Guidance for Data and Safety Monitoring Plans: Sponsor-Investigator Initiated Clinical Trials

Transcription

1 ICTR DDRS: Guidance for Data and Safety Monitoring Plans Version 2.0 Guidance for Data and Safety Monitoring Plans: Sponsor-Investigator Initiated Clinical Trials ICTR Navigators July 20, 2011 Version 2.0 Page 1 of 45

2 ICTR DDRS: Guidance for Data and Safety Monitoring Plans Version 2.0 Table of Contents 1. INSTRUCTIONS FOR USE 2. ABBREVIATIONS 3. RESOURCE LINKS 4. TERMS AND DEFINITIONS 5. MONITORING PLAN OVERVIEW (Sections 5.A - 5.C) and EXAMPLE/TEMPLATE (Sections 5.D -5.G) 5. A SELECTION AND QUALIFICATION OF MONITORS 5. B PURPOSE OF A MONITORING PLAN 5. C NATURE OF MONITORING 5. D MONITORING VISIT PREPARATION 5. E MONITOR RESPONSIBILITIES 5. F COMMUNICATION OF FINDINGS AND DOCUMENTATION 5. G EXTENT OF DATA MONITORING APPENDICES I. JHM INVESTIGATOR GCP CHECKLIST-Sample II. III. IV. ESSENTIAL DOCUMENTS-Listing ESSENTIAL STANDARD OPERATING PROCEDURES-Sample Templates REGULATORY AND PARTICIPANT BINDERS-Organization and Form Templates/Samples Page 2 of 45

3 ICTR DDRS: Guidance for Data and Safety Monitoring Plans Version INSTRUCTIONS FOR USE The following guidance outlines the general process of data and safety monitoring, including review procedures necessary to ensure and document data integrity and protocol compliance. Italicized text inside of brackets are the instructions or suggestions for each section. This guidance provides is a generic framework that should be further modified according to the specifics of each individual protocol. The extent and frequency of monitoring activities are decided by the sponsor-investigator based on risk assessment and the complexity of the individual study. Sponsor- Investigators must be aware that the final monitoring plan they create becomes the standard to which their study will be held at the time of monitoring. Additionally, this resource speaks to clinical trial monitors as persons external to the study team. The Sponsor-Investigator may choose a monitor from within the study team as long as the individual selected is qualified by training and experience to monitor the progress of the investigation. (See Section 1 of this resource for additional information.) 2. ABBREVIATIONS AE CFR CRF FDA GCP ICH IDE IND RAC RDRC SAE Adverse Event Code of Federal Regulations Case report form U.S. Food and Drug Administration Good Clinical Practices International Conference on Harmonization Investigational Device Exemption Investigational New Drug Recombinant-DNA Advisory Committee Radioactive Drug Research Committee Serious Adverse Event 3. FDA WEBSITES AND RESOURCE LINKS FDA Title 21 Regulations Search Engine (e.g., IND regulations 21CRF312) FDA Code of Federal Regulations (CFR) Title 21 SECTION 312 Investigational New Drug Applications (Subpart D) Responsibilities of Sponsors and Investigators SECTION 812 Investigational Device Exemptions (Subpart C) Responsibilities of Sponsors Page 3 of 45

4 ICTR DDRS: Guidance for Data and Safety Monitoring Plans Version 2.0 FDA Running Clinical Trials FDA Guidance for Industry Investigator Responsibilities Protecting the Rights, Safety, and Welfare of Study Subjects International Conference on Harmonization (ICH) Guideline for Good Clinical Practice E6 Johns Hopkins Medicine IRB Guidelines and Policies Regulatory Definitions Application of GCP to the Conduct of Clinical Research Research Using FDA test Articles Pharmacy and Investigational Drug Service (IDS) at The Johns Hopkins Hospital Reporting Protocol Deviations Investigator Responsibilities Principal Investigators, Co-Investigators and Consent Designees, Post-Doctoral Fellows, and Ph.D. s 103.6b Organization Policy on Reports of Unanticipated Problems Involving Risks to Participants or Others 103.6bi Organization Policy on Reporting Death of a JHM Research Participant Submission of Sponsor IND Safety Reports 4. TERMS AND DEFINITIONS Essential Documents: Essential Documents are those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor and monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements. Essential Documents also serve a number of other important purposes. Filing essential documents at the investigator/institution and sponsor sites in a timely manner can greatly assist in the successful management of a trial by the investigator, sponsor and monitor. These documents are also the ones which are usually audited by the sponsor's independent audit function and inspected by the regulatory authority as part of the process to confirm the validity of the trial conduct and the integrity of data collected. Page 4 of 45

