Irb - Sop VA

INSTITUTIONAL REVIEW BOARD
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Standard Operating Procedures Manual

PART I POLICIES AND PROCEDURES
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VA Long Beach Healthcare System
VALBHS IRB SOPs Version date: 5/20/2008 Replaces version: 12/14/2007
TABLE OF CONTENTS
4 5 6 8 I 19 25 II 27 31 35 III 37 40 IV 43 59 66 70 74 81 85 89 95 104 107 111 V 115 VI 121 125 128 131 VII 135 145 148 VIII 152 161 IX 166 168 GA 100 101 102 200 201 202 203 300 301 302 400 401 402 403 404 405 406 407 408 409 410 411 412 500 501 600 601 602 603 604 700 701 702 703 800 801 802 900 901 902 Introduction Abbreviations Listing of Attachments Definitions GENERAL ADMINISTRATION Statement of Authority and Purpose Review of Policies and Procedures IRB ORGANIZATION AND PERSONNEL Composition of Board Member Appointment, Compensation and Responsibilities Orientation and Training FUNCTIONS AND OPERATIONS IRB Meetings Documents Required For IRB Review ROUTINE IRB REVIEW Initial Review Continuing Review/Modification/Completion Criteria For Approval Of Research Proposals Review of Research Involving Vulnerable Populations Review of Research on Human Subjects Likely to Need Surrogate Consent Financial Disclosure and Conflict of Interest Audits and Third Party Verification Investigational Devices HIPAA Requirements and Privacy Protection International Research Data Safety Monitoring Procedures Multi-Site Research EXPEDITED IRB REVIEW Expedited Review Process and Documentation POST-REVIEW ACTIONS Categories of Action Investigator Notification of IRB Action Reporting Relationships Reporting to Regulatory Agencies and Institutional Officials INFORMED CONSENT Informed Consent Requirements and Documentation Emergency Use and Informed Consent Research Using Human Biological Material and Genetic Research RESPONSIBILITIES OF INVESTIGATORS Duties and Responsibilities of Research Investigators Educational Requirements for Investigators, Research Personnel, and Study Monitors QUALITY ASSURANCE AND EDUCATION Quality Improvement and Quality Assurance Procedures Maintenance of Documentation and Record Retention
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Problems, Adverse Events and Non-Compliance APPENDICES Appendix A Timetable for Actions Described in This Manual Appendix B- Chart 1 Determining Whether an Activity is Human Subjects Research Appendix B-Chart 2 Waiver or Alteration of Informed Consent Decision Chart
INTRODUCTION
Scope and Responsibility: These Standard Operating Policies and Procedures apply to the day-to-day operations of the Institutional Review Board (IRB) of the VA Long Beach Healthcare System (VALBHS). The IRB is responsible for ensuring that research using human subjects is conducted in a manner that protects the safety, rights, welfare and other interests of the human subjects enrolled in that research under the applicable statutes of the Common Rule (38 CFR 16), the Federal Policy for the Protection of Human Subjects (45 CFR 46), the regulations of the Food and Drug Administration (FDA) (21 CFR 50, 54, 56, 312, and 812), International Conference on Harmonisation Good Clinical Practices Guidelines (E6), VA Handbook 1200.5, and the State of California Health and Safety Code. The IRB will also conform to the policy guidance of the Office for Human Research Protections (OHRP) and the Office of Research and Development, VA Central Office. These policies and procedures apply to: All human subjects research conducted completely or partially at the VALBHS or at approved off-site locations. All human subjects research conducted by employees or agents of the VALBHS while on VA official duty time, regardless of location. Recruitment or advertising at VALBHS for research at non-VA sites. Other institutions or investigators who may enter into agreements with the IRB to review their human subjects research. IRB members and all persons conducting IRB business. All others who must subscribe to its decisions and requirements including but not limited to clinical investigators, research managers/coordinators, research nurses, support staff, etc. At VALBHS the IRB also serves as the Privacy Board. In this capacity, the IRB is charged with safeguarding the privacy and confidentiality of human research subjects and deceased individuals who would not otherwise be considered as participants in human subjects research. These additional authorities and responsibilities are outlined in section RR 409.
ABBREVIATIONS ACOS ADE ADR AE CFR COS CPRS CRA CRF CRO CRADO FDA GCP HIPAA HIV HRPP HUD IB IRB ICF ICH IDE IND IRB NIH OHRP ORD ORO PHS PI R&D RCO SAE SCIRE SOP SOPP UCI VA VAMC WOC Associate Chief of Staff Adverse Drug Event/Experience Adverse Drug Reaction Adverse Event Code of Federal Regulations Chief of Staff Computerized Patient Record System Clinical Research Associate Case Report Form Contract Research Organizations Chief Research and Development Officer Food and Drug Administration Good Clinical Practice Health Insurance Portability and Accountability Act Human Immunodeficiency Virus Human Research Protection Program Humanitarian Use Device Investigator Brochure Institutional Review Board Informed Consent Form International Conference on Harmonisation Investigational Device Exemption Investigational New Drug Institutional Review Board National institutes of Health Office for Human Research Protections Office of Research and Development, VA Central Office Office of Research Oversight Public Health Service Principal Investigator Research & Development Research Compliance Officer Serious Adverse Event Southern California Institute for Research and Education Standard Operating Procedures Standard Operating Policies and Procedures University of California, Irvine Veterans Administration VA Medical Center Without Compensation
LISTING OF REFERENCED ATTACHMENTS AND FORMS
1. VALBHS FWA 2. IRB Exempt Eligibility Determination Form 3. IRB Roster 4. VA Form 10-1436 5. Abstract Form 6. Application for IRB Review Form 7. Informed Consent Guidance Template 8. VA Form 10-9012 9. Initial Project Submission Checklist 10. IRB Reviewer Worksheet for New Projects 11. IRB Reviewer Worksheet for Informed Consent Forms/HIPAA Authorization 12. Medical Device Risk Determination Form 13. IRB Application for Continuing Review Form 14. IRB Reviewer Worksheet for Continuing Review 15. Disclosure of Relationships and Financial Interests 16. Expedited Review Criteria Worksheet 17. IRB Request for Modification Form 18. Non-Local Adverse Event Notification Form 19. Local Serious or Unexpected Adverse Event Notification Form 20. VALBHS Research and Development Education Plan 21. VALBHS Policy on the Use of Investigational Drugs 22. VALBHS Policy on the Use of Investigational Devices 23. Prospectus of Research Study Form 24. Application for IRB Review-Supplement 25. Investigator Device Plan/Device Information Form 26. HIPAA Forms 27. Standardized Template for CPRS Notes 28. Deviation/Unanticipated Problem Reporting Form 29. IRB Pre-Reviewer Worksheets 30. IRB Exempt Project Submission Checklist 31. Continuing Review Project Submission Checklist 32. Modification Submission Checklist 6
33. VHA Handbook 1200.5 Appendix A Timetable for Actions Described in This Manual Appendix B Chart 1 Chart 2
DEFINITIONS Act means the Federal Food, Drug, and Cosmetic Act, as amended (21 CFR) Adverse Drug Reaction (ADR): In the pre-approval clinical experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be established: all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. The phrase "responses to a medicinal product" means that a causal relationship between the medicinal product and an adverse event is at least a reasonable possibility, i.e.: the relationship cannot be ruled out. Regarding marketed medicinal products: a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis or therapy of diseases or for modification of physiological function. (ICH 1.1) Adverse Event (AE): Any untoward medical occurrence in a patient or research subject administered a pharmaceutical product or other research intervention and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product or research procedure, whether or not related to the medicinal (investigational) product or procedure. (ICH 1.2) Approval Date: The IRB Approval Date is the date that the IRB approval memo for a project is signed as approved by the IRB Chair or his/her designee. Approved Off-Site Location: A research site outside of the VA medical center or approved VA-leased space which has been approved for the conduct of VA-funded research through an off-site waiver as described in VA Handbook 1200.16. Associated with the use of the drug: There is a reasonable possibility that the experience may have been caused by the drug (21 CFR 312.32). Audit: A systematic and independent examination of trial-related activities and documents to determine whether the evaluated trial-related activities were conducted, and the data were recorded, analyzed, and accurately reported according to the protocol, sponsors standard operating procedures (SOPs), good clinical practice (GCP), and the applicable regulatory requirement(s) (ICH 1.6). Case History: Includes the case report forms and supporting data including signed and dated consent forms, and medical records including, but not limited to: progress notes of the physician, the individuals hospital chart(s) and nurses notes. Clinical Privileges: If the person's license allows for independent practice and the facility chooses to allow independent practice, privileges must be granted in accordance with VHA Handbook 1100.19 and the facility's Medical Staff Bylaws, Rules and Regulation prior to performing the interventions covered under the privileges they have been granted. 8
Coded Sample: A coded sample is one that is associated with a code that could permit an agent of the repository to link it with the subject. Even though the investigator may not be able to directly link the sample with a subject, research using such samples is subject to IRB review. Co-investigator: Any individual member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and/or to make important trial-related decisions (e.g., associates, residents, research fellows) (ICH 1.56). Confidentiality: Refers to the researchers agreement with the participant about how the participants identifiable private information will be handled, managed and disseminated. Prevention of disclosure, to other than authorized individuals, of a sponsors proprietary information or of a subjects identity. (ICH 1.16) Conflict of Interest: A convergence of an investigator's private interests with his or her research interests, such that an independent observer might reasonably question whether the investigator's professional actions or decisions are improperly influenced by considerations of personal financial gain. Continuing Review Deadline: The Continuing Review Deadline is exactly one year after the date of the most recent review of the study at a convened IRB meeting, or shorter if required by the IRB. Beyond this date, study approval expires and a study cannot continue. Credentialing: Credentialing is the systematic process of screening and evaluating qualifications and other credentials, including licensure, registration, certification, required education, relevant training and experience, and current competence. Debarment List: The debarment list is a list maintained by the Food and Drug Administration (FDA) which includes individuals or firms barred from participating in the drug industry because they have been convicted of crimes related to FDA's regulation of drugs. From the FDA's web site you can also review the Disqualified/Restricted/Assurances List for Clinical Investigators. This list identifies clinical investigators who have, or have agreed to, certain restrictions on their conduct in future studies, as well as access to The Public Health Service Administrative Actions, a list of researchers who have had administrative actions imposed against them by the Office of Research Integrity (ORI). De-identified Information: Personal health information that has had identifying characteristics removed. This form of data was historically called anonymous although it is now recognized that health information is so rich in potentially identifying characteristics that it can never be truly anonymous; there will always be some potential for re-identification of an individual. HIPAA considers information to be de-identified if 18 different elements are removed. Department or Agency Head: The head of any Federal Department or Agency and any other officer or employee of any Department or Agency to whom authority has been delegated. (38 CFR, 45 CFR). 9
Direct Access: Permission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a clinical trial. Any party (e.g., domestic and foreign regulatory authorities, sponsors, monitors, and auditors) with direct access should take all reasonable precautions within the constraints of the applicable regulatory requirement(s) to maintain the confidentiality of subjects identities and sponsors proprietary information (ICH1.21). Disability: A substantial disruption of a persons ability to conduct normal life functions (21 CFR 312.32). Documentation: All records, in any form (including, but not limited to, written, electronic, magnetic, and optical records; and scans, x-rays, and electrocardiograms) that describe or record the methods, conduct, and/or results of a trial, the factors affecting a trial, and the actions taken. (ICH 1.22) Emergency Use means the use of a test article on a human subject in a life-threatening situation, in which no standard acceptable treatment is available, and in which there is not sufficient time to obtain IRB approval. Exclusionary Lists: The List of Excluded Individuals and Entities (also known as the LEIE), the sanctions list or the exclusionary list, is a list of persons and organizations that have been excluded from participation in federal health care programs, e.g., Medicare, Medicaid, VA health care. It is maintained by the Department of Health and Human Services, Office of Inspector General (HHS OIG). Individuals are placed on the LEIE for such things as conviction for defrauding Medicare or Medicaid, Patient Abuse, Licensing board actions, or default on government-sponsored student loans. Exculpatory: To clear from a charge of fraud or guilt. Exempt Research is research determined by the Institutional Review Board (IRB) to involve human subjects only in one or more of certain categories (38 CFR 16.101(b)) as described in Section 101. Expedited Review is research initially reviewed and approved outside of a convened IRB meting. The research must present no more than minimal risk to human subjects and involve only procedures in certain specific categories, as described in section 501. Minor changes to previously approved research during the period for which approval is authorized may also be approved through the expedited process (38 CFR 16.110(b)). Family member: Any one of the following legally competent persons: Spouse; parents; children (including adopted children); brothers, sisters, and spouses of brothers and sisters; and any individual related by blood or affinity whose close association with the subject is the equivalent of a family relationship. (21 CFR) Good Clinical Practice (GCP): A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected. (ICH 1.24) 10
Human biological material: Any material derived from human subjects, such as blood, urine, tissues, organs, hair, nail clippings, genetic material, or any other cells or fluids, whether collected for research purposes or as residual specimens from diagnostic, therapeutic or surgical procedures. Humanitarian Use Device (HUD): A device that has been granted FDA marketing approval for the treatment or diagnosis of diseases or conditions that affect or are manifested in fewer than 4,00 individuals in the United States per year. Human Research Protection Program (HRPP): The systematic and comprehensive approach by an organization to ensure human subject protection in all research. The Human Research Protection Program (HRPP) consists of all committees, individuals or entities involved in the protection of human subjects in research, including the Medical Center Director, Associate Chief of Staff for Research and Development (ACOS/R&D), the Human Research Protection Program Officer, the Administrative Officer for Research and Development (AO/R&D), Research Compliance Officer (RCO), the Research and Development (R&D) Committee, the Institutional Review Board (IRB), other committees or subcommittees addressing human subjects protection, investigators, IRB staff, research staff, and research pharmacy staff. The objective of this system is to assist the institution in meeting ethical principles and regulatory requirements for the protection of human subjects in research. Human subject: as defined by DHHS regulations means a living individual about whom an investigator (whether professional or student) conducting research obtains (1) data through intervention or interaction with the individual, or (2) identifiable private information. [45 CFR 46.102(f)] i. Intervention as defined by DHHS regulations means both physical procedures by which data are gathered (for example, venipuncture) and manipulations of the subject or the subjects environment that are performed for research purposes. [45 CFR 46.102(f)] ii. Interaction as defined by DHHS regulations means communication or interpersonal contact between investigator and subject. [45 CFR 46.102(f)] iii. Private information as defined by DHHS regulations means information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place, and information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (for example, a medical record). [45 CFR 46.102(f)] iv. Identifiable information as defined by DHHS means information that is individually identifiable (i.e., the identity of the subject is or may readily be ascertained by the investigator or associated with the information). Human Subject as defined by FDA regulations means an individual who is or becomes a subject in research, either as a recipient of the test article or as a control. A subject may be either a healthy human or a patient. [21 CFR 50.3(g), 21 CFR 56.102(e)] A human subject includes an individual on whose specimen a medical device is used. [21 CFR 812.3(p)] 11
Identifiable information: as defined by DHHS means information that is individually identifiable (i.e., the identity of the subject is or may readily be ascertained by the investigator or associated with the information). Identified sample: A sample that is associated with a personal identifier such that the researcher could directly link it with a subject. Research involving this sample is subject to IRB review and approval. Impartial witness: A person, who is independent of the trial, who cannot be unfairly influenced by people involved with the trial, who attends the informed consent process if the subject or the subjects legally acceptable representative cannot read, and who reads the informed consent form and any other written information supplied to the subject. (ICH 1.26) Implant: A device that is placed into a surgically or naturally formed cavity of the human body and is intended to remain there for a period of 30 days or more. In order to protect public health, FDA may determine that devices placed in subjects for shorter periods are also implants. Individually-Identifiable Information: Any information, including health information maintained by the VHA, pertaining to an individual that also identifies the individual and, except for individually-identifiable health information, is retrieved by the individuals name or other or other unique identifier. Individual-identifiable health information is covered regardless of whether or not the information is retrieved by name. Informed Consent: A process by which a subject or their legally authorized representative voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subjects decision to participate. Informed consent is documented by means of a written, signed, and dated informed consent form (ICH 1.28). Institutional Review Board (IRB): Any board, committee, or other group formally designated by an institution to review biomedical research involving human subjects, to approve the initiation of, and to conduct continuing review of such research (21 CFR, 38 CFR, 45 CFR). An independent body constituted of medical, scientific, and nonscientific members, whose responsibility it is to ensure the protection of the rights, safety, and well-being of human subjects involved in a trial by, among other things, reviewing, approving, and providing continuing review of trials, of protocols and amendments, and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects (ICH 1.31). Within VHA, an IRB was formerly know as the Subcomittee on Human Studies. Interaction: Interaction as defined by DHHS regulations means communication or interpersonal contact between investigator and subject. [45 CFR 46.102(f)] International Research: International Research for the purposes of this guidance is defined as any VA-approved human subjects research conducted at international sites (not within the United States (U.S.), its territories, or any VA-approved research using either human biological specimens or human data originating from international sites. 12
Multi-site trials are only covered under this definition if: VA is the sponsor, VA functions as the coordinating center, VA subcontracts to a foreign site, or the principal investigator (PI) for the total project is a VA investigator. Intervention: Intervention as defined by DHHS regulations means both physical procedures by which data are gathered (for example, venipuncture) and manipulations of the subject or the subjects environment that are performed for research purposes. [45 CFR 46.102(f)] Investigational Product: A pharmaceutical form of an active ingredient (21 CFR 312.3), device (21 CFR 812.3(g)) or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use (ICH 1.33). An investigational drug may also be an approved drug that is being studied for a previously unapproved use and/or efficacy. Investigator: An individual who is under the direction of the principal investigator (PI) who is involved in some or all aspects of the research project, including the design of the study, conduct of the study, analysis and interpretation of the collected data, and writing of resulting manuscripts. An investigator may be either compensated by VA, be appointed to work without compensation (WOC), or may be an employee assigned to VA through the Intergovernmental Personnel Act of 1970. The FDA considers an investigator and a principal investigator to be synonymous. Investigator's Brochure (IB): A compilation of the clinical and nonclinical data on the investigational product(s), which is relevant to the study of the investigational product(s) in human subjects (ICH 1.36). This document is also known as an Investigational Drug Brochure. Ionizing Radiation: Particles or rays with sufficient energy to cause the ejection of orbital electrons from absorber atoms. Includes diagnostic and therapeutic procedures done for research purposes. Sources of radiation include: nuclear medicine, radiation therapy and radiology. IRB approval: The determination of the IRB that the human subjects research has been reviewed and may be conducted at an institution within the constraints set forth by the IRB and by other institutional and Federal requirements. Lapse: A condition that exists when a study has failed to be re-approved within the time frame that was specified at the time of the previous approval. Unlike suspensions and terminations, a lapse results from a failure to act, by either the investigator or the IRB, rather than as a result of an IRB action. All research activities must stop except for the continuation of follow-up activities necessary to protect the participants safety. Unlike suspended studies, lapsed studies are not approved. Unlike terminated studies, lapsed studies may be re-approved. Legally Authorized Representative (LAR): An individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the 13
subject's participation in the procedure(s) involved in the research (21 CFR, 38 CFR. 45 CFR). In the State of California, a LAR is currently interpreted as including only court appointed conservators of the person. Licensed Independent Practitioners (LIP): The term Licensed Independent Practitioner is any individual permitted by law and the facility to provide patient care services independently (i.e., without supervision or direction, within the scope of the individual's license and in accordance with individually granted clinical privileges). Life-threatening adverse drug experience: Any adverse drug experience that places the patient, in the view of the investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that, had it occurred in a more severe form, might have caused death (21 CFR 312. 32) Linked sample: A sample associated with a personal identifier or a code that allows it to be linked with a subject, even if the investigator may not be able to directly link the sample with a subject. Research using such samples is subject to IRB review. Minimal risk: The probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests (21 CFR 56.102, 45 CFR 46.102(i), 38 CFR) Principal Investigator: An individual who conducts a research investigation, i.e., under whose immediate direction research is conducted, or in the event of an investigation conducted by a team of individuals, is the responsible leader of that team. The FDA considers an investigator and a principal investigator to be synonymous. Privacy: Refers to a persons desire to control the access of others to themselves. Private Information: defined by DHHS regulations means information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place, and information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (for example, a medical record). [45 CFR 46.102(f)] Protocol: A document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial. The protocol usually also gives the background and rationale for the trial, but these could be provided in other protocol referenced documents (ICH 1.44) Protocol Amendment: A written description of a change(s) to or formal clarification of a protocol (ICH 1.45). Randomization: The process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce bias (ICH 1.48). 14
Quorum: More than half of the voting members are present including at least one nonscientist. In order for research to be approved, it must receive the approval of a majority of those members present at the meeting Recusal: When an IRB or R&D Committee or other committee member declines to participate in a matter because of a potential conflict of interest under the Code of Ethics. As distinguished from abstention, the official recusing him/herself will not be present in or participate in deliberations or voting on the matter where there are potential conflicts of interest. Regulatory Noncompliance: Failure to adhere to institutional policies and procedures, state laws, federal laws or other regulations governing the conduct of human subjects research including failure to follow the requirements of VHA Handbook 1200.5. This includes such acts as failure to obtain or maintain approval for research or to adhere to an approved protocol, failure to obtain informed consent when required, coercion of human subjects, performance of an unapproved procedure, performance of research at an unapproved site, or failure to file protocol modifications, applications for study continuing reviewl, and adverse event reports. Research: as defined by DHHS regulations means a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge. [45 CFR 46.102(d)] Research as defined by FDA regulations means any experiment that involves a test article and one or more human subjects, and that either must meet the requirements for prior submission to the Food and Drug Administration under section 505(i) or 520(g) of the Federal Food, Drug, and Cosmetic Act, or need not meet the requirements for prior submission to the Food and Drug Administration under these sections of the Federal Food, Drug, and Cosmetic Act, but the results of which are intended to be later submitted to, or held for inspection by, the Food and Drug Administration as part of an application for a research or marketing permit. The terms research, clinical research, clinical study, study, and clinical investigation are synonymous for purposes of FDA regulations. [21 CFR 50.3(c), 21 CFR 56.102(c)] Experiments that must meet the requirements for prior submission to the Food and Drug Administration under section 505(i) of the Federal Food, Drug, and Cosmetic Act means any use of a drug other than the use of an approved drug in the course of medical practice. [21 CFR 312.3(b)] Experiments that must meet the requirements for prior submission to the Food and Drug Administration under section 520(g) of the Federal Food, Drug, and Cosmetic Act means any activity that evaluates the safety or effectiveness of a medical device. [21 CFR 812.2(a)] Any activity in which results are being submitted to or held for inspection by FDA as part of an application for a research or marketing permit is considered to be FDA-regulated research. [21 CFR 50.3(c), 21 CFR 56.102(c)]
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Research Involving Human Subjects: any activity that either meets the DHHS definition of research and involves human subjects as defined by DHHS; or meets the FDA definition of research and involves human subjects as defined by FDA.
Researcher: Principal investigator or the investigator Scientific Misconduct: Serious deviation from accepted practice in carrying out research or in reporting the results of research, or material failure to comply with Federal requirements affecting specific aspects of the conduct of research, such as the protection of human subjects. This may include plagiarism, misrepresentation of authorship, fabrication falsification or destruction of data, or other serious deviations from accepted scientific practices, such as obstruction of anothers research, violation of confidentiality, intentional deception, omission, research dishonesty, or repeated incidents of regulatory noncompliance (VA Handbook 1200.14). Scope of Practice or Functional Statement: A Scope of Practice or Functional Statement outlines all the duties of employees. These duties must: 1) be consistent with the occupational category under which they are hired, 2) allowed by the license, registration or certification they hold, 3) consistent with their qualifications (education & training), and 4) be agreed upon by the person's immediate supervisor and the ACOS. Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR): An AE or ADR occurring in a patient or subject enrolled in a research study is serious if it results in any of the following outcomes: death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization, may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalizations, or the development of drug dependency or drug abuse (21 CFR 312. 32). Source Documents: Original documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at medical or technical departments involved in the clinical trial)(ICH 1.52) Sponsor: A person or other entity that initiates human subjects research, but that does not actually conduct the investigation, i.e., the test article is administered or dispensed to, or used involving, a subject under the immediate direction of another individual. A corporation or agency that uses one or more of its own employees to conduct an 16
investigation that it has initiated is considered to be a sponsor (not a sponsorinvestigator), and the employees are considered to be investigators (21 CFR) Sponsor-investigator: An individual who both initiates and actually conducts, alone or with others, human subjects research, i.e., under whose immediate direction the test article is administered or dispensed to, or used involving, a subject. The term does not include a corporation or agency. The obligations of a sponsor-investigator under FDA regulations include both those of a sponsor and those of an investigator. (21 CFR) Standard Operating Policy and Procedures (SOPs): Detailed, written instructions to achieve uniformity of the performance of a specific function (ICH 1.55). Suspension: An action issued by the IRB that temporarily or permanently stops all or some of the research activities must stop until issues have been satisfactorily resolved. Suspended projects still have IRB approval and must undergo continuing review. Termination: An action issued by the IRB that permanently stops all research. Terminated projects are closed, do not have IRB approval, and are not subject to continuing review requirements. Test article: Any drug (including a biological product for human use), medical device for human use, human food additive, color additive, electronic product, or any other article subject to regulation under the Act or under sections 351 and 354-360F of the Public Health Service Act (21 CFR) Unexpected Adverse Drug Experience: Any adverse experience the specificity or severity of which is not consistent with the current Investigator Brochure, or if an Investigator Brochure is not required or available, the specificity or severity of which is not consistent with the risk information described in the general investigational plan or elsewhere in the current application, as amended. For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the investigator brochure only referred to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the investigator brochure only listed cerebral vascular accidents. "Unexpected" as used in this definition, refers to an adverse drug experience that has not been previously observed (e.g., included in the investigator brochure) rather that from the perspective of such experience not being anticipated from the pharmacological properties of the pharmaceutical product (21 CFR 312.32). Unexpected Adverse Event (UAE): An unexpected adverse event is any adverse event and/or reaction, the specificity or severity of which is not consistent with the informed consent, current investigator brochure or product labeling. Further, it is not consistent with the risk information described in the general investigational plan or proposal. Unidentified Sample: An anonymous or unidentified sample is one supplied to the researcher from a repository that has a collection of unidentified human specimens. There is no possibility of linking such samples to the individual. This differs from 17
samples that have been anonymized or unlinked by removal of identifiers (see Unlinked Sample). Unlinked Sample: A biological sample that lacks any identifier or code that may link the sample to an individual. An investigator must differentiate between an unlinked sample that is provided to him by a third party and a sample under the investigator's control from which the investigator proposes to remove any identifying material (anonymize) for the purposes of research. Unapproved medical device: A device that is used for a purpose or condition for which the device requires, but does not have, an approved application for pre-market approval under section 515 of the Federal Food, Drug, and Cosmetic (FD&C) Act [21 U.S.C. 360(e)]. An unapproved device may be used in human subjects only if approved for clinical testing under an approved application for an Investigational Device Exemption (IDE) under section 520(g) if the Act [21 U.S.C. 360(j)(g)] and 21 CFR part 812. Medical devices that have not received marketing clearance under section 510(k) of the FD&C Act are also considered unapproved devices. Vulnerable subjects: Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent. (ICH 1.61) Mentally disabled individuals are a vulnerable population. Well-being (of the trial subjects): The physical and mental integrity of the subjects participating in a clinical trial (ICH 1.62). Witness: VA regulations (VHA 1200.5) require the signature of a witness on all consent documents. A witness is a person who has been present while the consent document was signed by the participating subject and the person who has administered the consent process. In some circumstances regulations may require the signature of an impartial witness.
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GA 101 STATEMENT OF AUTHORITY AND PURPOSE 1. POLICY A. Authority of the IRB The VA is one of 17 departments and agencies that have agreed to follow the Federal Policy for the Protections of Human Subjects, effective August 19, 1991, generally known as the "Common Rule". This policy is incorporated in 38 CFR 16. The Institutional Review Board (IRB) at the VA Long Beach Healthcare System (VALBHS) was established by the Office of Research and Development of the Department of Veterans Affairs (ORD). It is constituted under an active Federal-wide Assurance (FWA) filed with the Office of Human Research Protections (OHRP) and operates in compliance with VA Handbook 1200.5 and all VA-wide standards for human research protection. It is currently seeking NCQA accreditation. It is authorized by VALBHS policy to set requirements and standards for the informed consent process for treatment or procedure performed under a research protocol (VALBHS Policy 12-1). The VALBHS FWA number is 00004435. The Medical Center Director is the assurance signatory institutional official and is ultimately responsible for overseeing the protection of human subjects within the facility. As stipulated in the Belmont Report and based upon the principles of autonomy, beneficence and justice, the primary responsibility of the IRB is to protect the rights and welfare of human subjects to ensure that: b. The sum of the benefits to the subject and the importance of the knowledge to be gained so outweigh the risks to the subjects as to warrant a decision to allow the subject to accept these risks. c. Legally effective informed consent is obtained, unless the requirements for waiver of informed consent are met by adequate and appropriate methods in accordance with the provisions of applicable regulations d. The selection of subjects is equitable and is representative of the group that will benefit from the research. The IRB was founded to review research for investigators performing such research at this institution. The IRB is constituted to ensure compliance with existing Federal laws and regulations for the protection of human subjects of medical and behavioral research. The IRB assures that human research subjects receive the highest level of protection possible and that any questions or any legal or ethical ambiguities always be resolved in favor of the human research subject. The IRB is responsible for ascertaining the acceptability of proposed research in terms of medical center commitments and policies, applicable law, validity of study design as it relates to risks and benefits, sensitivity to community standards and attitudes, as well as standards of professional conduct and practice. The IRBs composition plays a pivotal role in its 19
ability to fulfil its role. The IRB must promote respect for its advice and counsel in safeguarding the rights and welfare of human participants; and possess the professional copetence necessary to review specific research activities. The IRB has the authority to disapprove, require modifications to secure approval, and approve research protocols based on its consideration of the risks and potential benefits of the research, and whether or not the rights and welfare of human subjects are adequately protected; to require applications for study continuing review from investigators; to oversee conduct of the study; to suspend or terminate a study; and to place irreversible restrictions on a study. Although the IRB is a subcommittee of the R&D Committee, the institution, its officials, or other institutional committees cannot approve research that has been disapproved by the IRB. If, in the course of its review, the R&D Committee requires changes to the protocol that relate to the protection of human subjects, the R&D Committee must refer those changes to the IRB for its approval before the R&D Committee can give final approval. These policies apply to all research involving human subjects conducted completely or partially in this VA facility or approved off-site locations/facilities, irrespective of funding source. The policies apply to all human subjects research performed by employees or agents of the VALBHS while on VA official duty time, regardless of the location of the research. The policy applies to recruitment or advertising at VALBHS for research at non-VA sites. These policies also apply to other institutions or investigators who may enter into agreements with the IRB to review their human subjects research. An entity to which these policies apply may not engage the services of another IRB for the purposes of avoiding the rulings of the IRB of record, nor are they permitted to use a commercial IRB. In addition to these policies, research that receives support from other Federal agencies must meet the human subjects requirements of all funding sources. Where FDA regulated test articles are used, the FDA regulations (21 CFR 11, 50, 54, 56, 312, 314, 812, and 814) apply regardless of funding source. Investigators who have submitted grant proposals involving human subjects to the NIH or other external funding agency should defer submitting to the IRB until funding by the agency is determined to be likely. Investigators may submit for IRB approval prior to receiving funding notification if they wish, or if the funding agency requires it. B. Research at Non-VA Sites When a VA staff member is studying human subjects exclusively, or in part, at another institution, or when a project involves the use of VA facilities or includes VA subjects (recruitment, use of laboratory, etc.), the investigator must obtain IRB approval. The IRB must assure that, when subjects are identified in materials of record, patient privacy is ensured. The consent form must include the role of the VA laboratory as appropriate. (For example, in the consent form, the patient may give permission for a blood sample to be studied in a VA Laboratory.) In situations where all of the research activities occur outside of the VA, the IRB must still be assured that the protocol and consent form from the other institution are adequate for these purposes; if not, it may request that the investigator process a modification through the IRB of the other institution.
