Investigator Manual Revised August 19, 2013

Transcription

1 Investigator Manual Revised August 19, 2013

2 Investigator Manual Page 2 of 31 Table of Contents What is the purpose of this manual?... 3 What is Human Research?... 3 What is the Human Research Protection Program?... 3 What training does my staff and I need to conduct Human Research?... 3 How do I submit new Human Research to the IRB?... 4 How do I complete the FORM HRP-211: Application for Human Research?... 4 How do I write a protocol using the MSSM template?... 7 How do I activate a protocol at a new MSSM site if it has already been approved by the MSSM IRB for another site?... 8 How do I create a consent document?... 8 What are the different regulatory classifications that research activities may fall under?... 9 What are the decisions an IRB can make when reviewing a protocol?... 9 How does the IRB decide whether to approve Human Research? What will happen after IRB review? What are my obligations after IRB approval? How do I document consent? How do I submit a modification? How do I submit for a continuing review? How do I close out a study? How long do I keep records? What if I need to use an unapproved drug or device in a life-threatening situation and there is no time for prior IRB review? How do I get additional information and answers to questions? Appendix A-1 Additional Requirements for DHHS-Regulated Research Appendix A-2 Additional Requirements for FDA-Regulated Research Appendix A-3 Additional Requirements for Clinical Trials (ICH-GCP) Appendix A-4 Additional Requirements for Department of Defense (DOD) research Appendix A-5 Additional Requirements for Department of Navy (DON) Research Appendix A-6 Additional Requirements for Department of Energy (DOE) Research Appendix A-7 Additional Requirements for Department of Education (ED) Research... 31

3 Investigator Manual Page 3 of 31 What is the purpose of this manual? The Investigator Manual is designed to guide you through policies and procedures related to the conduct of Human Research that are specific to this organization. General information regarding Human Research protections and relevant federal regulations and guidance is incorporated into the required human protections training. For additional information, see below: What training does my staff and I need in order to conduct Human Research? What is Human Research? An algorithm for determining whether an activity is Human Research can be found in the WORKSHEET HRP-309: Human Research Determination, located on the PPHS website. Use this document for guidance as to whether an activity meets either the DHHS or FDA definition of Human Research, keeping in mind that the PPHS makes the ultimate determination in questionable cases as to whether an activity constitutes Human Research subject to IRB oversight. You are responsible not to conduct Human Research without prior PPHS review and approval. If you have questions about whether an activity is Human Research, contact the PPHS office who will provide you with a determination. If you wish to have a written determination, provide a written request to the PPHS office. The document HRP-101: HUMAN RESEARCH PROTECTION PROGRAM PLAN defines the activities that this organization considers to be Human Research as defined in DHHS regulations at 45 CFR (d) and 45 CFR (f) and as defined in FDA regulations at 21 CFR (c), 21 CFR (e), and 21 CFR 812.3(p). What is the Human Research Protection Program? The document HRP-101: HUMAN RESEARCH PROTECTION PROGRAM PLAN describes this organization s overall plan to protect subjects in Human Research. The mission of the Human Research Protection Program. The ethical principles that the organization follows governing the conduct of Human Research. The applicable laws that govern Human Research. When the organization becomes engaged in Human Research and when someone is acting as an agent of the organization conducting Human Research. The types of Human Research that may not be conducted. The roles and responsibilities of individuals within the organization. What training does my staff and I need to conduct Human Research? Investigators and staff will be required to complete the online Collaborative Institutional Training Initiative (CITI) human subjects protection online training program. The CITI site can be accessed at This training is valid for 3 years, after which time a refresher CITI course or additional training must be completed. Further information on this training requirement and others will be available on the PPHS website.