5 ICTR DDRS: Guidance for Data and Safety Monitoring Plans Version 2.0 The minimum list of essential documents which has been developed follows. The various documents are grouped in three sections according to the stage of the trial during which they will normally be generated: 1) before the clinical phase of the trial commences, 2) during the clinical conduct of the trial, and 3) after completion or termination of the trial. A description is given of the purpose of each document, and whether it should be filed in either the investigator/institution or sponsor files, or both. It is acceptable to combine some of the documents, provided the individual elements are readily identifiable. Protocol Deviation: For the purposes of Johns Hopkins Medicine (JHM), a protocol deviation is a minor or administrative departure (see definitions below) from the protocol procedures approved by the Institutional Review Board (IRB) that was made by the Principal Investigator (PI) without prior IRB approval. Please note: Eligibility exceptions (or eligibility waivers granted by a sponsor) for enrollment of a specific individual who does not meet the inclusion/exclusion criteria in the IRB approved protocol are not deviations. Eligibility exceptions are considered changes in research that require IRB review and approval before a subject who does not meet the approved protocol inclusion/exclusion criteria may be enrolled. Source Document: A source document is defined as any original record or data related to the trial or to subject treatment or medical history. Source documents include: original hospital, clinical, and office charts, laboratory notes, subject diaries or evaluation checklists, pharmacy records, recorded data from automated instruments, transcriptions (certified to be accurate after verification), magnetic media, or x-rays. Sponsor-Investigator Clinical trial: Sponsor-Investigator clinical trials are defined as those conducted under an Investigational New Drug (IND) or an Investigational Device Exemption (IDE) which is held by a Johns Hopkins University (JHU) faculty or staff member. 5. MONITORING PLAN OVERVIEW and EXAMPLE/TEMPLATE [Sections 5.A through 5.C present general guidance information regarding selection of trial monitors and the goals of monitoring activities. Sections 5.D through 5.G review the responsibilities of the clinical trial monitor and comprise the general elements of a Monitoring Plan. The Sponsor-Investigator should review the general framework described in Sections 5.D through 5.G and modify them by removing items which are not applicable and adding items not addressed in order to create a Monitoring Plan tailored to the needs of their specific trial. Once created, the Monitoring Plan should be maintained in the Regulatory Binder and the clinical trial monitor should conduct monitoring activities in accordance with the final study specific plan.] Page 5 of 45

6 ICTR DDRS: Guidance for Data and Safety Monitoring Plans Version A. SELECTION AND QUALIFICATIONS OF MONITORS Per good clinical practice (GCP) guidelines (5.18.2) and Food and Drug Administration (FDA) regulations (21 CFR 312 and 812): Monitors should be appointed by the Sponsor-Investigator. Monitors should be appropriately trained, and should have the scientific and/or clinical knowledge needed to monitor the trial adequately. A monitor s qualifications should be documented. Monitors should be thoroughly familiar with the investigational product(s), the protocol, written informed consent form and any other written information to be provided to subjects, the Sponsor-Investigator s standard operating procedures (SOPs), GCP, and the applicable regulatory requirement(s). For additional information, see the FDA Guidance for Industry entitled Investigator Responsibilities Protecting the Rights, Safety, and Welfare of Study Subjects 5.B. PURPOSE OF A MONITORING PLAN The purpose of the monitoring plan is to facilitate compliance with GCP guidelines (GCP ), FDA guidelines and FDA regulations (21 CFR 312 and 21 CFR 812) which require clinical trial monitors to verify that: The rights and well-being of human subjects are protected. Reported trial data are accurate, complete, and verifiable from source documents. The conduct of the trial is in compliance with the currently approved protocol, with GCP, and with applicable regulatory requirements. 5.C. NATURE OF MONITORING Per International Conference on Harmonization (ICH) Guideline for Good Clinical Practice (GCP ), the Sponsor-Investigator should ensure that their trial is adequately monitored. The Sponsor-Investigator should determine the appropriate extent and nature of monitoring based on considerations such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial. 5.D. MONITORING VISIT PREPARATION After scheduling a monitoring visit, the monitor will: Review the current IRB approved protocol version Review blank current case report forms (CRF) Review previous monitoring reports to identify any unresolved issues Page 6 of 45

7 ICTR DDRS: Guidance for Data and Safety Monitoring Plans Version E. MONITOR RESPONSIBILITIES The monitor s primary responsibilities (GCP ) are to ensure that the trial is conducted and documented properly by carrying out the following activities when relevant and necessary to the clinical trial. [Please review this list of responsibilities and delete or add any activities not directly applicable to your individual trial.] 1. INVESTIGATOR QUALIFICATIONS AND RESPONSIBILITIES a) Verify that the Investigator/Sponsor-Investigator has adequate qualifications to safely and properly conduct the trial. To accomplish this, the monitor will: (1) Review the study regulatory file to verify there is curriculum vitae (CV) or other documentation of qualification for each investigator listed in the IRB application. (2) Verify that each CV was current at the time of study initiation. 2. STUDY TEAM a) Verify that the Sponsor-Investigator has adequate study team, is supervising study team members, and study team has adequate qualifications to conduct the trial according to the duties and responsibilities the Sponsor-Investigator has delegated. To accomplish this, the monitor will: (1) Review study regulatory file to verify the names and qualifications of each study team member is adequately documented. (2) Adequate documentation can include but not limited to CVs, resumes, licenses, certifications, and training documentation. 3. DELEGATION OF DUTIES a) Review study regulatory file to verify the Sponsor-Investigator has adequately documented the delegations of duties and responsibilities, and that the study team members are qualified for the delegated duties and responsibilities. b) Ensure trial staff is adequately informed about the trial and has not delegated responsibilities to unauthorized individuals. To verify this, the monitor will: (1) Note the identity of all persons and locations involved in the collection of data by looking at the Delegation of Responsibility Log. Page 7 of 45