20
The IRB may be designated for review of research under another institutions assurance only with the written agreement of the Medical Center Director and in accordance with applicable ORD and OHRP requirements. Any such designation must be accompanied by a written agreement specifying the responsibilities of the facility and its IRB under the other institutions assurance. IRBs operated by the VAMC have no authority over, or responsibility for, research conducted at other institutions in the absence of such a written agreement. If the outside institution does not have an IRB, they must agree to comply with the policies and procedures of the VALBHS IRB. If the outside facility does have an IRB or an affiliation, then the project must be reviewed and approved by that body before work may commence at that site. Prior to performing ANY study procedures on human subjects at an outside facility or institution, the investigator must obtain IRB approval. For each outside facility that will involve human subjects in a research study, the investigator must provide the IRB with the following, which must be reviewed and approved by the IRB: 1) A detailed plan outlining how patient safety will be monitored at outside facility. (Note that a VA contract facility is not a VA facility and must conform to requirements for outside facilities. 2) A description of the education and training of study personnel involved at the outside facility. 3) An educational plan describing how personnel at the outside facility will be trained, including such materials as fact sheets, instructional materials, and sample tests as appropriate. 4) A letter of compliance from each facility involved. The letter should be written on the facilities letter head and should state that the facility is aware that we will be enrolling VA and non-VA patients to participate in this study and that they will follow the policies and regulations of the HHS. 5) Work may not commence until start at a given facility until appropriate in-service education is completed and Letter of Compliance is received. Each facility must receive a copy of the LBVAHS FWA. C. Participation Of Non-Veterans As Research Subjects Non-veterans may be entered into VA-approved research studies only when there are insufficient veterans available to complete the study. All regulations pertaining to the participation of veterans as research subjects including requirements for indemnification in case of research-related injury pertain to non-veteran subjects enrolled in VAapproved research. A VA medical record must normally be created for all subjects for whom a consent waiver has not been granted. All requirements that govern the documentation of consent and research procedures in CPRS notes that apply to veterans are also applicable for non-veterans. Subject to the provisions of 38 CFR 17.62(g) and 38 CFR 17.101, any person who is a bona fide volunteer may be admitted to or furnished outpatient treatment at a Department of Veterans Affairs hospital when the treatment to be rendered is part of an approved Department of Veterans Affairs research project and there are insufficient veteran-patients suitable for the project. 21
D. Exemption from IRB Review Exemption from IRB review may be permitted under some circumstances, in accordance with existing regulations, as determined by the Chair. However, the IRB and the Chair always retain the authority to require full review of any research project involving human subjects. Unless otherwise required by Department or Agency head, research activities in which the only involvement of human subjects will be in one or more of the categories listed on the IRB Exempt Eligibility Determination Form are exempt from the requirements for IRB review. Research may also be eligible for exemption from IRB review when the FDA has authorized a waiver of local IRB review under a parallel track/expanded access program [57 FR 13250-59] or other situations authorized under 21 CFR 56.105, and where no VA regulations prohibit it. Waiver from DHHS may also be required, if it is involved in the funding of the research or is responsible for the project or institutional assurance. Such exemptions should only be permitted when the IRB and/or Chair judge that requiring full review would expose subjects or potential subjects to unacceptable additional risk. Treatment IND studies [21 CFR 312.34, 312.35 and 312.80 to 88] are not exempt from IRB review. The IRB Chair will review research that the investigator believes to be exempt under the above provisions, and make a determination of whether exempt status is appropriate or whether expedited or full committee review is required. The Investigator does not make the determination of whether a research activity is exempt. As a matter of local policy, exemptions will not be permitted for research that utilizes a written Informed Consent Form, involves genetic research, or involves vulnerable subjects. Exemptions will not be permitted if there are ethical concerns regarding the conduct of research. Human subjects research meeting the exemption criteria may be granted exemption from IRB review by the Chair. An evaluation will be made by the IRB Chair and/or the IRB pertaining to whether exempt research fulfills the organizations ethical standards using the review criteria listed on the IRB Exempt Eligibility Determination Form.. The IRB will be notified of all exemptions granted by the Chair at the next convened meeting. At that time the members will have the opportunity to further review, discuss, perform full review, disapprove, or require modifications. This serves to satisfy notification requirements but is not a requirement for approval. The IRB Coordinator will communicate decisions regarding the exemption request to the Principal Investigator by providing them with a copy of the IRB Exempt Eligibility Determination Form reviewed and completed by the IRB Chair and/or the IRB immediately following the determination. Some projects that are otherwise exempted from IRB review may still be subject to HIPAA review (see section RR 409). At VALBHS the IRB also serves as the Privacy Board. Autopsy tissue, cadavers, and de-identified human cell lines do not meet the definition of human subject and it is therefore not required to submit to the IRB for review, however, such projects must obtain approval from the R&D Committee. Further, projects involving cadavers must be subject to HIPAA requirements as described in RR 409.
22
The determination of whether or not a project is considered to involve research may be a complicated process. Whenever there is any question about whether an activity is human subjects research (as defined in DEFINITIONS section of this manual), please contact the Human Research Protection Program Officer or the IRB Chair and submit a copy of the narrative/protocol for review by either of these individuals. The individuals who have the authority to make a determination as to whether an activity constitutes human subjects research include the Human Research Protection Program Officer or the IRB Chair. The determination as to whether an activity constitutes human subjects research will be made using the definition of human subjects research (as defined in DEFINITIONS section of this manual and Chart 1 in Appendix B of this manual). The communication of such decisions to the person seeking a decision will be done in writing. 2. APPLICABLE REGULATIONS AND GUIDELINES 21 CFR 56. 104 VA Handbook 1200.5 21 CFR 56. 105 VHA Handbook 1200.16 21 CFR 56. 108(a)(1) The Belmont Report 21 CFR 56.108(b)(3) 38 CFR16. 16.101 21 CFR 56. 109(a, f) 38 CFR16. 109(a, e) 21 CFR 312.34 and 312.35 38 CFR 16.113 21 CFR 312.80 to 88 38 CFR 17.45 21 CFR 56.112 38 CFR 17.62 21 CFR 56.113 38 CFR 17.101 ICH 3.1.1 38 CFR 17.92 ICH 3.3.1 45 CFR 46.101 57 FR 13250 45 CFR 46. 109(a, e) California Health and Safety Code 45 CFR 46. 113 24170-24179.5 21 CFR 50.20 VALBHS Policy 12-1 21 CFR 50.23-25, 27 21 CFR 56. 101(a)
3.
PROCEDURE Medical Center Director Provide IRB with a copy of VALBHS FWA Ensure ongoing authority of IRB to perform its function File FWA as required and maintain on behalf of the institution Maintain IRB SOPs Retain copy of VALBHS FWA and SOPs Conduct administrative review of all new research proposals for completeness and forward all submissions requesting exemption to Chair for evaluation and action 23
HRPP Officer
IRB Coordinator
Document determinations of exemptions and expedited reviews. Prepare and distribute summary of Exempt Review actions to IRB members at next convened meeting and document discussions of actions in minutes Confirm and approve determination that submission qualified for expedited review on Exempt Review Determination form.
IRB Chair (or delegated designee)
ATTACHMENTS VALBHS IRB MPA IRB Exempt Eligibility Determination Form
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GA 102 REVIEW OF POLICIES AND PROCEDURES
1.
POLICY
This Standard Operating Policy and Procedure (SOP) Manual of the IRB must remain current and in compliance with all applicable regulations. To remain current, this SOP Manual must be reviewed and periodically updated. In general, this review will occur at least triennially. The HRPP Officer and the Research Compliance Officer will review these policies and procedures for compliance with the most recent VA and federal regulations, especially those pertaining to initial review, continuing review, expedited review, and the process for determining exempt status. Proposed changes will be presented to the IRB for input. Revisions will be implemented upon review and approval of a majority of the Committee. The revised version will then be forwarded to R&D Committee for approval. Notifications of changes and an updated Policies and Procedures Manual will be distributed to members as appropriate. Other documents used by the IRB for its day-to-day functions, including but not limited to investigator submission forms, investigator's manual, guidance documents, reviewer forms, and checklists, etc. will also be reviewed at least annually and revised as needed. Revised forms and documents will be approved by the IRB and by R&D Committee.
2. APPLICABLE REGULATIONS AND GUIDELINES 45 CFR 46.108 (a) VA Handbook 1200.5 45 CFR 46. 115 (6) 38 CFR 16.104 (b) (4) 21 CFR 56.108(a) 38 CFR 16.108(a) 21 CFR56.115 (6) 38 CFR 16. 115 (6) 45 CFR 46.103 (b) (4) 3. PROCEDURE IRB Chair HRPP Officer IRB Coordinator
Review this Policy and Procedure Manual at least annually, and at other times as needed, as determined by the Chair or a majority of the IRB members. Document the continuing review and updating. Notify members of changes by memo when implemented. Provide updated version of Policies and Procedures Manual to members annually Discuss and vote on changes made in continuing review Retain file copies of current SOP Manual and archive copies.
IRB Members IRB Coordinator
25
HRPP Officer RCO
Update Policies and Procedures to comply with the most recent VA and Federal regulations
26
OP 201 COMPOSITION OF THE IRB 1. POLICY The IRB consists of at least five regular, voting members. The IRB members must be sufficiently qualified to review the research through their experience, expertise, and diversity, including consideration of race, gender, cultural backgrounds, and sensitivity to community issues and/or attitudes. The IRB is knowledgeable about the community from which the subjects are drawn to ensue that subject rights will be protected and the consent process is appropriate for the subject population involved. The IRB has adequate knowledge of information on conditions surrounding the conduct of the research and the continuing status of the research. The IRB has people knowledgeable about and can ascertain the acceptability of proposed research in terms of institutional commitments, regulations, applicable law, and standards of professional conduct and practice. Every effort will be made to ensure that IRB membership will not consist entirely of men, women or of members of one profession, though no appointment to the IRB will be made solely on the basis of gender. Equal consideration will be given to qualified persons of both genders and every non-discriminatory effort will be made to ensure that the IRB membership does not consist entirely of men or entirely of women. The institution will make every effort to have a diverse IRB, within the scope of available expertise needed to conduct its functions, and that the IRB possesses appropriate knowledge of the local context in which research for which it is responsible will be conducted. The IRB will include a representative(s) who is knowledgeable about, or has experience with, vulnerable populations involved in research, either as members, or as ad hoc consultants. Membership and composition of the IRB is periodically reviewed and adjusted to meet regulatory and organizational requirements with each change in membership at both IRB and R&D Committee meetings and yearly via the HRPP Annual Report. IRB membership consists of: A. Regular Members There will be at least one member whose primary concerns are in scientific areas and at least one member whose primary concerns are in nonscientific areas. These members are to be selected primarily to reflect the values of the research community and the community from which the research participants are drawn with respect to the rights and welfare of human research subjects The non-scientists primary concerns are unambiguously in nonscientific areas, meaning little or no scientific or medical training or expertise. Nurse, pharmacists, and other biomedical health professionals are no considered to have primary concerns in the non-scientific area.There will be one member who is not otherwise affiliated with this institution, and who is not part of the immediate family of a person who is affiliated with the medical center. It is recommended that members of the community be considered, such as clergy, teachers, attorneys,veterans, representatives of legally recognized veterans organizations, or practicing physicians. R&D administration officials (including, but not limited to the ACOS, R&D and Administrative Officer, R&D) may not serve as voting members of the IRB. They may 27
serve as non-voting members and must be sensitive to the occurrence or appearance of conflict of interest. The professional, and personal backgrounds of the regular members will be varied in order that the IRB can conduct complete and adequate reviews of the types of research activities commonly reviewed by this institution. In addition, efforts should be made to ensure racial, cultural, and gender diversity among members. The regular members will be capable of reviewing research proposals in terms of scientific merit, protection for the rights and welfare of human subjects, regulations, applicable law, and standards of professional conduct and practice. Since the VALBHS reviews studies involving the mentally ill, the IRB will always have at least one professional member with expertise in mental health. Regular members are expected to make every effort to attend each meeting of IRB, and their presence or absence will be used in establishing a quorum for each meeting. A quorum is composed of a majority of the regular members of the IRB (see Section 301). One regular member, who has a VA appointment, will be designated as the Chair. The R&D Committee will carefully evaluate the qualifications and experience of any member being considered for the position of Chair. The Chair will serve as the official representative of the IRB, and will chair all IRB meetings. In the absence of the Chair, the Associate/Alternate Chair will lead the IRB meeting. In the event that the Associate/Alternate Chair is unavailable as well, the Chair or Associate Chair will designate another regular IRB member to chair the meeting. B. Alternate Members Alternate members are qualified voting members who replace regular IRB members who are, on occasion, unable to attend convened meetings of the IRB. Alternate members must be listed on the IRBs official membership IRB Roster, which will specify which member(s) the alternate is qualified to replace. The backgrounds of alternate members should be similar to the member they are replacing or they should be able to represent similar interests. Terms of appointment, education, length of service, and duties are exactly as for regular IRB members. An alternate member may be designated to serve as the alternate for more than one regular member, but may substitute for only one member at any given meeting. When an alternate serves in place of a regular member, this will be noted in the minutes. When alternates substitute for a primary member, the alternate member should receive and review the same material that the primary member would receive. Alternates are also encouraged to attend IRB meetings when not representing an absent regular member, or when requested by the Chair to provide their expertise. In such cases the alternate may participate in the discussion but cannot vote and their presence is not used to establish a quorum for the meeting. C. Ex-Officio Members The IRB may include members that regularly advise or otherwise participate in IRB deliberations as a result of their official duties within the Human Research Protection Program. These may include the Chair of the R&D Committee, the Human Research 28
Protection Officer and the Research Compliance Officer. Ex-officio members have the same obligations as regular or alternate members and may participate in IRB discussions, but may not vote on IRB actions. The presence, or absence of ex-officio members will not be used in establishing a quorum for an IRB meeting. D. Special Consultants The IRB evaluates each research proposal to decide whether there Is a need for consultants with additional expertise. When the IRB encounters studies that involve science, medical questions, or other issues that lie beyond the expertise of the members, the Chair will invite consultation from individual(s) who have competence in such areas from the staff that is available within the Medical Center or the affiliate (and who do not have a conflict of interest). These individuals will be asked to submit a written evaluation of the protocol and may be invited to address the IRB, however, they may not vote with the regular and alternate members of the IRB and their presence or absence will not be used in establishing a quorum for an IRB meeting. IRB members may also obtain consultations by directly contacting colleagues for information as long as it follows suit with conflict of interest guidelines and consultations are documented. Determinations of conflicts of interest for consultants are described in section RR406. Key information provided by consultants will be distributed to all members and documented in the IRB minutes. 2. APPLICABLE REGULATIONS AND GUIDELINES 45 CFR 46.103 (b) (3) VA Handbook 1200.5 38 CFR 16.107 (a-d, f) 21 CFR 56. 107 (a-d, f) 21 CFR 56.115 (a)(5) 38 CFR103 (b) 38 CFR 16.115 (a) 45 CFR46.107 (a-d, f) 45 CFR 46.115(a) (5) ICH 3.2 3. PROCEDURE IRB Coordinator Maintain a roster of all regular and alternate members for inspection purposes. Maintain a file on all members, to include their curriculum vita and other evidence of professional ability. Maintain a roster of available consultants who are eligible and qualified to attend meetings as invited consultants. Ensure the overall diversity of the IRB membership (gender, race, ethnicity, community affiliation and professional experience) through non-discriminatory selection methods. Ensure that one member representing scientific interests and one member representing non-scientific interests is available for each meeting.
IRB Chair HRPP Officer IRB Coordinator
29
HRPP Officer
Submit updated IRB Roster to OHRP as changes are made and approved by both IRB and R&D Committee.
4.
ATTACHMENTS IRB Roster
30
OP 202 APPOINTMENT, COMPENSATION AND RESPONSIBILITIES OF MEMBERS 1. POLICY Potential voting members of the IRB and alternate members will be nominated by members of the IRB and then forwarded to the R&D Committee for consideration. Such names are then forwarded to the Medical Center Director for consideration and formal appointment in writing. (Other VA personnel may also submit names to the IRB or Research and Development Committee to be forwarded to the Medical Center Director for consideration.) Voting members serve 3-year staggered terms and may be reappointed on an indefinite basis. One member is designated the Chairperson. The Chair will be nominated by members of the IRB and the R&D Committee, and the nominations approved by the IRB at a convened meeting by a majority vote. The Chair should have at least 1 year of experience as a regular IRB member, expertise/knowledge in ethics and demonstrated management/leadership skills. and may be re-appointed on an indefinite basis. The IRB Chairperson may not simultaneously chair the R&D Committee or another subcommittee thereof. The IRB Chair should have expertise/knowledge in ethics. A member may resign before the conclusion of his/her term. The vacancy will be filled as quickly as possible. A member who is not performing his/her responsibilities as expected may be removed by a two-thirds vote of the full membership at a convened meeting. The Chair may also be removed from that position by a two-thirds vote of the full membership at a convened meeting. When unexpected vacancies occur, an alternate member may be selected to fill the vacancy. The Chair may appoint an Associate/Alternate Chair to assist or act on behalf of the Chair in particular IRB matters and at IRB meetings, either as a general procedure, or on a case-by-case basis. The Chair also may delegate any of his/her responsibilities as appropriate to other qualified individual(s). Non-affiliated members will be reimbursed for travel and their time. The IRB Coordinator and the IRB Administrative Staff will be clerical and administrative personnel with full responsibility for the day-to-day management of the IRBs activities. The IRB Coordinator and Administrative Staff will be employees of the VA and/or the Southern California Institute for Research and Education (SCIRE) assigned to perform the clerical and administrative tasks of IRB operations under the direction of the HRPP Officer. One member of the IRB, usually the Chair, will also be a voting member of the R&D Committee. The responsibilities of the members of the Board and Staff are summarized as follows:
31
A. BOARD MEMBERS Chairperson: Chair convenes meetings. Calls special meetings when necessary. Makes decisions in emergency situations to protect subjects and remain in compliance with regulations. Prior to meeting, IRB Chair or his/her designee, designates one primary reviewer whose professional interests are consistent with protocol content and reviewer expertise and one secondary reviewer. Appoints Associate/Alternate Chair. Reviews SAEs and IND Safety Reports and determines which ones require review by the full board. Determines whether studies qualify for exemption from review. Determines whether studies qualify for expedited review (Section 501) Performs or delegates review of applications and revisions meeting expedited review criteria. Reviews all submitted investigator reports and determine if there is reason for full IRB review. Reviews policies, procedures and forms on an ongoing basis. Relate concerns of IRB staff and members to administration regarding issues in human research review. Acts as an advisor and educator in the institution's research community. B. Associate/Alternate Chairperson: Performs duties of the Chair in his/her absence. Assists the Chairperson as needed. C. IRB Members: Reviews research applications and other appropriate materials prior to convened meetings. Provides sufficient advance notice if unable to attend a meeting. Attends convened meetings and contributes to Board discussion. Review studies according to approval criteria offered in the regulations and SOPs. Serves as primary or secondary reviewer on selected applications. Discloses any potential conflict of interest to the IRB chair as soon as it is recognized (see section RR 406). Maintains confidentiality regarding any information contained in any review. Performs audits as needed. Reviews policies, procedures and forms on an annual basis. Understands these operating procedures and applicable Federal and VA regulations regarding human subjects research. D. IRB Coordinator Understands policies, procedures and regulations regarding human subjects research and IRB operations. Develops and implements procedures to effect efficient document flow and maintenance of all IRB records. 32
Maintains the official roster of IRB members. Schedules IRB meetings. Distributes pre-meeting materials. Compiles the minutes of IRB meetings in compliance with regulatory requirements. Maintains all IRB documentation and records in accordance with regulatory requirements. Ensures continuing review requirements are met. Assists HRPP Officer in orienting and educating new IRB members Ensures that all IRB records are secured and properly archived. Facilitates communication between investigators and the IRB. Tracks the progress of each research protocol submitted to the IRB. Maintains a computerized database for tracking purposes. Serves as a resource for investigators on general regulatory information, and providing guidance about forms and submission procedures. Assists HRPP Officer in the training of research investigators and staff. Drafts reports and correspondence to research investigators on behalf of the IRB or IRB Chairperson regarding the status of the research, including conditions for approval of research and cases of adverse events or unanticipated problems. Drafts reports and correspondence directed to research facility officials, federal officials, and others on behalf of the IRB or IRB Chairperson. Assists in evaluation, audit, and monitoring of human subject research as directed by the IRB, the R&D Committee, HRPP Officer or the ACOS/R&D. Assists in keeping IRB investigators manual, IRB forms and IRB SOPs up to date. Assists during regulatory inspections, site visits and accreditation visits. Assumes additional duties and responsibilities as delegated by the HRPP Officer or the Chairperson. The IRB Coordinator is responsible for ensuring that documentation of IRB activities and decisions fully satisfies all regulatory requirements. The IRB Coordinator should have a detailed, working knowledge of relevant regulatory requirements. E. HRPP Officer Serves as the primary institutional contact for the Human Research Protection Program Responsible for the management of the Human Research Protection Program Provides direct oversight of IRB personnel Trains, supervises and evaluates IRB staff Oversees development of education program for varying roles within the human research community Updates the IRB on any guidance related to the HRPP from VA Central Office and other entities Files and maintains FWA Oversees HRPP budget Implements quality improvement activities for the Human Research Protection Program Serves in an advisory role for HRPP related issues, policies and procedures to the IRB 33
Promptly reports changes in IRB membership to ORO. Once ORO has reviewed it, ORO will forward this documentation to OHRP. Orients new IRB members in completing orientation procedures and meeting required education standards Maintains training documentation and reference materials related to human subject protection requirements Drafts reports and correspondence directed to research facility officials, federal officials and others on behalf of the Human Research Protection Program Updates policies and procedures to comply with the most recent VA and Federal Regulations Coordinates all regulatory inspections, site visits and accreditation visits pertaining to the Human Research Protection Program with the assistance of the IRB Coordinator
F. IRB Administrative Staff Understands policies, procedures and regulations regarding human subjects research and IRB operations. Perform administrative duties to assure systematic flow of work through the IRB. Prepare and distribute review materials to members and consultants. Maintain files. Prepare and distribute minutes. Assure accurate and timely documentation, data input, and database up-keep. Send out notification of IRB decisions, requests for additional information, and correspondence to investigators in a timely manner. Send out timely reminders and notification to investigators when applications for study continuing review are due.
2.
APPLICABLE REGULATIONS AND GUIDELINES VA Handbook 1200.5 21 CFR 56.107(a) 45 CFR 46.107(a) 38 CFR 16.107 (a) PROCEDURE IRB Chair IRB Members HRPP Officer
3.
Solicit regular and alternate IRB members from within and outside the institution, and the local community, following an appropriate schedule. Following established criteria, select new members Replace members who resign or leave IRB service.
IRB Coordinator
Maintain roster of IRB membership
34
GA 203 ORIENTATION AND TRAINING OF IRB MEMBERS 1. POLICY Training of Investigators, IRB members and IRB staff, and research personnel conducting research involving human subjects should meet the requirements set forth in the most recent version of the PHS Policy On Instruction In The Responsible Conduct Of Research and any applicable VA guidelines. The IRB will provide training for its members and staff. The institution will provide or recommend a program of instruction for investigators and research staff to comply with this policy and will document its adherence to the provisions of this policy. Training requirements for investigators and research personnel are described in Section 802. A. Training for IRB members: Prior to attending his/her first IRB meeting as a member, all regular and alternate members should receive and review the following: Regulations and Guidance: VALBHS IRB SOP Manual VALBHS FWA The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects VA Handbook 1200.5 Human Research Protection Program Policy In addition, all IRB members must have completed an IRB-approved educational program prior to starting as active members, and this must be documented. Prior to attending their first meeting as a voting member, a new committee member must meet with the Chairperson to discuss specific responsibilities and duties and familiarize himself or herself with the committee meeting format. Committee members are also encouraged to attend external meetings where regulatory issues are discussed in order to be knowledgeable about current issues. At the introduction of new/revised SOP's, or at least annually, all IRB members and staff will be provided a documented training session. B. Training for IRB staff members: In addition to the training listed above for IRB members, new IRB staff should also receive orientation in: Support staff responsibilities HRPP structure and lines of authority Scheduling meetings Computer database management IRB reporting requirements Paper files and archiving Interactions with Sponsors & Investigators Application for study continuing review and correspondence 35
In addition, all IRB staff members must have completed an IRB-approved educational program and this must be documented.
2.
APPLICABLE REGULATIONS AND GUIDELINES VA Handbook 1200.5 45 CFR 46.107 (a) 38 CFR 16.107 (a) 21 CFR 56.107 (a) PHS Policy On Instruction In The Responsible Conduct Of Research 12/01
3. PROCEDURE IRB Chair HRPP Officer
Establish new IRB member and IRB staff orientation as described in this section Establish new staff training as described in this section. Conduct and document education of new members and staff and periodic continuing education of existing members and staff Maintain access to relevant regulatory and clinical reference materials and training records
HRPP Officer
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FO 301 IRB MEETINGS 1. POLICY Except when an expedited review process is used, the IRB will review proposed research at convened meeting (at which a quorum is present including at least one member shoes primary concern is in a non-scientific area and at least one non-affiliated member). The IRB will meet at least monthly, or more often as needed, at a date and frequency determined by the Chair and the IRB Coordinator. Unless otherwise noted, the meetings will be held at the VALBHS in the Research Conference Room. A. Meeting Procedures: The IRB will convene meetings when a quorum is present. The Chair will determine that quorum is present and of that quorum, at least one non-affiliated and non-scientific member is present prior to the start of the meeting. The Chair is responsible to monitor the members present at convened meetings and determine that meetings are appropriately convened and remain so. A quorum will consist of at least a majority of the voting members as listed on the IRB membership roster and will include: at least one member whose primary concerns are in scientific areas, one member whose primary concerns are in nonscientific areas, and one member who is a physician when FDA-regulated research is reviewed. An alternate member may attend in the place of an absent regular member in order to meet the quorum requirements outlined above, however, the majority of those present will be regular members. The special consultant(s) will not be used to establish a quorum. The ACOS/R&D may not serve as a reviewer and may not participate in voting but may attend meetings and contribute to discussion for the purpose of providing administrative assistance and regulatory guidance as needed. Quorum must be established and maintained during the meeting for discussion and deliberation, and must be present at the time of voting (on all matters requiring a vote), not including those who have been recused. In order for research to be approved, it must receive the approval of a majority of those present at the meeting. If quorum is not maintained, the proposal must be tabled or the meeting must be terminated. Prior to the meeting, the IRB Chair or his/her designee will designate one primary reviewer with the relevant scientific and scholarly expertise consistent with protocol content, and one secondary reviewer to conduct an in-depth review. The reviewer(s) must be voting members or alternate members who will vote. Physicians and PhD level physical, biological, or social scientists are considered to have primary concerns in the scientific area. Also included in this group are nurses, pharmacists and other biomedical health professionals. The IRB Chair will defer review or obtain consultation if there is not a primary reviewer with appropriate scientific expertise. Additional reviewers or special consultants may also be designated. In general, two reviewers will be assigned, but for proposals of low risk and/or complexity, the Chair may choose to assign a single reviewer. The primary reviewer leads the discussion of the protocol (with the assistance of the secondary reviewer when designated). All members are required to read all project submissions. If the IRB will review research that involves 37
categories of participants vulnerable to coercion or undue influence, the IRB Chair will ensure that one or more individuals who are knowledgeable about or experienced in working with such participants will be present at the meeting. If the IRB will review research that involves persons with impaired decision-making capacity, the IRB Chair will ensure that the IRB membership includes at least one member who is an expert in the area of the research. A meeting agenda will be prepared by the IRB Coordinator or designee and distributed with the meeting materials to IRB members one week prior to each meeting. A copy of the agenda and attached materials will be maintained on file with the meeting minutes. A summary of expedited reviews conducted since the previous meeting will be distributed to IRB members either prior to or during the next meeting and time will be allotted during the meeting for discussion. A summary of any projects granted exempt status since the previous meeting will also be distributed to IRB members either prior to or during the next meeting, and time will be allotted for discussion. The IRB Coordinator or designee will take minutes of each meeting. Minutes will be written in sufficient detail to document the activities of the IRB listed in Section 902. Draft minutes will be distributed to members prior to the next IRB meeting. The draft minutes will be discussed at the meeting and corrections requested by the IRB members will be made by the coordinator or designee. The minutes will then be printed in final form and made available for members. Once finalized, no one may make any substantive changes in the final minutes except the IRB at a convened meeting. Minutes are forwarded to the Research and Development Committee for review at a subsequent meeting. The IRB Coordinator will maintain copies of the minutes. B. Telephone Conference Call Meetings: Every effort will be made to convene meetings at a central location (e.g. VALBHS Research Conference Room) at which all members are present. However, should a member not be able to be physically present during a convened meeting, but is available by telephone, the meeting can be convened using a speakerphone. The member who is not physically present will be connected to the rest of the members via speakerphone. In this manner, all members will be able to discuss the protocol even though one member is not physically present. Members participating by conference call may vote and be counted as part of the quorum; provided they have had an opportunity to review all the material the other members have reviewed and are able to participate actively and equally in all discussions. No member who is absent from a convened meeting and is not participating in the conference call may vote on an issue discussed during a convened meeting (no proxy written or telephone polling). Rarely, in an emergency, meetings may be convened via a telephone conference call. A quorum (as defined above) must participate for the conference call meeting to be convened. To allow for appropriate discussion to take place, all members must be connected simultaneously for a conference call to take place -- "telephone polling" (where members are contacted individually) will not be accepted as a conference call. 38
2.
APPLICABLE REGULATIONS AND GUIDELINES VA Handbook 1200.5 21 CFR 56. 108(c) 45 CFR 46.101(a) 38 CFR 16. 101 (a) 38 CFR 16.107 (e) 45 CFR 107 (e) 38 CFR 16. 108 (b) 45 CFR 108 (b) ICH 3.2-3.5 21 CFR 56. 103(a) 21 CFR 56. 107(e)
3.
PROCEDURE IRB Coordinator IRB Chair IRB Coordinator IRB Staff Reviewers (primary and secondary) Schedule meetings Distribute notice of meeting and all meeting materials Review all relevant meeting materials Prepare IRB meeting presentation (summary, issues and recommendations) Complete reviewer worksheets Review materials for all projects prior to meeting
IRB Members
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FO 302 DOCUMENTS REQUIRED FOR IRB REVIEW 1. POLICY Projects are submitted by the Principal Investigator. Only individuals who are VALBHS employees or have a VALBHS appointment may serve as Principal Investigator. Trainees should document that they have sufficient experience and supervision to carry out the proposed research, have the approval of their faculty mentor, and the mentor's signature on the application. Investigators with part-time or WOC appointments may be required to document that they will have a sufficient presence at VALBHS to adequately conduct the planned research. At the discretion of the IRB, other investigators may also be asked to do so. Investigators without an appointment at VALBHS or an adequate on-site presence will be asked to submit the project with a principal investigator from the VALBHS or execute an assurance with the VALBHS IRB in the form of an Unaffiliated Investigator Agreement, as recommended by OHRP. An investigator cannot submit a project unless it has been documented that the investigator has completed an institutionally approved education program. Submissions will be pre-reviewed for completeness by the IRB Coordinator. In addition, designated pre-reviewers will review all initial reviews and provide services for other special circumstances. Incomplete applications will not be accepted for review until the investigator has provided all necessary materials. The submitting investigator will be notified and must provide any outstanding documentation or additional information before the application is distributed to members for review. Prior to the meeting, the primary and secondary reviewers will have reviewed all materials in detail. A. DOCUMENTS REQUIRED / TO BE REVIEWED 1. Investigators applying for initial approval of a proposed human research protocol, either expedited or full review, must submit documents listed on the Initial Project Submission Checklist. 2. Investigators applying for continuing review of a previous research approval must submit the documents listed on the Continuing Review Project Submission Checklist at least 60 days prior to the Continuing Review Deadline of the study, as defined in Section 401. 3, Investigators requesting a modification of a current research approval must submit the documents listed on the Modification Submission Checklist 4. Investigators submitting a proposed research protocol for consideration of exempt status must submit documents listed on the IRB Exempt Project Submission Checklist. B. DISTRIBUTION AND REVIEW OF MATERIALS Complete applications (including the complete protocol) for which expedited review has been requested will be provided to the IRB Chair or his/her designee, who will determine if it meets expedited review requirements. If the Chair or his/her designee determines that the requirements for expedited review have been met and that 40
expedited review is appropriate, the review will be performed as described in Section 501 (Expedited Review Process and Documentation). In every case where expedited review is considered, the Chair and the IRB have the ability to require full IRB review for the project. All other applications will be reviewed by the full Board as described in Section 401, Initial Review. The amount of information provided in protocol documents is often formidable, and is not always relevant to the IRBs purposes. At the discretion of the Chair, a modified review procedure can be used. Under this system the primary and secondary reviewers will receive all materials to review, including the entire protocol and the Investigators Brochure (if one exists). The other members will review all materials except the full protocol and the Investigators Brochure (if one exists), and will review the Narrative Summary instead. The Narrative Summary must contain sufficient detail to allow the member to determine the appropriateness of the study-specific statements in the consent documents. The complete protocol will be available to all members for their review before and during the meeting. Upon request, any IRB member can readily access the complete IRB protocol file and relevant IRB minutes prior to or during the convened IRB meeting. For continuing review of research by a convened IRB, at least one IRB member is provided and reviews the complete protocol including any protocol modifications previously approved by the IRB. Each regular member of the IRB, any alternate members who will attend, and any consultants invited by the Chair to attend the meeting and discuss the study, will receive a copy of the meeting materials (described in Section A). Members should receive materials one week prior to regularly scheduled meetings, though this period may of necessity be shorter for special or emergency meetings. The Investigators Brochure and complete sponsor protocol will be provided to the primary and secondary reviewers and will be made available to the other members and invited consultants at the meeting. All material received by the IRB will be considered confidential and will be distributed only to meeting participants (regular members, alternate members and special consultants) for the purpose of review. All application materials will be stored in an IRB study file with access limited to the IRB Coordinator, IRB Chair, HRPP Officer and their designees. 2. APPLICABLE REGULATIONS AND GUIDELINES VA Handbook 1200.5 45 CFR 46.115 (a) (1) 21 CFR 56.108(a) 38 CFR 16.115 (a)(1) 45 CFR 46.108 (a) 21 CFR 312 38 CFR 16. 108(a) 21 CFR 812 21 CFR 56.115 (a) (1) ICH 3.1.2
3.
PROCEDURE IRB Coordinator
Pre-review all initial and continuing review packages for completeness Establish file for each new research project. 41
Communicate gaps to the investigator Consult with IRB Chair if any questions arise during prereview Forward potential expedited review projects and exemption requests to the Chair Consult with Coordinator on issues identified in prereview Review expedited review candidate submissions for decision Reviews or assigns reviewer if expedited review criteria met
IRB Chair
4.
ATTACHMENTS Initial Project Submission Checklist VA Form 10-1436 Abstract Form Application for IRB Review Form Informed Consent Guidance and Template VA Form 10-9012
42
RR 401 INITIAL REVIEW 1. POLICY During initial review, the IRB reviews proposals for research involving human subjects submitted by investigators. The purpose of initial review is to ensure compliance with existing Federal laws and regulations for the protection of human subjects. The IRB has the authority to disapprove, require modifications to secure approval, and approve research protocols based on its consideration of the risks and potential benefits of the research, and whether or not the rights and welfare of human subjects are adequately protected. At the meeting the IRB, led by the primary reviewer, will: (1) review and discuss the proposal in detail, (2) provide an assessment of the soundness and safety of the protocol, (3) make recommendations for protocol and informed consent revisions and (4) take appropriate action(s) regarding approval. Members will use new project reviewer worksheets to assist them in the review process. The Principal Investigator may attend the meeting at the invitation of the IRB or the Chair. The Principal Investigator may answer questions or provide additional clarification, but may not be present during deliberations or voting on the proposal. If a reviewer is absent from the meeting a new reviewer can be designated, as long as the new reviewer has reviewed the requisite materials prior to the meeting, or the secondary reviewer can serve as the primary reviewer. An absent reviewer can submit their written comments to be read at the meeting, as long as another reviewer is present to serve as primary reviewer. For each protocol and investigative site, the IRB will determine the frequency of continuing review of the research, designating an interval appropriate to the degree of risk, but not less than once per year from the meeting date. The expiration date is defined as the first date that the protocol is no longer approved (expiration date is the date of IRB approval or contingent approval + approval interval). For example: Contingent approval for one year on April 15, 2007, final approval April 22, 2007: Expiration date is April 15, 2008. (April 15, 2007 + 1 year) Contingent approval for six months on April 15, 2007, final approval April 22, 2007: Expiration date is October 15, 2007 (April 15, 2007 + 6 months) More frequent review may be appropriate if the research is a Phase I or II study or a Significant Risk device study, if it involves vulnerable populations, if the IRB believes that previous studies indicate high incidence of adverse events, or if the IRB believes that close monitoring is indicated. The reasons for such a determination will be included in the minutes. Members of the IRB vote upon the recommendations made by the reviewers according to the criteria for approval in Section 403. A majority of voting members present must 43
vote in favor of an action for that action to be accepted by the IRB. Only regular members, or in their absence alternate member(s), may vote. A record of the vote will be recorded in the minutes, including the vote on actions, the number of members voting for, against, abstaining and recused, and names of members recused. Any member with a conflict of interest must disclose that conflict of interest before the project is discussed and recuse themselves. The recused member may not be present during the discussion and voting, though they may provide information, if requested, prior to deliberations.