4 Investigator Manual Page 4 of 31 Investigators and staff who are involved in FDA-regulated research will also be required to complete either the online Collaborative Institutional Training Initiative (CITI) Good Clinical Practice (GCP) course, or the Mount Sinai Research Compliance department s Clinical Research: Are You Doing It Right? course. Please note that all members of the research team involved in design, conduct, or reporting of the research are required to complete this training. IRB approval will not be granted for protocols in which members of the research team have not completed human research protections training. How do I submit new Human Research to the IRB? Complete the FORM HRP-211: Application for Human Research, attach all requested documents per the instructions, obtain all required signatures, and provide the requested number of copies to the PPHS office. Maintain electronic copies of all information submitted to the PPHS. How do I complete the FORM HRP-211: Application for Human Research? Form Header (Basic Protocol Information) 1) Protocol Name Enter the full protocol name and, where applicable, the protocol code or number in parentheses (such as a cooperative group or sponsored protocol). 2) Principal Investigator Name the person with overall responsibility for the conduct of the Human Research. There can be only one investigator with this overall responsibility. If the PI is new to the institution or the PPHS application process, or if there has been a change in the PI s contact information, include that information within the other submission materials. 3) Primary Contact Name Name the person who will receive a copy of all communications in addition to the principal investigator. Leave blank if there is no contact other than the principal investigator. There can only be one contact. If this person is new to institution or the PPHS application process, or if there has been a change in their contact information, mention that within the other submission materials. 4) Contact Info Provide that person s and direct phone number in the area provided. 5) Date Revised Provide the date that the application form is being filled out. 6) Study Number Provide the study number when known. It may not be known at time of initial submission. Section A: Elements of the Research Check each applicable item to indicate whether the Human Research involves the following and complete the associated forms:

5 Investigator Manual Page 5 of 31 a) Use of any external (i.e. non-mssm) sites at which Human Research activities will be conducted For example, if you are conducting research in a school, nursing home, or other external facility or site, list it here. Research affiliates such as the Queens Hospital Network, Elmhurst Hospital Network, Jewish Home and Hospital, and Bronx VA are considered external sites. b) Use of drugs other than the use of approved drugs in the course of medical practice c) Use of a device to evaluate its safety or effectiveness d) Use of a HUD to evaluate its safety or effectiveness e) Submission of a protocol already approved by the MSSM IRB under a different principal investigator. Your intention is to activate the same protocol at a different site(s) for which you are taking separate and full responsibility. Section B: Approvals Required Prior to Initiating Research Check all additional approvals that are required: a) Radiation being used for reasons other than clinical care b) Use of materials requiring approval from the Institutional Biosafety Committee. This would include biohazards, toxins, infectious agents (of biological origin or otherwise), recombinant DNA, etc. Check the IBC website for materials that require IBC submission and approval. c) Cancer research that requires approval from the Protocol Monitoring & Review Committee. Check with the PR&MC for the kinds of projects that require PR&MC submission and approval. d) Investigators or research staff with a significant financial conflict of interest in the research. Refer to the FCOIR website or committee for definitions, disclosure requirements, and management plans (if applicable). e) Pathological specimens that require approval from the Pathology department. Check with the Department of Pathology for materials that require submission and approval. f) Human embryonic stem cells. Check with the ESCRO committee for materials that require ESCRO submission and approval. g) Study of use/outcomes for a product sold to Mount Sinai at full price and sponsored by entity with economic interest in sale of product. Check with the Registry Committee for additional information regarding their review and approval process. h) Submission required by the Grants and Contracts Office. Check with the GCO regarding their submission requirements i) Submission required by the Clinical Trials Budget and Billing Compliance (CTBB). Check with the Office of Clinical Research (OCR) regarding their CTBB checklist, submission requirements, coverage analysis (MCA) and approvals. Section C: Funding Sources List all funding sources. For each, list the associated grant number and Infoed/GCO ID#, if known. Note: modifying funding sources requires that you inform GCO and make appropriate FCOIR disclosures. Section D: Reserved

6 Investigator Manual Page 6 of 31 Section E: Names of all research personnel involved in the design, conduct, or reporting of the research List all Human Research personnel involved in the design, conduct, or reporting of the Human Research and their roles. This includes all co-investigators, sub-investigators, coordinators, assistants, students, and collaborators who have a role in the design, conduct, or reporting of the Human Research. Indicate each person s department(s). If personnel have multiple department appointments, list the department that may be related to the topic of this research first. Indicate each person s role in the research. If this person is new to institution or the PPHS application process, or if there has been a change in their contact information, submit that information with the other submission materials. Check the box if the person will have contact with subjects or access to private identifiable data and whether the person will be involved in the consent process. Check the box if the person has fulfilled their PPHS education requirements. The research will not be approved if all individuals have not completed the requirements. Further information regarding the requirements is available in the What training does my staff and I need to conduct Human Research? section of this document. Indicate the location of evidence of qualifications. The location may vary by role in the research. Typically investigators submit a copy of their CV or biosketch, and others provide a resume or a summary description of their qualifications. Indicate whether the person has a significant financial interest related to the Human Research. The definition of significant financial interest related to the Human Research is included on the application and in the institutional Financial Conflict of Interest in Research policies. Section F: Other Documents Provide the requested copies of additional documents. Section G: Principal Investigator signature Personally sign and date the application. Section H: Departmental/Designee Approval Have your department chair or their official designee sign and date the application. Follow any departmental procedures that are required in order to obtain their approval. This signature is in addition to signatures obtained for other institutional requirements (such as GCO submissions). Note: if the research involves personnel from multiple departments, the Chair of each department represented must sign and date the application. A standalone document HRP-211h: Application for Human Research Standalone Chair Signoff Section is available on the PPHS website for this purpose.