8 ICTR DDRS: Guidance for Data and Safety Monitoring Plans Version 2.0 (a) If there is no Delegation of Responsibility log, the monitor will require that one be completed and updated throughout the trial. (2) Check documentation for information about distribution of the currently approved protocol and Investigator Brochure (IB) to the study team. (3) Check documentation of any protocol specific training of authorized individuals (4) Compare study documents, the IRB application, and the Delegation of Responsibility log to determine whether responsibilities have been delegated to unauthorized individuals. 4. FACILITIES a) Verify that facilities, including laboratories and equipment, remain adequate throughout the trial. To accomplish this, the monitor will: (1) Verify that the regulatory file contains current licenses and/or certifications, and lab normal ranges for the laboratory performing protocol-required procedures or tests. (2) Verify that all equipment has the proper certifications, is in working order and/or calibrated. This is particularly important if a piece of equipment is being used to verify eligibility and/or collect data for a trial endpoint, e.g., EKG machine. 5. INVESTIGATIONAL PRODUCT ACCOUNTABILITY a) Verify storage, dispensing, instructions for use, and disposition of the investigational product complies with regulatory requirements. (1) Drugs and Biologics The monitor will review the IRB application to obtain pertinent information regarding the investigational drug or biologic. For all protocols which require drug preparation and dispensing for inpatients, the Investigational Drug Service (IDS) will manage and control the drug supply. For studies enrolling outpatients, either the IDS or the Sponsor - Investigator can manage the drug supply according to the guidelines of the Organizational Policy on the Drug Use in Clinical Investigation. Please see the full policy at: Page 8 of 45

9 ICTR DDRS: Guidance for Data and Safety Monitoring Plans Version uidelines_policies/organization_policies/103_19a.html (a) If the trial is receiving full IDS service, the monitor will: (i) (ii) Verify that the protocol and the regulatory file documents how subjects are provided with necessary instruction regarding use, handling, storage, and return of residual product. Consult with an IDS Pharmacist who will manage all aspects of the drug supply (receipt, storage, preparation, dispensing, documentation, etc.) (b) If the trial is not receiving services from the IDS and the Sponsor-Investigator is managing the investigational drug supply, the IDS Pharmacist will: (i) (ii) (iii) (iv) (v) (vi) Audit the Sponsor-Investigator s product receipt records, product disposition records, product administration records, product storage, and product labeling Assess whether the Sponsor-Investigator stores the product under the conditions specified in the protocol or by product labeling or packaging. Verify that the protocol or the regulatory file documents how subjects are provided with necessary instruction on how to use, handle, store, and return the investigational product. Verify that documentation of an expiration date, retest date or letter from sponsor indicating the ongoing stability monitoring is maintained and that the drug supply provided to subjects meets the requirements of the documentation. Verify the Sponsor-Investigator has documentation in the regulatory file of receipt of disposition/use and return of product. Verify that the Sponsor-Investigator maintains and is compliant with the manufacturer guidelines or other instructions for handling product. Verify that the labeling on the product that is given to the subject is compliant with internal and external regulations. Page 9 of 45

10 ICTR DDRS: Guidance for Data and Safety Monitoring Plans Version 2.0 (vii) (viii) (ix) (x) Verify the physical inventory of the investigational product. Communicate the findings of the audit to the principal investigator, monitor and to the IRB. Follow-up on any audit findings to assure compliance Verify that the Sponsor-Investigator maintains records that indicate product has been supplied only to eligible subjects at protocol specified doses. (2) Devices (a) (b) Sponsor-Investigators are responsible for preparing and maintaining product disposition records. The monitor will look in the protocol, regulatory file, or subject files to: (i) (ii) (iii) Verify that there are records of shipment of the device including name and address of consignee, type and quantity of the device, date of shipment and batch number or code Verify that there are records of the disposition of the device including batch number or code of any devices returned to the sponsor. Verify records of receipt, use or disposition of the device including type and quantity, date, batch number or code, name of person that received, used or disposed of each device, and why and how many units of the device were returned to the sponsor or otherwise disposed of. (3) Combination Products 6. PROTOCOL ADHERENCE (a) Verify compliance for applicable components per requirements of 5.a.i and 5.a.ii above. a) Verify that the Sponsor-Investigator follows the IRB approved protocol. To accomplish this, the monitor will: (1) Verify the (current) IRB approved protocol and the (current) protocol in the regulatory file are the same. Page 10 of 45