A. Initial Review Process: These guidelines should be followed in the conduct of the initial review of all proposals: The primary reviewer should lead the discussion by presenting his/her findings and recommendations resulting from the review of the application materials listed on the Initial Project Submission Checklist. Review of the Investigator and Investigative Site: Members will review the qualifications of the investigator, research staff and investigative site using application materials provided by the investigator as described in Section 302. This may include appropriate sections on the initial application form, the investigators current curriculum vitae, and/or other documents that the IRB may require. For a study involving more than one site, the IRB may decide that the Chair or his/her designee can review those sites. Review of Non-local Sites (if any): The Application for Initial Review form captures important information regarding the local community that may be relevant to the conduct of the study and the protection of the rights and welfare of participants. If, based on the proposed research, the IRB determines that some clarification or verification of the information is needed, the IRB can use measures for verifying the information that are described in Section 407. If further information is needed from a site, the IRB will request this in writing from the investigator. Review of the Protocol: The protocol and/or Narrative Summary will be reviewed by the full IRB to determine if it meets the criteria for approval in Section 403. If the protocol does not contain the inclusion/exclusion criteria then the investigator will be asked to provide a completed narrative that contains this information before the project will be approved. Recommendations for protocol modifications will be made by the reviewers and voted upon. The reviewer may utilize a worksheet such as the IRB Reviewer Worksheet for New Projects to document that each of the specific criteria for approval were discussed and have been met. All worksheets will then be filed in the appropriate study file. Review of the Informed Consent Form: The informed consent form will be reviewed by the full IRB to determine if it meets the criteria outlined in Section 701. The IRB may approve consent forms with minor changes only at the meeting (e.g.: spelling or grammar changes). Such changes can be reviewed and approved by the Chair and/or primary reviewer. If more significant revisions are required the consent form must be reviewed again by the full IRB prior to approval. 44
Protection of Vulnerable Populations: If the research study proposes to recruit vulnerable populations of subjects, the Committee will review, discuss, and/or require modification to secure approval of the investigator's plan for minimizing undue influence on vulnerable subjects in accordance with Section 404. Protection of Privacy and Confidentiality: The IRB will determine whether there is an appropriate plan to protect the confidentiality of research data that may include coding, removal of identifying information (in order to protect personally identifiable information), limiting access to data, use of Certificates of Confidentiality, waiver of documentation of consent, physical or computerized methods for maintaining the security of stored data, or other effective methods. The IRB will evaluate the nature, probability, and magnitude of harms that would be likely to result from a disclosure of collected information outside the research and the effectiveness of the proposed methods. The IRB will also determine whether methods used to identify and recruit and obtain information about potential participants protect subject privacy and confidentiality and whether the informed consent form adequately discloses the risks to privacy and confidentiality. The IRB may require that the investigator obtain a Certificate of Confidentiality if it determines that special protections are needed to protect subjects from the risks of investigative or judicial processes. The IRB will ensure that the required language for a valid authorization to release health information under HIPAA is included as part of the informed consent document(s). The IRB may waive the requirement for an authorization or may alter the form or content of the authorization as permitted by HIPAA and described in Section 409. These actions and their justification will be documented in the minutes. Disclosure of Relationships and Financial Interest: The IRB will review any findings of the Conflict of Interest Committee as well as any financial conflict of interest disclosures that are submitted by the investigator. The Committee will then make a determination as to the presence of conflicts of interest and a plan for their management, in accordance with the policies in Section 406. Payment to subjects: The IRB will determine whether proposed payments to subjects are appropriate and are not coercive or present an undue influence on the trial subjects. Payment for research subjects for participation in studies is not considered a benefit, but a recruitment incentive. Payments to a subject should be prorated and not wholly contingent on completion of the trial by the subject. The method, amount, and schedule of payment should be stated in the consent form and presented to the IRB at the time of initial review. Subject payment is intended to reflect the time and inconvenience of the subjects participation in the study. VA policy prohibits paying subjects when the research is an integral part of a subjects medical care and when it makes no special demands on the subject beyond those of medical care. Payment may be permitted with IRB approval in studies where there is no direct subject benefit, where there is significant inconvenience or discomfort, where such payment is the standard of practice in comparable studies and institutions, for travel expenses (when incurred by the participant that would not be incurred in the normal course of receiving treatment and which are not reimbursed by any other mechanism), or in other situations at the discretion of the IRB. The 45
investigator is also permitted to reimburse subjects for direct travel expenses that exceed the standard per visit payment, if necessary, on a case-by-case basis without prospective IRB approval. Such payments have been determined to not represent undue influence, though they must be disclosed at the time of continuing review. Unless it creates undue inconvenience or a coercive practice, payment to participants who withdraw from the study may be made at the time they would have completed the study (or completed a phase of the study) had they not withdrawn. While the entire payment should not be contingent upon completion of the entire study, payment of a small proportion as an incentive for completion of the study is acceptable, providing that such incentive is not coercive. The IRB should determine that the amount paid as a bonus for completion is reasonable and not so large as to unduly induce subjects to stay in the study when they would otherwise have withdrawn. Compensation for participation in a trial offered by a sponsor may not include a coupon good for a discount on the purchase price of the product once it has been approved for marketing. The IRB and Research and Development Committee must review all proposals for payment of participants to ensure conformity with VA policies. The facility research office is responsible for ensuring that IRB-approved payment to subjects is made from a VA approved funding source for research activities. Prospective investigators who wish to pay research participants must in their proposal: substantiate that proposed payments are reasonable and commensurate with the expected contributions of the subject; state the terms of the subject participation agreement and the amount of payment in the informed consent form; and substantiate that: subject payments are fair and appropriate: they do not constitute (or appear to constitute) undue pressure or influence on the perspective research subjects to volunteer for, or continue to participate in, the research study; and that the payments do not constitute (or appear to constitute) coercion to participate in, or continue to participate in, the research study. The IRB will determine that credit for payment accrues as the study progresses and is not contingent upon the participant completing the study and that any amount paid as a bonus for completion is reasonable and not so large as to unduly induce participants to stay in the study when they would otherwise withdraw. Payment for referral of subjects: California law (HSC 445) states that "No person, firm, partnership, association or corporation, or agent or employee thereof, will for profit refer or recommend a person to a physician, hospital, health-related facility, or dispensary for any form of medical care or treatment of any ailment or physical condition." On this basis, cash or cash-equivalent payment to health care providers for referral of subjects or potential subjects is not permitted. Other types of compensation (e.g.: books, other non-cash gifts) must be disclosed. According to the American Medical Association, all referral fees are unethical. Finders fees (payment from the investigator or sponsor to a person who refers a potential subject) are not authorized. Recruitment bonuses are not authorized. Review of Advertisements and Recruitment Methods: The IRB reviews direct advertising for research participants, which is defined as advertising that is intended to be seen or heard by prospective participants to solicit their participation in a study. Members will review the content of all submitted proposed advertisements, proposed recruitment methods, and all other written material to be provided to subjects. The 46
IRB should review the information contained in the advertisement and the mode of its communication, to determine that the procedure for recruiting participants is not coercive. The IRB should review the final copy of printed advertisements to evaluate the relative size of type used and other visual effects. When advertisements are to be taped for broadcast, the IRB should review the final audio/video tape. The IRB may review and approve the wording of the advertisement prior to taping to preclude re-taping because of inappropriate wording. The review of the final taped message prepared from IRB-approved text may be accomplished through expedited procedures. The IRB should review advertising to assure that advertisements do not: state or imply a certainty of favorable outcome or other benefits beyond what is outlined in the consent document and the protocol; make claims, either explicitly or implicitly that the drug or device is safe or effective for the purpose under investigation, or that the drug or device is superior to any other drug or device (this is especially critical when a study may involve subjects who are likely to be vulnerable to undue influence); use terms such as new treatment, new medication or new drug without explaining that the test article is investigational; or promise free medical treatment, when the intent is only to say participants will not be charged for taking part in the investigation. Advertisements may state that participants will be paid, but should not emphasize the payment or the amount to be paid, by such means as larger or bold type. No advertisement should include any exculpatory language. According to FDA, advertisements should be limited to information the prospective subjects need to determine their eligibility and interest. When appropriately worded, the following items may be included in advertisements: Name and address of the clinical investigator or research facility Purpose of the research and summary of eligibility criteria Straightforward and truthful description of the benefits to the subject Time or other commitment required of the subjects; and Location of the research and who to contact for information All print advertisements will be stamped with the IRB name and telephone number. 1) Safety Monitoring: The IRB will determine appropriate measures to insure adequate Data Safety monitoring as described is section RR411. Translations: All translated documents (including informed consent forms, questionnaires, interview guides, and recruitment notices) must be approved by the IRB before they can be used.
Approved Enrollment. The IRB will specify a specific number of subjects who are approved for enrollment in all studies that are approved. Enrollment is defined as the number of subjects who will be permitted to sign consent forms. All subjects who give informed consent are considered to be enrolled. The number of subjects who are enrolled is distinguished from the number who are entered. An entered subject is any person who has been subjected to any study condition other than the consent process. The number of subjects who are to be entered into , included in, studied by, or randomized by a project may be specified on the consent document rather than the number who are to be enrolled. In cases where the IRB has granted a waiver of the consent document, the number of subjects who are 47
considered to be enrolled, will be the same as the number of subjects who have been entered. Drugs and devices. Studies involving an IND or IDE will undergo initial and continuing review at a convened meeting of the IRB that includes at least one physician or pharmacist unless the study meets the criteria for expedited review (i.e. all treatment components are complete, in follow-up only, data analysis only). The IRB will review the information submitted on the IRB application form and will determine if the sponsor has been required to obtain an IND or IDE. If an IND or IDE has been required, then the IRB will review the documentation requested on the IRB application that supports that it has been granted, eg. FDA letter of receipt or assignment with IND or IDE number. If an IDE or IND has been required then the study will not be approved until FDA approval has been documented. The IRB will determine if the drug or device has been approved by the FDA for marketing or is a investigational drug or device. Approved articles may be considered to be investigational if the intended use differs substantially from the approved use, if the article is being used for an unapproved indication, or if there has been a significant modification of the article. In making this determination the IRB will consider packaging inserts, investigator brochures, and sponsor protocols that are submitted with the application form. The IRB will review package inserts, investigator brochures, and sponsor protocols in order evaluate evidence that the sponsor or the investigator-sponsor has adhered to federal regulations in the manufacture and formulation of investigational or unlicensed test articles. If such evidence is lacking, or insufficient, then the IRB will require that the investigator provide written assurance from the sponsor or sponsor-investigator. Procedures for the review of Investigational Devices are described in section RR 408. B. Initial Review of Investigational New Drugs: When an investigational drug is used in human research, or an approved marketed product is used in the context of a clinical research protocol, an approved IND must be on file with the FDA and documented unless ALL five of the following conditions are met [21 CFR 312.2]: (1.) The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication for use nor intended to be used to support any other significant change in the labeling for the drug; (2.) If the drug that is undergoing investigation is lawfully marketed as a prescription drug product, the investigation is not intended to support a significant change in the advertising for the product; (3.) The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks 48
(or decreases the acceptability of the risks) associated with the use of the drug product; (4.) The investigation is conducted in compliance with the requirements for institutional review set forth in part 56 and with the requirements for informed consent set forth in part 50; and (5.) The investigation is conducted in compliance with the requirements of 21 CFR 312.7.
Other circumstances in which an investigation may be exempt from the requirement for an IND are described in 21 CFR 312.2(b)(2-6). If the FDA has determined that an IND is required then the IRB will also require an IND. The IRB may also require that the investigator or sponsor obtain an IND if it judges that the criteria in 21 CFR 312 are met. If an IND is required then documentation of FDA approval must be submitted to the IRB before final approval can be given or any subjects can be enrolled in the study. In studies using pharmaceutical products (particularly when an investigational product is involved), a pharmacist should review the Investigators Brochure and VA Form 10-9012 forms and communicate any concerns or suggested modifications to the Committee. This may be either a pharmacist member of the IRB, the Investigational Drug Pharmacist, or his/her designee. Once approved the investigator submits the IRB Approval Letter to the Pharmacy Service, notifying them that the study has been approved, and also notifies them when the study is completed or terminated.
C. Review and Use of Investigational Devices: IRB policies and procedures for review of research involving investigational devices are found in Section RR 408. D. Review of the Requirements of Investigator Sponsors: As an institution, VALBHS does not serve as sponsor for investigational drug or device clinical trials. VALBHS researchers who serve as a sponsor/investigator are required to follow all applicable FDA regulations including 21 CFR 312 (INDs) and 21 CFR 812 (IDEs). Investigator responsibilities are defined in section IR 801 section B4. The IRB will conduct an in depth review prior to the approval of any project that involves an investigational drug or investigational device where the investigator is the holder of the IND or IDE. This review will include: 1) A review of all general criteria and criteria that are specific to investigational drugs and/ or devices (as apply), credentialing, and education, as specified in this SOPP. 2) A review of completed FDA forms FD 1571 and/ or FD 1572 (as apply). 3) An on site audit to evaluate the investigators plan for compliance with FDA regulations. 49
4) A review of evaluations by the Biomedical Engineering Service if electrical power will be used 5) A review of evaluations by the Research Pharmacy if a drug will be used 6) A determination of whether a follow-up audit will be required at the time of continuing review. If a follow-up audit by the IRB is not required, then the project will still be subject to routine compliance reviews as outlined in the Compliance and Quality Assurance SOP. 7) Approvals by the Chief of Staff, ACOS R&D, and/ or Chief, Support Services Healthcare Group, as specified in section IR 801 if the drug or device is to be manufactured at VALBHS. E. Ionizing Radiation: Studies employing ionizing radiation may need to be approved by the Radiation Safety Committee, as well as by the IRB. While the IRB evaluates the overall risks and benefits of the research, which includes the radiation exposure, the Radiation Safety Committee also reviews the science of the radiation dose absorbed and performs an additional risk assessment particular to the use of radiation. Ionizing radiation should be addressed within the protocol and the informed consent when its use is part of the research study. In the research plan, the investigator must clearly indicate the types and number of the procedures using ionizing radiation and differentiate between procedures, which are standard of care and those that are being performed for research purposes only, the dose and risk for each procedure and the total dose for the study in relationship to established exposure limits. In reviewing the study, the IRB will determine whether the planned exposure is within the allowable established limit of 3 rem to any tissue within a 13-week period and 5 rem annually and the informed consent form adequately reflects the risks to subjects. During IRB deliberations, the IRB will utilize the following guidelines when evaluating overall risk and the risk-benefit ratio: Radiation exposure being done for the standard of care and uses routine procedures: The IRB may request review or consultation by the Radiation Safety Officer or the Radiation Safety Committee. The informed consent form will frequently make only general mention of the exposure. Radiation exposure exceeds the standard of care, using routine procedures, and offers the prospect of direct benefit to the subject: The IRB may request review or consultation by the Radiation Safety Officer or the Radiation Safety Committee. The informed consent form must differentiate which procedures are being done for standard of care and which are being done solely for research. The informed consent form must state that the total dose exceeds the standard of care, and what risks may occur versus standard of care. When radiation exposure is researchrelated, the informed consent form should clearly describe in lay language the quantity, significance, and risk, if any, of the radiation absorbed dose. Radiation exposure exceeds the standard of care, using routine procedures, and offers no prospect of direct benefit to the subject: Approval by Radiation Safety 50
Committee is required. When radiation exposure is research-related, the informed consent form should clearly describe in lay language the quantity, significance, and risk, if any, of the radiation absorbed dose. The informed consent form must state the following: This radiation exposure is necessary only for this research study, and is not essential for your medical care". F. Radioactive Drugs and Radioactive Compounds: FDA is responsible for regulating radioactive drugs and radioactive compounds used in healthcare and research. Oversight is handled by the Radiation Safety Committee, which will evaluate studies involving such materials according to its policies and procedures. Certain kinds of research using radioactive drugs generally recognized as safe and effective must be approved by an appropriately authorized Radioactive Drug Research Committee (RDRC) and meet other conditions in accordance with 21 CFR 361.1 prior to review by the IRB. The RDRC evaluates the justification for the study, pharmacological dose and radiation dose are within limits established in 21 CFR 361.1(b)(2-3). It will determine whether the exposure is justified by the quality of the study and the importance of the information it seeks to obtain, and whether the study meets additional criteria described in 21 CFR 361.1(d). The IRB is expected to approve such studies prior to RDRC approval, but the IRB may consult with the RDRC as a part of their deliberations. RDRC approval must be obtained before the R&D Committee may approve the study. In reviewing studies involving radioactive drugs and radioactive compounds, the IRB must consider the following categories when evaluating the overall risk and the riskbenefit ratio: Whether the total dose to an adult research subject (either from a single study or cumulatively from a number of studies conducted within 1 year) from both clinical and research procedures will exceed the allowable established limit specified by 21 CFR 361.1(b)(3)(i). Whether the informed consent form adequately reflects the risks to subjects, and Whether the amount of radioactive material to be administered is the smallest radiation dose the subject can practically receive to perform the study without jeopardizing the benefits to be obtained from the study. G. Expanded Access Programs: 1. Expanded Access to Investigational Drugs and Other Programs Investigational products are sometimes used for treatment of serious or life-threatening conditions either for a single subject or for a group of subjects. The procedures that have evolved for an IND used for these purposes reflect the recognition by the FDA that, when no satisfactory alternative treatment exists, subjects are generally willing to accept greater risks from test articles that may treat life-threatening and debilitating illnesses. The following mechanisms expand access to promising therapeutic agents without compromising the protection afforded to human subjects or the thoroughness and scientific integrity of product development and marketing approval (21 CFR 312.34, 312.35-6, and 312.83). All research under an Expanded Access program requires 51
prospective IRB review, except in certain very restricted circumstances described in Section 101. a. Open Label Protocol or Open Protocol IND. These are usually uncontrolled studies, carried out to obtain additional safety data (Phase III studies). They are typically used when the controlled trial has ended and treatment is continued so that the subjects and the controls may continue to receive the benefits of the investigational drug until marketing approval is obtained. These studies require prospective IRB review and informed consent. b. Parallel Track Studies. FDA also permits wider access to promising new drugs for HIV/AIDS related diseases under a separate access protocol that parallels the controlled clinical trials that are essential to establish the safety and effectiveness of new drugs. These so-called parallel track studies require prospective IRB review and informed consent. c. Treatment INDs. These protocols are added to an existing IND to make promising new drugs available to desperately ill patients as early in the drug development process as possible, and to obtain additional data on the drug's safety and effectiveness. There must be preliminary evidence of drug efficacy and the drug must be intended to treat a serious or life-threatening disease, or if there is no comparable alternative drug or therapy available to treat that stage of the disease in the intended patient population. Treatment INDs require prospective IRB review and informed consent.
2. Expanded Access to Investigational Devices. According to statute and FDA regulations, an unapproved medical device may normally only be used in human subjects when the device is under clinical investigation and when used by investigators participating in the clinical trial. FDA recognizes, however, that there may be circumstances under which a health care provider may wish to use an unapproved device to save the life of a patient, to prevent irreversible morbidity or to help a patient suffering from a serious disease or condition for which there exists no alternative therapy. Four main mechanisms are utilized by FDA to make unapproved devices available to patients/physicians faced with circumstances such as those described above. These mechanisms are consistent with the Expanded Access provisions of the FDA Modernization Act of 1997 (Section 561 of the Federal Food, Drug, and Cosmetic Act). The sponsor must agree and FDA must approve the use. Under most circumstances such studies require IRB review and informed consent. The mechanisms are described below. a. Emergency Use of Unapproved Medical Devices FDA regulations and IRB policy permit deviations from the investigational plan when necessary to protect the life or physical well-being of a subject in an emergency. IRB policies and procedures are described in Section 702. b. Individual Patient Access to Investigational Devices Intended for Serious Diseases ("compassionate use")
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There are circumstances in which an investigational device is the only option available for a patient (or small number of patients) faced with a serious, albeit not life-threatening condition (known as compassionate use). Prior FDA and prospective IRB approval are needed before compassionate use may occur. In order to obtain FDA approval, the sponsor or sponsor-investigator submits an IDE supplement requesting approval for a protocol deviation as described in 21 CFR 812.35(a). The patient(s) identified in the supplement must not be treated until use of the device under the proposed circumstances is approved. If the request is approved, the attending physician should devise an appropriate schedule for monitoring the patient(s), taking into consideration the investigational nature of the device and the specific needs of the patient(s). The patient(s) should be monitored to detect any possible problems arising from the use of the device. Following the compassionate use of the device, a follow-up report should be submitted to FDA as an IDE supplement. Any unanticipated problems that occurred as a result of device use should be discussed in the supplement and reported to the IRB as soon as possible. c. Treatment Use of Investigational Devices (Treatment IDE) Procedures to permit the treatment use of investigational devices have been established (62 FR 48940) in order to facilitate the availability of promising new therapeutic and diagnostic devices to desperately ill patients as early in the device development process as possible and to obtain additional data on the device's safety and effectiveness. These procedures apply to patients with serious or immediately lifethreatening diseases or conditions for which no comparable or satisfactory alternative device, drug, or other therapy exists. Treatment use of an investigational device may be considered only when: 1. The device is intended to treat or diagnose a serious or immediately lifethreatening disease or condition; 2. There is no comparable or satisfactory alternative device available to treat or diagnose the disease or condition in the intended patient population; 3. The device is under investigation in a controlled clinical trial for the same use under an approved IDE, or all clinical trials have been completed; and 4. The sponsor of the controlled clinical trial is pursuing marketing approval/clearance of the investigational device with due diligence. Requests for treatment use should be submitted to the FDA as a supplement to the existing IDE as described in 21 CFR 812.36. A treatment IDE must comply with all of the requirements and safeguards applied to IDEs in general and with all IRB requirements for study review and investigational device research, plus whatever additional safeguards may be required by IRB or FDA as a result of review. H. Humanitarian Devices.
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The FDA may grant marketing approval for certain devices that may benefit persons who have rare diseases. The use of a HUD does not in itself constitute research although IRB approval is required. 1. IRB Review of HUDs. The IRB is responsible for both initial and continuing reviews of the use of HUDs. Full board review is required for initial approval. The IRB may grant approval for a protocol or on a case by case basis but should be cognizant that the device should not exceed the scope of the FDA approved indication. The IRB does not need to review individual uses of a HUD but must conduct a continuing review. For continuing review, the IRB may utilize an expedited review process unless it determines that a full review is appropriate. 2. Waiver of Consent (HUDs). The FDA does not require the administration of informed consent. The IRB may still require informed consent if it determines that this is appropriate. 3. Off-Label Use of HUDs. a. Emergency Use. A HUD may be used to save the life, or to protect the physical well-being of a patient. However, the following conditions apply: Prior approval of the IRB Chair should be obtained if at all possible. Informed consent should be obtained. A separate determination should be obtained from an uninvolved physician. Prior authorization is required form the HDE holder. After emergency use, a follow-up report on the patients condition and information concerning patient protection measures must be submitted to the HDE holder.
b. Compassionate Use. A HUD may be used for compassionate use. However, the same conditions apply as are outlined for emergency use. In addition the following also apply: Prior approval from the FDA must be obtained. The follow-up report must also include a discussion of why alternative therapies are unsatisfactory. The treating physician must also devise an appropriate schedule for monitoring the patient, taking into consideration the limited information that is available regarding the potential risks and benefits of the device and the specific needs of the patient. I. Gene Transfer Research. Gene transfer involves the administration of genetic material to alter the biological properties of living cells for therapeutic use. Gene transfer activities in humans are 54
investigational and are regulated by the both the FDA and the National Institutes of Health (NIH) Office of Biotechnology Activities. FDA regulations require the submission of an IND for human gene transfer research through the FDA Center for Biologics. DHHS regulations specify that no individual may be enrolled in human gene transfer research until review has been completed by the NIH Recombinant DNA Advisory Committee (RAC), local Institutional Biosafety Committee (IBC) approval has been obtained, local IRB approval has been obtained, and the investigator has obtained all other regulatory authorizations from the subject (FR 196, October 10, 2000). While the RAC is advisory to the Director of the NIH, compliance with its guidelines is mandatory for all investigators at institutions that receive NIH funds for research involving recombinant DNA.
J. Genetic Research Information obtained through genetic research may have serious repercussions for the subject or the subjects family members. Genetic studies that generate information about subjects' personal health risks can provoke anxiety and confusion, damage familial relationships, and compromise the subjects' insurability and employment opportunities. For many genetic research protocols, these psychosocial risks warrant careful IRB review and discussion. Detailed guidance for investigators and IRB members is contained in Section 703 and in the VALBHS Investigators Manual. In brief, IRB review of genetic research will address, at a minimum, these specific issues: Possible psychological and social risks to subjects and family members; Protection of subjects from disclosure of their medical or other personal information to family members; Protection of the confidentiality of the personal information of family members (secondary subjects) and the limits of those protections; Provisions for re-contact of subjects or family members; Any planned future use of data or samples; Counseling to subjects before or after the study; Confidentiality measures and extent of possible disclosure to third parties. K. Approval and Documentation The IRB will vote according to the categories of action described in Section 601. The IRB will document in the meeting minutes and reviewer worksheets that the criteria for approval of the project (in Section 403) and of the informed consent documents (in Section 701) have been discussed at the meeting and that the criteria have been met. The IRB will also determine the duration of approval. If a study is determined to require review more than annually, the reasons for this will be documented in the minutes. The IRB will also determine and document whether a study requires external verification. The results of IRB review and actions taken by the IRB will be communicated to the R&D Committee, the investigator, and institutional officials in writing and in a timely manner. IRB approvals will be conveyed to the Principal Investigator using VA form 101223 or an approved equivalent. If the research involves the use of investigational drugs 55
or devices, then a copy of VA form 10-1223, or an approved equivalent, will be sent to the Research Pharmacy. L. Approval of Modifications Required to Secure Approval: Minor revisions to the informed consent and other documents required as a condition for approval during initial IRB review may be reviewed and verified by the Chair, his/her designee, or the primary reviewer. This can only occur if authorized by the IRB at the time of initial review. The reviewer reviews the modifications and verifies that the requirements for IRB approval have been met. Approval can be issued providing the revisions, documentation or clarifications do not indicate or result in a substantive change to the study design and procedures or change the risk/benefit ratio. If the modifications required represent substantive changes or involve greater than minimal risk to subjects, then approval by the full Committee at a convened meeting will be required. M. Verification from Sources The IRB will determine, based upon study design and risks, if it will require verification from sources other than the investigator at the time of Continuing Review to assure that no additional risks have been identified since previous IRB review.
2.
APPLICABLE REGULATIONS AND GUIDELINES 45 CFR 46.111 21 CFR 312.34 38 CFR 16.108 (a, b) 50 FR 4286621 38 CFR 16.103 (b) (4-5) 21 CFR 56.107(e-f) 38 CFR 46.107 (a, e, f) 21 CFR 56.108(a)(1-2) 38 CFR 16.109 (a-e) 21 CFR 56.108(c) 38 CFR 16.111 21 CFR 56.109(a-f) ICH 3.1 21 CFR 361.1 California Health and Safety Code 445 21 CFR 812.140 FDA Information Sheets October 1, 45 CFR 46.108 (a, b) 1995 45 CFR 46.103 (b) (4-5) HIPAA Privacy Rule (45 CFR 164.508) 45 CFR 46.107 (e, f) VHA Handbook 1605.1 45 CFR 46 109 (a-e) 21 CFR 814.124 FDA Policies and Procedures Guidance VHA Handbook 1200.5 VA form 10-1223 PROCEDURE Reviewer(s) Present an oral summary of the investigational plan Make assessments as to risks, benefits and the adequacy of subject protections Make recommendations as to the appropriate IRB action Complete protocol and consent worksheets 56
3.
IRB Members
If questions arise, contact the IRB Chair for additional input Make assessments as to risks, benefits and the adequacy of subject protections Review the informed consent form according to the criteria outlined in Section 701. Ensure that informed consent documents and methods are in compliance with regulations Approve consent forms with minor changes at the meeting Determine if consent forms requiring major revisions need to be re-reviewed by the full IRB or by the Chair or designee via expedited review. Review advertising materials for regulatory compliance. Vote on all appropriate IRB actions. Make an assessment of PI and staff qualifications Disclose all apparent or potential conflicts of interest Take detailed notes of the meeting. Write draft minutes. Arrange for PI (or designee) and consultant(s) with appropriate expertise to be present, if necessary.
IRB Coordinator
4.
ATTACHMENTS Meeting Worksheet for New Projects IRB Reviewer Worksheet for New Projects IRB Reviewer Worksheet for Informed Consent Forms/HIPAA Authorization Medical Device Risk Determination Form
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RR 402 Continuing Review / Modification / Completion 1. POLICY
Investigators are responsible for obtaining continuing IRB review and approval and are required to submit an Application for Continuing Review Form 60 days prior to the Continuing Review Deadline. The Application for Continuing Review Form is used as 1) a request for continuing review of ongoing research where annual (or more frequent) review is required, 2) a final report to be used when research has been completed or terminated, or 3) an interim report (an IRB-required report of study progress that is not required for continuing review). Continuing review actions will be carried out at a convened IRB meeting, except in those cases where expedited review is permitted as described in Section 501. A study must remain active as long as continued interaction with human subjects or their samples or identifiable date is occurring, though expedited review of may be possible where activity is limited to data analysis. The IRB Coordinator will provide reminders to investigators about their continuing review dates, but the ultimate responsibility for timely submission of continuing review reports belongs with the investigator.
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At the time of Continuing Review and in reviewing modifications, the IRB will re-assess the risks to subjects to be sure that all risks have been articulated and considered; review if the protections for privacy and confidentiality remain adequate; review if, in fact, risks have been minimized; affirm that there are still potential benefits; and reaffirm that the risk continues to be reasonable in relation to expected benefits. The IRB will also set the next Continuing Review date based on the current risk assessment. A. Interim Reports: If the IRB determines that a study requires an Interim Report, the investigator may be asked to submit an Application for Continuing Review Form by a specified date, upon enrollment of a specified number of subjects, or upon reaching a specified point in the study. If interim reports are not received as scheduled, the IRB may suspend enrollment until reports are reviewed as described in RA 601 CATEGORIES OF ACTION. The IRB will review the Application for Continuing Review Form at a convened meeting, and may require modifications or take other actions within its authority. During a review of interim reports, the following must be considered: 1. Proposed changes (if any) to the research study and any accompanying changes to the informed consent form. 2. Adverse event reports 3. Reports of unanticipated problems impacting the risks to subjects 4. Summary of data safety monitoring board (DSMB) reports (if available) 5. Review of any protocol violations or deviations 6. Overall investigator compliance
B. Continuing Reviews: Investigators may not continue to conduct their investigations beyond the Continuing Review Deadline. Multi-center studies will have all sites reviewed at the time of study continuing review. Continuing review must occur as long as the research remains active for long-term follow-up of participants, even when the research is permanently closed to the enrollment of new participants and all participants have completed all research-related interventions and continuing review of research must occur when the remaining research activities are limited to collection of private identifiable data. Studies that have lapsed in approval before Continuing Review by the IRB are unapproved until the IRB review has been conducted. The investigator will be promptly notified of the lapse in approval by the Research Office via a memorandum from the Chair of the Institutional Review Board. The Principal Investigator will be notified that enrollment for new subjects cannot occur and continuation of research interventions or interactions in already enrolled subjects should only continue when the IRB or IRB Chair, in consultation with the Chief of Staff finds that it is in the best interest of individual subjects to do so. Once notified of the suspension, the PI must immediately submit to the IRB Chair a list of research subjects for whom suspension of the research would cause harm. The IRB Chair, with appropriate consultation with the Chief of Staff, 59
determines if the subject may continue in the research. If the study is FDA -regulated, the Chief of Staff and IRB Chair must follow FDA requirements in 21 CFR 56.108(b)(3) in making their decision. It is the responsibility of the Principal Investigator to notify the sponsor of the lapse in approval. The Research Office will notify ORD, ORO or other Federal agencies as appropriate. Once suspended, IRB review and re-approval must occur prior to the initiation of the research. The Chair will notify the ACOS/R&D and the RCO immediately of any such study expiration and the actions taken. The expired study will be reviewed at the next convened IRB meeting. The investigator will be required to submit the required reports and to indicate whether any research activity occurred after the expiration of the study. If the study is not re-approved within 3 months then it must be resubmitted as a new study. The IRB will also make additional provisions for the care and protection of subjects as may be required, or require third party verification that the investigator has complied with its requests. The IRB may take any of the actions or sanctions against the investigator that are available to it, according to the procedures described in section QA 903. In all cases the IRB will solicit and review appropriate completion paperwork, make inquiries to assure that subjects have been protected and that research does not continue without approval. C. Completion Reports: An Application for Continuing Review Form for completed studies should be submitted within 60 days after completion or termination of the study at the site. A study may be considered completed once all interactions with human subjects and their identifiable data, including subject follow up and data analysis, have been completed. In addition to the Application for Continuing Review Form, additional reports information about the status of the study, such as computer printouts, telephone reports, sponsor's completion summary, letter, etc. may be submitted. The Chair or a designated reviewer will review the report and present the findings at a convened meeting. D. Modifications: The IRB may use the expedited review process to review minor changes in ongoing previously approved research during the period for which approval is authorized, as permitted in Section 501. An expedited review may be carried out by the IRB chairperson or by one or more experienced reviewers designated by the chairperson from among members of the IRB. When a proposed change in a research study is not minor (e.g., procedures involving increased risk or discomfort are to be added, or substantive changes in study procedures or study design are proposed), then the IRB must review and approve the proposed change at a convened meeting before the change can be implemented. The only exception is a change necessary to eliminate apparent immediate hazards to the research subjects. In such a case, the IRB should be promptly informed of the change following its implementation and should review the change to determine that it is consistent with ensuring the subjects' continued welfare. Information relating to protocol changes will be provided to participants when such information may relate to the participants willingness to continue to take part in the research.
