SOPs

6. Monitor Responsibilities • Trained • Follow sponsor (CRO) SOPs • Conduct pre-study assessments • Support & Train the investigator site staff • Ensure compliance with the protocol through monitoring & quality assurance measures (Source Document Verification) Manage clinical data & CRFs • Confirm proper handling of Investigational Product (IP) & drug supply • Identify & ensure follow up of adverse events • Ensure local regulatory compliance

7. Institutional Review Board Responsibilities Establish and maintain IRB SOPs Review protocol within reasonable time; document in writing its views, identify trial/documents reviewed and dates of review Consider qualifications of the PI proposed for the study Conduct continuing review of ongoing trials at least once per year Review of Informed Consent form (often request additions or deletions of text) No coercion for subjects to participate Review amount of payment (PI and subject Where prior consent of a subject/legally acceptable representative is notpossible (e.g., emergency situations), determine that the protocol/other documents address ethical concerns & meet regulatory requirements Ensure that method of subject’s compensation is included in ICF; payment must be pro-rated Ensure additional safeguards are included in the study to protect the rights/welfare of vulnerable subjects (children, prisoners, pregnant women, handicapped, economically/educationally disadvantaged persons) Ref: ICH 3.1.9; FDA 21 CFR 56.111

8. Principal Investigator Responsibilities • Establish and maintain Standard Operating Procedures (SOPs) • Qualified to conduct the clinical trial • Read the protocol … then read it again • Understand properties, effects & safety of the investigational product and/or modality • Training • Good Clinical Practice • Protocol • Procedures • SOPs • Ensure all Site Staff Receives Training • Facilities, staff and time for the clinical trial

9. Principal Investigator Responsibilities • Review all study documentation: amendments, ICFs, handouts, etc. by an IRB/IEC • Present subjects with enough information (not just the Informed Consent procedure/document) • Ensure subject confidentiality • Employ unbiased selection of subjects • Document deviations/violations • Provide adequate & safe medical care & FU of subjects

10. Principal Investigator Responsibilities • Collect and record all data accurately & appropriately document all corrections • Notify the sponsor & IRB of SAEs, violations/deviations, annual summary • Be available for monitoring visits • Manage accountability of drug supplies • Accept source document verification & other quality assurance procedures • Maintain study records as required by the health authorities and the sponsor (regulatory files/source documents) • Retain study related documents

11. Source Documentation • Original documents, data, and records (hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification, x-rays, subject files, Informed Consent Form, Appointment Book, consultants’ letters….. Definition: (ICH 1.52) • For all data entered onto the CRF identical source documentation must exist where the data was first recorded. • No photocopies or “shadow charts”. • Source document file containing original documentation is acceptable. • All source documentation should be initialed/signed and dated by the PI or a delegated member of the study team

12. The site must have the following materials prior to initiation: • Site Regulatory Binder • Central Laboratory Supplies and Manual (If applicable) • IVRS and IWRS Manual with worksheets, Site number, access code envelope, IVRS PIN number/ password and/or IWRS UserName/Password (If applicable) • Imaging Binder (to include Image Operations Manual, Image Acquisition Guidelines, transmittal forms) • Subject Binders • Screen Failure Binder • Case Report Forms (CRFs) (this may be electronic) • Protocol • Investigator’s Brochure • IRB/EC approval of protocol, Informed Consent and Investigator’s Brochure • Investigational Medicinal Product (interchangeable with Investigational Product)

13. Site Regulatory Binder Example Each site is responsible for maintaining the Site Regulatory Binder in accordance with local regulations. • Protocol • Protocol Amendments • Informed Consent • Templates of all approved versions • Note to File indicating location of the original signed and dated ICF for each subject • Protocol/Amendment Signature Page(s) • Investigator Drug Brochure (all versions received by the site) • Sample Drug Label(s) • IND Safety Reports (may be maintained in a separate binder) • Form FDA 1572

14. Site Regulatory Binder Example (continued) • Curriculum Vitae (CV) of all study personnel listed on the Form FDA 1572 will be filed. In addition, CV of all study personnel listed on the Site Signature of Duties and Delegation Log will be filed. CVs of all study personnel should be updated every two years during the study or initialed and dated as current every two years. • Licensure all study personnel listed on the Form FDA 1572 will be filed in. Wherever requested by the local legal requirements, documentation stating investigator’s medical license number will be filed instead of the licensure. • Institutional Review Board (IRB)/Ethics Committee (EC) Approvals • IRB/EC membership list or multiple assurance number (where applicable) • IRB/EC approval of protocol and amendments • IRB/EC approval of informed consent form (all versions) • IRB/EC approval of CRF (where required) • IRB/EC approval of subject recruitment and retention procedures and materials • IRB/EC approval renewals/updates • IRB/EC correspondence • IRB/EC notification of study termination • IRB/EC approval of patient privacy authorization form (where applicable) • IRB/EC acknowledgement of IND Safety Reports (where applicable)