11 ICTR DDRS: Guidance for Data and Safety Monitoring Plans Version 2.0 (2) Compare data to be collected on case report forms (CRFs) with the IRB approved protocol (data collection should not exceed the limits defined by the protocol). (3) Verify the number and type of subjects entered into the study was confined to the number and type the protocol defined eligible. (4) Verify that no deviations from or changes to the protocol have been implemented without prior review and documented approval of the IRB (except where necessary to eliminate an immediate hazard to trial subjects or when the change involves only logistical or administrative aspects of the trial. (5) Verify the labels on the individual patient medication bottles/medical devices comply with the requirements for investigational drug or device labeling. (6) Verify that the Sponsor-Investigator maintains records that indicate product has been supplied only to eligible subjects at protocol specified doses. 7. RECRUITMENT AND ENROLLMENT RATES a) Report on subject recruiting and enrollment rates. To accomplish this, the monitor will: (1) Count the number of subjects enrolled (defined by this plan as having signed a consent form) and compare this number to the limit approved by the IRB. (2) Check subject screening/enrollment log to document subjects who entered pretrial screening but did not give consent to participate. (The enrollment log may be incorporated within the screening log.) 8. PARTICIPANT BINDERS/DATA: CONSENT a) Verify that written consent was obtained before subjects participation. To accomplish this, the monitor will: (1) Verify correct version of IRB-approved consent form was used (2) Verify the date the consent form was signed and dated Page 11 of 45

12 ICTR DDRS: Guidance for Data and Safety Monitoring Plans Version 2.0 (3) Verify, against the subject s medical record, source documentation that the consent was signed before any research test or procedure was performed. (4) Verify the subject signed and dated a HIPAA form prior to enrollment, as applicable. 9. PARTICIPANT BINDERS/DATA: ELIGIBILITY a) Verify that only eligible subjects are enrolled. To accomplish this, the monitor will: (1) Verify whether the existence of the condition for which the investigational product is being studied is documented by a compatible history. (2) Determine, when possible, whether the existence of the condition is documented by notation made prior to the initiation of the study. (3) Compare the protocol inclusion/exclusion criteria against the subject s medical record, or other source documentation, to determine whether the enrolled subject is eligible for inclusion in the study. 10. PARTICIPANT BINDERS/DATA: COMPLETENESS AND ACCURACY a) Verify that trial records are accurate, complete, and current and check the accuracy and completeness of CRF entries, source documents, and other trialrelated records against each other. To accomplish this, the monitor will: (1) Verify that the Sponsor-Investigator or assigned designee has completed current CRFs and that they are signed and dated appropriately. (2) Verify that source documentation was used to complete CRFs. (3) Verify that the protocol identifies source data which will be recorded directly on CRFs (with no prior written or electronic record of data). (4) Verify whether clinical laboratory testing (including EKGs, X-rays, eye exams, etc.), as noted in the case report forms, is/are documented by the presence of completed records within the source documents. (5) Verify the Sponsor-Investigator s data and source documents in terms of organization, condition, completeness, and legibility. Page 12 of 45

13 ICTR DDRS: Guidance for Data and Safety Monitoring Plans Version 2.0 (6) Verify that the Sponsor-Investigator has made required reports and submissions to the IRB (7) Verify that the Sponsor-Investigator has made required reports and submissions to the FDA. (8) Verify that the Sponsor-Investigator has made required reports and submissions to additional regulatory bodies (e.g. Biosafety Committee, RDRC, or RAC.) (9) Verify that the information in the reports and the information in the Regulatory file and source documents match and are accurate and complete, including reports of any adverse experiences (AEs). (10) Verify the data required by the protocol are reported accurately on the CRFs and are consistent with the source data/documents. (11) Verify any dose or therapy modifications are well documented. (12) Verify concomitant medications, and underlying illnesses are reported accurately on the CRFs, in accordance with the protocol. (13) Verify that CRFs reflect all visits that subjects fail to make and all tests or examinations that are not performed. (14) Verify, by looking at the CRFs in the subject binder/folder, that all applicable forms are completely filled out if any subject has withdrawn or dropped out of the study since enrollment and that an explanation is provided. (15) Verify subject visits have taken place as stated in protocol by checking the subject tracking log. (16) Verify all tests have been completed as stated in the protocol by looking at source documentation and CRFs. (17) Verify any noncompliance issues with protocol (subject) by looking at CRFs and other source documentation. 11. ADVERSE EVENT AND PROTOCOL DEVIATION DOCUMENTATION & REPORTING a) Determine whether all events, i.e., adverse events, SAEs, deaths, deviations, and/or violations, are reported appropriately. To accomplish this, the monitor will: Page 13 of 45