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Documents required for submission for modification requests are listed on the Modification Submission Checklist. All IRB members receive and review all modified documents. During the review of modifications of previously approved research, the following must be considered: 1. Proposed changes (if any) to the research study and any accompanying changes to the informed consent form. 2. Adverse event reports 3. Reports of unanticipated problems impacting the risks to subjects 4. Summary of data safety monitoring board (DSMB) reports (if available) 5. Review of any protocol violations or deviations 6. Overall investigator compliance 7. Risks are minimized by using procedures that are consistent with sound research design and that do not unnecessarily expose subjects to risk and whenever possible, by using procedures already being performed on the subjects for diagnostic or treatment purposes. Whenever possible, the IRB should require each revision to a research protocol to be incorporated into the written protocol. If the amendment addresses an issue related to biosafety or radiation safety, the appropriate committee or subcommittee must first approve the amendment.
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E. Process for Conducting Continuing Review: When reviewing a project for continuing review, the IRB will assess all of the same criteria for approval that were evaluated during initial review (Section 401E). Routine continuing review will include review of documents listed on the Continuing Review Project Submission Checklist including sources of information pertinent to the assessment of risks and benefits, including: Application for Continuing Review Form and other materials on file or submitted by the investigator, including the abstract, which includes a brief summary of the research methodologies and procedures. The application should contain sufficient information to permit review of the progress of the entire study and determination of the current risk-benefit assessment based on study results. Special attention should be paid to determining whether new information or unanticipated risks were discovered since the previous IRB review. Any significant new findings that may relate to the subjects' willingness to continue participation should also be included. The consent document currently in use, in order to determine whether the information contained in it is still accurate and complete, including whether new information that may have been obtained during the course of the study needs to be added. Obtaining the consent document also provides a check on whether the document being used by the clinical investigator has current IRB approval. A copy of the current HIPAA Authorization document A copy of the study protocol currently in use. Approved or proposed amendments, including minor changes, (if any) and the IRB action on each amendment. Number of subjects enrolled in the study for the review period and since the project began Number of subjects enrolled in the study by gender. Number of minority subjects enrolled in the study for the review period Summary of subjects withdrawn by self and by investigator, and reasons for withdrawal. Number of subjects withdrawn for the review period and since the project began. Number of subjects considered as members of specific vulnerable populations for the review period. Research findings to date. Summary of Adverse event reports from investigators, sponsor safety reports (e.g., IND or IDE Safety Reports). Documentation of protocol violations and/or deviations, or non-compliance with applicable regulations in the study file. 62
All reports of injuries to subjects, unanticipated problems, risks, complaints from subjects or others, or any information that may change the risk/benefit ratio for subjects. A statement from the investigator that all adverse events have been reported as required. Amended or updated Investigator Brochures. Summary of the DSMB or data monitoring committee meetings (if applicable) or findings based on information collected by the data and safety monitoring plan submitted in the original proposal. (IRBs conducting continuing review may rely on a current statement from the DSMB or sponsor indicating that it has reviewed interim findings since the last review) Any new recruitment documents. Summary of participant benefits In addition to copies of the documents required for continuing review, the IRB may consider the following information, where applicable, for continuing review: Recent published medical or scientific studies, relevant recent literature, and new scientific findings applicable to the protocol since the last review. Number of subjects considered to part of a vulnerable population. Overall compliance of the investigator. Any updates of Conflict of Interest Disclosure Forms Study monitor follow-up reports Any relevant multi-center trial reports For continuing review of research by a convened IRB, at least one IRB member is provided and reviews the complete protocol including any protocol modifications previously approved by the IRB. In conducting continuing reviews, the IRB uses reviewer worksheets for continuing review and will consider whether there have been any changes that may 1) affect the rights and welfare of study subjects, 2) have the potential to increase risk or discomfort to study subjects (including the aggregate change in risk resulting from multiple minor modifications), 3) involve significant changes in study procedures, 4) substantially alter study design, 5) increase the number of subjects enrolled to a level beyond that previously approved by the IRB, 6) significantly reduce the qualifications of the research team, 7) affect the facilities and financial resources that are available to support the safe conduct of the research 8) diminish the responsibilities of the Principal Investigator who was approved to perform the study. Based on its review of the above information the IRB determines for each approved research protocol whether the research is re-approved, requires modifications to secure continuing review, is suspended or disapproved (terminated). The IRB may also require appropriate changes to the informed consent form content, frequency of continuing review, level of safety monitoring, and may determine whether the project requires verification from sources other than the investigator that no material changes have occurred since previous IRB review. The IRB will vote upon the recommendations 63
made by the reviewers according to the criteria for approval in Section 403, and will determine the frequency of review. Reports of the continuing review process will be reported in a timely manner to the investigator, the R&D Committee, and institutional officials as required. 2. APPLICABLE REGULATIONS AND GUIDELINES 21 CFR 56.108(b)(1) 21 CFR 56.109 (f) 21 CFR 50.25(b)(5) 21 CFR 812.150(a)(6) OHRP Guidance, IRB Approval Periods 38 CFR 16.109 (e) 45 CFR 46.109(e) and Continuing Review of Research, 21 CFR 56.110(b) January 20,2000 21 CFR 56.108(a)(4) VHA Handbook 1050.1 VHA Handbook 1058.1 PROCEDURE IRB Chair IRB Members
3.
CONTINUING REVIEW: Review the information in the Application for Continuing Review Form, adverse experience reports submitted by the investigator, proposed revisions to the approved research protocol, if any, and any significant new findings which may affect the welfare and safety of the subjects Review the consent form and update it if needed based upon review of above items Review any other pertinent reports in the study file (e.g.: audit reports, correspondence, complaints, etc.) Vote on a category of action as described in Section 601
ADVERSE EVENT REPORTS: Review reports promptly, determine whether changes in protocol or consent may be necessary, determine which reports will be reviewed by full IRB, take initial action as needed to ensure subject welfare IRB Coordinator Check Interim, Continuing Reviewl and Completion Reports for completeness Request further information from the investigator to clarify any questions, as needed Make copies of reports available to IRB members prior to next convened meeting 64
Notify members of continuing review actions by the Chair using expedited review process Notify investigators of continuing review and other report submission deadlines Maintain documentation of any new significant findings relevant to study subjects and how the information was provided.
4.
ATTACHMENTS Application for Continuing Review Form IRB Reviewer Worksheet for Continuing Review Local Serious or Unexpected Adverse Event Notification form Non-Local Adverse Event Notification Form
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RR 403 CRITERIA FOR APPROVAL OF RESEARCH PROPOSALS 1. POLICY In order to be approved, the IRB must carefully review all material (Protocol, Grant application, Application for IRB Review Form) submitted by the investigator and evaluate whether the project meets the criteria for approval in this section. This is true of projects reviewed through the full IRB or expedited review, and during both initial approval and continuing review. These criteria will be addressed at the time of review and documented in the meeting minutes, reviewer worksheets, and other sources. A. Required Criteria: For a list of all required criteria which must be satisfied and documented in order for the IRB to approve proposed research (45 CFR 46.111),please see the IRB Reviewer Worksheet-Criteria for Approval. B. Determination of Risk: Risk to benefit comparisons will be made at the time of initial review, and at each subsequent continuing review. In evaluating risks and benefits, the IRB will restrict its considerations to risks that may result from research, or that may result from experimental conditions requiring the discontinuation or modification of alternative therapies. The IRB does not consider the risks and benefits of therapies that subjects would receive if not participating in the research. The IRB does not consider possible long-range effects of applying knowledge gained in the research (i.e., the possible effects of the research on public policy) as being among those research risks that fall within its purview of responsibility. Risk determinations will distinguish between the risks of the experimental conditions and those inherent to the study population. Validity of research design must be taken into consideration in determining the risk/benefit ratio. The IRB must consider the risks and benefits related to both biomedical (including genetic) research and non-biomedical research. Risks associated with the experimental condition will be used in the assessment of riskbenefit comparisons. Assessments will consider potential psychological, social and economic risks in addition to physical risks to the degree that these are imposed by the experimental condition itself. Procedures that involve minimal risk will have no potential for harm that exceeds that which would be expected in the absence of the experimental condition. Procedures that involve significant risk will include any of the following: Those which may result in a condition which is life threatening. Those with a potential for permanent impairment of bodily function. Those with a potential to permanently alter body structure. Those that may necessitate medical or surgical intervention to preclude any of the above. Those that have been associate with a relatively high number of serious adverse events (SAEs) 66
Those with the potential to alter the diagnosis or treatment of participating subjects. Those that involve the use of placebo or double-blind conditions where the withholding of treatment or relevant medical information may result in any of the above conditions. Those with the potential to result in irreversible social harm.
Procedures that involve moderate risk will have greater than minimal risk and less that significant risk. Risk assessments for the purpose of determining the period of review will include all of the above criteria, but will also include any additional risks which might be inherent to the nature of the study population. All projects will be reviewed at least yearly. More frequent re-reviews will be considered in a manner which is in proportion to the degree of risk. The period of re-review will be reassessed at the end of each continuing review period. In assessing risks, the IRB will also determine: the adequacy of any steps that have been proposed to minimize physical, psychological, and economic risks. if any additional steps might be taken to minimize these risks.
C. Educational Requirements: The IRB must determine that the principal investigator and all other investigators and staff have met all current educational requirements for the VALBHS approved Educational Plan prior to initial approval or continuing review of research projects that involve human subjects. The IRB must also determine that the investigator(s) is qualified through education, training, and experience to conduct the research D. Additional Criteria: The IRB will consider the following additional criteria, when appropriate: 1. Where some or all of the subjects are likely to be vulnerable to coercion or undue influence, such as children, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons, appropriate additional safeguards have been included in the study to protect the rights and welfare of these subjects. 2. The soundness of research design and the scientific basis for the proposed research. The IRB will review the design and scientific basis to the extent that it relates to the risks to subjects and the benefits of the study, including the generalized knowledge to be gained. 3. Where some or all of the subjects are likely to have reduced decision-making capacity or require surrogate consent, appropriate additional safeguards have been included in the study and the review process to protect the rights and welfare of these subjects, as described in Section 405. 67
4. The IRB may also consider any or all of the following criteria during initial review: Whether the purpose of study is clear Results of any related studies The number of subjects and duration of participation is stated and appropriate Duration of the study and frequency of activities are clear and appropriate Wash-out period is appropriate and safeguards are in place to assure subject's condition will be adequately monitored during that period Use of placebo is appropriate The setting in which research occurs is appropriate. Plan for recruiting subjects including recruitment and enrollment procedures and appropriateness of claims made in advertising. The nature or amount of the compensation offered to subjects for participation in research does not create undue influence, particularly for economically disadvantaged subjects. The risks of research activities are clearly distinguished from the risk of therapeutic activities. Physical, psychological, social and economic risks, including risks to privacy and the probability of occurrence posed by research design, interventions and procedures. When reviewing a research proposal with elements warranting special attention (e.g., placebos, challenge studies, radiation exposure, deviations from standards of care), the IRB specifically considers the appropriateness of, and rationale for, such elements and documents such consideration. Attestation, when required, by the investigator as to whether the proposal, or one substantially similar to it, has been disapproved by another IRB. Process for monitoring and reporting adverse events. The protocol describes who should be notified of any SAE within appropriate time frame. Presence of a DSMB if applicable. Other information to be used for recruitment or to inform subjects or potential subjects about the nature of the research. Whether the investigator and research staff have appropriate scientific and human subject protection training to conduct the study. Investigator potential financial conflicts. Criteria for when research protocols should include a DSMB as required by VA, DHHS, and FDA. 2. APPLICABLE REGULATIONS AND GUIDELINES 21 CFR 812.2(b)(1)(ii) 38 CFR 16.103 (b) (4-5) 21 CFR 812. 66 38 CFR 16.111 21 CFR 56.108(a)(1-2) ICH 3.1 45 CFR 46. 109 (a-e) PROCEDURE Reviewer(s) Assess risks, benefits and the adequacy of subject protections Determine whether approval criteria have been met 68
3.
Make recommendations as to IRB action Complete reviewer worksheets Discuss project in light of approval criteria and vote on approval Document in minutes that approval criteria have been met, file reviewer worksheets
IRB Members IRB Coordinator
69
RR 404 REVIEW OF RESEARCH INVOLVING VULNERABLE POPULATIONS
1.
POLICY Most studies have the potential to recruit subjects who are economically or educationally disadvantaged. The IRB will assume that such subjects may be included and will evaluate the measures that are taken for the protection of participants on the basis of this assumption. In studies where subjects likely to be vulnerable to coercion or undue influence are likely to participate, appropriate additional safeguards must be included in the study to protect their rights and welfare. In such cases, the investigator must provide sufficient scientific and ethical justification for inclusion of vulnerable populations and a plan for how the rights of these subjects will be protected from possible coercion. The IRB must determine whether the involvement of such populations in research is justified and determine whether the proposed study minimizes or eliminates the risks to vulnerable subjects. In making such determinations, the IRB will consider the nature and degree of risk, the condition of the particular population involved, and the nature and level of the anticipated benefits, e.g. the likelihood of benefit to the subject. The IRB will also determine whether relevant risks and benefits are thoroughly presented in documents and procedures used in the informed consent process. Issues that should be addressed by the IRB and documented in the meeting minutes include whether: any monetary payments to subjects are not so great as to constitute an undue inducement; the study procedures, risks and benefits, and the degree of the subjects involvement, will be explained in a manner that is appropriate to the subjects level of education; the proposed safeguards are adequate to protect the rights and welfare of the subjects; minorities receive an equal share of the benefits of research and do not bear a disproportionate burden; the possibility of exploitation can be reduced or eliminated. the study over-selects or excludes certain groups based on perceived limitations or complexities associated with those groups; special disclosures or restrictions should be required if an investigator is to enroll his/her own patients into a study for which they are an investigator. The above criteria should be considered for all studies. The policies in the following sections apply to the following specific vulnerable populations: a) pregnant women and fetuses, b) prisoners, c) children, and e) students and employees. The policies pertaining to the mentally ill, those with impaired decision-making capacity, and those likely to need surrogate consent are discussed separately in Section 405.
70
A. Pregnant women and fetuses: VA Directive 2001-028 prohibits research involving a fetus, in-utero or ex-utero (including human fetal tissue) or in vitro fertilization by VA investigators while on official duty or at VA facilities or approved off-site facilities. The VALBHS does not conduct research that involves a fetus. With regard to research involving the participation of pregnant women as research subjects, the following requirements must be met: Appropriate studies on animals and non-pregnant individuals have been completed; The purpose of the activity is to meet the health needs of the mother and the fetus will be placed at risk only to the minimum extent necessary to meet such needs or the risk to the fetus is minimal. Individuals engaged in the activity will have no part in any decisions as to the timing, method, and procedures used to terminate the pregnancy or determining the viability of the fetus at the termination of the pregnancy. No procedural changes that may cause greater than minimal risk to the fetus or the pregnant woman will be introduced into the procedure for terminating the pregnancy solely in the interest of the research activity. No inducements, monetary or otherwise, may be offered to terminate pregnancy for purposes of research activity. Research activity as described in paragraph 4.d(3) (a)-(b) above may be conducted only if the mother and father are legally competent and have given their informed consent after having been fully informed regarding possible impact on the fetus, except that the father's informed consent need not be secured if the purpose of the activity is to meet the health needs of the mother, his identity or whereabouts cannot reasonably be ascertained, he is not reasonably available, or the pregnancy resulted from rape. IRB will determine that adequate consideration has been given to the manner in which potential subjects will be selected, and adequate provision has been made to monitor the actual informed consent process such use of consent observers, audits, and/or site visits. These determinations will be documented in the IRB minutes. B. Prisoners as a vulnerable population in research: Prisoners are considered a vulnerable population because both their incarceration and the constraints imposed on them during their incarceration may render them unable to make a truly informed and voluntary decision regarding whether or not to participate as subjects in research. Therefore, research involving prisoners must not be conducted by VA investigators while on official duty or at VA or approved off-site facilities unless a waiver has been granted by the Chief Research and Development Officer. The VALBHS does not currently conduct research that involves prisoners. If a subject becomes incarcerated in the course of their participation, then the Principal Investigator is required to follow the proscribed procedures for withdrawing the subject from the study. 71
C. Children: The VALBHS does not currently conduct research that involves Children. It is VHA policy that children cannot be included in VA-approved research conducted by VA investigators while on duty, or conducted at VA facilities or approved off-site locations, unless a waiver has been granted by the CRADO. Congressionally mandated research programs that involve children are exempt from this policy. D. Students and Employees: Students (undergraduate, graduate, and medical students), and employees of VALBHS, UCI or SCIRE (administrative, clerical, nursing, lab technicians, post-doctoral fellows and "house" staff, etc.) are considered vulnerable to undue influence. Such individuals may feel some pressure to participate in a researcher's study, especially if the requesting researcher is their supervisor, instructor, or someone who might be in a position to influence their future. Investigators must exercise great caution to avoid even the appearance of pressuring such individuals into enrollment or continued participation. When a VALBHS research investigator wishes to include such individuals as human subjects, he or she must indicate so on the initial application or request a modification to an approved protocol. In general, the IRB does not permit recruitment of employees or students from the investigators own lab, department, or office, as a matter of local policy. However, for minimal risk studies the IRB will consider requests for waivers of this policy on a caseby-case basis. Employees or students from an investigator's own lab or class may not be actively recruited into their research studies, but such persons may freely volunteer to participate, to the same extent as anyone is free to respond to general recruitment advertisements. When students participate in research studies for class credit they should be provided alternative methods of getting that credit that do not include participating in an experiment, and it is the investigator's responsibility to determine that those alternative methods exist. Wherever possible, student should be provided with a choice of research opportunities, including some not under the investigator. The IRB may require the informed consent form to state whether alternatives are available and what those alternatives are. The investigator must provide assurance that a student's experimental results, performance, or any confidential data will not be given to whomever is grading the student, except for stating whether the student participated or not. Recruitment of students from off-campus sites may be covered by the off-campus IRB if one exists. Recruitment advertisements need to be approved by the IRB according to previously stated policy. Hospital volunteers are free to participate in research studies, but volunteers working in the investigators own area or lab should be afforded similar protections as described above for students. E. Decisionally Impaired Subjects: Policies pertaining to research involving decisionally impaired individuals are described in Section 405. 72
2.
APPLICABLE REGULATIONS AND GUIDELINES 45 CFR 46.301-306 VA Handbook 1200.5 VHA Handbook 1200.5 California Penal Code, Sections 3500VA Directive 2001-028 3524 PROCEDURE IRB Chair IRB Members Review the benefits of participation to ensure there are no coercive elements Ensure that the protocol and consent provide adequate protections for vulnerable populations Verify that research is in compliance with VHA directives regarding vulnerable populations Review initial application to ascertain if vulnerable populations are likely to be recruited Secure a voting member who is a prisoner/advocate for reviews of research involving prisoners Secure additional consultants to provide additional expertise on special populations
3.
IRB Coordinator
73
RR 405 REVIEW OF RESEARCH ON HUMAN SUBJECTS LIKELY TO NEED SURROGATE CONSENT
1.
POLICY No person who has the capacity for consent may be enrolled in a study without his or her informed consent In some cases a subjects ability to provide informed consent, or to document the provision of such consent may be compromised either through a lack of mental capacity to understand the conditions of their proposed involvement, a physical disability, a judicial order. In such cases, informed consent must involve the use a person who will act on the subjects behalf to provided surrogate consent. Whenever feasible, the proposed research must still be explained to the research subject even if a surrogate provides informed consent. Subjects may not be forced or coerced to participate in a research study. A. Impaired Decision-Making Capacity: Research involving subjects who are mentally ill or subjects whose decision-making capacity may be otherwise impaired by a serious medical condition, warrant special attention. Subjects who have been legally declared to be incompetent are considered to have an impaired decision-making capacity. Research involving these populations frequently presents greater than minimal risk, may not offer direct medical benefit to the subject, and may include a research design that calls for washout, placebo or symptom provocation. In addition, these populations are considered to be vulnerable to coercion. 1. Criteria for Inclusion of Incompetent Subjects: This policy is designed to protect incompetent subjects from exploitation and harm, and at the same time make it possible to conduct essential research on problems that are unique to subjects who are incompetent (e.g. study of treatment options for comatose patients can only be done with incompetent subjects). Before incompetent persons may be considered for participation in any VA research, the IRB must find that the proposed research meets all of the following conditions: (i) Only incompetent persons suitable. Competent persons are not suitable for the proposed research. The investigator must demonstrate to the IRB that there is a compelling reason to include incompetent individuals or subjects. Incompetent persons must not be subjects in research simply because they are readily available. Favorable risk/benefit ratio. The proposed research entails no significant risks, or if the research presents some probability of harm, there must be a greater probability of direct benefit to the participant. California law further limits the type and nature of research that can be performed, requiring that informed 74
(ii)
(iii)
(iv)
(v)
consent given by a person other than the human subject shall only be for medical experiments related to maintaining or improving the health of the human subject or related to obtaining information about a pathological condition of the human subject (HSC 24175). Voluntary participation. Although incompetent to provide informed consent, some persons may resist participating in a research protocol approved by their legally authorized representatives. Under no circumstances may subjects be forced or coerced to participate. Well- informed representatives. Procedures have been devised to assure that participants' representatives are well informed regarding their roles and obligations to protect incompetent subjects. Legally authorized representatives must be given both a description of the proposed research studies and the obligations of the subjects representatives. The representative will base decisions about participation upon a best estimation of what the subject would have chosen if capable of making a decision, based upon personal knowledge of the subject and other sources of information about the potential subjects values and preferences. He or she will be available for appropriate involvement with the research subject through the process of recruitment for participation in and withdrawal from the research protocol. IRB Procedure. The IRB will make a determination in writing of each of the criteria listed above. If these criteria are met, the IRB may approve the inclusion of incompetent subjects in research projects based on informed consent from the legally authorized representative.
A person who is incompetent or has been determined to lack capacity to consent to participate in a research study should be informed about the trial to the extent compatible with the subjects understanding and, if possible, the subject should give their assent to participate, sign and date the written informed consent or a separate assent form. If the person objects to participating, this objection should be heeded. If IRB finds that these criteria have been met, incompetent subjects may be enrolled. Such approval may be sought with the initial application, may be requested later as a study modification, or approval may be sought as needed on a case-by-case basis. 2. Inclusion of subjects who may lack capacity for informed consent: The decisional capacity of a potential research subject should be evaluated when there are reasons to believe that the subject may not be capable of making voluntary and informed decisions about research participation. The investigator and research staff must have adequate procedures in place for assessing and ensuring subjects capacity, understanding, and informed consent or assent. For research protocols that involve subjects with mental disorders, or serious conditions, that may affect decision-making capacity, the IRB may determine that capacity assessments are necessary, unless the investigator can justify why such assessments would be unnecessary for a particular group. The requirement for an independent evaluator becomes increasingly justified as the risks to subjects increase. 75
For research that poses greater than minimal risk, the IRB should generally require investigators to use independent and qualified professionals to assess whether potential subjects have the capacity to give voluntary, informed consent. Even in research involving only minimal risk, the IRB may still require that the study include a capacity assessment if there are reasons to believe that potential subjects capacity may be impaired. It is not necessary to require a formal capacity assessment by an independent professional for all potential research subjects with mental disorders. For research protocols involving subjects who have fluctuating or limited decisionmaking capacity the IRB should ensure that investigators establish and maintain ongoing communication with involved caregivers. Periodic re-consent should be considered in some cases. Third party consent monitors may be used during the recruitment and consenting process, or waiting periods may be required to allow more time for the subject to consider the information that has been presented. It is often possible for investigators and others to enable persons with some decisional impairments to make voluntary and informed decisions to consent or refuse participation in research. Potential measures include repetitive teaching, group sessions, audiovisual presentations, and oral or written recall tests. Other measure might include follow-up questions to assess subject understanding, videotaping or audio-taping of consent interviews, second opinions, use of independent consent observers, interpreter for hearing-impaired subjects, allowing a waiting period before enrollment, or involvement and/or concurrent consent of a trusted family member or friend in the disclosure and decision-making process. 3. Determination of Decisional Capacity: Decisional capacity in the research context has been interpreted by the American Psychiatric Association as requiring: (1) ability to evidence a choice; (2) ability to understand relevant information; (3) ability to appreciate the situation and its likely consequences; and (4) ability to manipulate information rationally. This may include any unreasonable expectations that the subject may have with regard to the outcome of research that involves any serious condition. A range of professionals and methods may be utilized to assess capacity. In general the consent assessor should be a researcher or consultant familiar with dementias and qualified to assess and monitor capacity and consent in such subjects on an ongoing basis. The IRB will consider the qualifications of the proposed individual(s) and whether he or she is sufficiently independent of the research team and/or institution. The protocol should describe who will conduct the assessment, the method by which prospective subjects decisional capacity will be evaluated, and the criteria for identifying incapable subjects. Consultation with a psychiatrist or licensed psychologist must be obtained when the determination that the prospective research participant lacks decision-making capacity is based on a diagnosis of mental illness. In other cases, less formal procedures to assess potential subjects capacity may be permitted if a formal assessment is not feasible. Less formal procedures could include the ways professionals often make judgments about capacity in routine interactions. In making such evaluations the practitioner must consult with the chief of service, or Chief of Staff. 76
Findings of impaired decision-making capacity must be documented in the persons medical record in a signed and dated progress note prior to requesting any consent to participate in the proposed research. A person who has been determined to lack capacity to consent to participate in a research study must be notified of that determination before permission may be sought from his or her legally authorized representative to enroll that person in the study. If permission is given to enroll such a person in the study, the potential subject must then be notified. Should the person object to participating, this objection should be heeded. 4. Loss of Decisional Capacity: In some circumstances a subject who had adequate decision-making capacity at the time that consent was granted, may subsequently lose this capacity during the course of a study. In such cases it will be the responsibility of the Principal Investigator to contact one, or more, of the acceptable decision-maker(s), that are listed below, and to inform them of the subjects participation in the study and of their rights as a decisionmaker to withdraw the subject from the study. Attempts to make such contacts should be documented in CPRS notes. Should the subject later regain his or her decisionmaking capacity then the original consent will take precedence over any subsequent actions that may have been made by other decision-makers. If such a subject has been withdrawn by another decision-maker then the re-instatement of consent should be documented in a CPRS note. 5. Persons Who May Provide Authorized Consent: Federal Regulations (21CFR part 50.20) state that except for provisions made in 21CFR 50.23 and 50.24, no clinical investigator may involve a human being as a subject in research involving an investigational drug unless the investigator has obtained the legally effective informed consent of the subject or the subjects legally authorized representative. A legally authorized representative means an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subjects participation in the procedure(s) involved in the research.
The VA (VHA 1200.5) defines a legally authorized representative as an individual or body authorized under applicable law to provide permission on behalf of a prospective subject to the subjects participation in the procedure(s) involved in the research.
Consent by a legally authorized representative is limited to situations where the prospective participant is incompetent or has impaired decision-making capacity. Any determination of decision-making capacity must be made and documented as described in section 3 above. 77
Research conducted at the VALBHS is subject to the laws of the State of California. California law does not specifically refer to a legally authorized representative but rather refers to informed consent given by a person other than the human subject. Such consent is limited to medical experiments related to maintaining or improving the health of the human subject or related to obtaining information about a pathological condition of the human subject. California law refers to such a person as the decision maker. Since California law is applicable to VALBHS such an individual would also be considered to fulfill the requirements of CFR 21 part 50 and VHA 1200.5 for a legally authorized representative. The California Protection of Human Subjects in Medical Research Act (January 1, 2003) established a priority of those persons who may serve as decision makers and provide consent . The same priority applies to the withdrawal of consent. This general priority is listed below but is subject to some limitations as noted. In all cases a decision-maker is expected to have a reasonable knowledge of the subject. Acceptable decision-makers in descending order of priority are: (1) The person's agent pursuant to an advance health care directive. (2) The conservator or guardian of the person having the authority to make health care decisions for the person. (3) The spouse of the person. (4) A domestic partner as defined in Section 297 of the Family Code. (5) An adult son or daughter of the person. (6) A custodial parent of the person. (7) Any adult brother or sister of the person. Limitations on the above priorities are based upon the research setting or the legal status of the potential research subject. a. Non-emergency room environment, The research subject must not express dissent or resistance to participate. If any of the persons of the same order of priority dissent, then the consent is in valid. Refusal to consent, or withdrawal of consent, by person of higher priority may not be superceded by a person of lower priority. Persons who provide surrogate consent may not receive financial compensation for providing consent. Emergency room environment. The research subject must not express dissent or resistance to participate. .Research conducted in this setting will adhere to federal regulations that govern the obtaining of informed consent pursuant to Section 46.116 of Title 45 of the Code of Federal Regulations. In this case, any person who is listed as a potential decision-maker (regardless of priority) may refuse to grant consent or may withdraw consent. Persons who provide surrogate consent may not receive financial compensation for providing consent. Legal status. Participation of subjects in research may be further restricted under certain other circumstances. These included (i) Persons who are 78
b.
c.
involuntarily committed pursuant to Part 1 (commencing with section 5000) of Division 5 of the Welfare and Institutions Code, and (ii) Persons who have been admitted upon the request of a conservator pursuant to Chapter 1 (commencing with section 6000) of Part 1 of Division 6 of the Welfare and Institutions code. California law recognizes court appointed guardians and court appointed conservators of the person as legally authorized representatives acceptable for providing surrogate consent B. Impaired Physical Capacity: The signature of a surrogate may also be required in cases where there is no evidence of an impairment of decision-making capacity but where subjects are physically unable to provide signatures on the consent document. A surrogate is a person who performs an action at the request of another. California and Federal law do not provide guidance under such circumstances. A person who provides surrogate consent is not authorized to make legal decisions and is not a legally authorized individual or a decision maker. At VALBHS, the person who administers the consent process will be permitted to sign for the research subject provided that this is clearly noted on the consent document. The Witness to the signature is further charged with the responsibility that that research subject has given a clear indication that this signature is in accord with his or her intention. The nature of how this agreement was communicated (verbal or otherwise) must be described in the CPRS note that documents the completion of the consent process. C. IRB Procedures: In cases where a subject may have an impaired decision-making capacity, the IRB will document that all of the criteria listed in section A above have been met and/or the guidelines in subsections 1 through 3 above have been considered. If these criteria are met, the IRB may approve the inclusion of incompetent subjects or subjects with impaired decision making capacity in research projects. In considering such studies, it is recommended that the IRB include one or more regular or ad hoc members who is familiar with the population to be recruited, and another member who is a member of the population, a family member of such a person or a representative of an advocacy group for that population. The IRB is encouraged to utilize ad hoc members as necessary to assure appropriate expertise. Such ad hoc members may not vote with the IRB or contribute to the quorum. The IRB has the authority to require review of the study at earlier intervals, to impose conditions on the use of surrogate consent or prohibit its use entirely, or to require additional reporting by the investigator. With approval of the IRB the investigator may obtain the legally effective consent of the participants legally authorized representative.
2.
APPLICABLE REGULATIONS AND GUIDELINES VA Handbook 1200.5 California Health and Safety Code, Section 24170-24179.5 79
National Bioethics Advisory Commission. Research Involving Persons with Mental Disorders That May Affect Decision-making Capacity, December 1998. American Psychiatric Association, "Guidelines for Assessing the Decisionmaking Capacities of Potential Research Subjects with Cognitive Impairments," American Journal of Psychiatry 155 (1998): 164950. California Welfare and Institutions Code Divisions 5 and 6.
3.
PROCEDURE IRB Chair and Reviewer(s) Determine what human subjects protections are appropriate to a study and to the needs of decision-impaired individuals, according to this policy. Verify during continuing review that the policy has been followed. Select appropriate individuals and methods for capacity determinations. Contact decisionmakers in the event that a subject looses decision-making capacity. Document in the file that additional approval criteria in this section have been met.
Investigator
IRB Coordinator
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RR 406 FINANCIAL DISCLOSURE AND CONFLICT OF INTEREST
1.