7 Investigator Manual Page 7 of 31 Note: if facilities/resources are required for this Human Research which the listed personnel do not have formal authority to provide (e.g. radiology scanning time), it is the PI s responsibility to obtain permission for these resources prior to the PPHS submission to assure the feasibility of the Human Research. Appendix A: External Site Approvals If applicable, list any non-mssm study sites/facilities in which human research activities will be conducted, and provide a contact name and contact information for each site. Indicate whether an authorized representative of the site has granted permission for you to conduct the Human Research and provide evidence of this permission when available. Indicate if the site s IRB will review the Human Research (answer No if the site does not have an IRB). Answer whether the site will request to rely on our IRBs, or another IRB. Research affiliates such as the Queens Hospital Network, Elmhurst Hospital Network, Jewish Home and Hospital, and Bronx VA are considered external sites. Appendix B: Drugs/Biologics Complete Appendix B for the drug(s) or biologic(s) being used in the Human Research (FDA approved and unapproved). This form does not need to be completed for FDA-approved drugs or biologics whose use in a protocol is totally up to the discretion of an attending physician (not specifically prescribed by the protocol.) Each Appendix B form needs to be signed by the Research Pharmacy. Follow Research Pharmacy policy regarding their submission requirements. Appendix C: Devices Complete one Appendix C form for each device being evaluated for safety or effectiveness (approved and unapproved). Please obtain any necessary departmental approvals for device use/storage prior to the submission to the PPHS. How do I write a protocol using the MSSM template? Use the HRP-503a: Template Protocol and accompanying HRP-503: Template Protocol Instructions as a starting point for drafting a new protocol, and reference the instructions in italic text for the information the PPHS looks for when reviewing protocols. Here are some key points to remember when developing a protocol: The italicized bullet points in the HRP-503: Template Protocol Instructions serve as guidance to investigators when developing a Human Research Protocols for submission to the PPHS. All italicized comments are meant to be deleted prior to submission. For any items described in a sponsor s protocol or other documents submitted with the application, investigators may simply reference the page numbers of these documents within the protocol template rather than repeat information. When writing a protocol, always keep an electronic copy. You will need to modify this copy when making changes to the protocol. If you believe your activity may not be Human Research, contact the PPHS office prior to developing your protocol. Note that, depending on the nature of your research, certain sections of the protocol template may not be applicable. Indicate this as appropriate by marking N/A after each section heading.

8 Investigator Manual Page 8 of 31 How do I activate a protocol at a new MSSM site if it has already been approved by the MSSM IRB for another site? In some cases (e.g. multi-site drug trials), the same protocol may be submitted to the IRB by separate principal investigators for separate sites under MSSM jurisdiction. If you are trying to activate a protocol at a new site/sites for which you will serve as the principal investigator, and the MSSM IRB has already approved the protocol for another principal investigator at another site, you may develop and submit a protocol that omits the following sections from the Human Research Protocol template: Objectives Background Inclusion and Exclusion Criteria Study Timelines Study Endpoints Procedures Involved in the Human Research Specimen Banking Data Management and Confidentiality Provisions to Monitor the Data to Ensure the Safety of Subjects Withdrawal of Subjects Risks to Subjects Provisions for Research Related Injury Potential Benefits to Subjects Multi-Site Human Research (Coordinating Center) Complete the Human Research Protocol template by describing information specific to the site(s) for which you will serve as Principal Investigator. Do not repeat information in the approved protocol that applies to all site(s). When submitting the Application for Human Research form and the additional required appendices and documents, you may omit the following when they exist: Evaluation instruments and surveys Grant application Complete sponsor protocol including DHHS-approved protocol (e.g., an NIH-sponsored Cooperative Group Clinical Trial protocol) DHHS-approved sample consent document ((e.g., sample consent from an NIH-sponsored Cooperative Group Clinical Trial) Current investigator brochure for each investigational drug Current package insert for each marketed drug Current product information for each investigational device If the research is conducted or funded by the Department of Energy, a completed Checklist for IRBs to Use in Verifying that HS Research Protocols are In Compliance with DOE Requirements How do I create a consent document? Use the HRP-502 TEMPLATE CONSENT DOCUMENT to create a consent document.