14 ICTR DDRS: Guidance for Data and Safety Monitoring Plans Version 2.0 1) Verify that, in accordance with the protocol, adverse events have been documented appropriately and accurately by comparing subject medical records and the CRFs, 2) Verify that serious adverse events have been reported to the IRB, and, if applicable, the Sponsor, by looking at correspondence files and comparing against subject medical records verifying that they are also reported accurately on the CRFs, in accordance with the protocol. 3) Verify, by reviewing correspondence files and comparing against subject medical records, that the JHM IRB guidelines have been followed specifically that any of these events is reported to the IRB within 10 days of learning of the event: (a) (b) (c) (d) (e) (f) (g) Any serious event (including on-site and off-site adverse events, injuries, side effects, deaths or other problems) which, in the opinion of the local investigator, was unanticipated, involved risk to subjects or others, and was at least possibly related to the research procedures; Any serious accidental or unintentional change to the IRBapproved protocol that involves risk or has the potential to recur; Any deviation from the protocol taken without prior IRB review to eliminate apparent immediate hazard to a research subject Any publication in the literature, safety monitoring report (including Data and Safety Monitoring Reports), interim result or other finding that indicates an unexpected change to the risk/benefit ratio of the research; Any breach in confidentiality that may involve risk to the subjects or others; Any complaint of a subject that indicates an unanticipated risk or that cannot be resolved by the research staff; or Any other serious and possibly related event which, in the opinion of the investigator, constitutes an unanticipated risk 4) Verify, by looking at subject medical records, that events not meeting the IRB reporting requirement are captured on the IRB continuing review report. 5) Verify that all adverse events that are required by FDA regulation to be reported to the FDA have been reported within the specified time frames. Page 14 of 45

15 ICTR DDRS: Guidance for Data and Safety Monitoring Plans Version 2.0 6) Verify if any visit was out of allowable time deviation by looking at subject visit schedule. 7) Verify any other protocol deviations by comparing the protocol with source documentation and/or subject CRFs. 11. ESSENTIAL DOCUMENT MAINTENANCE a) Verify that all essential documents are maintained. [See Appendix II-Essential Documents 12. COMMUNICATION AND DOCUMENTATION OF FINDINGS a) Communication of Deviations and Errors (1) Deviations from the protocol, GCPs, or regulatory requirements will be communicated to the investigator and appropriate action to prevent recurrence of the deviations will be taken. To accomplish this, the monitor will: (a) (b) (c) Meet with the investigator or coordinator, at the end of each monitoring visit, to go over any findings of the visit Inform the investigator of any CRF errors and ensuring appropriate corrections are made, dated, explained (if necessary), and initialed by the investigator or designee. Inform the investigator of any CRF entry error, omission, or illegibility. (2) Ensure that appropriate corrections, additions or deletions are made, dated, explained (if necessary), and initialed by the investigator or his/her designee authorized to make such changes. (This authorization must be documented on the responsibility log). Page 15 of 45

16 ICTR DDRS: Guidance for Data and Safety Monitoring Plans Version DOCUMENTATION OF FINDINGS a) The monitor will send a monitoring report to the study sponsor and to the study investigator (if the sponsor is not also the investigator). The report will describe the progress of the study, the findings of the visits, unresolved issues, and follow-up required. b) The monitor will keep an electronic copy of the report and a signed copy will be maintained in the Regulatory file. c) Follow-up items will be checked and documented at the next monitoring visit. The report will include, but will not be limited to, the following: (1) A list of records reviewed, i.e. subject charts, hospital records, lab slips, etc. (2) Number of case report forms reviewed by research subject number and visit date; (3) Statement that test article accountability records were or were not sufficient; (4) Statement regarding whether there was any evidence of underreporting of adverse events; (5) Statement regarding protocol adherence 14. EXTENT OF DATA MONITORING a) Study Endpoints (1) Monitors will review clinical data that affect study endpoints defined in the protocol. The extent of subject data monitoring will include verifying: (a) (b) (c) Initial study consent for 100% of enrolled subjects Study eligibility for 100% of enrolled subjects; Data to support protocol defined endpoints for 100% of completed subjects b) Regulatory File (1) In addition to monitoring subject data, the monitor will review the regulatory file for any additions to GCP-required documents since the last visit. Monitors will, at their first and last monitoring visits, review Page 16 of 45

17 ICTR DDRS: Guidance for Data and Safety Monitoring Plans Version 2.0 the regulatory file for the presence, completeness, and accuracy of all GCP-required documents. 15. FREQUENCY OF MONITORING a) In general, monitoring visits will be scheduled: (1) After IRB approval but prior to enrolling the first subject; (2) As soon as possible after the first subject is enrolled; (3) Every 6-8 weeks during the study data collection phase; (4) After the last subject has completed his/her participation in the study b) This monitoring schedule may be revised based on the following considerations: (1) Accrual rate (2) History of protocol deviations or non-compliance with GCPs (3) Number of data corrections required (4) Study stage (e.g. start-up or follow-up) (5) Complexity of the trial (6) IRB request Page 17 of 45