POLICY All research performed at the VALBHS will conform to the policies and procedures set forth in the VALBHS Management of Conflicts of Interest SOP. A. Financial Disclosure and Conflict of Interest for IRB Members and Consultants: No regular member, alternate member, or consultant may participate in the review of any project in which the member, or consultant, has a significant financial interest or a conflict of interest, except to provide information as requested. Types of review include: Initial & continuing reviews Reviews of modifications Reviews of unanticipated problems involving risks to participants or others Reviews of non-compliance with the regulations or the requirements of the IRB Any type of expedited review The policy pertains to interests in business, non-profit and public entities in an area related to the research, where the entity could reasonably appear to affect or be affected by the review, conduct, or reporting of the sponsored project. A conflict of interest is defined as direct participation in the research (e.g., protocol development, principal or sub-investigator), or any significant financial interest in the sponsoring company. (i.) Determination of Conflicts of Interest: A significant financial interest is any interest in the Sponsor of the project that is under review that exceeds the thresholds defined in the VALBHS Disclosure of Relationships and Financial Interests Form. Significant financial interests are considered to be conflicts of interest. A conflict of interest is also present if: there is close professional, personal, or financial relationship between an IRB member, or consultant, and an investigator; if the IRB member, consultant, or a person in the IRB members, or consultants, immediate family is involved in the research; the IRB member, or consultant, and the investigator compete for the same immediate funding or other resources. All IRB members and consultants will disclose conflicts of interest, potential conflicts of interest, and financial conflicts of interest annually using the VALBHS Disclosure of Relationships and Financial Interests Form. The IRB chair, or the chairs designee, will review conflict of interest declarations and will: 81
Avoid the selection of reviewers who may have a conflict of interest. Ensure that IRB members are recused from the consideration of any study in which they may have a conflict of interest. Avoid the selection of Consultants that have a financial, or other, conflict of interest. (ii.) Consultants: Consultants who have previously been consulted will be asked to provide disclosure forms on a yearly basis. Consultants are also required to disclose non-financial conflicts of interest (as described above). The IRB chair will select consultants from the consultant pool at such time that there is a need for their particular expertise. In the event that the IRB requires the consultants expertise then the IRB chair will examine the disclosure form in order to determine if there is a conflict of interest. If there is no financial conflict of interest then the IRB Coordinator will contact the consultant and will provide the Consultant with: The name of the Investigator The name of the Sponsor The Title of the project The Consult must excuse him or herself if there may be any conflict of interest (including non-financial conflicts . If there is no apparent conflict of interest then the Consultant will notify the IRB Coordinator of this fact and will the IRB Coordinator will provide the Consultant with appropriate materials for review. If at any time the consultant recognizes the possibility of a conflict of interest then the consultant must inform the IRB chair of this fact. If the IRB Chair determines that any consultant may have a potential conflict of interest, then that consultant generally will not be permitted to provide information to the IRB. The consultant may be permitted to provide information only if: The required information may not reasonably be obtained in another manner; and The potential for bias is considered by the IRB and described in the IRB minutes. If the IRB requires the expertise of a consultant that has not previously been utilized, then the consultant must provide a copy of the disclosure form prior to any participation in any project review. All Consultants will be provided with a copy of the IRB Conflict of Interest Policy contained in this section RR 606 and will be interviewed by the Chair of the IRB in order to review the policies. (iii.) IRB Members: IRB members are informed of potential conflicts through a review of meeting agendas. Agendas are distributed no later than one week prior to each IRB meeting and contain information about the investigators, sponsors and primary reviewers of each project that will be under review. IRB members review the agenda and will declare any potential conflicts of interest prior to the beginning of project reviews. In general, the IRB member, will recuse him or herself from participation in the discussion and vote. If there is any question as to whether or not a conflict exists then the full IRB will discuss the conflict of interest without the member present to determine 82
if a conflict of interest is present. If a conflict of interest is present then recusal will be required. (iv.) Others: Other individuals have conflicts of interest inherent in their positions, and may not serve on the IRB as consultants or voting members. This includes, but is not limited to, officers of SCIRE, other grants contracts or fiscal officers affiliated with the institution, and the ACOS/R&D. B. Financial Disclosure and Conflict of Interest for Investigators: The principal investigator and all sub-investigators must report all actual or potential significant financial interests and any conflicts of interest using an approved Conflict of Interest Disclosure Form. This disclosure policy applies to the principal investigator, sub-investigators, and all personnel responsible for the design, conduct or reporting of the study. The policy pertains to interests in business, non-profit and public entities in an area related to the research, where the entity could reasonably appear to affect or be affected by the design, conduct, or reporting of the sponsored project. The IRB will review any prior determinations that have been made by the R&D Committee and will consider these in determining whether the potential conflicts of interests might adversely affect subject welfare If so, it will take steps to reduce or eliminate the conflict. The IRB may impose additional restrictions or conditions but may not diminish any restrictions that have been imposed by the R&D Committee without the approval of that committee. In making its determinations, the IRB will conform to the standards set forth in the VALBHS Conflict of Interest SOP. If any potential conflicts of interest are present, the informed consent document should include a statement indicating that one or more investigators has a personal financial interest in the Sponsor company or other interested entity. The nature of the interest should be disclosed as well. C. Review and Management of Conflicts of Interest: During the review process, the IRB will review any potential conflicts of interest that may be present. If the IRB determines that the investigator's financial or other interest could adversely affect subject welfare, the IRB will take appropriate action within the scope of its authority to approve, disapprove, or require modifications to reduce the conflict. The determination will appear in the meeting minutes. The matter will also be referred to R&D Committee for further action as per institutional policy. In evaluating potential conflicts of interest the IRB will consider: Risks to participants Anticipated benefits, if any, to participants The scientific or scholarly integrity of the research The selection of participants The possibility of coercion or undue influence during the consent process The information provided to the participant Provisions for monitoring the data collected to provide for the safety of participants Provisions to protect the privacy interests of participants and to maintain the confidentiality of identifiable data 83
The credibility of the human research protection program
Possible conditions that may be imposed by the IRB to reduce conflict of interest include: reduction or elimination of financial interests or relationships, disclosure of financial interests to subjects, interim reports, modification of the research plan, education of research personnel, monitoring by a third party or ad hoc committee, disclosure of financial interests to journal editors and in presentations, and disqualification from participation in all or a portion of the project. If no conflict of interest is found, the informed consent may include a statement to the effect that the IRB has determined that the investigator's financial interest will not adversely affect subject welfare. The IRB will document the nature of any review of conflicts of interest in the meeting minutes. This documentation will include a summary of the plan to manage the conflict of interest. If the matter is referred to the R&D committee then this will be so noted. If any member of the IRB has a potential conflict of interest that is associated with the review process, then the discussion and resolution of this potential conflict will be documented in the meeting minutes. The IRB will inform the principal investigator in writing the nature of the conflict of interest(s), and any conditions that have been imposed by the IRB and/or R&D Committee for the management of the conflict of interest. When the IRB concludes that such a conflict of interest is and cannot be resolved by the IRB, they will refer their concerns to the R&D Committee.
2.
APPLICABLE REGULATIONS AND GUIDELINES 42 CFR 50.601-607 21 CFR 54.4-6 VALBHS Standard Operating Procedures for Managing Conflicts of Interest
3.
PROCEDURE IRB Members, including Chair, alternates, and consultants Investigators Declare any potential conflicts of interest prior to the review of studies where such conflicts may exist. Report potential COIs on approved Conflict of Interest Declaration Forms and update as needed. Refer potential COIs to COI Review Committee Review potential COIs that are identified on Conflict of interest Declaration Forms or that are referred by the IRB, R&D, or ACOS/R&D Maintain records that document the declaration and management of Conflicts of Interest. 84
R&D Committee R&D Committee
R&D Committee Coordinator
RR 407 AUDITS AND THIRD PARTY VERIFICATION
1.
POLICY The IRB has the authority to observe, or have a third party observe, the consent process and the research it has approved, and to verify that the study is being conducted as required by the IRB. When the IRB opts to assess the conduct of the study or the consent process as part of providing adequate oversight, an audit is conducted. An audit may be also be classified as routine (part of the normal oversight process) or for cause. Routine audits may be conducted by the institution's RCO and/or other qualified individuals designated by the IRB. "For cause" audits will be 85
conducted by the IRB Chair and/or designated IRB members, a member of another IRB or an unaffiliated party. An audit may be study-oriented (focused on a specific study) or investigator-oriented (focused on all the studies of a particular investigator). A for cause audit may be initiated in response to any of the following findings: an allegation of or evidence suggesting noncompliance with applicable regulations or institutional policies non-compliance with policies of the IRB as outlined in this document ongoing research is identified which has not been approved by the IRB expressed concerns by the sponsor regarding the investigators work a complaint by a subject in a study about protocol or subject's rights violations a potential high risk to subjects, recruitment of vulnerable populations, studies that involve large numbers of subjects, investigators who are conducting multiple studies under IRB jurisdiction research by an investigator outside of their specialty areas safety or effectiveness findings that are inconsistent with those of other investigators studying the same test article too many subjects with a specific disease given the locale of the investigation are claimed laboratory results that are outside the range of expected biological variation studies selected at the discretion of the IRB an allegation of or evidence suggesting abuse of research subjects an allegation of or evidence suggesting scientific misconduct Investigators are required to submit reports to the IRB if they are informed of problems that were revealed as a result of any audit visit. The procedures for submitting reports are summarized in section QA 903. A. Audit Procedures: In order to determine the facts surrounding the conduct of the study, the auditor may review the protocol and any modifications, Investigational Drug Brochure, the informed consent, the investigators and the IRB files, subjects medical and/or research records, case report forms, literature and other documents that could serve to provide factual information regarding the conduct of the study. Although not generally recommended, the auditor may conduct interviews with the Investigator, members of the study team, or research subjects. A written report of findings will be provided to the IRB for further review. The IRB will assess the Audit Report as follows (Audit Conclusion): Investigator in full compliance with the regulations; no deficiencies noted Objectionable practices or conditions noted, but no major departures from regulations Investigator has objectionable practices or conditions representing major departures from regulations Investigator will be notified of any findings that require changes
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Investigators found to have objectionable practices or conditions noted, but no major departures from regulations, may have additional stipulations or restrictions placed on his/her research effort, be required to attend additional training sessions or other reasonable remedial actions taken as agreed upon by a majority of IRB members at a convened meeting. Investigators found to have objectionable practices or conditions representing major departures from regulations may have additional stipulations or restrictions placed on his/her research effort, be required to attend additional training sessions or other reasonable remedial actions taken as agreed upon by a majority of IRB members at a convened meeting. In addition, the audit will be referred to the ACOS/R&D for further investigation. Possible actions that may be taken against investigators and reporting responsibilities are described in Section 903. B. Third Party Verification: Third party verification of information provided by an Investigator may be necessary to ensure protection of subjects. The IRB has the authority to require verification of any information provided by an investigator as part of an initial application or as part of a continuing review,, interim or completion report and may do so at its own discretion. Such verification may be random or based on factors such as study complexity, previous noncompliance, information in reports submitted, or evidence from other sources. The IRB also has the authority to observe, or have a third party observe, the consent process and the research it has approved. The need to verify any information, the information that needs verification and the extent to which the information will be verified will be determined by the IRB at a convened meeting. Interviews will study personnel and/or observations of consent procedures will generally be required if there has been a complaint to the research office or if a question as to the adequacy of the consent process has been raised in the course of routine quality assurance audits. Methods of third party verification include: Direct observation of research procedures by an IRB member Direct request to sponsor for information Direct request to DSMB for information Require the use of an independent consent monitor in some or all cases C. External Study Monitors: 1. Education and Certification. All external study monitors must satisfy the educational requirements that are specified under section IR802 and must complete an AIS form to request computer access. In addition: Study Coordinators must notify the Research Office prior to any visit by a study monitor and must escort the monitor to the Research Office to sign in. Study Coordinators must escort the monitor to the IRM office to obtain permission for computer access. Access may be granted for the duration of the visit. Upon completion of the visit, access privileges will be deactivated but will not be deleted. 87
Study Coordinators must also escort the monitor to the VA Police Station in order to obtain a visitor badge that specifies the dates of the visit. Upon completion of the visit the Study Coordinator will escort the monitor to the Research Office to sign out and return the visitor badge.
2. Reporting of Audit Results. Any suspicions or concerns that are raised in the course of a monitor visit must be conveyed to the Investigator and the HRPPO, or designee(s), at an exit interview. These include any instances of noncompliance with the study protocol, IRB requirements, or applicable regulations or policies (eg. failure to consent subjects who do not meet inclusion and exclusion criteria, failure to report promptly to the IRB the problems that require prompt reporting to the IRB as defined in QA 903. Problems will be evaluated and managed as described in section QA 903. If a monitor records no findings or concerns, as listed above, then the study investigator or research coordinator must notify the research office in writing that there were no such findings identified by the monitor and must submit copies of any monitoring reports to the IRB with continuing review submissions. 2. APPLICABLE REGULATIONS AND GUIDELINES 38 CFR 16. 109(e) 38 CFR 16. 103(b) (4)(ii) VA Handbook 1200.5 Reporting of All Study Site-Monitoring 21 CFR 56.108(a)(2) Visit Results (VA Memorandum 21 CFR 56.109 (f) 10/14/2004) 45 CFR 46.109(e) 45 CFR 46. 103 (b)(4)(ii) PROCEDURE ACOS R&D Meet (or select designee to meet) with the auditor or study monitor during an exit interview should any potential or actual serious findings be identified. Forward reports of serious findings to the IRB Verify that the training requirements of study monitors have been met. Serve as a liaison between investigators or study coordinators, auditors or monitors, and the ACOS R&D or his or her designee. Ensure that any additional reporting requirements are met in the event of serious findings or concerns. Provide auditor with a copy of the protocol and any modifications, Investigational drug brochure, informed consent, IRB files and any other documents that could provide factual information regarding the conduct of the study. 88
3.
HRPP Officer
IRB Coordinator
Auditor or monitor
Contact Investigator to arrange audit logistics. Review all documents that could provide factual information regarding conduct of the study. Confirm that the study is being conducted in compliance with the documents provided, by observation if possible, especially: Methods of subject recruitment, and or safeguards for subjects vulnerable to coercion or undue influence Process for obtaining informed consent Version of informed consent used Facilities available in an emergency Adherence to inclusion/exclusion criteria Confirm information about any adverse events that may have been reported. Obtain information about any adverse events that may not have been reported. Confirm status of project (enrolling, inactive etc) Complete Audit Report within 5 working days of completing the audit. Review Audit /Study Monitoring Reports Review reports of serious findings as provided by the ACOS/R&D or his/her designee Assess the need for additional information. Determine audit conclusion. Vote on remedial action imposed on investigator, as necessary.
IRB Members
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RR 408 INVESTIGATIONAL DEVICES 1. POLICY A medical device is defined, in part, as any health care product that does not achieve its primary intended purposes by chemical action or by being metabolized. Medical devices include, among other things, surgical lasers, wheelchairs, sutures, pacemakers, vascular grafts, intraocular lenses, and orthopedic pins. Medical devices also include diagnostic aids such as reagents and test kits for in vitro diagnosis (IVD) of disease and other medical conditions such as pregnancy. Clinical investigations of medical devices must comply with the Food and Drug Administration (FDA) informed consent and Institutional Review Board (IRB) regulations [21 CFR parts 50 and 56, respectively]. Federal requirements governing investigations involving medical devices were enacted as part of the Medical Device Amendments of 1976 and the Safe Medical Devices Act of 1990. These amendments to the Federal Food, Drug, and Cosmetic Act (the Act) define the regulatory framework for medical device development, testing, approval, and marketing. Except for certain low risk devices, each manufacturer who wishes to introduce a new medical device to the market must submit a premarket notification to FDA. FDA reviews these notifications to determine if the new device is "substantially equivalent" to a device that was marketed prior to passage of the Amendments (i.e., a "pre-amendments device"). If the new device is deemed substantially equivalent to a pre-amendments device, it may be marketed immediately and is regulated in the same regulatory class as the pre-amendments device to which it is equivalent. (The premarket notification requirement for new devices and devices that are significant modifications of already marketed devices is set forth in section 510(k) of the Act. Devices determined by FDA to be "substantially equivalent" are often referred to as "510(k) devices". If the new device is deemed not to be substantially equivalent to a pre-amendments device, it must undergo clinical testing and premarket approval before it can be marketed unless it is reclassified into a lower regulatory class. Investigational Device Exemption (IDE) An investigational device is a medical device which is the subject of a clinical study designed to evaluate the effectiveness and/or safety of the device. Clinical investigations undertaken to develop safety and effectiveness data for medical devices must be conducted according to the requirements of the IDE regulations [21 CFR part 812]. An IDE study may not necessarily commence 30 days after an IDE submission to FDA. Certain clinical investigations of devices (e.g., certain studies of lawfully marketed devices) may be exempt from the IDE regulations [21 CFR 812.2(c)]. Unless exempt from the IDE regulations, an investigational device must be categorized as either "significant risk" (SR) or "nonsignificant risk" (NSR). The determination that a device presents a nonsignificant or significant risk is initially made by the sponsor. The proposed study is then submitted either to FDA (for SR studies) or to an IRB (for NSR studies).
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The IRB's SR/NSR determination has significant consequences for the study sponsor, FDA, and prospective research subjects. SR device studies must be conducted in accordance with the full IDE requirements [21 CFR part 812], and may not commence until 30 days following the sponsor's submission of an IDE application to FDA. Submission of the IDE application enables FDA to review information about the technical characteristics of the device, the results of any prior studies (laboratory, animal and human) involving the device, and the proposed study protocol and consent documents. Based upon the review of this information, FDA may impose restrictions on the study to ensure that risks to subjects are minimized and do not outweigh the anticipated benefits to the subjects and the importance of the knowledge to be gained. The study may not commence until FDA has approved the IDE application and the IRB has approved the study. In contrast, NSR device studies do not require submission of an IDE application to FDA. Instead, the sponsor is required to conduct the study in accordance with the "abbreviated requirements" of the IDE regulations [21 CFR 812.2(b)]. Unless otherwise notified by FDA, an NSR study is considered to have an approved IDE if the sponsor fulfills the abbreviated requirements. The abbreviated requirements address, among other things, the requirements for IRB approval and informed consent, recordkeeping, labeling, promotion, and study monitoring. NSR studies may commence immediately following IRB approval. A. Initial IRB Review of Medical Device Research: 1. Materials to be Reviewed In addition to all standard materials required for initial IRB review, projects involving medical device research must specifically include: a. Review of prior data including risk assessment data previously done by the sponsor and FDA; b. Source of the device; c. Initial risk assessment whether it is a significant or non-significant risk device; d. Copy of IDE application and FDA letter indicating receipt of application, if applicable; e. Copy of the FDA assignment letter and IDE number, if applicable. f. Copy of the package insert if the device is FDA approved. g. The investigators proposed plan for receipt, storage, security, dispensation, and destruction of the device; h. The investigators proposed plan for ensuring that appropriate emergency information is available in case of device recall; i. The investigators proposed plan for documenting device use in the subjects medical records; j. The expiration date of the device. k. Evaluations of the safety of the device that are made by the Biomedical Engineering Department, if the device requires the use of electrical power. The IRB may also ask the sponsor whether other IRBs have reviewed the study and what determinations were made. The IRB may also request the sponsor or clinical investigator to provide documentation of appropriate FDA clearances, and may consult the FDA for its opinion on risk. 91
2. Devices Exempt from IDE Requirements: Some medical devices are exempted from 21 CFR 812 filing requirements and do not require an approved investigational device exemption, provided certain conditions are met. However, these kinds of device investigations still require IRB review and informed consent compliance. These exemptions are: A device, other than a transitional device, in commercial distribution immediately before May 28, 1976, when used or investigated in accordance with the indications in labeling in effect at that time. A device, other than a transitional device, introduced into commercial distribution on or after May 28, 1976, that FDA has determined to be substantially equivalent to a device in commercial distribution immediately before May 28, 1976, and that is used or investigated in accordance with the indications in the labeling FDA reviewed under subpart E of part 807 in determining substantial equivalence. A diagnostic device, if the sponsor complies with applicable requirements in 21 CFR 809.10(c) and if the testing: (1) Is noninvasive, (2) Does not require an invasive sampling procedure that presents significant risk, (3) Does not by design or intention introduce energy into a subject, and (4) Is not used as a diagnostic procedure without confirmation of the diagnosis by another, medically established diagnostic product or procedure. Note: In vitro diagnostic (IVD) device research where there is NO possibility of linkage between a sample and subject identification (e.g., surplus blood sample that is coded but the coding cannot be linked to the source subject) does not require Informed Consent compliance. A device undergoing consumer preference testing, testing of a modification, or testing of a combination of two or more devices in commercial distribution, if the testing is not for the purpose of determining safety or effectiveness and does not put subjects at risk. A device intended solely for veterinary use. A device shipped solely for research on or with laboratory animals and labeled in accordance with 21 CFR 812.5(c). A custom device as defined in 21 CFR 812.3(b), unless the device is being used to determine safety or effectiveness for commercial distribution. 3. Significant Risk Device Definition A significant risk device (SR) is one that presents a serious risk to the health or safety of the research subjects. Whether or not a device is an SR device is determined as described in section 4 below. A non-significant risk device (NSR) is one that does not present significant risk to the research subjects. Examples are daily wear contact lenses, conventional gastrointestinal and urology endoscopes and accessories, dental filling materials, etc. The IRB may refer to the FDA Information Sheets concerning Medical Devices for additional examples of NSR devices 4. Review Procedures: The IRB will determine if the medical device is an approved medical device or an investigational device as described in RR 401 section A. (drugs and devices). 92
The IRB will determine if the FDA has required the Sponsor to obtain an IDE as described in section RR 401. If the FDA has required an IDE for the device then the IRB will consider the device to be an investigational device and will require documentation that the IDE has been granted. If the medical device is an investigational device then the IRB will make two separate determinations: (1) whether a device study presents SR or NSR; and (2) whether the study should be approved. (a.) Distinguishing Between SR and NSR Device Studies The effect of the SR/NSR decision is very important to research sponsors and investigators. SR device studies are governed by the IDE regulations [21 CFR part 812]. NSR device studies have fewer regulatory controls than SR studies and are governed by the abbreviated requirements [21 CFR 812.2(b)]. The major differences are in the approval process and in the record keeping and reporting requirements. The SR/NSR decision is also important to FDA because the IRB serves, in a sense, as the Agency's surrogate with respect to review and approval of NSR studies. FDA is usually not apprised of the existence of approved NSR studies because sponsors and IRBs are not required to report NSR device study approvals to FDA. If an investigator or a sponsor proposes the initiation of a claimed NSR investigation to an IRB, and if the IRB agrees that the device study is NSR and approves the study, the investigation may begin at that institution immediately, without submission of an IDE application to FDA. If the IRB believes that a device study is SR, the investigation may not begin until both the IRB and FDA approve the investigation. To help in the determination of the risk status of the device, the IRB will review information such as reports of prior investigations conducted with the device, the proposed investigational plan, a description of subject selection criteria, and monitoring procedures. The IRB will review the sponsors risk assessment and the rationale used in making its determination [21 CFR 812.150(b)(10)]. (b.) SR/NSR Studies and the IRB The NSR/SR Decision The assessment of whether or not a device study presents a NSR is initially made by the sponsor. The Investigator is responsible for providing the IRB with the Sponsors determinations. If the sponsor considers that a study is NSR, the sponsor provides the reviewing IRB an explanation of its determination and any other information that may assist the IRB in evaluating the risk of the study. The sponsor should provide the IRB with a description of the device, reports of prior investigations with the device, the proposed investigational plan, a description of patient selection criteria and monitoring procedures, as well as any other information that the IRB deems necessary to make its decision. The sponsor should inform the IRB whether other IRBs have reviewed the proposed study and what determination was made. The sponsor must inform the IRB of the Agency's assessment of the device's risk if such an assessment has been made. The IRB may also consult with FDA for its opinion.
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The IRB may agree or disagree with the sponsor's initial NSR assessment. If the IRB agrees with the sponsor's initial NSR assessment and approves the study, the study may begin without submission of an IDE application to FDA. If the IRB disagrees, the sponsor should notify FDA that an SR determination has been made. The study can be conducted as an SR investigation following FDA approval of an IDE application. The risk determination should be based on the proposed use of a device in an investigation, and not on the device alone. In deciding if a study poses an SR, the IRB will consider the nature of the harm that may result from use of the device. A device will be determined to be a SR device if any of the following criteria apply: The device is intended as an implant; The device supports or sustains life; Use of the device is of substantial importance in diagnosing, curing, mitigating or treating disease, or preventing impairment of health; The device could cause significant harm to any subjects; Subjects must undergo a procedure as part of the device study; The study device appears on the FDA list of significant risk devices; The study or any of the study procedures could cause harm to the subjects which: o Could be life threatening; or o Could cause permanent impairment of a body structure, or o Could necessitate medical or surgical intervention to preclude permanent impairment of a body function or preclude permanent damage to a body structure. FDA has the ultimate decision in determining if a device study is SR or NSR. If the Agency does not agree with the IRB's decision that a device study presents an NSR, then the IRB will require that an IDE application must be submitted to FDA. (c.) IRB and Sponsor Responsibilities Following SR/NSR Determination If the IRB decides the study is Significant Risk: The IRB will notify the sponsor and investigator of SR decision The Sponsor will be required to submit an IDE to FDA or, if electing not to proceed with study, notify FDA (CDRH Program Operations Staff 301-5941190) of the SR determination;
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The Study may not begin until 1) the FDA approves the IDE ; 2) the investigator provides documentation of FDA approval; and 3) the IRB approves the study. The Sponsor and investigator(s) must comply with IDE regulations [21 CFR part 812], as well as informed consent and IRB regulations [21 CFR parts 50 and 56]. If the IRB decides the study is Nonsignificant Risk:
When the IRB determines that the device is a NSR device, it proceeds to review the study under requisite criteria for any study. A NSR device investigation does not require the sponsor to first obtain an approved IDE before beginning the study provided certain other requirements are met. If those abbreviated requirements are met, the sponsor is considered to have an approved IDE in place. (c.) IRB Approval. Once the final SR/NSR decision has been rendered by the IRB (or FDA), the IRB must consider whether or not the study should be approved. In considering whether a study should be approved, the IRB should use the same criteria it would use in considering approval of any research involving an FDA regulated product [21 CFR 56.111]. Some NSR studies may also qualify as "minimal risk" studies, and thus may be reviewed through an expedited review procedure [21 CFR 56.110]. FDA considers all SR studies to present more than minimal risk, and thus, full IRB review is necessary. In making its determination on approval, the IRB should consider the risks and benefits of the medical device compared to the risks and benefits of alternative devices or procedures. The IRB will pay careful attention to the investigators plan for receipt, storage, security, dispensation and destruction of the device. The IRB will also consider the investigators plan for ensuring that appropriate emergency information is available in case of recall as well as whether sufficient clinical information will be included in the subjects medical record. The IRB will review the plan, and may approve, disapprove, or require modification to the plan. Protocols involving significant risk devices do not qualify for expedited review at initial review. If a project involves the use of a Device that has be assessed as SR by the sponsor, investigator or IRB, the IRB will not approve the use of the device until an FDA approved IDE or a 510(k) approval has been documented for the device. B. Required Investigator Documentation: 1. Investigator records. A participating investigator will maintain the following accurate, complete, and current records relating to an investigation involving an investigational device, as described in the IRB SOP Manual, Section 401. All correspondence with another investigator, an IRB, the sponsor, a monitor, or FDA, including required reports; Records of receipt, use, or disposition of the investigational device, including the type and quantity of the device, the dates of its receipt, the batch number or code mark, the names of all persons who received, used, or disposed of each device, 95
and why and how many units of the device have been returned to the sponsor, repaired, or otherwise disposed of; 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 chart(s), and the nurses' notes. Such records shall include: 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. The case history for each individual shall document that informed consent was obtained prior to participation in the study. 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. A record of the exposure of each subject to the investigational device, including the date and time of each use, and any other therapy. The protocol, with documents showing the dates of and reasons for each deviation from the protocol; and Any records that FDA requires to be maintained by regulation or by specific requirement for a particular investigation.
All IRB records will be retained for at least 5 years. Records relating to research that is conducted will be retained for 5 years after the completion of the study at the sites. Investigators should always contact study sponsor prior to disposal of documentation. An investigator may withdraw from the responsibility to maintain records for the time required by transferring custody to another person who will accept responsibility for them. If an investigator transfers custody of the records to another person, the investigator must notify the IRB, the sponsor and the FDA (if the sponsor does not so notify) within 10 working days after the transfer occurs. 2. Sponsor-investigators. Additional record-keeping and reporting requirements for Sponsor-Investigators who employ investigational devices are described in section IR 801.
2.
APPLICABLE REGULATIONS AND GUIDELINES
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21 CFR 812.150(a) 21 CFR 812.2(b)(1)(ii) 21 CFR 812.66 21 CFR 812.35, 36 21 CFR 812.7 FDA Information Sheet. : "Significant Risk and Nonsignificant Risk Medical Device Studies Guidance for Institutional Review Boards and Clinical Investigators 1998 Update. VALBHS Policy on Use of Investigational Devices California Health and Safety Code 445 CDRH; Guidance on IDE policies and procedures 1/20/98 Medical Device Reporting, VHA 10-94-010 Medical Device Amendments of 1976 [P.L. 94-295, 90 Stat. 539 (May 28, 1976)] Safe Medical Devices Act of 1990 [P.L. 101-629]
3.
PROCEDURE Document plan for compliance with device regulations Maintain required documentation and records Make all assessments required for initial or continuing review described in Section 401 Make significant/non-significant risk determination for device Assess whether investigators plans for receipt, storage, disposal and tracking of the device usage are appropriate Make an assessment of PI and staff qualifications regarding device usage Review reporting of device usage and adverse effects Make assessments as to risks, benefits and the adequacy of subject protections Make recommendations as to the appropriate IRB action and vote on actions
Investigator IRB Members
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RR 409 HIPAA REQUIREMENTS AND PRIVACY PROTECTION 1. POLICY The IRB also serves as the Privacy Board at the VALBHS. In this capacity, the IRB is responsible for maintaining VHA policies, responsibilities, and standards for the use and disclosure of individually-identifiable information and individuals rights in regards to VHA data. This responsibility and authority includes research that involves human subjects but also extends to research that involves deceased individuals that is not otherwise considered to be human research. VALBHS investigators must obtain written authorization or a waiver of the authorization requirement from the IRB for using VHA individually-identifiable health information involving non-employee research subjects for research purposes. When PHI must be reviewed or recorded prior to obtaining authorization from the subject, the IRB (Privacy Board) must have granted a waiver of authorization. A. HIPAA Requirements Individually-identifiable information is to be disclosed to requestors with the understanding that it is confidential information that needs to be handled with appropriate sensitivity. Information from VHA records can only be disclosed or released with the prior signed authorization of the individual or other legal authority. The individually-identifiable information of research subjects in their capacity as VHA Employees, excluding Health information, is disclosed to non-VHA Investigators for research purposes without written authorization only in accordance with Privacy Act and applicable VA Privacy Policy. California law requires that language that entails the waiver or authorization for the use and/or disclosure of Protected Health Information must be in a in a typeface no smaller than 14 point and must be clearly separated from any other language that is present on the same page (CA Civil Code sect. 56.10). Waiver or alteration of authorization for the use and/or disclosure of Protected Health Information (PHI) may be reviewed by expedited review. Neither written authorization nor an IRB or Privacy Board waiver of authorization is required for a VHA Investigator to conduct a review of individually-identifiable information in preparation of a research protocol (45 CFR 164.512(i)(1)).
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Information that is restricted to, and for the purpose of, the preparation of research proposals is recorded without identifiers and not used to recruit subjects.
1. Authorization (a.) Process. Written authorization for the disclosure of information is required when: VA health care facilities need to utilize individually-identifiable health information for purposes other than treatment, payment, and/or health care operations and other authority, as specifically noted by VHA Handbook 1605.1 does not exist. VA health care facilities disclose information for any purpose where other legal authority dos not exist. VA health care facilities conduct marketing except when communicated face-to-face to an individual. Authorization may be given on VA Form 3288 Request for and consent to Release of Information; VA Form 10-5345 Request for and Consent to Release Medical Records, or any subsequent authorization form approved to replace these forms. An authorization for the use or disclosure of individually-identifiable health information for a research study may be combined with any other type of written permission for the same research study, including the Informed Consent or consent to participate in research. Authorization may be given by: The individual. A court-appointed legal guardian. An individual who has written authorization to act on the individuals behalf (e.g. power of attorney) The executor of Estate, next-of kin, or any one with a significant personal relationship to the individual (as defined by VHA 1605.1) if the individual is deceased. In cases where information may be released that involves the diagnosis, treatment, or research of HIV, Sickle Cell Anemia, Drug and/or Alcohol Abuse, authorization may only be provided by the individual whose records are involved, the legal guardian of an incompetent individual, or the next-of kin of a deceased individual. An authorization for the release of information is only valid for the period that is specified on the authorization. The IRB needs to ensure that the required language for a valid authorization to release health information (Health Insurance Portability and Accountability Act (HIPAA) Authorization) is included with the informed consent document. The IRB may waive the requirement for an authorization or may alter the form or content of the authorization only in accordance with and as permitted by the HIPAA Privacy Rule (45 CFR 164.508). Such actions and the justification for them must be fully documented in the minutes of the IRB meeting where the action was taken or reported (if approved by expedited review). 99
(b.) Required Elements. HIPAA Privacy rule authorization must be in plain language and must include: The identity of the individual to whom the information pertains (i.e., name and social security number). A description of the information to be used or disclosed that identifies the information in a specific and meaningful fashion. If HIV, sickle cell anemia, drug and/or alcohol abuse treatment information is to be disclosed this information must be specifically identified in the discussion. The name or other specific identification of the person(s), class of persons, or office designation(s) authorized to make the requested use or disclosure. The name or other specific identification of the person(s), class of persons, or office designation(s) to whom the agency may make the requested use or disclosure. A description of each purpose of the requested use or disclosure. The statement at the request of the individual is sufficient when an individual initiates the authorization and does not, or elects not to provide a statement and does not, or elects not to, provide a statement of the purpose. An expiration date or event that relates to the individual or the purpose of the use or disclosure. Examples of appropriate expiration date language arte as follows: O The statement end of the research study or similar language is sufficient if the authorization is for use or disclosure of individuallyidentifiable health information for research. O The statement none or similar language is sufficient if the authorization is for the agency to use or disclose individuallyidentifiable health information, including for the creation and maintenance of a research database or research repository. The signature of the individual, or someone with the authority to act on behalf of the individual, and date signed. A statement that the individual has the right to revoke the authorization in writing except to the extent that the VHA has already acted in reliance on it, and a description of how the individual may revoke the authorization (e.g., to whom the revocation is provided). For a use or disclosure of individiually identifiable health information related to research the statement end of the research study, none, or similar language is sufficient. A statement that VHA may not condition treatment, payment, enrollment, or eligibility for benefits based upon the individual completing an authorization. A statement that individually identifiable health information disclosed pursuant to the authorization may no longer be protected by Federal laws or regulation and may be subject to re-disclosure by the recipient.