9 Investigator Manual Page 9 of 31 Note that all consent documents must contain all of the required and all additional appropriate elements of informed consent disclosure. Review section 7 of the PPHS s WORKSHEET HRP-311: Criteria for Approval and Additional Considerations, to ensure that these elements are addressed. We require that you date the revisions of your consent documents to ensure that you use the most recent version approved by the IRB with prospective subjects, and to fulfill your researcher record-keeping responsibilities. What are the different regulatory classifications that research activities may fall under? Submitted activities may fall under one of the following four regulatory classifications: Not Human Research : Activities must meet the DHHS or FDA definition of research involving human subjects for the activity to fall under PPHS oversight. Activities that meet neither definition of research nor human Subjects are not subject to PPHS oversight or review. Review the PPHS office s WORKSHEET HRP-309: Human Research Determination for reference. Contact the PPHS office in cases where it is unclear whether an activity meets the regulatory definition of Human Research. Exempt: Certain categories of Human Research may be exempt from regulation applicability but still require review and a determination made by someone other than the investigator. Review the PPHS s WORKSHEET: Exemption Determination for reference on the categories of research that may be exempt. If your department has a PPHS-certified Exempt Determiner, that individual is authorized to provide an unofficial exemption determination. Official exempt determinations can only be made by the PPHS office (official determination may be required by an external funder or journal). Review Using the Expedited Procedure: Certain categories of non-exempt Human Research may qualify for review that does not require convened IRB review (called an expedited procedure). Review the PPHS s CHECKLIST HRP-413: Eligibility for Review Using the Expedited Procedure for reference on the categories of research that may be reviewed using the expedited procedure. Review by the Convened IRB: Non-Exempt Human Research that does not qualify for review using the expedited procedure must be reviewed by the convened IRB. What are the decisions an IRB can make when reviewing a protocol? An IRB may approve research, require modifications to secure approval, table research, or disapprove research: Approval: Made when all criteria for approval are met. See How does the IRB decide whether to approve Human Research? below. Response to PPHS Required to Secure Approval: Made when IRB members require specific affirmations or modifications to a protocol before approval can be finalized. Response to PPHS Required to Determine Not Human Subject Research: Made when specific affirmations or modifications to a protocol are required before a determination that a protocol does not involve human subject research can be finalized.

10 Investigator Manual Page 10 of 31 Tabled: Made when the IRB cannot approve the research at a meeting for reasons unrelated to the protocol, such as loss of quorum. When taking this action, the IRB automatically schedules the protocol for a subsequent meeting. Deferred: Made when the IRB determines that the board is unable to approve a protocol and the IRB suggests modifications the might make the research approvable. When making this motion, the IRB describes its reasons for this decision, describes modifications that might make the research approvable, and gives the investigator an opportunity to respond to the IRB in person or in writing. Disapproval: Made when the IRB determines that it is unable to approve a protocol and the IRB cannot describe modifications the might make the research approvable. When making this motion, the IRB describes its reasons for this decision and gives the investigator an opportunity to respond to the IRB in person or in writing. How does the IRB decide whether to approve Human Research? The criteria for IRB approval can be found in the WORKSHEET: Exemption Determination for exempt Human Research and the CHECKLIST HRP-311: Criteria for Approval and Additional Considerations for non-exempt Human Research. The latter checklists reference other checklists that might be relevant. All checklists can be found on the IRB Web site. These checklists are used for initial review, continuing review, and review of modifications to previously approved Human Research. You are encouraged to use the checklists to write your protocol in a way that addresses the criteria for approval. What will happen after IRB review? The IRB will provide you with a written decision indicating that the IRB has approved the Human Research, requires modifications to secure approval, or has disapproved the Human Research. If the IRB has approved the Human Research: The Human Research may commence once all other organizational approvals have been met. IRB approval for non-exempt research is good for a limited period of time, as noted in the approval letter. If the IRB requires a response to secure approval and you are agreeable to the modifications or confirmations required, make the requested modifications or confirmations and submit them to the IRB within 30 days using FORM HRP-214: Response to PPHS If all requested modifications or confirmations are made, the IRB will issue a final approval. Research cannot commence until this final approval is received. If you do not respond to the IRB within 30 days, the offer of approval with the requested responses will be withdrawn. If you do not accept the requested modifications or confirmations, write up your response and submit it to the IRB within 30 days. If you do not provided additional information or correspondence within 30 days, the IRB will require a complete new protocol submission. If the IRB requires a response to determine that a protocol is not human subject research, and you are agreeable to the modifications or confirmations required, make the requested modifications or confirmations and submit them to the IRB within 30 days. You may find using FORM HRP-214: Response to PPHS helpful. If all requested modifications or confirmations are made, the IRB