18 ICTR DDRS: Guidance for Data and Safety Monitoring Plans Version 2.0 APPENDICES Page 18 of 45

19 Appendix I Sample JHM Investigator Checklist Good Clinical Practice (GCP) Guidance Investigators should be fully aware of their obligations and responsibilities required by the JHM IRB and applicable regulatory agencies prior to conducting research. This checklist provides a summary of investigator responsibilities pertinent to data and document management in accordance with Good Clinical Practice (GCP) Guidance. Yes No N/A GCP E6 4.1 Investigator Qualifications and Agreements As the investigator, are you qualified by education, training, and experience to assume responsibility for the proper conduct of the trial? The investigator should meet all the qualifications specified by the applicable regulatory requirement(s), and should provide evidence of such qualifications through up-to-date curriculum vitae and/or other relevant documentation requested by the sponsor, the IRB/IEC, and/or the regulatory authority(ies) As the investigator, are you thoroughly familiar with the appropriate use of the investigational product(s), as described in the protocol, in the current Investigator's Brochure, in the product information, and in other information sources provided by the sponsor? As the investigator, are you aware of Good Clinical Practice guidance and the applicable regulatory requirements? As the investigator, are you aware that you must permit monitoring and auditing by the sponsor, and inspection by the appropriate regulatory authority(ies)? As the investigator, are you aware that you must maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties? Yes No N/A GCP E6 4.2 Adequate Resources As the investigator, are you able to demonstrate (e.g., based on retrospective data) a potential for recruiting the required number of suitable subjects within the agreed recruitment period? As the investigator, do you have sufficient time to properly conduct and complete the trial within the agreed trial period? As the investigator, do you have available an adequate number of qualified staff and adequate facilities for the foreseen duration of the trial to conduct the trial properly and safely? As the investigator, can you ensure that all persons assisting with the trial are adequately informed about the protocol, the investigational product(s), and their trial-related duties and functions?

20 Appendix I Sample JHM Investigator Checklist Good Clinical Practice (GCP) Guidance Yes No N/A GCP E6 4.3 Medical Care of Trial Subjects As the investigator, can you ensure a qualified physician (or dentist, when appropriate), either yourself or a sub-investigator for the trial, will be responsible for all trial-related medical (or dental) decisions? As the investigator, can you ensure that adequate medical care is provided to a subject for any adverse events (including clinically significant laboratory values) related to the trial, both during and following a subject's participation in a trial? The investigator should inform a subject when medical care is needed for intercurrent illness (es) of which the investigator becomes aware As the investigator, will you inform the subject's primary physician about the subject's participation in the trial if the subject has a primary physician and if the subject agrees to the primary physician being informed? Although a subject is not obliged to give his/her reason(s) for withdrawing prematurely from a trial, as the investigator, will you make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights? Yes No N/A GCP E6 4.4 Communication with the IRB As the investigator, do you have written and dated approval from the IRB for the research application, written informed consent form, consent form updates, subject recruitment procedures (e.g., advertisements), and any other written information to be provided to subjects? As the investigator, did you provide the IRB with a current copy of the Investigator's Brochure? If the Investigator's Brochure is updated during the trial, you must provide a copy of the updated Investigator's Brochure to the IRB As the investigator, did you provide the IRB with all documents subject to review according to the IRB s requirements? Yes No N/A GCP E6 4.5 Compliance with the IRB-Approved Research Application As the investigator, will you conduct the research in compliance with the research application that was given approval by the IRB? As the investigator, you must sign the research application to confirm agreement As the investigator, can you ensure that you will not implement any deviation from the IRB-approved research application without prior review and documented approval from the IRB of a modification? If necessary to eliminate an immediate hazard to research subjects, a investigator may deviate from the IRB-approved research application without prospective IRB approval As the investigator, will you document and explain any deviation from the approved protocol that occurs without prospective IRB approval? As the investigator, if you deviate from the IRB-approved research application to eliminate an immediate hazard(s) to research subjects without prospective IRB approval, will you submit a modification and explain the deviation to the IRB?

21 Appendix I Sample JHM Investigator Checklist Good Clinical Practice (GCP) Guidance Yes No N/A GCP E6 4.6 Investigational Product(s) As the investigator, will you take responsibility for investigational product(s) accountability at the research site(s)? As the investigator, will you assign some or all of your duties for investigational product(s) accountability at the research site(s) to an appropriate pharmacist or another appropriate individual who is under your supervision? As the investigator, will you, or a designee you have appointed, maintain records of the product's delivery to the research site, the inventory at the site, the use by each subject, and the return to the sponsor or alternative disposition of unused product(s)? These records should include dates, quantities, batch/serial numbers, expiration dates (if applicable), and the unique code numbers assigned to the investigational product(s) and research subjects. Investigators should maintain records that document adequately that the subjects were provided the doses specified by the protocol and reconcile all investigational product(s) received from the sponsor As the investigator, will you ensure that the investigational product(s) will be stored as specified by the sponsor and in accordance with applicable regulatory requirement(s)? As the investigator, will you ensure that the investigational product(s) are used only in accordance with the IRB-approved research application? As the investigator, will you, or a designee you have appointed, explain the correct use of the investigational product(s) to each subject? Will you, or a designee you have appointed, periodically check that each subject is following the instructions properly? Yes No N/A GCP E6 4.7 Randomization Procedures and Unblinding As the investigator, will you follow the trial's randomization procedures, if any? Will you ensure that the code is broken only in accordance with the IRB-approved research application? If the research is blinded, will you promptly document and explain to the sponsor any premature unblinding (e.g., accidental unblinding, unblinding due to a serious adverse event) of the investigational product(s)? Yes No N/A GCP E6 4.8 Informed Consent of Trial Subjects As the investigator, will you comply with the applicable regulatory requirement(s) and adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki in obtaining and documenting informed consent? Prior to the beginning of the research study, the investigator must have the IRB's written approval of the written informed consent form and any other written information to be provided to subjects As the investigator, will you ensure that the written informed consent form and any other written information to be provided to subjects will be revised whenever important new information becomes available that may be relevant to the subject's consent? Any revised consent form and other written information provided to subjects must receive the IRB s approval in advance of use. The subject or the subject's legally acceptable representative should be informed in a timely manner if new information becomes available that may be relevant to the subject's willingness to continue participation in the research, and the communication of this information should be documented As the investigator, will you ensure that neither you nor the research staff will coerce or unduly influence a subject to participate or to continue to participate in the research? As the investigator, will you ensure that none of the oral and written information concerning the trial, including the written informed consent