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2. Waiver or Alteration of Authorization. The Health Insurance portability and Accountability Act (HIPAA) Privacy Rule requires that, if an IRB grants a waiver or alteration of the HIPAA Authorization, the Institutional Review Board (IRB) document the findings on which it based its decision. A request from an investigator to waive or alter the HIPAA authorization needs to be accompanied by information sufficient to make the required findings listed in the following. The documentation must include all of the following: (a) Identification of the IRB (b) Date of IRB Approval of waiver of authorization (c) Statement that alteration or waiver of authorization satisfies the following criteria: i. The use or disclosure of the requested information involves no more than a minimal risk to the privacy of individuals based on, at least, the presence of the following elements: An adequate plan to protect the identifiers from improper use and disclosure. An adequate plan to destroy the identifiers at the earliest opportunity consistent with conduct of the research, unless there is a health or research justification for retaining the identifiers or such retention is otherwise required by law; and Adequate written assurances that the requested information will not be reused or disclosed to any other person or entity, except as required by law, for authorized oversight of the research study, or for other research for which the use or disclosure of the requested information would be permitted by the Privacy Rule;
(ii.) The research could not practicably be conducted without the waiver or alteration; and ( iii.) The research could not practicably be conducted without access to and use of the requested information. (d) A brief description of the Protected Health Information (PHI) for which the IRB has determined use or disclosure to be necessary (e) Identification of the review procedure used to approve the waiver of authorization (either normal review procedures (38 CFR 16.108(b) or expedited review procedures (38 CFR 16.110)). (f) Signature of Chair of the IRB, or member designated by the Chair, to approve the waiver of authorization. 3. Recruitment and Screening. (a) CPRS Records. Authorization is not required when investigators access the medical records of their own patients for purposes of recruitment and screening. If investigators would like to search CPRS for the sole purposes of recruitment and screening then a 101
Request for Waiver of Authorization to Release Medical Records or Health Information for the Sole Purpose of Recruitment and Screening form must be submitted to, and approved by, the IRB. (b) Physician Referrals. If subject recruitment involves the use of referrals from physicians that are not a part of the study, then the waiver noted above in section (a) is also required. In such cases, a Physician Referral HIPAA Authorization and Revocation form must also be submitted to the IRB. Upon approval, the following actions are required: Copies of both forms must be provided to physicians who will refer subjects. Subjects who are referred by physicians who have not signed the authorization form should not be contacted for recruitment. The referring physician must explain the authorization and revocation process to the subject to be referred, and must complete the documentation as indicated on the Physician Referral Authorization Form. The referring physician should retain one copy, provide one copy to the referred subject, and provide one copy to the principal investigator. The referring physician should retain blank revocation forms and provide these to subjects upon requests by such subjects for a revocation of the referral. Completed forms should be forwarded to the Release of Information Office.
B. Use of VA Records for Research and Development 1. All VHA employees must comply with all Federal laws and regulations, VA regulations and policies, VHA policies and the policies of the VALBHS. These include all legal and ethical requirements to protect the confidentiality of information that can be identified with a person as specified by VHA Handbook 1605.1. All employees must conduct themselves in accordance with the rules of conduct concerning the disclosure or misuse of information in the government-wide and VA Standards of Ethical Conduct and Related Responsibilities of Employees (5 CFR 2635.101, 5 CFR 2635.703, 38 CFR 0.735-10). VHA records may only be used for VA-approved research purposes as authorized by law. VALBHS investigators must use the requested data only in a manner that is consistent with the approved research protocol for which the information was requested. Access to data is restricted to those: I) individuals named in the research protocol, on the informed consent and HIPAA-compliant authorization forms; ii) individuals who are responsible for oversight of research programs; and iii) VA investigators who require access preparatory to research if their activity meets requirements set forth in VHA policy. 102
2.
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Personally Identifiable information may not be reviewed or recorded prior to informed consent unless the IRB has granted a waiver of informed consent or the exceptions noted in sections 1A or 3(a) apply. All VHA employees must only access or use the minimum amount of information from VHA records that is necessary to fulfill or complete their official duties. No personal copies of VHA records can be maintained by VHA employees. VHA employees may not access, transmit or transport equipment, information, or software that contains VHA protected information to offsite locations without prior authorization by supervisors VHA protected information may not be electronically accessed from, or transmitted to, non-VA locations without the prior review and approval of the Information Security Officer (ISO). Hard copies with individually identifiable information must be received or stored in a manner that avoids access by unauthorized workforce members, patients, visitors, and others.
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10. Hard copies that are to be transmitted to non-VALBHS sites must be physically carried by research personnel or must be sent by Federal Express (VHA authorized carrier). If Federal Express is to deliver the hard copies to a non-VALBHS site then the signature required option must be specified. Hard copies may not be delivered to sites that have not been approved by the IRB. 11. Information obtained by VA employees in the performance of official VA duties must not be used for research purposes or publications without approval through appropriate VA authority in accordance with VHA Handbooks 1200 and 1605.1. 12. Obtaining and using medical, technical, and administrative records from other VA facilities or VA databases (national, regional, or subject specific) for R&D purposes must be in compliance with all VHA regulations and with the Standards for Privacy of Individually-Identifiable Health Information (45 CFR Parts 160 and 164; VHA Handbook 1605.1) as well as any limitations imposed by the Computer Matching and Privacy Act. The OMB guidelines 54 FR 25818 and 65 FR 77677 must be followed when conducting the automated matching of two or more systems of records (VA Handbook 6300.7). All requests that involve computer matching between databases must be reviewed and approved by the VALBHS Data Integrity Board prior to IRB approval.
13. Persons not employed by VA can be given access to medical and other VA records for R&D purposes only within the legal restrictions imposed by such laws as the Privacy Act of 1974 and 38 U.S.C. Requests for 103
such use must be submitted to the CRADO in VA Central Office at least 60 days before access is desired. Requests for information filed pursuant to the Freedom of Information Act ordinarily requires a response within 10 working days. VA guidelines and policy must be followed when making such requests to allow for a timely reply. This does not apply to those individuals having access for the purpose of monitoring the research. Obtaining and using the records must be in compliance with all VHA regulations and with the Standards for Privacy of Individually-Identifiable Health Information (45 CFR Parts 160 and 164). Individually-identifiable health information may be provided to non-VHA Investigators for research purposes provided that there is prior written authorization. If there is no prior authorization, such information, excluding 38 U.S.C. 7332 protected information, may be provided to Federal Investigators if the Under Secretary for Health, or designee has approved the research and the IRB / Privacy Board has granted a waiver of authorization. Information that is protected under 38 U.S.C. 7332 may only be disclosed under special circumstances as specified by VHA Handbook 1605.1 and must meet the security requirements of 38 CFR 1.466.
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Information disclosed via facsimile (fax) or e-mail must strictly adhere to VHA directive 6210, Automated Information Security. VHA sensitive information must be encrypted prior to any communication.
15. Any individually-identifiable information related to VHA treatment of drug abuse, alcoholism, sickle cell anemia, and testing or treatment for HIV has special protections under 38 U.S.C. 7332 and the implementing VA regulations 38 CFR 1.460-1.496. 16. The HRPP Officer or his/her designee will report to the VA Long Beach Privacy Officer, via email or telephone, any unauthorized use, loss, or disclosure of individually-identifiable patient information immediately or no later than 60 minutes after the breach/suspected breach. 17. The HRPP Officer or his/her designee will report violations of VA information security requirements to the VA Long Beach Information Security Officer, via email or telephone, immediately or no later than 60 minutes after the breach/suspected breach. 18. All media must be appropriately destroyed after information is no longer to be retained. Destroyed media must be rendered unreadable, undecipherable, and irretrievable as prescribed in the most current version of Fixed Media Sanitization (VA Memo April 20, 2004) and its attachment. Paper records must be disposed of in locked and secured collection boxes. Collection boxes must be frequently collected for 104
transfer to an approved shredding facility. Personal shredders, including cross-cut shredders do not satisfy VA requirements. C. Storage of Research Information on Electronic Devices. 1. Employees must use only computers and electronic storage media configured to use and access VA Protected Information. The following conditions apply: Passwords must be used that meet VA password requirements. Passwords or other authentication information may not be stored on remote systems unless encrypted. The save password feature must not be used for passwords that provide access to the operating system or VA network services. Blank and default user names and passwords must not be used. User credentials including passwords are considered VA sensitive information and must be protected appropriately. A shared file or drive containing VA Protected Information must not be created on a device used for remote computing. File sharing of VA Protected Information must only be accomplished through the use of authorized VA servers. VA Protected Information and VA-specific software must be segregated in dedicated directories that are protected. If VA Protected Information such as Protected Health Information (PHI), privacy information, or information that could be used by unauthorized persons to gain access to VA systems is to be stored outside the VA intranet or outside of the physical protection of VA facilities, it must be protected. Non-VA servers where VA data will reside must be certified and accredited as required by the Federal Information and Security Management Act of 2002 (FISMA).
2. Principal Investigators who intend to store research information on laptop computers or other portable electronic devices must justify the need for this method of storage and must obtain the prior approval of the IRB. 3. Data sets that are maintained on such devices must satisfy HIPAA guidelines for de-identified information (removal of 18 key elements) or must be encrypted using at minimum a 128 bit encryption algorithm. 4. For this purpose, subjects may be identified by individual codes provided that such codes may not be otherwise linked to any individually-identifiable information. Codes that utilize a subjects initials or any portion of a social security number are not acceptable. The key that links the code to any personally identifiable information must be stored only on within the VA and on VA servers. 5. Portable computers that have VA Protected Information on their storage device(s) or have software that provides access to VA private networks must be secured under lock and key when not in the immediate vicinity of the responsible employee. Portable devices must be secured with physical locks to an immovable object if the devices must be left in a meeting room or other semi105
public area to which individuals other than the authorized employee(s) have access. When traveling, employees must keep portable computers or storage devices in their possession, and not in check-in baggage. 6. Approved encryption software must be used when VA Protected Information is to be stored in a mobile environment, eg. Laptop computer, Personal Data Assistant (PDA), memory device or media etc. 7. Essential business and research data and software that is used on portable devices should be regularly copied to backup files that are maintained within protected locations on VA servers. D. Loss or Theft of Data / Information 1. When there is a loss or theft of VA research data/information or portable media, the loss/theft is reported immediately to security/police officers and to the Principal Investigator. 2. The Principal Investigator must immediately report the incident to the HRPPO. 3. The HRPPO will report the incident to: a) the IRB Chair, b) the facility Privacy Officer (PO), and the facility Information Security Officer (ISO). 4. The ISO will convene a facility response team to investigate the matter. 5. The Facility Response Team will: Determine a course of corrective action. Determine if research subjects must be notified and the content of any notification communication. Determine if Credit Protection Services may be required. Determine who will perform any notification communication and how it will be performed. Report findings and recommendations to the facility Director. 6. The Director will consult with the VISN Director, The VACO-assigned VISN Deputy Under Secretary for Health for Operations & Management (DUSHOM), or designee, before approving of any notifications to research participants. 7. The Director will arrange for an 800-number or local call line so that impacted subjects may ask questions about the incident and subsequent actions. No Notification Letters will be mailed without first obtaining DUSHOM and VHA Privacy Office concurrence. 2. APPLICABLE REGULATIONS AND GUIDELINES 5 CFR 2635.101 5 CFR 2635.703 38 CFR 0.735-10 38 CFR 16.108(b) 38 CFR 16.110 38 CFR 1.460-1.496 45 CFR 164.512(i)(2) (45 CFR 164.508 45 CFR Parts 160 and 164 VA Directive 6210 VHA Handbook 1605.1 VHA Handbook 1200 VA Handbook 6300.7 California Civil Code sections 1798.24-1708.25, 56.10-56.17 106
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PROCEDURE Investigator IRB / Privacy Board Obtain prior written authorization or a waiver of such authorization. Review submitted documents for compliance with all applicable policies and regulations.
RR 410 INTERNATIONAL RESEARCH 1. POLICY It is VHA policy that permission must be obtained from the CRADO (Chief Research and Development Officer) or designee prior to initiating any VA-approved human subjects research conducted at international sites (not within the U.S., its territories, or Commonwealths) or to VA-approved research using either human biological specimens or human data originating from an international site. NOTE: This policy applies regardless of the funding source (funded or unfunded) and to research conducted through any mechanism of support including agreements, Memoranda of Understanding (MOU), Cooperative Research and Development Agreements (CRADA), grants, or contracts. International Research for the purposes of this guidance is defined as any VA-approved human subjects research conducted at international sites (not within the United States (U.S.), its territories, or any VA-approved research using either human biological specimens or human data originating from international sites. Multi-site trials are only covered under this definition if: VA is the sponsor, VA functions as the coordinating center, VA subcontracts to a foreign site, or The principal investigator (PI) for the total project is a VA investigator Prior to the conduct of any human research falling under the definition of international research (as described above), the following is required: PI must prepare written request for permission to conduct international research following guidance from VA Central Office entitled: Requirements for International Research Involving Living Human Subjects or Requirements for International Research that Involves ONLY Human Biological Specimens or Data Derived from Persons. 107
PI must submit written request (with approval from Medical Center Director) to the CRADO, or designee and obtain permission to initiate international research subject to VHA policy. PI must notify the IRB and R&D Committee upon receipt of approval. PI must conduct research in compliance with all applicable VHA and other Federal regulations and policies including those for protecting human subjects, tissue banking, use of databases, Federal criminal laws, and the Standards of Ethical Conduct for Employees of the Executive Branch PI must inform the IRB, the R&D Committee, the ACOS R/D, ORO and other individuals or entities (as required by local policy and VHA Handbook 1058.1) of all problems that require prompt reporting to the IRB as defined in QA 903
2. APPLICABLE REGULATIONS AND GUIDELINES VHA Directive 2005-050 VHA Handbook 1058.1 3. PROCEDURE Medical Center Director Approve the request for permission to conduct international research prior to forwarding it to the CRADO for action Ensure permission has been obtained from the CRADO, or designee, for the international research prior to its initiation by an investigator at the facility Investigator Complete the request for permission to conduct international research Obtain VA Long Beach Healthcare System Directors approval on request for permission to conduct international research Obtain permission from the CRADO, or designee, that allows the initiation of international research subject to VHA policy Conduct research in compliance with all applicable VHA and other Federal regulations and policies including those for protecting human subjects, tissue banking, use of databases, Federal criminal laws, and the Standards of Ethical Conduct for Employees of the Executive Branch Inform the IRB, the R&D Committee, the ACOS R/D, 108
ORO and other individuals or entities (as required by local policy and VHA Handbook 1058.1) of all problems that require prompt reporting to the IRB as defined in QA 903. IRB Members R&D Members Receive notification indicating permission from the CRADO, or designee, to initiate international research
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RR 411 DATA SAFETY MONITORING PROCEDURES 1. POLICY All studies that have greater than minimal risk must have a research plan that includes adequate provisions to monitor the data to ensure the safety of participants. Problems that require prompt reporting to the IRB must be reported as described in section QA 903. A. Required Information. For research that involves more than minimal risk to participants, Investigators are required to provide in the research plan adequate provisions to monitor the data to ensure the safety of participants including a description of the following information with the application for Initial Review: Description of the data or events that will be captured under the monitoring plan. Description of who will gather, evaluate and monitor the data. Provide evidence of a DSMB or DSMC if such is required. Provide a summary of the functions of such a board or committee. Description of who will verify the accuracy of the data collected Description of the frequency of monitoring and how often the collected data are evaluated. Description of the triggers that will dictate when some specified action is required. Description of how interim reports will be disseminated if the study involves multiple sites. B. Monitoring Entities. Examples of monitoring entities include: Industry sponsored data monitoring committee (DMC) DSMB or a DSMC NIH sponsored cooperative group Monitoring committee formed by sponsor other than NIH Medical monitor Independent physician C. IRB Actions. The IRB will review the investigators Data Safety Monitoring Plan (provisions to monitor the data collected to ensure the safety of participants) at the Time of Initial Review. In determining the adequacy of the Data Safety Plan the IRB will: o Consider the degree of risk that is involved. o Determine that the research plan makes adequate provisions for monitoring the data to ensure the safety of participants
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o Consider the size and complexity of the study. Depending upon the complexity of the research, the plan may include assessments of data quality, timeliness, participant recruitment, accrual and retention. o Determine the reporting requirements to be imposed. These may include the timeliness of reporting and to where the reports must be submitted. Considerations will include the reporting requirements of sponsors, the FDA, and NIH. If the project is sponsored by NIH and involves gene transfer therapy, then reports must be sent to the NIH Office of Biotechnology Activities (OBA). o Consider the adequacy of the investigators plan for the detection, monitoring and reporting of adverse events, unexpected adverse events, unanticipated problems, and serious adverse events. The IRB will determine if additional safeguards are required in addition to the requirements imposed under section RR 402. o Consider whether the study is likely to be stopped earlier than anticipated. o Consider whether a DSMB may be necessary to obviate a potential conflict of interest. If there is a DSMB then copies of the plan or charter will be excerpted from the protocol and will be distributed to, and reviewed by, the convened IRB. The IRB will consider the nature of the risks, the adequacy of the monitoring procedures, and the number of subjects that are involved. The IRB will consider the qualifications of persons who are to perform the monitoring. The IRB will determine if the investigators plan is adequate to monitor the data collected to ensure the safety of participants or if additional measures are required to monitor the data collected to ensure the safety of participants. Investigator Compliance with Data Safety Monitoring Plan will be assessed at the time of Continuing Review (as described in section RR 402). In Assessing compliance the IRB will in addition to the considerations made at continuing review: o Review reports of protocol deviations, unanticipated problems that involve risks to subjects or others. o Evaluate the seriousness and frequency of the above o Review reports by the SAE Ad Hoc Chair o Review reports by the RCO o Determine if the Data Safety Plan remains adequate. The Data Safety Monitoring Plan will be reassessed if a modification is submitted that will increase the risk to subjects or others, or will alter the procedures used to monitor such risks.
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Investigators submit reports of problems that require prompt reporting to the IRB as described in section QA 903. Submitted reports are evaluated to determine whether or not they describe events or conditions that constitute an unanticipated problem that involves a risk to participants or others. This determination is made as is described in section QA 903. The SAE Ad Hoc Chair is the primary reviewer for the determinations that are described in section QA 903. D. Investigator Compliance. Investigator compliance is monitored through: Reports made by external monitors Ongoing site audits by the RCO as described in the Compliance and Quality Assurance Standard Operating Procedures. 2. APPLICABLE REGULATIONS AND GUIDELINES 38 CFR 16.111(a)(6) 45 CFR 46.111(a)(6) 21 CFR 56.111(a)(6) VHA Handbook 1200.5 3,7,10 National Cancer Institute Guideline:http://www.cancer.gov/clinicaltrials/conduction/dsm-guidelines NIH policy: http://grants.nih.gov/guid/notice-files/not98-084.html and http://grants.nih.gov.grants/guid/nitice-files/NOT-OD-00-038.html
3. PROCEDURE Investigator Submit and implement Data Safety Monitoring Plan Promptly report to the IRB problems that require prompt reporting to the IRB as described in QA 903. Collect an analyze reports from investigators Report findings to IRB Perform audits of Investigator records Report findings to IRB Review Data Safety Monitoring Plan Reassess plan if there is a change Review reports of SAE Ad Hoc Chair and RCO Determine if corrective actions are required
SAE Ad Hoc Chair
RCO IRB members
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RR 412 MULTI-SITE RESEARCH 1. POLICY A. Research Performed at Non-VALBHS sites. When the IRB reviews research conducted at multiple sites, there may be multiple IRBs involved. For example, the IRB may review research to be conducted at a nursing home, school, or company where the nursing home, school, or company has its own IRB. Alternatively, databases may be maintained that contain records from more than one site. Each Institution is responsible for safeguarding the rights and welfare of participants at their own institution. The Principal investigator has additional responsibilities if the research is to be performed at multiple sites. It is VA policy that VA facilities may not serve as the IRB of record for non-VA sites that are engaged in human subjects research. Engaged in research means that the employees or agents of the facility intervene or interact with living individuals for research purposes or obtain release or access to individually identifiable private information for the purpose of research.
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The VALBHS IRB may permit VALBHS investigators to perform research at non-VA sites that are not engaged in the research. In such cases non-VALBHS personnel may distribute approved advertising but may not solicit or refer individual subjects, perform screening evaluations, or otherwise participate in the research. Non-VALBHS personnel may obtain non-VALBHS HIPPA consent or serve to witness the signatures of research subjects but may not otherwise participate in the informed consent process. If the PI will recruit subjects, obtain data or specimens, from a non-VALBHS site then the PI must provide the following: Written agreement from the appropriate responsible official of the non-VALBHS site, that the VALBHS IRB will have authority to (a) inspect all records that pertain to the research study including the medical records of any participants; (b) observe the conduct of any VALBHS research procedures that are to be performed at the non-VALBHS site. Written agreement from the appropriate responsible official of the non-VALBHS site that the site is aware that any approval by the VALBHS IRB is limited to VA Research projects and may not be construed as approval for research that is performed by non-VALBHS personnel or institutions. Justification for the inclusion of any subjects who are not veterans. VA medical records must be created for any non-veterans and the same documentation requirements in CPRS apply as if the subjects were studied at the VALBHS. OR documentation of approval by an IRB that has authority over the non-VALBHS site. If the non-VALBHS site is under the authority of a non-VALBHS IRB, e.g. UC Irvine, then: The non-VALBHS IRB must be subject to a currently approved Federal-wide agreement. If tests or procedures are to be performed on VALBHS subjects at a nonVALBHS site, e.g. PET scans, biochemical tests, or if data or specimens from VALBHS subjects are to be transferred to the non-VALBHS site, then approval must be granted by the VALBHS IRB. Additional conditions apply (see section B below). The VALBHS investigator must be named as a co-investigator on the protocol that is approved by the non-VALB IRB. Investigators at non-VALBHS sites who have face to face contact with VALBHS subjects will be required to satisfy the same educational requirements as if they were VALBHS investigators. All requirements of the non-VALBHS IRB must be satisfied for any subjects that are recruited from, data that are obtained from, or specimens that are obtained from the non-VALBHS site. Any problems that require prompt reporting to the IRB, and that occur at the non-VALBHS site, must be reported to the VALBHS IRB as described in section QA 903. 114
The VALBHS investigator must satisfy all reporting requirements of the Sponsor and DSMB (if applicable), including the requirements for reporting adverse events and unanticipated problems. If the LBVAHS investigator is a Sponsor-Investigator then the responsibilities of a Sponsor-Investigator also apply. These include the distribution of reports of adverse events, unanticipated problems, and DSMB reports to investigators at participating sites, the FDA, and any funding agency that may be appropriate (see section IR 801). The VALBHS IRB will monitor the responsibilities of the Sponsor-Investigator and will notify any other non-VALBHS IRBs of any changes in status of the project approval. Such notifications will be from the IRB, through the COS and the Director. If the non-VALBHS site is not under the authority of a non-VALBHS IRB then the research is considered to be a VALBHS study and the VALBHS IRB assumes no authority or responsibilities other than for the research that is to be performed by VALBHS personnel. The following apply: The research will be reviewed and monitored as if it were performed at a VALBHS site. The appropriate institutional official, from the non-VALBHS site, who granted approval (see above) will be notified of any change in the approval status of the project. Such notifications will be from the IRB, through the COS and the Director. B. Research Performed at Both VALBHS and non-VALBHS sites. If research procedures are to be performed on a given subject at both VALBHS and at a non-VALBHS site then the Principal investigator must obtain the approval of all sites that will be involved. In considering the rights and welfare of research subjects, the VALBHS IRB will evaluate all procedures that are to be performed, including those at non-VALBHS sites. If the non-VALBHS site is under the authority of a non-VALBHS IRB then each site will have primary responsibility for that portion of the research that is performed at their respective sites. In ambiguous situations, e.g. in cases where data records are maintained that include information from more than one site, then the research plan that is submitted to each institution must clearly define which institution will assume responsibility for that component of the project design. In such cases, the principal investigator is still responsible for satisfying the reporting requirements of both institutions, including the requirements that apply if personal information is compromised (see section RR 409). In the event that problems arise, the respective IRBs will communicate with each other directly and will arrive at a course of action. In establishing such communications, the Human Research Protection Officer will contact that appropriate responsible authority at the non-VA site by e-mail within 10 working days of being informed of such problems and will promptly inform the non-VALBHS authority of any subsequent VALBHS IRB actions. C. VALBHS Investigators Who Have Joint Appointments. VALBHS investigators may have joint appointments with the University of California or other institutions. Such institutions, e.g. The University of California, may require that 115
research that is to be performed by investigators who hold such appointments must be reviewed by their IRB(s) if the name of the institution is to be used in presentations or publications. It is the investigators responsibility to seek such approvals. In most cases, such approvals do not entail changes to the project design or documentation. If changes are required, then these must be submitted to the VALBHS IRB as modifications.
2. APPLICABLE REGULATIONS AND GUIDELINES 38 CFR 16.114 45 CFR 46.114 21 CFR 56.114 FDA Information Sheets: Non-Local IRB Review.
3. PROCEDURE Medical Center Director Review and Communicate changes in the approval status of multi-site studies to institutional officials at non-VALBHS sites. Obtain approval from non-VALBHS sites. Distribute reports to investigators at non-VALBHS sites as required. Conduct research in compliance with all applicable VHA and other Federal regulations and policies including those for protecting human subjects, tissue banking, use of databases, Federal criminal laws, and the Standards of Ethical Conduct for Employees of the Executive Branch Inform all IRBs of all problems that require prompt reporting to the IRB as defined in section QA 903. HRPPO IRB Members R&D Members Communicate with non-VALBHS sites if problems arise that involve shared authority. Review approvals by non-VALBHS IRBs and Institutional Officials Forward changes in approval status to the COS
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EX 501 EXPEDITED REVIEW PROCESS AND DOCUMENTATION
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POLICY The expedited review process consists of a review of research involving human subjects by the IRB Chair or by one experienced reviewer designated by the Chair from among members of the IRB. IRB members are considered experienced after one year of service. The IRB Chair provides a list of those designated experienced members who can conduct expedited review to the IRB Coordinator. Research reviewed by the expedited review process will undergo the same careful review by its reviewer as one subjected to full review. All expedited reviews will be reported to the full IRB at the next convened meeting. A. Categories of Research Appropriate for Expedited Review: 1. New Studies The categories of research that may be reviewed by the IRB through an expedited review process include research activities that (1) present no more than minimal risk or discomfort to human subjects, and (2) involve only procedures in one or more of the categories listed below. Minimal risk is defined in 45 CFR 46.102(i) and 21 CFR 56.102(i) as ...the probability and magnitude of harm or discomfort anticipated in the 117
research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. This assessment should take into account both the likelihood of harm and the severity of that harm if it occurs. The categories of minimal risk research eligible for expedited review are found below (DHHS-FDA list of research eligible for expedited IRB review, November 9, 1998, FR 60364-60367 and FR 60353-60356). The activities listed should not be deemed to be of minimal risk simply because they are included on this list. Inclusion on this list merely means that the activity is eligible for review through the expedited review process when the specific circumstances of the proposed research involve no more than minimal risk or discomfort to human subjects. The categories in this list apply regardless of the age of subjects, except as noted. The categories listed pertain to both initial and continuing IRB review: (1) Clinical studies of drugs and medical devices only when condition (a) or (b) is met. (a) Research on drugs for which an investigational new drug application (21 CFR 312) is not required. Research on marketed drugs that significantly increases the risks or decreases the acceptability of the risks associated with use of the product is not eligible for expedited review. (b) Research on medical devices for which (i) and investigational device exemption application (21 CFR 812) is not required; or (ii) the medical device is cleared/approved for marketing and the medical device is being used in accordance with its cleared/ approved labeling (2) Collection of blood samples by finger heel or ear stick, or venipuncture, as restricted in: (a) from healthy, non-pregnant adults who weigh at least 110 lbs. The amounts drawn may not exceed 550 ml in an 8 week period and collection may not occur more frequently than 2 times per week. (b) from other adults and children, considering the age, weight, and health of the subjects, the collection procedure, the amount of blood to be collected, the frequency with which it will be collected. For these subjects, the amount drawn may not exceed the lesser of 50 ml or 3 ml per kg in an 8 week period and collection may not occur more frequently than 2 times per week. (3) Prospective collection of biological specimens for research purposes by noninvasive means, including: (a) Hair and nail clippings in a non-disfiguring manner. (b) Deciduous teeth at time of exfoliation or if routine patient care indicates a need for extraction. (c) Permanent teeth if routine patient care indicates a need for extraction. (d) Excreta and external secretions (including sweat). (e) Uncannulated saliva collected either in an unstimulated fashion or stimulated by chewing gumbase or wax or by applying a dilute citric solution to the tongue. (f) Placenta removed at delivery. (g) Amniotic fluid obtained at the time of rupture of the membrane prior to or during labor. (h) Supra- and subgingival dental plaque and calculus, provided the collection procedure is not more invasive than routine prophylactic scaling of the teeth and the procedure is accomplished in accordance with accepted prophylactic techniques. (i) Mucosal and skin cells collected by buccal scraping or swab, skin swab, or mouth washings. (j) Sputum collected after saline mist nebulization. 118
(4) Collection of data through noninvasive procedures (not involving general anesthesia or sedation) routinely employed in clinical practice, excluding procedures involving x-rays or microwaves. Where medical devices are employed, they must be cleared/ approved for marketing. Note: Studies intended to evaluate the safety and effectiveness of the medical device are not generally eligible for expedited review, including studies of cleared medical devices for new indications. (a) Physical sensors that are applied either to the surface of the body or at a distance and do not involve input of significant amounts of energy into the subject or an invasion of the subject's privacy. (b) Weighing or testing sensory acuity. (c) Magnetic resonance imaging. (d) Electrocardiography, electroencephalography, thermography, detection of naturally occurring radioactivity, electroretinography, ultrasound, diagnostic infrared imaging, Doppler blood flow, and echocardiography. (e) Moderate exercise, muscular strength testing, body composition assessment, and flexibility testing where appropriate given the age, weight, and health of the individual. (5) Research involving materials (data, documents, records, or specimens) that have been collected or will be collected solely for non-research purposes (such as medical treatment or diagnosis). Note: some research in this category may be exempt from VA regulations for the protection of human subjects (38CFR16.10(b)(4)). This listing only refers to research that is not exempt. (6) Collection of data from voice, video, digital, or image recordings made for research purposes. (7) Research on individual or group characteristics or behavior (including, but not limited to, research on perception, cognition, motivation, identity, language, communication, cultural beliefs or practices, and social behavior) or research employing survey, interview, oral history, focus group, program evaluation, human factors evaluation, or quality assurance methodologies. (Note: Some research in this category may be exempt from the DHHS regulations for the protection of human participants. This listing refers only to research that is not exempt.) The expedited review process may not be used where identification of the subjects and/or their responses would reasonably place them at risk of criminal or civil liability or be damaging to the subjects' financial standing, employability, insurability, reputation, or be stigmatizing, unless reasonable and appropriate protections will be implemented so that risks related to invasion of privacy and breach of confidentiality are no greater than minimal. Furthermore, the expedited review process may not be used for classified research involving human subjects. The expedited review process may not be used for procedures involving collection of samples for genetic analysis, unless collected anonymously. When an investigational device meeting NSR criteria is used in a study that also meets minimal risk criteria, the study may be reviewed by the expedited review process. NSR medical device research not meeting minimal risk criteria will be reviewed by the full IRB as described in Section 400. If the IRB reviews the research, the IRB also will make the final determination to concur or not concur with the sponsors assessment of the devices NSR or SR status. 2. Minor Changes in Approved Studies and Informed Consent Documents: 119
In some cases the Chair or his/her designee may use the expedited review process to approve minor changes to previously approved human research procedures or informed consent documents during the period for which approval is authorized. Any revision that entails any increase in risk or discomfort to the participants, or which substantively changes the study design or study procedures, must be reviewed by the full IRB at a convened meeting before the change can be implemented. The determination of whether a modification qualifies for expedited review should be made after careful consideration. Minor changes are those which, in the judgment of the reviewer: 1)do not involve the addition of procedures that involve more than minimal risk; 2) do not involve the addition of procedures that are not in categories (1)-(7) of research that can be reviewed using the expedited procedure (see IRB Reviewer Worksheet for Expedited Review); 3) make no substantial alteration in: a) the level of risk to subjects; b) the research design or methodology; c) the number of subjects enrolled in the research; d) the qualifications of the research team; e) the facilities available to support safe conduct of the research; and f) any other factor that would warrant review of the proposed changes by the convened IRB. Other cases can and should be referred for review by the full IRB at the discretion of the reviewer. When advertisements are easily compared to the approved consent document, the expedited review process may be used. When the IRB reviewer has doubts or other complicating issues are involved, the advertising should be reviewed at a convened meeting of the IRB. 3. Continuing Review, Interim and Completion Reports: Continuing Review, Interim and Completion Reports may be reviewed using the expedited review process only if: (a) the research is permanently closed to the enrollment of new subjects, all subjects have completed all research-related interventions, and the research remains active only for long-term follow-up of subjects; or (b) no subjects have been enrolled and no additional risks have been identified; or (c) the remaining research activities are limited to data analysis; or (d) for research not conducted under an investigational new drug application or investigational device exemption where other categories of expedited review do not apply and the IRB has determined and documented at a convened meeting that the research involves no greater than minimal risk and no additional risks have been identified; or (e) for research appearing on the list (section A.1 above) and determined and documented by the IRB at a convened meeting that the research involves no more than minimal risk and no additional risks have been identified. Classified research may not be reviewed by expedited review procedures at the time of continuing review. 4. Site Reviews: Sites participating in approved studies involving marketed drugs or devices which do not involve invasive study procedures, which do not put subjects at risk, or do not involve procedures inconsistent with standard care may be reviewed via expedited review. Once the IRB has approved the protocol, informed consent and established 120
requirements to determine site and investigator qualifications, the Chair or his/her designee may review individual sites. 5. Modifications in advertisements: The Chair or his/her designee may approve minor modifications to approved recruitment advertisements using the expedited review process, including changes from one medium to another (e.g. a flyer advertisement posted on a web site), if they determine that the change in medium and/or content does not significantly alter the meaning or impact of the advertisement. 7. Serious Adverse Event and Safety Reports: The Chair may review Serious Adverse Events Reports (including IND Safety Reports) by expedited review, as described in Section QA 903. 8. Serious Non-compliance and Unanticipated Problems that involve a Risk to Subjects or Others. The Chair is empowered to temporarily suspend the conduct of human research deemed to place individuals at unacceptable risk pending IRB review. The Chair is also empowered to temporarily suspend the conduct of a study pending IRB review if he/she determines that an investigator is not following the IRBs guidelines. Procedures for the Suspension of approval are described in section RA 601. 9. Translations: Translations of consent forms and other documents submitted for IRB approval may be reviewed by an expedited review process providing one of the following procedures are followed: 1) The IRB-approved consent form is translated by the sponsor or site and submitted to the IRB. The IRB will have a member or consultant fluent in the language of the consent review the translated document for accuracy. It must match the English version; or 2) The sponsor or investigator may submit the IRB-approved version of the consent to a certified translator for translation. The proof of certification is also required. B. Expedited Review Process: The Chair can require full review of any research at his/her discretion, even if the research would otherwise qualify for expedited review status. The decision to actually grant expedited review status is initially made by the Chair. If it is determined that expedited review is appropriate for a study or one of the other activities described above, and the Chair or his/her designee wishes to utilize this procedure, the Chair or designee will document his/her determination of risk. The Chair must also determine if there is any conflict of interest associated with the proposed, or continuing, project (Investigator(s) or the review process (reviewer) as described in section RR406. In the event that the Chair may have a conflict of interest then the determination will be made by the alternate IRB Chair. The review is then performed by one or more experienced voting members of the IRB designated by the Chair. A member designated to review research by expedited review should be a scientific member with at least one year of IRB experience and be qualified to serve as a sole reviewer. The Chair or designee 121
may exercise all of the authorities of the IRB, except that he/she may not disapprove the research. A research proposal may be disapproved only after review by the IRB at a convened meeting. The Chair is encouraged to use the expedited review process judiciously. If research is approved by expedited procedures, the continuing review date does not change, but remains the same as determined at the most recent review. When the expedited review process is used for any purpose, the IRB members will be informed of actions taken by the IRB Chair or designee via the IRB agenda at the next convened meeting. At that time the members will have the opportunity to further review, discuss, perform full review, disapprove, or require modifications. All expedited actions will be documented in the IRB minutes along with the expedited review eligibility category that the research meets. All decisions regarding review by expedited procedure must be communicated in writing to the investigator. When expedited review is used, the Continuing Review Deadline will be the date that a project is signed as approved by the IRB Chair or his/her designee (different than when full IRB review is used). All review requirements and approval criteria for initial and continuing review described in Sections 401, 402, 403, 601, and 602 continue to apply to research reviewed under the expedited review process.