11 Investigator Manual Page 11 of 31 will issue a final determination. Research cannot commence until this final determination is received. If you do not respond to the IRB within 30 days, the offer of determination given the requested responses will be withdrawn. If you do not accept the requested modifications or confirmations, write up your response and submit it to the IRB within 30 days. If you do not provided additional information or correspondence within 30 days, the IRB will require a complete new protocol submission. If the IRB defers the Human Research: The IRB will provide a statement of the reasons for deferral and may provide suggestions on how to make the study approvable, and will give you an opportunity to respond in writing. In most cases if the IRB s reasons for the deferral are addressed by a subsequent modification, the Human Research can be approved. You may submit a response to the IRB using FORM HRP-214: Response to PPHS. If the IRB disapproves the Human Research: The IRB will provide a statement of the reasons for disapproval and give you an opportunity to respond in writing. In all cases, you have the right to request to address your concerns to the IRB directly at an IRB meeting. What are my obligations after IRB approval? 1) Do not start Human Research activities until you have the final IRB approval letter. NOTE: If you are in receipt of an approved pending funding letter from the IRB, you must take the required action stipulated in the letter before you will receive the final IRB approval letter and be able to begin any Human Research activities. 2) Personally conduct or supervise the Human Research. a) Conduct the Human Research in accordance with the relevant current protocol as approved by the IRB. b) When required by the IRB ensure that consent or permission is obtained in accordance with the relevant current protocol as approved by the IRB. c) Do not modify the Human Research without prior IRB review and approval unless necessary to eliminate apparent immediate hazards to subjects. i) Report any changes in approved research initiated without prior IRB approval to eliminate apparent immediate hazards to subjects promptly (within 5 days) to the IRB using FORM HRP-224: Reportable New Information ii) The IRB will review this information to determine whether each change was consistent with ensuring the subject s continued welfare d) Protect the rights, safety, and welfare of subjects involved in the research. 3) Submit to the IRB: a) Proposed modifications as described in this manual. (See How do I submit a modification? ) b) A continuing review application as requested in the approval letter and as described in this manual. (See How do I submit continuing review? c) A final review application when the Human Research is closed. (See How Do I Close Out a Study? ) 4) Report any of the information items on the FORM HRP-224: Reportable New Information to the IRB within five business days. 5) Do not accept or provide payments to professionals in exchange for referrals of potential subjects ( finder s fees. ) 6) Do not accept payments designed to accelerate recruitment that were tied to the rate or timing of enrollment ( bonus payments. )

12 Investigator Manual Page 12 of 31 7) Maintain signed and dated consent documents for three years after completion of the research. Maintain signed and dated HIPAA authorizations and consent documents that include HIPAA authorizations for six years after completion of the research. 8) See additional requirements of various federal agencies in Appendix A of this document. How do I document consent? The document HRP SOP - Written Documentation of Consent, establishes the process to document the informed consent process in writing. Use the signature block approved by the IRB on the consent document. Complete all items in the signature block, including dates and applicable checklists. The following are some requirements for consent documentation: The subject or representative signs and dates the consent document. The individual obtaining consent signs and dates the consent document. Whenever required by the IRB, the subject s or representative s signature is to be witnessed by an individual who signs and dates the consent document. For subjects who cannot read, and whenever required by the IRB or the study sponsor, a witness to the oral presentation signs and dates the consent document. A copy of the signed and dated consent document is to be provided to the subject. For subjects who cannot provide a signature, refer to the procedures in HRP SOP - Written Documentation of Consent. How do I submit a modification? Complete the FORM HRP-213: Modification of Approved Human Research, attach all requested supplements, have the formed signed by the individuals listed in the form, and provide the requested number of copies to the PPHS office. Maintain electronic copies of all information submitted to the IRB. Please note that research must continue to be conducted without inclusion of the modification until IRB approval is received. If the research is determined to be exempt, and a proposed modification affects the design and conduct of the research in the approved protocol (including the subjects, sources, or mechanisms of data/material collection), complete the FORM HRP-213: Modification of Approved Human Research, attach all requested supplements, and provide the requested number of copies to the PPHS office How do I submit for a continuing review? Complete the FORM HRP-212: Continuing/Final Review Progress Report, attach all requested supplements, have the formed signed by the individuals listed in the form, and provide the requested number of copies to the PPHS office. Maintain electronic copies of all information submitted to the IRB. If the continuing review involves modifications to previously approved research, submit those modifications as a separate request for modification using the FORM HRP-213: Modification of Approved Human Research. If the continuing review application is not received by the date requested in the approval letter, you will be restricted from submitting new Human Research until the completed application has been received.