22 Appendix I Sample JHM Investigator Checklist Good Clinical Practice (GCP) Guidance form, contains any language that causes the subject or the subject's legally acceptable representative to waive or to appear to waive any legal rights, or that releases or appears to release the investigator, the institution, the sponsor, or their agents from liability for negligence? As the investigator, will you ensure that you, or a designee you have appointed, will fully inform the subject or, if the subject is unable to provide informed consent, the subject's legally acceptable representative, of all pertinent aspects of the research including the written information and the approval by the IRB? As the investigator, will you ensure that the language used in the oral and written information about the research, including the consent form, will be as non-technical as practical and will be understandable to the subject or the subject's legally acceptable representative and the impartial witness, where applicable? As the investigator, will you ensure that you, or a designee you have appointed, will provide the subject or the subject's legally acceptable representative ample time and opportunity to inquire about details of the trial and to decide whether or not to participate in the research? All questions about the trial should be answered to the satisfaction of the subject or the subject's legally acceptable representative As the investigator, will you ensure that the written consent form is signed and personally dated by the subject or by the subject's legally acceptable representative, and by the person who conducted the informed consent discussion prior to a subject's participation in any research procedures? As the investigator, will you ensure that, if a subject is unable to read or if a legally acceptable representative is unable to read, an impartial witness will be present during the entire informed consent discussion? After the written informed consent form, and any other written information to be provided to subjects, is read and explained to the subject or the subject's legally acceptable representative, and after the subject or the subject's legally acceptable representative has orally consented to the subject's participation in the trial and, if capable of doing so, has signed and personally dated the informed consent form, the witness should sign and personally date the consent form. By signing the consent form, the witness attests that the information in the consent form and any other written information was accurately explained to, and apparently understood by, the subject or the subject's legally acceptable representative, and that informed consent was freely given by the subject or the subject's legally acceptable representative As the investigator, will you ensure that, the informed consent discussion and the written informed consent form and any other written information to be provided to subjects should include explanations of the following: That the trail involves research. The purpose of the trial. The trial treatment(s) and probability for random assignment to each treatment. The trail procedures to be followed, including all invasive procedures. The subject s responsibilities. Those aspects of the trial that are experimental. The reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an embryo, fetus, or nursing infant. The alternative procedure(s) or course(s) of treatment that may be available to the subject, and their important potential benefits and risks. The compensation and/or treatment available to the subject in the event of trial-related injury. The anticipated prorated payment, if any, to the subject for participating in the trial. The anticipated expenses, if any, to the subject for participating in the trial.

23 Appendix I Sample JHM Investigator Checklist Good Clinical Practice (GCP) Guidance That the subject's participation in the trial is voluntary and that the subject may refuse to participate or withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is otherwise entitled. That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be granted direct access to the subject's original medical records for verification of clinical trial procedures and/or data, without violating the confidentiality of the subject, to the extent permitted by the applicable laws and regulations and that, by signing a written informed consent form, the subject or the subject's legally acceptable representative is authorizing such access. That records identifying the subject will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly available. If the results of the trial are published, the subject s identity will remain confidential. That the subject or the subject's legally acceptable representative will be informed in a timely manner if information becomes available that may be relevant to the subject's willingness to continue participation in the trial. The person(s) to contact for further information regarding the trial and the rights of trial subjects, and whom to contact in the event of trial-related injury. The foreseeable circumstances and/or reasons under which the subject's participation in the trial may be terminated. The expected duration of the subject's participation in the trial. The approximate number of subjects involved in the trial As the investigator, will you ensure that, prior to participation in the research, the subject or the subject's legally acceptable representative will receive a copy of the signed and dated consent form and any other written information provided to the subject. During a subject's participation in the research, the subject or the subject's legally acceptable representative should receive a copy of the signed and dated revised consent form and a copy of any updates to the written information provided to subjects As the investigator, will you ensure that when research (therapeutic or non-therapeutic) includes subjects who can only be enrolled in the research with the consent of the subject's legally acceptable representative (e.g., minors, or patients with severe dementia), the subject will be informed about the research to the extent compatible with the subject's understanding and, if capable, the subject will be given the opportunity to sign and personally date the written informed consent? As the investigator, will you ensure that, except as described in (below), non-therapeutic research (i.e., research in which there is no anticipated direct clinical benefit to the subject), will be conducted in subjects who personally give consent and who sign and date the written informed consent form? Non-therapeutic research may be conducted in subjects with consent of a legally acceptable representative provided the following conditions are fulfilled: The objectives of the research can not be met by means of research in subjects who can give informed consent personally. The foreseeable risks to the subjects are low. The negative impact on the subject's well-being is minimized and low. The research is not prohibited by law. The approval of the IRB is expressly sought on the inclusion of such subjects, and the IRB s written approval covers this aspect. Such research, unless an exception is justified, should be conducted in patients having a disease or condition for which the investigational product is intended. Subjects in these studies should be particularly closely monitored and should be withdrawn if they appear to be unduly distressed.