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APPLICABLE REGULATIONS AND GUIDELINES 38 CFR 16.110 21 CFR 56.110 45 CFR 46.101 (b)(2) and (b)(3) Federal Register Vol. 63, No. 216, 11/9/98, pp. 60353-60356 45 CFR 46.110
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PROCEDURE IRB Coordinator Review new submissions requesting expedited review with the Chair to determine if they qualify for expedited review. Prepare and distribute summary of expedited review actions to IRB members at next convened meeting. Document discussions of actions in minutes. IRB Chair or designee Confirm and approve determination that submission qualified for expedited review on Expedited Review Determination form. Make and document determination of minimal risk research. Designate an appropriate IRB member (including self) to conduct the expedited review. Conduct review (including protocol, informed consent 122
Designated Reviewer
form) and document on Expedited Review Criteria Worksheet 4. ATTACHMENTS Expedited Review Criteria Worksheet
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RA 601 CATEGORIES OF ACTION 1. POLICY The IRB has the authority to take one of the actions outlined below after reviewing a research proposal. Except when the expedited review process is used, these actions will be taken by a vote of a majority of the regular and alternate members present, except for those members present but unable to vote in accordance with IRB's conflict of interest policies. A. Categories of Action: 1) Approval: The protocol and accompanying documents are approved as submitted. The standard conditions of approval, as described in Section 602C will be clearly stated in the approval letter. If the conditions of the approval are not met, approval may be withdrawn. 2) Modification Required to Secure Approval (conditional approval): Minor modification of, addition to, or clarification of a research plan or accompanying document is required. Required changes will be voted upon during the IRB meeting, as well as the terms of approval. The IRB will determine at that time whether the modifications will be reviewed at a convened meeting, or whether they can be approved using an expedited review process, using criteria described in Section 501. The investigator will be informed in writing of the required changes and requested information and must provide the IRB with the changes or information. If the modifications are to be reviewed via expedited review, the Chair, the primary reviewer or another member designated by the Chair will review the modifications and confirm that the required changes have been made on behalf of the IRB. The modifications may then be approved, or additional review by the full IRB may be required. The approval or the Chair, or designee, must be documented in the minutes of the first IRB meeting that takes place after the date of the approval. The date of approval is the date the fully convened IRB approved the protocol rather than the date that the minor changes were approved by the IRB, Chair,or designee. Subjects must not be recruited into the study until IRB approval has been issued and the approval of R&D and any other required institutional committees has also been given. Contingent approval of research without subsequent review by the convened IRB of responsive material may occur only: when the convened IRB stipulates specific revisions requiring simple concurrence by the investigator or if the IRB Chair or another IRB member designated by the Chair may subsequently approve the revised research protocol on behalf of the IRB under an expedited review procedure. 3) Table: Significant questions are raised by the proposal requiring its reconsideration after additional information is received from the investigator and/or sponsor. For research that the IRB approves contingent upon substantive modifications or clarifications to 124
the protocol or informed consent, IRB approval must not occur until subsequent review by the convened IRB of the materials the PI submitted. 4) Disapproval: The proposal fails to meet one or more of the criteria used by the IRB for approval of research. Disapproval cannot be given through the expedited review process and may only be given by majority vote at a convened meeting of the Board. Projects may also be disapproved that have been inactive (no work done or planned and no subjects enrolled) for an extended period. In such cases the investigator will be notified that the project must be closed unless corrective action has not been taken. Notifications will specify: that no subjects may be enrolled into the study until IRB approval has been given. any other actions that the IRB requires in order to protect the safety and welfare of the participants. any actions that the investigator must take in order to retain approval of the project. a deadline for the completion of such actions. If the required actions are not completed prior to the stated deadline, then the IRB, or the IRB chair acting on behalf of the IRB, will determine and implement a plan for the closure of the study. 5) Suspension or termination: The IRB has the authority to suspend or terminate approval of research that is not being conducted in accordance with the IRB's policies or that has been associated with unexpected harm to subjects. The IRB chair has the authority to temporarily suspend approval of research as is described in section 501. Actions taken by the IRB chair must be reported promptly to the full IRB. Such reports must be no later than the next scheduled meeting of the convened IRB. Actions that may result in a suspension or termination include but are not limited to: Unanticipated problems that involve risks to subjects or others. Serious or Continuing Non-compliance Failure to Obtain appropriate Informed Consent Change in risks in relation to benefits If IRB approval is suspended or terminated the following apply: Enrollment for new subjects cannot occur. Continuation of research interventions or interactions in already enrolled subjects should only continue when the IRB or IRB Chair, in consultation with the Chief of Staff finds that it is in the best interest of individual participants to do so.
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Once notified of the IRB action, the principal investigator must immediately submit to the IRB Chair, a list of research subjects for whom suspension or termination of the research would cause harm. The IRB Chair, with appropriate consultation with the Chief of Staff, determines if the subjects participation may continue. If the study is FDA-regulated, the Chief of Staff and IRB Chair must follow FDA requirements in 21 CFR 56.108(b)(3) in making their decision. The sponsoring agency, private sponsor, Office of Research and Development, Office of Research Oversight, or other Federal agencies must be informed, as appropriate. If approval is suspended, IRB review and approval must occur prior to reinitiation of the research.
Other procedures that are invoked in the event of Suspension or Termination include: The procedures for the reporting, evaluation, and required actions that are associated with such conditions are described in section QA 903. The procedures for notification of Principal Investigators, and required action by Principal Investigators, are described in section RA 602. The procedures for appeal of IRB decisions are described in section RA 602. The procedures for the reporting of Suspensions and Terminations to Institutional Officials and External Agencies are described in section RA 604.
B. Consequences of Actions: If the IRB, or the IRB chair, take any of the above actions, other than approval, then the IRB, or the IRB chair acting on behalf of the IRB, will determine if subjects are currently enrolled in the study that is under review. If subjects are enrolled the IRB will: Consider actions to protect the rights and welfare of currently enrolled participants. Consider whether the procedures for withdrawal of enrolled participants ensure the rights and welfare of the participants. Consider whether participants need to be informed of the action. Require that any subsequent adverse events or outcomes, that may possibly be study related, continue to be reported to the IRB.
C. Approval and Continuing Review Dates: 126
IRB approval is effective as of the date of signature of the approval letter by the IRB Chair, indicating that all modifications requested during initial review, if any, have been made. This is the IRB Approval Date. IRB approval, as well as approval of the Safety Subcommittee, and other appropriate institutional committees is required before the research can go forward to the Research and Development Committee for review. All proposed research involving human subjects must be reviewed and approved by the Research and Development Committee prior to the initiation of the research project and enrollment of subjects The approval period will expire exactly one (1) year from the date of the most recent convened IRB meeting at which the project was reviewed (not 1 year from the IRB approval date), unless a shorter period is specified by the IRB during its review of the application. If the project was reviewed at several meetings, the date of the last convened meeting at which the project was reviewed will be used. This is the Continuing Review Deadline. Beyond this date, study approval lapses and a study cannot continue. When a project undergoes continuing review, the new Continuing Review Deadline is set to one year after the date of the most recent review of the study at a convened IRB meeting. However, OHRP permits the IRB to re-approve the research up to 30 days prior to the continuing Review Deadline and still maintain the same date for the Continuing Review Deadline. Study modifications are effective as of the date of signature of the approval memo by the IRB Chair after either expedited or full committee review. D. Approval and Documentation: The IRB will document that the criteria for approval of the project (in Section 403) and the informed consent documents (in Section 701) have been discussed at the meeting and that the criteria have been met. This will be documented in the meeting minutes, reviewer worksheets, and other sources. The results of IRB review and actions taken by the IRB will be communicated to the R&D Committee, the investigator, and institutional officials in writing and in a timely manner. Along with written notification of approval, a copy of the approved consent form containing the stamped approval and date of the approval on each sheet must be sent to the investigator and must be filed in the protocol files maintained by the research office. 2. APPLICABLE REGULATIONS AND GUIDELINES 21 CFR 56.110(b) 38 CFR 111 21 CFR 56. 111 ICH 3.1.1 45 CFR 46. 110(b) ICH 3.3.9 45 CFR4 46. 111 VHA Directive 2001-028 38 CFR 16. 110 (b)
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PROCEDURE IRB Coordinator Document all member votes (for, against, abstaining, 127
recused) in the minutes. Summarize relevant discussions in the minutes, in particular, decisions to disapprove or to modify the research. Summarize in detail, all controverted discussions and their resolution. Conduct voting process for each submission. Review submitted changes for completeness and complete approval by Expedited review process.
IRB Chair
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RA 602 INVESTIGATOR NOTIFICATION OF IRB ACTION
1.
POLICY Investigators will be notified in writing of the IRBs decisions and the reason(s) for the decisions within 5 working days after the meeting. IRB communications to Investigators are prepared by the IRB Coordinator and are reviewed and signed by the Chair of the IRB. A. Notification of Approval: The IRB approved consent form will be dated with the period of approval and supplied to the investigator with the approval. The approval letter will state the investigators responsibilities that are standard conditions of approval, plus any other specified conditions. Standard investigator responsibilities are summarized in section IR 801: B. Continuing Reviews and Revisions: Investigators will be notified in writing as soon as possible as to the action taken by the IRB for any continuing reviews or revisions. C. Notification that Modifications are Required to Secure or Continue Approval: The investigator will be provided a precise description of the modifications required by the IRB to achieve approval. It will be clearly stated that the study is not approved. The IRB must receive the investigators response within 90 days of the date of notification. However, this period may be extended if the investigator communicates a need for an extension. D. Notification of Disapproval: Disapproval correspondence will provide the reason(s) for disapproval, and instructions to the investigator for appealing this decision. E. Non-Compliance: If the IRB has determined that serious or continuing noncompliance has occurred, or that a study must be suspended of terminated, the procedure in RA 601 CATEGORIES OF ACTION will be followed. The investigator will be notified by telephone within 24 hours of its meeting and in writing within 3 working days. In all other cases, the results of IRB Review will be communicated in writing within 5 working days. A response from the investigator specifying corrective actions will be required within 10 working days of notification. The response should include a formal corrective action plan, the actions to be taken, responsibility, and when the actions will be effective. In all cases, the study sponsor and appropriate state and federal authorities will also be notified in writing of the action being taken by the IRB in accordance with RA 604 REPORTING TO REGULATORY AGENCIES AND INSTITUTIONAL OFFICIALS. An investigator may appeal the decisions of the IRB within 90 days of receiving notification of the action. The IRB will make available to the investigator, in writing, the reasons for its actions and any sanctions imposed. Appeals will be submitted in writing 129
to the IRB Coordinator. The investigator will submit clarification, modifications, additional references, consultants' reports, or other material to support his/her case. The appeal will then be reviewed by the full IRB at a convened meeting. After considering the investigator's response, the Committee's findings will be submitted as final. F. Investigator Appeal of IRB Action: An investigator may appeal the decisions of the IRB, including study disapproval, protocol revisions, or informed consent form revisions within 90 days of receiving notification of the disapproval or action. The IRB will supply the investigator, in writing, with its reasons for disapproval or for requiring changes. The investigator will then have the option to appeal the decision(s). Appeals will be submitted in writing to the IRB Coordinator. The investigator will submit clarification, modifications, additional references, consultants' reports, or other material to support his/her case. The investigator may attend the meeting to present his/her appeal and answer questions at the discretion of the IRB, but may not be present during deliberation or voting. Appeal of the disapproval of a study and appeals of other IRB actions must be reviewed by the full IRB at a convened meeting. The IRB will re-review the study as during initial review and approve, require modifications to secure approval, or disapprove the modified study, considering all required review criteria and the prior reasons for disapproval. If the appeal is denied and the study disapproved, the institution cannot override the IRBs decision. The IRB may consider subsequent requests for re-review if the investigator has made significant changes to the study or has significant new information to present.
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APPLICABLE REGULATIONS AND GUIDELINES 21 CFR 56. 115(a)(4) VA Handbook 1200.5 21 CFR 56.108(a)(1) 38 CFR 16. 109 (d) 45 CFR 46.109 (d) 21 CFR 56. 109(b, c, e)
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PROCEDURE IRB Coordinator Maintain file of all investigator correspondence Distribute decision correspondence within 5 working days of the IRB meeting date Provide investigator responses to the Chair in a timely manner and file in study folder
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RA 603 REPORTING RELATIONSHIPS 1. POLICY The IRB has important relationships with the R&D Committee, executive management, federal regulatory agencies, and other committees and individuals within the institution to which it is accountable. This section described those relationships and reporting requirements, which are derived from federal regulations and guidance, VA policy and local policy. The principal mechanism of IRB reporting is through the R&D Committee. IRB activities are normally reported from IRB to R&D Committee, and to the Medical Center Director through the ACOS/R&D. For research under an FDA-regulated product, the normal reporting responsibilities are from investigator to sponsor to FDA, and from investigator to IRB. Reporting of IRB activities to OHRP, ORO, and other outside agencies generally occurs through the ACOS/R&D by the Medical Center Director. However, direct reporting by the IRB is not to be discouraged if it is appropriate and notification is made to institutional officials and committees as required. A. Research and Development Committee: The R&D Committee provides the overall oversight of the HRPP and the activities of the IRB to assure regulatory compliance. Generally, this is exercised by review and approval of the IRB actions, minutes, policies and periodic reports. Actions of the IRB and IRB Chair are communicated to the R&D Committee through several mechanisms: 1. All IRB meeting minutes will be reviewed and discussed at R&D Committee meetings, and any R&D Committee concerns communicated back to IRB as an agenda item at the next scheduled IRB meeting; 2. The IRB Chair will have regularly scheduled meetings, at least monthly, and additional ad hoc communication with the R&D Chair; 3. The IRB Chair or other IRB member selected to be a member of the R&D Committee will verbally communicate with the R&D Committee at their meetings. 4. Reports or correspondence to or from outside agencies by the IRB will be provided to the R&D Committee, which will determine whether any additional notifications are necessary. 5. R&D Committee actions will be communicated to the IRB Chair through R&D Committee minutes and direct communication between the Chairs. 6. The R&D Committee will receive reports of QI activities and a program evaluation of the HRPP. B. Associate Chief of Staff for Research and Development (ACOS/R&D): The ACOS/R&D has overall responsibility for the entire research program at VALBHS including the implementation of the HRPP. The ACOS/R&D is responsible for reviewing and evaluating actions and reports of the R&D Committee and its subcommittees including the IRB, compliance, quality assurance and quality improvement activities, and other responsibilities. Day to day operation of the HRPP is delegated to the HRPP 131
Officer who reports directly to the ACOS/R&D. The ACOS/R&D maintains communication with the IRB in the following ways: 1. Meets regularly with the IRB Coordinator and the IRB Chair regarding the program. 2. Reviews minutes of IRB and R&D Committee and provides feedback to their Chairs. 3. Attends IRB meetings as a guest when appropriate (Section 301). 4. Reviews audits and quality assurance reports and makes recommendations for improvements or changes in IRB procedures as needed. C. Medical Center Director: As the signatory official to the institutions FWA, the Medical Center Director is ultimately responsible for overseeing the protection of human subjects within the facility. This includes: 1. Fulfilling all educational requirements mandated by VA ORD, the facilitys assurance, funding institutions, and OHRP. 2. Developing and monitoring procedures to assure the safety of subjects in research either directly or by delegating the responsibility to other qualified VA staff. 3. Ensures that adequate administrative support, including personnel and space sufficient to provide privacy for conducting sensitive duties and storage of records, is provided for IRB activities. 4. Provides appropriate educational opportunities for IRB members and staff, and for researchers. 5. Meets regularly with the ACOS/R&D concerning all aspects of Research. 6. Reviews and approves all IRB and R&D Committee minutes and receives notification of the specific IRB actions described in section D below. The Director attends IRB meetings as needed. 7. Oversees both the IRB and all VA investigators (compensated, WOC, or IPA); 8. Assures that IRB members and investigators are appropriately knowledgeable to conduct research in accordance with ethical standards and all applicable regulations, including the development and implementation of an educational plan for IRB members, staff and investigators. 9. Provides reports to outside agencies as are required by Subparagraph D, below. D. Reporting to Outside Agencies: Procedures for reporting to outside agencies are described in section RR604. E. Sponsor-Investigator-IRB Interrelationship: The interrelationship and interaction between the research sponsor, investigator and the IRB may be very complex. Customarily the clinical investigator provides the communication link between the IRB and the sponsor. Direct sponsor-IRB contact is not forbidden, and may be useful to facilitate resolution of concerns about study procedures, specific wording in an informed consent document, or to verify information reported by an investigator. The investigator should be kept apprised of such interactions. 132
F. Other Institutional Committees: Projects reviewed by the IRB are reviewed in parallel by the other subcommittees of the R&D Committee as appropriate. However, the IRB may require projects to be reviewed and approved by other R&D or Medical Center committees such as the Radiation Safety Committee or the Biosafety Subcommittee, or by an ad hoc reviewer as a condition for approval.
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APPLICABLE REGULATIONS AND GUIDELINES VA Handbook 1200.5 FDA Information Sheet #4 VHA Handbook 1050.1 VALBHS MPA VHA Handbook 1058.1 VALBHS MPA, Appendix D 21 CFR 312.64(b) 21 CFR 812.150 38 CFR 16 45 CFR 46
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PROCEDURE IRB Coordinator Provide minutes, memoranda and other correspondence between IRB and R&D Committee, ACOS/R&D, and Director. Maintain regular communication with R&D Committee and their Chair. Provide notification to Director and to outside agencies, as appropriate. Provide notification to outside agencies, as appropriate.
IRB Chair ACOS/R&D HRPP Officer Medical Center Director
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RA 604 REPORTING TO REGULATORY AGENCIES AND INSTITUTIONAL OFFICIALS 1. POLICY This policy is invoked whenever: There has been a change in the status of the Federal Wide Assurance or IRB of record including notification of changes in institutional officials, IRB chair/membership, or contact staff. Changes in Memoranda of Understanding about shared responsibilities in the HRPP with other VA organizations or with UCI must also be reported. The IRB has taken a substantive action that materially alters the substance and meaning of a protocol, informed consent form or process, or investigator status, including, but limited to, restriction, suspension, or termination of a study or investigator participation, and actions taken to prevent future occurrence(s) of an adverse event in research. Not included in this category are discontinuations of projects that occur solely for the reasons of a lapse of review within the approval period. A problem is determined to represent an unanticipated problem involving risks to participants or others Non-compliance is determined to be serious or continuing There is a change in IRB membership or MPA signatory officials. Such changes must be reported promptly to OHRP and ORD. These will include any incidents or situations that have actually occurred but will also include any situations in which an adverse event in research has not actually occurred, but that the IRB has determined would have been likely to occur without preventative measures. A. Preparation of the Report: 1. Responsibility for Report Preparation. The HRPPO, or designee, will prepare the report. 2. Content of the Report. Reports to ORO. Reports will be written, and will follow the format described for VA form 10-0420. VA forms are available on the internet at http://www.va.gov/vaforms/search_action.asp. Changes in IRB membership or MPA signatory officials. Changes will be reported as is described in sect ion QA 902. Other Reports. Other reports will follow OHRP guidance and will specify: o The nature of the event (Unanticipated problem involving risks to participants or others, serious or continuing non-compliance, suspension or termination of approval of research). o Name of the institution conducting the research. o Title of the research project and/or grant proposal in which the problem occurred. 134
o Name of the principal investigator on the protocol. o Number of the research project assigned by the IRB and the number of any applicable federal award(s) (grant, contract, or cooperative agreement). o A detailed description of the problem including the findings of the organization and the reasons for the IRBs decision. o Actions the institution is taking or plans to take to address the problem (e.g., revise the protocol, suspend subject enrollment, terminate the research, revise the informed consent document, inform enrolled subjects, increase monitoring of subjects, etc.) o Plans, if any, to send a follow-up or final report by the earlier of: a. A specific date. b. When an investigation has been completed or a corrective action plan has been implemented. B. Review and Approval of the Report. All Reports will be reviewed and approved by the Chair of the IRB. All Reports will be reviewed and approved by the Director, or designee. C. Distribution of the Report. VALBHS Officials and Committees. The HRPPO, or designee, will distribute reports to the following VALBHS officials and committees: o The VALBHS Privacy Officer (if the report involves unauthorized use, loss, or disclosure of individually identifiable patient information). o The VALBHS Information Security Officer (if the report involves violations of information security requirements of that organization). o The RCO o The IRB o The R&D committee o The ACOS R&D o The Director VALBHS, or designee External Agencies and Officials. The Director, or designee, will send the report to the following external officials and agencies, as appropriate: o OHRP o Office of Research & Development o VAORD o VA VISN22 o VA ORO Western Region o The appropriate designee of the funding department or agency (if the study is funded by such an agency). o The appropriate designee of the sponsoring company or organization (if the study is supported by such an agency). o The FDA (if the study is subject to FDA regulations). 135
o VA ORO Central Office (if there is a change in the status of the Federal wide Assurance or IRB of record including notification of changes in institutional officials, IRB chair/membership, or contact staff. Changes in Memoranda of Understanding about shared responsibilities in the HRPP with other VA organizations or with UCI must also be reported. Reporting is not required if the problem occurred at a site that was not subject to the direct oversight of the organization, or the agency has been notified of the event by other mechanisms. D. Timeline for Report Distribution. The HRPPO will ensure that all steps of this policy will be completed within 15 days of the initiating action. For more serious actions, the HRPPO will expedite reporting. Some Reports to ORO Western Region have special requirements. These include: o Reports of Substantive Actions must be reported within 10 working days of the IRBs determinations to take such action. o Unexpected Deaths must be reported within 24 hours after the IRB determines that the death was unexpected. If the IRB is unable to determine whether a research subjects death was unexpected after 10 working days of being informed of a death, the death must then be reported. When a final determination is made as to whether or not the death was unexpected, a follow-up report must be made to the ORO regional office. o If the report involves an adverse event then copies of all IRB minutes from meetings in which the adverse event in research and subsequent actions were discussed, ratified, or summarized will be sent to the ORO regional office as soon as these are available, but in no case later than 4 weeks after the IRB meeting. The Medical Center Director, or designee, will inform the VISN22 office of all reports that are made to the ORO regional office.
2.
APPLICABLE REGULATIONS AND GUIDELINES VA Handbook 1200.5 Section 7.c.13 FDA Information Sheet #4 VHA Handbook 1050.1 VALBHS MPA VHA Handbook 1058.1 VALBHS MPA, Appendix D 21 CFR 56.108(b) 21 CFR 312.64(b) 21 CFR 812.150 38 CFR 16 45 CFR 46
3.
PROCEDURE 136
IRB Coordinator
IRB Chair HRPP Officer Medical Center Director
Provide minutes, memoranda and other correspondence between IRB and R&D Committee, ACOS/R&D, and Director. Maintain regular communication with R&D Committee and their Chair. Prepare and Distribute Reports Provide notification to outside agencies, as appropriate.
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IC 701 INFORMED CONSENT REQUIREMENTS AND DOCUMENTATION 1. POLICY No investigator may involve a human being as a subject unless he has obtained legally effective informed consent from the subject or the subject's legally authorized representative, or if the conditions for waiver of consent have been met. Consent will be sought only under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence. The information (whether oral or written) should be provided in language that is understandable to the subject or representative. The informed consent, whether oral or written, will not contain any exculpatory language through which the subject or representative is made to waive or appear to waive any of the subject's legal rights, or releases or appears to release the investigator, the sponsor, the institution, the sponsor or its agents from liability for negligence. The informed consent requirements in this policy are not intended to preempt any applicable Federal, State, or local laws which require additional information to be disclosed in order for informed consent to be legally effective. The IRB should be aware of who will conduct the consent interview as well as be informed of such matters as the timing of obtaining informed consent and of any waiting period (between informing the subject and obtaining the consent) that will be observed. For tissue banking or repository activities, the IRB makes determinations concerning the informed consent process for research using such samples A. General Requirements for Informed Consent: In recruiting a human being to become a subject in a research project, the investigator responsible for the project is required to obtain a legally effective informed consent of the candidate-subject, or the candidate's legally authorized representative (except in cases where the documentation of informed consent is waived by the IRB). Informed consent process shall precede any involvement of the subject in the research. The informed consent process and the associated documents to be used in the research project must be reviewed and approved by the IRB. A basic principle of human subject research is that a subject decides to participate in the research voluntarily after being fully informed of what the research entails and what its risks and benefits are. The investigator has the obligation to assure that the subject or the subject's legal representative is fully informed about the research (by presenting the information in writing as well as orally) at a level the information can be understood readily, and by responding to any questions the subject may have, based on which the consent to participate is received. Federal regulations mandate that, whenever informed consent of the research subject is required, a written document must be prepared. The regulations anticipate that there will also be an oral exchange of information between the investigator and the subject in the process.
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B. Types of Informed Consent: Research Investigators shall be responsible for assuring that informed consent is documented by use of a written consent form approved by the IRB that is signed and dated by the subject or the subject's legally authorized representative except in cases where the documentation of informed consent is waived by the IRB. There are two basic formats of the informed consent form are used at VALBHS: the Standard Written Informed Consent document and the Short Form Written Consent document. VA Form 10-1086, or an approved electronic equivalent, shall be used to document informed consent, regardless of the format utilized. The consent form may be either of the following: 1. Standard Informed Consent - A consent document that embodies the elements of informed consent described in 21 CFR 50.25 and VHA 1200.5. This form may be read to the subject or the subject's legally authorized representative, but, in any event, the investigator will give either the subject or the representative adequate opportunity to read it before it is signed. Both the information and documentation of consent sections are incorporated into this comprehensive informed consent document. Following administration of the consent process, the consent document must be signed and dated by: a. the subject or the subjects legally authorized representative, and b. the person who has administered the consent, and c. a witness to these signatures. If the sponsor or IRB required a witness to the consenting process in addition to the participants signature and if the same person needed to serve both capacities, a note to that effect must be placed under the witnesss signature. A copy of the signed and dated consent document must be given to the participant or the participants legally authorized representative. This is the preferred and standard method of consent process. 2. Short Form Informed Consent - A "short form" consent document stating that the elements of informed consent as required above have been presented orally to the subject or the subject's legally authorized representative. The short form consent document may be approved by the IRB only if the risks of the research are no more than minimal and no vulnerable subject groups are involved. This method it is far more cumbersome than the standard method and its use is discouraged. In this method of informed consent process, the information section is separated from the documentation section. Both sections are to be prepared in writing. The information section may be concise and in the form of a summary, but shall include the essential and the appropriate additional elements. The information is intended to be provided orally to the subject or the subject's legally authorized representative; nevertheless, a copy of the written information section shall be given to the subject. The separate written documentation section shall be executed by affixing appropriate signatures. The process requires the involvement of an impartial witness to the consent-process, as described below in section G. The following steps are required: 139
a. Written summary of what is to be said to the subject or the representative (information section). b. Oral presentation of the contents of the written information section to the subject or the subject's legally authorized representative, in the presence of a witness (third-party). c. Short-form written documentation, stating that the information on the research (elements of informed consent) has been presented orally to the subject or the subject's legally authorized representative, and that consent has been received. d. Subject or the representative shall sign and date only the short form documentation section. e. Impartial Witness shall sign and date both the short form documentation section and information section. The signature must be identified as that of an Impartial Witness. f. Investigator (or designate) obtaining consent shall sign a copy of the information section. g. A copy of the information section and a copy of the documentation section shall be given to the subject or the representative. In summary, when this method is used, there will be an impartial witness to the oral presentation. The IRB will approve both the written summary of what is to be said to the subject or representative (information section) and the documentation section. Only the short form documentation section is to be signed by the subject or the representative. However, the witness will sign both the short form and a copy of the written summary, and the person actually obtaining the consent will sign a copy of the summary. A copy of the summary will be given to the subject or the representative in addition to a copy of the short form. A second copy shall be filed in the subjects medical record. The originals shall be placed in the Investigators research records. C. Required Elements of Informed Consent Forms: In accordance with 21 CFR 50.25, 38 CFR 16.116, 45 CFR 46.116 and VA Handbook 1200.5, the following information will be provided to each subject: 1. The name of the study. 2. The name of the Principal Investigator (PI). 3. A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental. 4. A description of any reasonably foreseeable tangible or intangible risks or discomforts to the subject including for example, Privacy risks (legal, employment, and social). 140
5. A description of any benefits to the subject or to others that may reasonably be expected from the research. 6. A disclosure of appropriate alternative procedures or courses of treatment, if any, which might be advantageous to the subject. 7. A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained. 8. For research involving more than minimal risk, an explanation as to whether any compensation, and an explanation as to whether any medical treatments are available, if injury occurs and, if so, what they consist of, or where further information may be obtained. 9. Accurate information about the availability of compensation and/or treatment for injury occurring in the research that it reviews, including a statement that veteransubjects will receive medical care and treatment for injuries suffered as a result of participating in a VA research program. (Any statement that compensation is not offered must avoid waiving or appearing to waive any of the subjects rights or releasing or appearing to release the investigator, sponsor, or institution from liability for negligence.) 10. An explanation of whom to contact for answers to pertinent questions about the research and research subjects' rights, and whom to contact in the event of a researchrelated injury to the subject. * 11. A statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled. 12. A statement that the subject will not be required to pay for treatment received as a subject in a VA research program. 13. For research involving more than minimal risk, a statement that the subject will receive medical care and treatment for injuries suffered as a result of participating in a VA research program at no cost, in accordance with Federal law. As a matter of local policy, this applies to research subjects that are non-veterans as well as to veterans. In addition, information on the responsibility of the research's sponsor for research-related injury must be included, if other than the VA. This policy does not apply to research conducted for VA under a contract with an individual or a non-VA institution, and this fact must be disclosed in the consent form where applicable. 14. If the research involves products regulated by the FDA or will be used to support applications for products regulated by the FDA (including a drug with an IND or a medical device with an IDE), a statement that the FDA may choose to inspect and copy medical or research records that identify the individual as a subject of the investigation. 141
15. A statement describing the extent to which confidentiality of records identifying the subject will be maintained. If appropriate, indicate which entities or federal agencies may have access to the records, e.g. ORO, OHRP, GAO. All informed consent forms should be written at a level appropriate for the potential population. Use of the second person is preferred. General formatting, readability and clarity must be acceptable and medical terminology must be defined. *This meets the VA requirement that the ICF include information about where and how a veteran could verify the validity of a study and authorized contacts. D. Additional Elements Of Informed Consent: The following additional elements are generally required unless it is clear that they are not applicable: 1. A statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus if the subject is or may become pregnant) that are currently unforeseeable. 2. Anticipated circumstances under which the subject's participation may be terminated by the investigator without regard to the subject's consent. This is required if the participation will involve more than one day. 3. Any additional costs to the subject that may result from participation in the research, with consideration of Federal laws concerning veterans' eligibility for medical care and treatment. 4. The consequences of a subject's decision to withdraw from the research and procedures for orderly termination of participation by the subject. This is required if it is anticipated that there be such consequences. 5. A statement that significant new findings developed during the course of the research which may relate to the subject's willingness to continue participation will be provided to the subject. This is required if the participation will involve more than one day. 6. The approximate number of subjects involved in the study must normally be stated. The number that is specified on the consent document may be the number who are to be entered rather than the number that the IRB has approved for enrollment as is described in section RR 401 (1.A). 7. If biological materials will be retained after the end of the study, additional information pertaining to the storage and use of these materials for research, as described in Section 703 and the VHA Handbook on Banking of Human Biological Specimens. If genetic testing is to be done, VA and IRB requirements pertaining to genetic testing must also be met. The consent process must not communicate that specimens are donated. 142
8. A statement that the human biologic specimens obtained could be part of or lead to the development of a commercially valuable product, if the investigators believe that this could occur. 9. The amount of payment, if any, the subject is to receive, and the schedule of payment. Any time payment is made, this will always be in the consent form. 10. A description of any financial or other arrangements with a sponsor or institution that may pose a conflict of interest. 11. Any additional information that may be required by state, federal, VA and/or other Federal regulations in order for informed consent to be legally effective. 12. Additional information that, in the judgment of the IRB, would add meaningfully to the protection of the rights, safety, and/or well being of the subjects. E. Waiver or Alteration of Requirement for Informed Consent: For studies involving products regulated by the FDA under an IND or IDE, waiver of written informed consent is not permitted. For other studies, the IRB may approve a consent procedure which does not include, or which alters, some or all of the elements of informed consent set forth in this section, or may waive the requirements to obtain informed consent provided the IRB finds and documents that: the research involves no more than minimal risk to the subjects, the waiver or alteration will not adversely affect the rights and welfare of the subjects, the research could not practicably be carried out without the waiver or alteration, and when ever appropriate, the subjects will be provided with additional pertinent information after participation. Waiver is possible if all four elements are present and documented, and the IRB approves the waiver or alteration. The IRB may require the investigator to provide subjects with oral or written information about the research. The IRB will document in the minutes its specific findings that conditions permitting waiver or alteration have been met. F. Documentation of the Informed Consent: 1. Except as provided by subparagraph E, above, informed consent must be documented by the use of a written consent form approved by the IRB and signed by: the subject or the subjects legally-authorized representative, a Witness (or Impartial Witness, if required). If the sponsor, or IRB, requires a witness to the consenting process in addition to the witness to the signature then the same person must serve both capacities and a note to this effect must be placed under the witnesss signature line. the person obtaining the informed consent. 2. The consent form must be the most recent IRB-approved consent form. The approval must be documented by the use of a stamp or pre-printed on each page of the consent 143
form that indicates the date of the most recent IRB approval on the form. Both the IRB, and investigator, must maintain copies of all approved forms in their records. 3. The original signed consent form must be filed in the subjects case history and a copy must be filed in the medical record. 4. A copy of the signed consent form must be provided to the subject or the subjects legal representative. 5. A progress note documenting the informed consent process must be entered into CPRS. At a minimum, the progress note must include: the full name of the study as specified on the IRB application. the person obtaining the informed consent. a statement that the study was explained to the subject. a statement that the subject or the subjects legally-authorized representative was capable of understanding the consent process. a statement that the subject was given the opportunity to ask questions. a statement of the duration of the subjects expected participation. 6. A progress note must also be entered into CPRS that documents when the subjects participation is completed.. This note may be omitted if the duration of the subjects participation is limited to one visit or if the duration of participation is indefinite, e.g. implanted device studies. G. Waiver of Documentation of Informed Consent: 1. Consent Document: The IRB may waive the requirement for the investigator to obtain a signed consent form for some or all subjects, if it finds either: that the only record linking the subject and the research would be the consent document, and the principal risk would be potential harm resulting from a breach of confidentiality. Each subject will be asked whether the subject wants documentation linking the subject with the research, and the subject's wishes will govern; or that the research presents no more than minimal risk of harm to subjects, and involves no procedures, for which written consent is normally required outside of the research context. In cases where written documentation of informed consent is waived, the IRB may require the investigator to describe verbal scripts or other information provided to patients. The IRB may require the investigator to provide subjects with a written statement containing information about the research and appropriate elements of informed consent. The IRB will document in the minutes its specific findings that conditions permitting waiver or alteration have been met. d. Flagging a Medical Record: The IRB needs to determine if the patients medical record (electronic or paper) must be flagged to protect the subjects safety by indicating the subjects participation in the study, and the source of more information on the study. The IRB may not want to require the medical record to be flagged if: 144
The subjects participation in the study involves: Only one encounter Only the use of a questionnaire, or The use of previously collected biological specimens The identification of the patient as a subject in a particular study (if the study is not greater than minimal risk) would place the subject at greater than minimal risk
H. Conduct of the Informed Consent Process: The principal investigator and investigative staff have a responsibility to conduct the informed consent process in accordance with the policies in this manual. During initial and continuing review, the IRB will attempt to determine the extent to which the investigative staff conducts the informed consent process appropriately. The IRB has the authority to observe the consent process. The investigator has a responsibility to ensure that: the training and qualifications of research staff who will inform prospective subjects about the trial and/or conduct the informed consent process are appropriate. CPRS is checked prior to consenting the subject to ensure that he/she is not currently enrolled in another study. the subjects capacity to consent to a research protocol has been assessed, if appropriate. information is given to the subject, or their legally authorized representative, in language that is understandable to the subject or representative. the prospective subject or the legally authorized representative is provided sufficient opportunity to consider whether or not to participate. the prospective subject or the legally authorized representative has the opportunity to ask questions and have those questions answered to their satisfaction. subjects give consent without coercion or undue influence. consent is obtained prior to the conduct of any procedures required by the protocol. the consent document is signed and dated by the subject. the consent document is signed by the person who administered the consent process. the consent document is signed by a witness to the other signatures, or a impartial witness if this is required. CPRS is updated with a research note immediately upon enrolling the subject. Simultaneous enrollment in more than one therapeutic research study is not permitted unless the IRB determines that such dual enrollment does not significantly increase the risks or discomfort to subjects and will have no conceivable medical or scientific impact on the studies involved. The IRB will only consider the granting of dual enrollment if: The sponsors of all projects involved have given consent. 145
The IRB has determined that one of the studies is of minimal risk and has no conceivable medical or scientific impact on any other study CPRS notes for studies that have been approved for multiple enrollment must indicate that the IRB has granted approval.,. When such dual enrollment occurs inadvertently, this should be reported immediately to the IRB as Protocol deviation. The IRB will allow dual enrollment for situations in which one of the studies is observational/non-therapeutic as long as the protocol and/or study sponsor permit such activity. According to IRB and hospital policy, if more than 30 days elapses between obtaining informed consent and beginning the research, informed consent should be obtained again. I. Obtaining Consent From Those Who Cannot Read Or Speak English Or Who Are Illiterate Individuals unable to speak English may not be excluded from participating in a study. The subject must be given an approved translation of the consent form and the Experimental Subject's Bill of Rights in their native language to sign. Unless the researchers are fluent in the subjects language, a qualified translator must be included in the consent process and then sign his or her name at the end of the approved translated consent form. A relative who speaks English does not usually qualify as an official translator unless the person has some training in medical terminology or has a medical background. If an investigator wishes to include a subject who is illiterate or cannot read the informed consent document either the consent form or the short form will be read to the subject in the presence of an impartial witness. Whenever possible, accommodations should be made to permit subjects to read the consent form if possible (e.g.: large type for individuals with visual impairments), rather than relying on verbal consent routinely. The information presented to the subject must include all of the required elements of consent and should be at least as extensive as found in the written consent form. An impartial witness will observe and/or take part in the consent process and then sign the consent form. The person who is illiterate will also sign their mark on the signature line. When a study is expected to include illiterate subjects, the investigator will describe during initial review how the consent process is to be carried out and will submit a short form for approval. If a competent subject is able to read and understand the consent form but is unable to sign it (e.g.: quadriplegic), the consent form may be signed by an individual not connected with the research team who has been designated by the subject. This individual will observe and participate in the consent process and then sign the consent form, observed by an impartial witness. 2. APPLICABLE REGULATIONS AND GUIDELINES 21 CFR 50.20 21 CFR 50.25 21 CFR 50.23(a-d) 21 CFR 50.27 146
21 CFR 56.104(c) 38 CFR 16.116, 117 45 CFR 46.116, 117 45 CFR 46.117(a, c) 38 CFR 17.85
45 CFR 46.116(c, d) VA Handbook 1200.5 OHRP Guidance
3.