15. Site Regulatory Binder Example (continued) • Subject Identification Code List (or Note To File indicating location of log) • Laboratory Information (reference ranges, certification, signed and dated CV of director, medical license for director). These documents should be updated every two years. • Monitoring Visit Sign-In Logs, including Qualification Visit Sign-In Log and Initiation Visit Sign-In Log • Any other written information given to the subject (i.e. patient brochures, etc) • Financial Documents to document the agreement between the sponsor and the investigator • Fully executed contract or Note to File indicating location of fully executed contract • Copy of site’s W-9 (where applicable) • Financial Disclosure Forms for all site staff listed on the Form FDA 1572 • IRE (Immediately Reportable Event) Forms • The original template form should be filed here. Subject specific forms should be filed in the appropriate Subject Binder • All versions of the IRE Forms issued for the duration of the study should be filed here.

16. Site Regulatory Binder Example (continued) • Drug Shipping/Return Records/Accountability Log/Study Medication Inventory Log/ Storage conditions/Procedures for handling investigational product • Signed Agreements • Confidentiality Disclosure Agreement • Insurance Statement (varies by region) • SDV agreement (for EU only) • Data protection form (for EU only) • Training Certifications/ Documentation • This documentation includes at least one documented Investigator GCP training. Examples of GCP training documentation include the Investigator Meeting attendance certificate for this study, Initiation Visit sign-in sheet for this study, as well as documentation of other types of GCP training meetings, sessions or presentations that may have been attended by the investigator (e.g. as documented in the form of a certificate, memo, or referenced within the investigator’s CV).

17. Site Regulatory Binder Example (continued) • Newsletters • Blank sample copy of the CRF and CRF completion instructions (all versions) • Study Correspondence • All study-related correspondence, including telephone contacts, relevant emails, faxes, and Sponsor and CRO Memos • Site Signature and Delegation of Duties Log • Copies of air waybills (if applicable or requested)

18. Central Imaging Laboratory Binder Example The Central Imaging Binder will contain study specific documents for sites to acquire study compliant imaging and properly transfer images to central lab. • Site Operations Manual with operational procedures and workflow definitions • Image Acquisition Guidelines define in detail the specific modalities, sequences, and parameters to be used when acquiring required clinical trial imaging. • Image Transmittal Form required to document patient demographics and critical image acquisition information • Image Shipment Tracker • Query & Reporting Procedures • Preprinted air bills and packaging material to transfer images

19. Subject Binder Example The Subject Binder will contain study specific documents for subjects in accordance with local regulations. Where applicable, the following documents should be filed in this binder: • Signed, dated Informed Consent Form (s) and any signed patient privacy documentation (if required) • All IVRS and IWRS worksheets (initialed and dated if used) and FAX back confirmation forms • Disease History and Disease Outcomes documentation if taken on a supplementary sheet (unless included in the subject’s source document) • A copy of the results (if not filed in the CRF), signed, dated and assessed by the investigator (or medically qualified designee), for each study visit for which it is a required procedure, Lab Reports and any fax data clarification forms received, signed and dated by the Investigator.

20. Subject Binder Example (continued) • Laboratory reports faxed from Lab or CRO, signed, dated and assessed by the investigator (or medically qualified designee), for each study visit for which laboratory analyses are required and laboratory requisition forms. • Investigational product Label Pages (if not filed in the CRF) • Drug dispensation/ return information • Immediately Reportable Event (IRE) Forms signed by the Investigator and completed for individual subjects, as required, and documentation of appropriate reporting procedures • All patient related communication between the site and the Imaging facility (inclusive of Imaging-related data case acceptance and case faxes, data queries/resolution and Imaging Transmittal Forms).

21. Reporting • Case Report Forms: Electronic vs. Paper • Demographic • Inclusion • Medication • SAE / AE • Imaging • ECG • Ongoing Visit Schedule • Screening, Screen Fails, Randomization.. Subject Status • Monitoring Visits • Trends • Queries

22. Site Training • Investigator Meetings • Regulatory Training • Operational Overview • Review criteria training • Documentation Review • Reporting • Web-Ex Training Sessions • Operational Overview • Analysis criteria specific training for site (imaging staff that could not attend IM) • Individual training for sites that are not performing to standard (trends & part of escalation plan) • Refresher or for new staff

23. Lessons Learned • DOCUMENT EVERYTHING! • Frequent Reporting • It will get the best of you if you don’t • Investigators Be Available • Communication! • Investigator – Study Coordinator – Radiology – Imaging Core lab – CRO MONITOR • All need to work together harmoniously to be successful