13 Investigator Manual Page 13 of 31 If the approval of Human Research expires all Human Research procedures related to the protocol under review must cease, including recruitment, advertisement, screening, enrollment, consent, interventions, interactions, and collection of private identifiable information. Continuing Human Research procedures is a violation of federal regulations. If current subjects will be harmed by stopping Human Research procedures that are available outside the Human Research context, provide these on a clinical basis as needed to protect current subjects. If current subjects will be harmed by stopping Human Research procedures that are not available outside the Human Research context, immediately contact the IRB chair and provide a written list of the currently enrolled subjects and why they will be harmed by stopping Human Research procedures. Human research that is determined to be exempt does not require continuing review. However, a "FORM HRP-212: Continuing/Final Review Progress Report should be submitted within 30 days of the completion of the study. How do I close out a study? Complete the FORM HRP-212: Continuing/Final Review Progress Report, attach all requested supplements, have the formed signed by the individuals listed in the form, and submit the documents to the PPHS office. Maintain electronic copies of all information submitted to the IRB. If you fail to submit a continuing/final review form to close out Human Research, you will be restricted from submitting new Human Research until the completed application has been received. If the continuing/final review application for closing out a Human Research study is not received by the date requested in the approval letter, you will be restricted from submitting new Human Research until the completed application is received. How long do I keep records? You are required to comply with Institutional record retention policy as outlined in the FACULTY HANDBOOK. Under federal regulations, you must maintain your Human Research records, including signed and dated consent documents, for three years after closing out the Human Research. Maintain HIPAA authorizations and other records related to HIPAA compliance for six years. If you are the sponsor-investigator of an IND or IDE, or if the Human Research is otherwise under the jurisdiction of the FDA, additional requirements for recordkeeping may be involved. Consult with the Compliance Department regarding your situation. If your Human Research has a financial sponsor, contact the sponsor before disposing of Human Research records. What if I need to use an unapproved drug or device in a life-threatening situation and there is no time for prior IRB review? Contact the Research Pharmacy immediately to discuss the situation. See the WORKSHEET HRP-317: Emergency Use of a Test Article in a Life Threatening Situation for the regulatory criteria allowing such a use and make sure these are followed. You will need to submit a report of the use to the IRB within five days of the use and an IRB application for initial review within 30 days. If you fail to submit the report within five days or the IRB application for initial review within 30

14 Investigator Manual Page 14 of 31 days, you will be restricted from submitting new Human Research until the report and IRB application for initial review have been received. Emergency use of an unapproved drug or device in a life-threatening situation without prior IRB review is research as defined by FDA, the individual getting the test article is a subject as defined by FDA, and therefore is governed by FDA regulations for IRB review and informed consent. Research Pharmacy has a form that they will provide to you to help them make the appropriate determination that the situation meets the criteria for an emergency use. Research Pharmacy also will provide you with a template information sheet to customize for the situation. Individuals getting an unapproved drug or device in a life-threatening situation without prior IRB review cannot be considered a subject as defined by DHHS and their results cannot be included in prospective research as that term is defined by DHHS. How do I get additional information and answers to questions? This document and the policies and procedures for the Program for Protection of Human Subjects are available on the IRB Web Site at If you have any questions or concerns, about the Human Research Protection Program, contact the PPHS office at: Phone: (212) If you have questions, concerns, complaints, allegations of undue influence, allegations or findings of non-compliance, or input regarding the Human Research Protection Program that cannot be addressed by contact the PPHS office, follow the directions in the HRP-101: HUMAN RESEARCH PROTECTION PROGRAM PLAN under Reporting and Management of Concerns.