24 Appendix I Sample JHM Investigator Checklist Good Clinical Practice (GCP) Guidance As the investigator, will you ensure that in emergency situations, when prior consent of the subject is not possible, the consent of the subject's legally acceptable representative, if present, will be requested? When prior consent of the subject is not possible, and the subject's legally acceptable representative is not available, enrollment of the subject requires measures described in the research application and/or elsewhere, with documented IRB approval to protect the rights, safety, and well-being of the subject and to ensure compliance with applicable regulatory requirements. The subject or the subject's legally acceptable representative must be informed about the research as soon as possible and consent to continue and other consent as appropriate (see above) should be requested. Yes No N/A GCP E6 4.9 Records and Reports As the investigator, will you ensure the accuracy, completeness, legibility, and timeliness of the data reported to the sponsor in the CRFs and in all required reports? As the investigator, will you ensure that data reported on the CRF derived from source documents are consistent with the source documents? If there are any discrepancies, they should be explained As the investigator, will you ensure that any change or correction to a CRF will be dated, initialed, and explained (if necessary) and will not obscure the original entry (i.e., an audit trail should be maintained)? This applies to both written and electronic changes or corrections. Sponsors should provide guidance to investigators and/or the investigators' designated representatives on making such corrections. Sponsors should have written procedures to assure that changes or corrections in CRFs made by sponsor's designated representatives are documented, are necessary, and are endorsed by the investigator. As the investigator, you should retain records of the changes and corrections As the investigator, will you maintain the research documents as required by the applicable regulatory requirement(s)? The investigator should take measures to prevent accidental or premature destruction of these documents As the investigator, will you ensure that essential documents will be retained until at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product? If required by the applicable regulatory requirements or by an agreement with the sponsor, these documents may need to be retained for a longer period. It is the sponsor s responsibility to inform the investigator as to when these documents no longer need to be retained As the investigator, will you ensure that the financial aspects of the study are documented in an agreement between yourself and the sponsor? As the investigator, will you make available for direct access all requested research-related records upon request of the monitor, auditor, IRB, or regulatory authority? Yes No N/A GCP E Progress Reports As the investigator, will you submit written summaries of the research status to the IRB annually, or more frequently if requested by the IRB? As the investigator, will you promptly provide written reports to the sponsor, the IRB and, where applicable, the institution on any changes significantly affecting the conduct of the research, and/or increasing risks to subjects? Yes No N/A GCP E Safety Reporting As the investigator, will you immediately report all serious adverse events (SAEs) to the sponsor, except for those SAEs that the protocol or other document (e.g., Investigator's Brochure) identifies as not needing immediate reporting? The immediate reports should be followed promptly by detailed, written reports. The immediate and follow-up reports should identify subjects by unique code numbers assigned to the

25 Appendix I Sample JHM Investigator Checklist Good Clinical Practice (GCP) Guidance research subjects rather than by the subjects' names, personal identification numbers, and/or addresses. As the investigator, you should also comply with the applicable regulatory requirement(s) related to the reporting of unexpected serious adverse drug reactions to the IRB and regulatory authority(ies) As the investigator, will you report adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluations to the sponsor according to the reporting requirements and within the time periods specified by the sponsor in the protocol? As the investigator, will you supply the sponsor and the IRB with any additional requested information for reported deaths (e.g., autopsy reports and terminal medical reports)? Yes No N/A GCP E Premature Termination or Suspension of a Trial As the investigator, if the trial is prematurely terminated or suspended for any reason, will you promptly inform the trial subjects, assure appropriate therapy and follow-up for the subjects, and, where required by the applicable regulatory requirement(s), inform the regulatory authority(ies)? As the investigator, if you terminate or suspend research without prior agreement of the sponsor, will you inform the sponsor and the IRB? The investigator should provide the sponsor and the IRB with a detailed written explanation of the termination or suspension If the sponsor terminates or suspends a trial, as the investigator, will you promptly inform the IRB and provide a detailed written explanation of the termination or suspension? If the IRB terminates or suspends its approval of your research, will you notify the sponsor and provide the sponsor with a detailed written explanation of the termination or suspension? Yes No N/A GCP E Final Report(s) by Investigator Upon completion of the research, as the investigator, will you inform the IRB and provide a summary of the research results, and provide any reports required by the regulatory authority(ies)?