15 Investigator Manual Page 15 of 31 Appendix A-1 Additional Requirements for DHHS-Regulated Research 1 1. When a subject decides to withdraw from a clinical trial, the investigator conducting the clinical trial should ask the subject to clarify whether the subject wishes to withdraw from all components of the trial or only from the primary interventional component of the trial. If the latter, research activities involving other components of the clinical trial, such as follow-up data collection activities, for which the subject previously gave consent may continue. The investigator should explain to the subject who wishes to withdraw the importance of obtaining follow-up safety data about the subject. 2. Investigators are allowed to retain and analyze already collected data relating to any subject who chooses to withdraw from a research study or whose participation is terminated by an investigator without regard to the subject s consent, provided such analysis falls within the scope of the analysis described in the IRB-approved protocol. This is the case even if that data includes identifiable private information about the subject. 3. For research not subject to regulation and review by FDA, investigators, in consultation with the funding agency, can choose to honor a research subject s request that the investigator destroy the subject s data or that the investigator exclude the subject s data from any analysis. 4. When seeking the informed consent of subjects, investigators should explain whether already collected data about the subjects will be retained and analyzed even if the subjects choose to withdraw from the research. 1

16 Investigator Manual Page 16 of 31 Appendix A-2 Additional Requirements for FDA-Regulated Research 1. When a subject withdraws from a study: 2 a. The data collected on the subject to the point of withdrawal remains part of the study database and may not be removed. b. An investigator may ask a subject who is withdrawing whether the subject wishes to provide continued follow-up and further data collection subsequent to their withdrawal from the interventional portion of the study. Under this circumstance, the discussion with the subject would distinguish between study-related interventions and continued follow-up of associated clinical outcome information, such as medical course or laboratory results obtained through non-invasive chart review, and address the maintenance of privacy and confidentiality of the subject s information. c. If a subject withdraws from the interventional portion of the study, but agrees to continued follow-up of associated clinical outcome information as described in the previous bullet, the investigator must obtain the subject s informed consent for this limited participation in the study (assuming such a situation was not described in the original informed consent form). IRB approval of informed consent documents is required. d. If a subject withdraws from the interventional portion of a study and does not consent to continued follow-up of associated clinical outcome information, the investigator must not access for purposes related to the study the subject s medical record or other confidential records requiring the subject s consent. e. An investigator may review study data related to the subject collected prior to the subject s withdrawal from the study, and may consult public records, such as those establishing survival status. 2. For FDA-regulated research involving investigational drugs: a. Investigators must abide by FDA restrictions on promotion of investigational drugs: 3 i. An investigator, or any person acting on behalf of an investigator, must not represent in a promotional context that an investigational new drug is safe or effective for the purposes for which it is under investigation or otherwise promote the drug. ii. This provision is not intended to restrict the full exchange of scientific information concerning the drug, including dissemination of scientific findings in scientific or lay media. Rather, its intent is to restrict promotional claims of safety or effectiveness of the drug for a use for which it is under investigation and to preclude commercialization of the drug before it is approved for commercial distribution. iii. An investigator must not commercially distribute or test market an investigational new drug. b. Follow FDA requirements for general responsibilities of investigators 4 i. An investigator is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of subjects under the investigator's care; and for the control of drugs under investigation

17 Investigator Manual Page 17 of 31 ii. An investigator must, in accordance with the provisions of 21 CFR 50, obtain the informed consent of each human subject to whom the drug is administered, except as provided in 21 CFR or of this chapter. iii. Additional specific responsibilities of clinical investigators are set forth in this part and in 21 CFR 50 and 21 CFR 56. c. Follow FDA requirements for control of the investigational drug 5 i. An investigator must administer the drug only to subjects under the investigator's personal supervision or under the supervision of a sub-investigator responsible to the investigator. ii. The investigator must not supply the investigational drug to any person not authorized under this part to receive it. d. Follow FDA requirements for investigator recordkeeping and record retention 6 i. Disposition of drug: 1. An investigator is required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects. 2. If the investigation is terminated, suspended, discontinued, or completed, the investigator must return the unused supplies of the drug to the sponsor, or otherwise provide for disposition of the unused supplies of the drug under 21 CFR ii. Case histories. 1. An investigator is required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation. 2. Case histories include the case report forms and supporting data including, for example, signed and dated consent forms and medical records including, for example, progress notes of the physician, the individual's hospital charts, and the nurses' notes. The case history for each individual must document that informed consent was obtained prior to participation in the study. iii. Record retention: An investigator must retain required records for a period of 2 years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or if the application is not approved for such indication, until 2 years after the investigation is discontinued and FDA is notified. e. Follow FDA requirements for investigator reports 7 i. Progress reports: The investigator must furnish all reports to the sponsor of the drug who is responsible for collecting and evaluating the results obtained. ii. Safety reports: An investigator must promptly report to the sponsor any adverse effect that may reasonably be regarded as caused by, or probably caused by, the drug. If the adverse effect is alarming, the investigator must report the adverse effect immediately. iii. Final report: An investigator must provide the sponsor with an adequate report shortly after completion of the investigator's participation in the investigation. iv. Financial disclosure reports:

18 Investigator Manual Page 18 of The clinical investigator must provide the sponsor with sufficient accurate financial information to allow an applicant to submit complete and accurate certification or disclosure statements as required under 21 CFR The clinical investigator must promptly update this information if any relevant changes occur during the course of the investigation and for 1 year following the completion of the study. f. Follow FDA requirements for assurance of IRB review 8 i. An investigator must assure that an IRB that complies with the requirements set forth in 21 CFR 56 will be responsible for the initial and continuing review and approval of the proposed clinical study. ii. The investigator must also assure that he or she will promptly report to the IRB all changes in the research activity and all unanticipated problems involving risk to human subjects or others, and that he or she will not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects. g. Follow FDA requirements for inspection of investigator's records and reports 9 i. An investigator must upon request from any properly authorized officer or employee of FDA, at reasonable times, permit such officer or employee to have access to, and copy and verify any records or reports made by the investigator pursuant to ii. The investigator is not required to divulge subject names unless the records of particular individuals require a more detailed study of the cases, or unless there is reason to believe that the records do not represent actual case studies, or do not represent actual results obtained. h. Follow FDA requirements for handling of controlled substances 10 i. If the investigational drug is subject to the Controlled Substances Act, the investigator must take adequate precautions, including storage of the investigational drug in a securely locked, substantially constructed cabinet, or other securely locked, substantially constructed enclosure, access to which is limited, to prevent theft or diversion of the substance into illegal channels of distribution. 3. For FDA-regulated research involving investigational devices: a. General responsibilities of investigators. 11 i. An investigator is responsible for ensuring that an investigation is conducted according to the signed agreement, the investigational plan and applicable FDA regulations, for protecting the rights, safety, and welfare of subjects under the investigator's care, and for the control of devices under investigation. An investigator also is responsible for ensuring that informed consent is obtained in accordance with 21 CFR 50. b. Specific responsibilities of investigators 12 i. Awaiting approval: An investigator may determine whether potential subjects would be interested in participating in an investigation, but must not request the written informed consent of any subject to participate, and must not allow any subject to participate before obtaining IRB and FDA approval

19 Investigator Manual Page 19 of 31 ii. Compliance: An investigator must conduct an investigation in accordance with the signed agreement with the sponsor, the investigational plan, and other applicable FDA regulations, and any conditions of approval imposed by an IRB or FDA. iii. Supervising device use: An investigator must permit an investigational device to be used only with subjects under the investigator's supervision. An investigator must not supply an investigational device to any person not authorized to receive it. iv. Financial disclosure: 1. A clinical investigator must disclose to the sponsor sufficient accurate financial information to allow the applicant to submit complete and accurate certification or disclosure statements required under 21 CFR The investigator must promptly update this information if any relevant changes occur during the course of the investigation and for 1 year following completion of the study. v. Disposing of device: Upon completion or termination of a clinical investigation or the investigator's part of an investigation, or at the sponsor's request, an investigator must return to the sponsor any remaining supply of the device or otherwise dispose of the device as the sponsor directs. c. Maintain the following accurate, complete, and current records relating to the investigator's participation in an investigation: 13 i. All correspondence with another investigator, an IRB, the sponsor, a monitor, or FDA, including required reports. ii. Records of receipt, use or disposition of a device that relate to: 1. The type and quantity of the device, the dates of its receipt, and the batch number or code mark. 2. The names of all persons who received, used, or disposed of each device. 3. Why and how many units of the device have been returned to the sponsor, repaired, or otherwise disposed of. iii. Records of each subject's case history and exposure to the device. Case histories include the case report forms and supporting data including, for example, signed and dated consent forms and medical records including, for example, progress notes of the physician, the individual's hospital charts, and the nurses' notes. Such records must include: 1. Documents evidencing informed consent and, for any use of a device by the investigator without informed consent, any written concurrence of a licensed physician and a brief description of the circumstances justifying the failure to obtain informed consent. 2. Documentation that informed consent was obtained prior to participation in the study. 3. All relevant observations, including records concerning adverse device effects (whether anticipated or unanticipated), information and data on the condition of each subject upon entering, and during the course of, the investigation, including information about relevant previous medical history and the results of all diagnostic tests. 4. A record of the exposure of each subject to the investigational device, including the date and time of each use, and any other therapy. 13