PROCEDURE Reviewers and IRB Members Review informed consent forms according to the IRB IRB Reviewer Worksheet for Informed Consent Forms/HIPAA Authorization; reviewer(s) will complete worksheet. Assess reading level and general readability of the form. Make recommendations on the adequacy of the form for its intended purpose and require changes if necessary.
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IC 702 EMERGENCY USE AND INFORMED CONSENT
1.
POLICY A. Emergency Exemption from Prospective IRB Approval: 1. Emergency Use of Investigational Products FDA regulations recognize that emergency situations may arise in which there will be a need to use an investigational product (drug, device, or biologic) in a manner inconsistent with the approved investigational plan or by a physician who is not part of the clinical study. Therefore, the FDA regulation and IRB policy permit deviations from the investigational plan when necessary to protect the life or physical well-being of a subject in an emergency. Prior approval for shipment or emergency use of the investigational product is not required, but the use must be reported to the IRB by the investigator and to the FDA by the IDE sponsor. Emergency use of an investigational product may be permitted in a human subject outside of an approved study without prior IRB approval if: 1. The patient is in a life-threatening condition that needs immediate treatment; 2. There is insufficient time to obtain IRB approval. 3. No generally acceptable alternative for treating the patient is available; and 4. Because of the immediate need to use the product, there is no time to use existing procedures to get FDA approval for the use. As a matter of practice, FDA has expanded the criteria of "life-threatening condition" to include serious conditions such as sight-threatening and limb-threatening conditions as well as other situations involving risk of irreversible morbidity. Prior to administering the test article, the investigator must: a) obtain an independent assessment by an uninvolved physician; b) obtain informed consent from the patient or a legal representative; c) notify the Chief of Staff (COS) and obtain his/her approval; d) obtain the concurrence of the IRB Chair and obtain his/her approval; and e) in the case of an investigational device, obtain authorization from the IDE holder, if an approved IDE for the device exists. Use under this mechanism does not constitute IRB approval. The IRB Chair will determine if the request fulfills FDA regulations. The IRB Chair will verify that the Investigator has not submitted a previous notification of intent to use the test article under this policy. The test article is expected to be administered to a single subject as a single course (may involve multiple dosing to achieve maximal efficacy). The subject to receive the test article should not be enrolled in a research study related to the test article, If subsequent use of the test article is contemplated in the same subject or in others, a new project application to the IRB is required in advance of use. 148
The IRB Chair will review any prior approval and will deny approval if a previous emergency use has been documented.
The IRB and FDA expect the physician to determine whether these criteria have been met, to assess the potential for benefits from the unapproved use of the test article, and to have substantial reason to believe that benefits will exist. The physician may not conclude that an emergency exists in advance of the time when treatment may be needed based solely on the expectation that approval procedures may require more time than is available. Physicians should be aware that FDA expects them to exercise reasonable foresight with respect to potential emergencies and to make appropriate arrangements under the IND/IDE procedures far enough in advance to avoid creating a situation in which such arrangements are impracticable. Following emergency use of the test article outside of an approved study, the investigator must submit relevant documentation to the IRB for review within 5 working days, indicating: 1. The conditions constituting the emergency, subject protection measures, and results, including copies of correspondence with FDA and sponsor, if any. 2. The likelihood of a similar need for the test article occurring again, and if future use is likely, immediately initiate efforts to obtain IRB approval and an approved IND or IDE for the product's subsequent use; and 3. For devices, that the sponsor (if an IDE for the use exists), or the FDA (if an IDE does not exist) has been notified of the emergency use, including a written summary of the conditions constituting the emergency, subject protection measures, and results (CDRH Program Operation Staff 301-594-1190). 2. Exception from Informed Consent Even for emergency use, the investigator is required to obtain informed consent from the subject or the subject's legally authorized representative if possible. If informed consent can not be obtained, the investigator and a physician not otherwise participating in the human subjects research must adequately certify the following in writing prior to use of the test article (21 CFR 50.23): 1. The human subject was confronted by a life-threatening situation necessitating the use of the test article. 2. Informed consent could not be obtained from the subject because of an inability to communicate with, or obtain legally effective consent from, the subject 3. Time was not sufficient to obtain consent from the subject's legal representative. 4. There was no alternative method of approved or generally recognized therapy available that provided an equal or greater likelihood of saving the life of the subject. If immediate use of the test article is, in the investigator's opinion, required to preserve the life of the subject, and time is not sufficient to obtain an independent physician's opinion prior to administering the test article, the clinical investigator should make the determination. The investigator must then have the determination reviewed and evaluated in writing within 5 working days after the use of the test article by a physician not otherwise participating in the human subjects research. In this event, a copy of the 149
independent review must be submitted to the IRB within 5 working days after the use of the test article. The IRB will review the submitted documents and will indicate the regulatory basis for the emergency use and that its use was appropriate. Data obtained from such emergency use may not be published or otherwise used for research purposes. Submission of a research proposal by the investigator is required if future use of the test article is anticipated. If the IRB approves the exemption, its evaluation and the regulatory basis for approving the exemption will be documented. If the IRB determines that it cannot approve human subjects research because the investigation does not meet the criteria for exemption in part B of this section (see below) or because of other relevant ethical concerns, the IRB will document its findings and provide these findings promptly in writing to the clinical investigator and to the sponsor of the human subjects research (see Section 602).
B. Exemption from Informed Consent Requirements for Planned Emergency Research: IRBs are authorized to approve proposals for emergency research without requiring that informed consent of all research subjects be obtained under 38 CFR 16.101(i) and 45 CFR 46.101(i), and implemented by HHS [FR 02oc96-22] and FDA [21 CFR 50.24) in 1996. However, VA has not adopted this policy and it is not implemented at the VALBHS.
2.
APPLICABLE REGULATIONS AND GUIDELINES 21 CFR 50.23 VA Handbook 1200.5 21 CFR 56.104(c) 21 CFR 50 [20, 23(a-d) 21 CFR 50.24 45 CFR 45.116 Guidance for the Emergency Use of Unapproved Medical Devices; 50 FR 42866 61 FR 51498 [Harmonisation of FDA and DHHS policies on informed consent in emergency research]
3.
PROCEDURE IRB Chair Review the Emergency Use documentation provided by the investigator in a timely manner Decide whether an emergency conference call of the IRB is indicated to discuss the matter Maintain telephone contact with investigator to quickly secure necessary documentation. Schedule emergency use review meeting by conference call or in person in a timely manner. 150
IRB Coordinator
Provide investigator with relevant correspondence in a timely manner.
IC 703 RESEARCH USING HUMAN BIOLOGICAL MATERIAL AND GENETIC RESEARCH
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POLICY Research involving material that can be linked, directly or indirectly by a code, to personal information concerning the source of the material constitutes research that is subject to federal regulations and IRB approval. Research using unlinked samples generally does not require IRB review because it is not human subjects research. Research using only unidentified samples may be exempt from IRB review if other criteria for exemption are met. Research using human genetic material or genetic testing poses special concerns and always requires IRB review. A. IRB Review Procedures: The Committee will consider the application by means of an expedited or full-committee review process. A project involving human biological materials may be reviewed through the expedited review process providing that the project meets the criteria for such review as described in Section 501. Genetic research may not be reviewed by expedited review. In order to facilitate review of the project, the investigator will set forth the following in the Application for IRB Review Form: a) a thorough justification of the research design, including a description of procedures used to minimize risk to subjects, b) a full description of the process by which samples will be obtained, c) any plans to obtain access to medical records of the subjects, and d) a full description of the mechanisms that will be used to protect against inadvertent release of confidential information. The investigator should address the relevant aspects of these issues in an appropriate manner in the Consent Document. The sections on Use of Human Biological Material and/or Use of Genetic Material on the initial application form must be completed. The principal risk of such research is primarily psychosocial in nature, resulting from the inappropriate release of information to the subject and third parties. The IRB will consider the research to be of minimal risk if: a) the study adequately protects the confidentiality of personally identifiable information, and isolates research results from the subject's general medical records b) the study does not involve the inappropriate release of information to third parties, including other researchers and institutions, and
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c) if appropriate, the study design incorporates a plan for whether, when and how to reveal findings to the sources or their physicians, with disclosure to the subject permitted only when all the following apply: i : the findings are scientifically valid and confirmed ii : the findings have significant implications for the subject's health concerns, and iii : a course of action to ameliorate or treat these concerns is actually available Expedited review may be permitted if it is determined that the investigator has adequately addressed these issues. B. Informed Consent Requirements: Informed consent from the subject is generally required for research involving human biological material and genetic research. In the case of research involving existent identified or coded samples, it may not be feasible to obtain such consent. If in the original consent document subjects anticipated and agreed to further participation in this way, then additional consent is unnecessary. However, documents may not exist or, when they exist, they are do not address the possibility of such research. In such cases, unlinking, or new consent may be necessary to conduct the research, unless a waiver of informed consent is possible. The IRB may waive the requirement for informed consent if the requirements in Section 701 are met. The determination of minimal risk must be made, as described above. In determining whether a waiver of consent would adversely affect the rights and welfare of subjects, the IRB will consider whether: a) the waiver would violate any state or federal statute or customary practice regarding an entitlement to privacy or confidentiality; b) the study will examine traits commonly considered to have political, cultural, or economic significance to the study subjects; and c) the study's results might adversely affect the welfare of the subject's community (if applicable). If the study poses more than minimal risk and consent cannot practicably be obtained, the removal of identifiers may be required. In general, a separate informed consent form should be used. In addition to the required and optional elements of informed consent described in Section 701, the informed consent form should contain the following additional elements, if applicable. a) If research results of the reuse of the specimen will be conveyed to the subject. b) If the subject will be re-contacted after the original study is completed. c) If the subject requests, the specimen and all links to the clinical data will be destroyed. d) That refusal to participate does not affect the subjects ability to participate in any associated therapeutic research. e) If the proposed research study involves the potential for psychosocial harm to the subject's family members, relatives or members of the subject's ethnic group f) If the research has a reasonable likelihood of leading to the development of a commercial product, subjects should be informed that they might not benefit from the product. g) If the investigator has any commercial interest from which he/she may benefit financially, directly or indirectly. 152
h) If the specimen will be used for future research and allow the subject the choice of how the specimen will be used. The consent should provide subjects with a sufficient number of options to help them and fully clarify the present and future uses of their samples. Options might include: refusal to use their samples in any research permitting use of their samples only in unidentified or unlinked form permitting coded or identified use of their samples for the present study only, with further contact required to do further studies permitting coded or identified use of their samples for any study relating to the condition for which the sample was originally collected, with further contact allowed to seek permission for other types of studies permitting coded use of their samples for any future study C. VA Policy on Storage and Reuse of Specimens: Human biological material is not considered to be "banked" (stored) if the specimens are used for only the specific purposes defined in the protocol and are destroyed either when the specific use is completed or at the end of the protocol. Specimens collected and stored for future research purposes are considered "banked" specimens. These specimens must be banked in a VA-sponsored or VA-approved tissue bank. Reuse of specimens must be consistent with the consent under which they were collected, and the reuse must only occur through a VA-approved protocol. If the specimens are sent to a non-VA institution for testing or use as defined in a VAapproved protocol, a written understanding between the VA investigator and the non-VA institution must specify the use of the specimens as defined in the protocol and that the specimens will be destroyed or returned to the VA once the analysis is completed. A copy of this written understanding must be on file before work may commence. Once the specific analyses are performed the remainder of the specimens must be destroyed or returned to the VA for destruction. The remaining quantity may not be retained or stored by the non-VA institution. If the specimens are destroyed at another institution, that institution must certify in writing to the VA Investigator the destruction of the specimen. The investigator will include this information with the final report. The investigator storing the banked specimens must retain a copy of the original consent, a record of the use of the specimens, and the protocols under which they were used. Linking of the data generated by the specimen and clinical data should occur within the VA by the VA investigator whenever possible. When this is not possible, the minimal amount of clinical data necessary should be shared with those doing the statistical analysis. The clinical information that is shared should not contain any unique identifiers, if possible. In some cases the IRB may require that a Certificate of Confidentiality be obtained. If specimens are to be sent to VALBHS for testing or use, the VALBHS investigator must obtain IRB approval or a determination of exemption before the work may begin. In addition, the investigator must provide a written letter of assurance between the VA 153
investigator and the non-VA investigator, indicating that samples were collected with appropriate institutional approvals and certifying that confidentiality will be maintained. The outside investigator will provide documentation of IRB approval or documentation of a determination of exemption. Consent forms, or protocols from the outside investigator may also be required. A copy of these documents will be placed in the study file.
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APPLICABLE REGULATIONS AND GUIDELINES VA Directive 2000-043; Banking of Human Research Subjects' Specimens Report and Recommendations of the National Bioethics Advisory Committee, 1999. 45 CFR 46.110
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PROCEDURE Investigator IRB Members
Provide necessary information and documentation Review the information provided and the informed consent form according to the criteria outlined in Section 703. Ensure that informed consent documents and methods are in compliance with regulations Make assessments as to risks, benefits and the adequacy of subject protections Make recommendations as to the appropriate IRB action
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IR 801 DUTIES AND RESPONSIBILITIES OF RESEARCH INVESTIGATORS 1. POLICY In the conduct of human research, the investigator has obligations and duties to act in accordance with the policies of the IRB and to report to the IRB as required. The IRB will investigate any allegations of research non-compliance, which affects a specific study protocol. This can be done either by the Chair, a subcommittee, or a full IRB. Serious or repeated non-compliance can result in halting enrollment, suspension of a study or termination of a study with all required reporting activities. These obligations and responsibilities are summarized as follows: A. Required Investigator Actions: Informed Consent: The investigator must obtain informed consent from participants prior to their enrollment into the research, using the informed consent document approved by the IRB. Consent documents are valid only during the dates indicated on the form, and the investigator may use the forms only during the period for which they are valid. The process for obtaining informed consent will conform to regulations of the VA and FDA, the procedures described in this manual, and guidance issued by OHRP and ORD. Changes in Approved Research: Changes in approved research, during the period for which approval has already been given, may not be initiated without IRB review and approval except where necessary to eliminate apparent immediate hazards to human subjects. Investigators must submit requests for changes, including proposed changes to consent forms to the IRB in writing. Where changes are implemented to eliminate hazards to subjects without IRB review or approval, the investigator must notify the IRB within 5 working days of making said changes. The IRB must then review and determine that the change is consistent with ensuring the participants continued welfare. All other changes must be submitted to the IRB for review and approval. If deviations from the approved protocol are discovered, they should be reported to the IRB as soon as possible. The investigator must also notify the IRB within 5 working days if FDA withdraws the approval of an approved IND or IDE or if a study is suspended or terminated by the sponsor. Continuing Review and Interim Reports: Investigators are responsible for requesting continuing review in anticipation of the expiration of the approval period (generally 60 days before the expiration date) or upon completion of the study. The investigator is required to submit any Interim Reports within 14 days of the date prescribed for the interim review. Completion Reports: Investigators are responsible for submitting completion reports to the IRB within 60 days of completion or termination of the study. The PI shall provide the sponsor with an adequate report shortly after completion of the investigators participation in the investigation.
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Conditions that Affect the Risk of Participants or Others: The PI is required to report promptly to the IRB the problems that require prompt reporting to the IRB as defined in section QA 903. B. Investigator Responsibilities: (i). General Responsibilities: In addition to the requirements noted above, the investigator has numerous responsibilities in the conduct of human research. The investigator will: Acknowledge and accept their responsibility for protecting the rights, safety, and welfare of human research subjects and for complying with all federal, state, VA and institutional regulations and the VALBHS MPA or FWA Design research studies so that the research will likely develop or contribute to generalizable knowledge. When investigators do not design a research study, they should judge the research design to be sound enough to meet its objective before agreeing to enroll participants. Design a research plan that is scientifically valid Personally conducting or supervising the investigation. Ensure that the investigation is conducted according to the written protocol, the sponsor agreement, and other applicable federal regulations and any conditions of approval imposed by the IRB and FDA. Disclose relevant financial information and conflicts of interest Ensure that all associates, colleagues, and employees assisting in the conduct of the investigation(s) are informed about their obligations in meeting Federal, state, local, and VALBHS requirements. Ensure that the FDA, any reviewing IRBs and all participating investigators are promptly informed of significant new information about an investigation. Understand and comply with the reporting requirements of the organization. When appropriate, investigators should include additional reporting mechanisms in the research protocol beyond those described by local policies and procedures. Ensure that he/she has the necessary resources to protect human subjects when conducting a research study. Submit proposed research for review and approval (or exemption) for IRB review Acknowledge and accept their responsibility for all activities related to the conduct of their research Submit to the IRB all requests for modifications to the protocol or the informed consent Make certain that a qualified clinician is responsible for all study-related healthcare decisions Develop a research plan that minimizes risk to the subjects Take actions that minimize the risk of harm to the subjects Obtain legally effective informed consent of the subject or the subject's legally authorized representative and legally effective authorization for the use and disclosure of the subjects protected health information
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Make certain that all he/she, as well as all research personnel have appropriate qualifications, training, experience, and be credentialed to perform the research activities they will carry out Make certain that neither the investigator nor the trial staff will attempt to coerce or unduly influence a subject to participate or to continue to participate in a trial Place the original signed informed consent form and appropriate progress notes documenting the consent process in the subject's medical record Document that subjects are informed in a timely manner if new information becomes available that may be relevant to the subjects willingness to continue participation in the trial. The communication of this information should be documented Provide the IRB with all required data necessary for continuing review, especially serious or unexpected adverse events and modifications Promptly report to the IRB any problems that require prompt reporting to the IRB as defined in QA 903. Furnish required reports to the sponsor, including reports of adverse events, unanticipated problems involving risks to participants or others, and study completion Keep copies of signed Informed Consent Forms readily accessible for review; Not seek to obtain research credit for, or use data from, patient interventions that constitute the provision of emergency medical care without prior IRB approval. Such activities will not be counted as research nor the data used in support of research Report any study suspension or termination by the sponsor Know the date of the continuing review and to be aware that the project becomes lapsed if continuing review does not occur on schedule. Lapsed projects are not approved and no research is permitted except as may be required to protect the rights and welfare of the current participants. Make provisions for retention of records at the institution if he/she leaves the VA facility Use fair and equitable recruitment practices in research and avoid practices that place participants at risk for coercion or undue influence. Respond to subjects complaints or requests for information. Understand when activities are subject to the HRPP and when to seek guidance Seek approval by the IRB of all amendments to, or modification of, the research proposal including the consent form prior to initiating the changes except when necessary to eliminate apparent immediate hazards to the subject. If the investigator leaves the facility, the original research records must be retained at the institution. Provide the IRB with sufficient information when requiring a waiver or alteration of the HIPAA Authorization for the IRB to find that such waiver or alteration is necessary. Prepare and maintain adequate, current and complete case histories. The case history for each individual must document that informed consent was obtained prior to participation in the study. Limit contact with veterans to those clinically essential or as outlined in IRB approved protocols. Contacts must not solicit sensitive information (e.g., SSNs). 157
During the recruitment process, researchers must make initial contacts with veterans in person and/or by letter prior to any telephone contact, and provide a telephone number or other means that veterans can use to verify the validity of the study. After recruitment and during follow-up phase, ensure that all staff begin calls by referring to previous contacts and the information provided on the informed consent document. Comply with the requirements of the Controlled Substance Act
(ii). Investigator Responsibilities in Using Investigational Drug or Devices: All of the general responsibilities of the investigator as described in section (i) above Supervise the use and disposition of the test article. The IND or IDE product must be stored, secured, dispensed, and documented in accordance with VALBHS policies for the handling of Investigational drugs and Devices (see Investigational Device and Investigational Drug SOPs). Comply with all FDA test article requirements Adequately maintaining control of test articles, including appropriate tracking documentation for test articles to the extent that such control and documentation are not centrally administered Retain records for two years following the date the marketing application is approved or withdrawn
(iii.). Investigator Responsibilities in Using Investigational Drugs: The complete institutional policy for investigational drugs is described in a separate document, Investigational Drug Policy. a. When investigational drugs are used in human research, the principal investigator is responsible for: All of the responsibilities of the investigator that are described in sections (i) and (ii) above. Establishing the research protocol for approval by the Research and Development Committee and sharing the investigational drug related information with the Investigational Pharmacist and the nurse who will administer the drug to the patient. The control of drugs under investigation. b. The PI shall administer the drug only to participants under the PIs personal supervision or under the supervision of a co-investigator responsible to the PI. c. The PI shall not supply the investigational drug to any person not authorized to receive it. d. The PI is required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by participants. e. If the investigation is terminated, suspended, or completed, the PI shall return the unused supplies of the drug to the Research Pharmacy. 158
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PIs are 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. Case histories include the case report forms, supporting data, and CPRS documentation in the medical record. CPRS documentation must include documentation of the consent process (see IC 701). The PI shall ensure that a signed copy of VA form 10-1086, must be sent to the Pharmacy Service to document each participants consent to participate in the study. The PI shall retain case histories 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 the application is not approved for such indication, until 2 years after the investigation is discontinued and FDA is notified. The PI shall furnish all reports to the sponsor of the drug who is responsible for collecting and evaluating the results obtained. The sponsor is required to submit reports to the FDA on the progress of the clinical investigations. All clinical investigators shall provide the sponsor with sufficient accurate financial information as may be required to support the sponsors application. This information shall be promptly updated if any relevant changes occur during the course of the investigation and for 1 year following the completion of the study. If the investigational drug is subject to the Controlled Substances Act, the PI shall 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. The PI shall upon request from any properly authorized officer or employee of the FDA, at reasonable times, permit such officer or employee to have access to, and copy and verify any records made by the investigator pursuant to 21 CFR 312.62 [21 CFR 312.68].
(iv.). Investigator Responsibilities in Using Investigational Devices: The complete institutional policy for investigational devices is described in a separate document, VALBHS Policy on Use of Investigational Devices. Policies and procedures for emergency use of unapproved medical devices are described in Section IC 702. When investigational devices are used in human research, the principal investigator is responsible all of the more general requirements that are described in sections (i) and (ii) above. The principal investigator is also responsible for complying with the FDA regulations in 21 CFR 812. The following additional requirements are specific to investigational devices: a. Obtain approval for use of the investigational device by preparing and submitting appropriate documents for review. b. Ensure that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations. 159
c. Protect the rights, safety, and welfare of the participants under the investigators care. d. The control of device(s) under investigation. The PI shall administer the device only to participants under the PIs personal supervision or under the supervision of a co-investigator responsible to the PI. The PI shall ensure that the investigational device is not supplied to any person not authorized to receive it. e. Ensure that the subject has read and signed the IRB approved patient informed consent. f. Properly documenting Informed Consent for the use of the investigational device and placing original in the subjects medical record. g. Storing the investigational devices in a locked, secure area. h. Ensure that all investigational devices are safe for human use, including electrical safety testing by the Biomedical Engineering department. i. Ensure proper dispensing and utilization of the investigational device as outlined in the approved protocol. j. Supervise device use, permitting use of the device only with subjects under his/her supervision and not supplying an investigational device to any person not authorized under the IDE regulation to receive it. k. Maintain records and tracking of all investigational devices which include: source of device, date device received, quantity received, IDE approval letter from the sponsor, prescription and patient receiving IDE and note about potential disposition of the device. l. Disposal of used devices. m. Return to the sponsor any remaining supply of the device or disposing of the device as the sponsor directs upon completion or termination of a clinical investigation or the investigator's part of the investigation or at the sponsor's request. n. Removal and return of non-functioning implants, where appropriate. o. Following all reporting requirements described in the VALBHS Device Policy and in Subpart G of the IDE regulation (21 CFR 812.140). p. Disclosing to the sponsor sufficient accurate financial information to allow the sponsor to meet its financial reporting requirements, and promptly updating this information if any relevant changes occur during the course of the investigation and for 1 year following completion of the study. q. For implanted devices, documenting the implantation and/or explanation of the device in the medical record. r. Documenting use or implantation in the medical record. s. Return of equipment supplanted by the device, if any. t. If the investigator leaves the facility, making provisions for follow up of research subjects with implanted devices. u. For implanted devices, permanently retaining appropriate emergency contact information. If the investigator leaves the institution they must either designate another investigator to retain this information or provide the information to the research department. v. Submitting complete, accurate, and timely reports of unanticipated adverse device effects to the IRB and the Sponsor. 160
w. Furnishing of all reports to the sponsor of the drug who is responsible for collecting and evaluating the results obtained. The sponsor is required to submit reports to the FDA on the progress of the clinical investigations. x. Complying with requests from any properly authorized officer or employee of the FDA, and at reasonable times, the permitting of such officer or employee to have access to, and copy and verify any records made by the investigator pursuant to 21 CFR 312.62 [21 CFR 312.68]. As part of the initial application, the investigator must provide a written plan for the device that adequately demonstrates his/her qualifications and how the above responsibilities will be met and documented. (v.) Requirements of the Sponsor and the Investigator as a Sponsor: The interrelationship and interaction between the research sponsor (e.g., drug, biologic and device manufacturers), the clinical investigator and the Institutional Review Board (IRB) may be very complex. The regulations do not prohibit direct sponsor-IRB contacts, although, the sponsor-IRB interaction customarily occurs through the investigator who conducts the clinical study. The clinical investigator generally provides the communication link between the IRB and the sponsor. Such linkage is agreed to by the sponsors and investigators when they sign forms FDA-1571 and FDA-1572, respectively, for drug and biologic studies or an investigator agreement for device studies. There are occasions when direct communication between the IRB and the sponsor may facilitate resolution of concerns about study procedures or specific wording in an informed consent document. The clinical investigator should be kept apprised of the discussion. VALBHS secures assurances from the sponsor or the Sponsor-investigator that the manufacture and formulation of investigational or unlicensed test articles conform to federal regulations. Sponsor-Investigator refers to a situation in which the individual investigator is a VALBHS investigator and is the holder of the IND or IDE and therefore assumes the duties of the sponsor of the clinical investigation under the applicable FDA regulations. a) Sponsors The sponsor takes responsibility for initiating the clinical investigation, and holding the IND or IDE, but does not usually conduct the investigation. Although the sponsor is usually a pharmaceutical, biotech, or medical device company, an individual or group of individuals or medical center can also be considered a sponsor for an investigation. The sponsors' responsibilities include the following: Selecting qualified investigators Providing investigators with the information they need to conduct the investigation properly Ensuring proper monitoring of the investigation (1.) Other Sponsor Responsibilities. Sponsors will provide such assurances through the sponsored research agreements, i.e., VA Cooperative Technology Administration Agreements (CTAA) or Cooperative Research and Development 161
Agreements (CRADA) Under FDA regulations and guidance, investigators (and investigator-sponsor) are responsible for the conduct of the study and for leading the team of individuals conducting the study. A Sponsor for an IDE protocol must follow the FDA regulations in 21 CFR 812 particularly Subpart C. These include: the record keeping requirements of 21 CFR 812.140(b), and the required notification under 21 CFR 812.150(b)(1) to the FDA and all participating investigators of any evaluation of an unanticipated device effect within ten (10) working days of first receiving notice of the effect. An investigator-sponsor for an IND protocol must follow the FDA regulations in 21 CFR 312 applicable to sponsor responsibilities, particularly Subpart D. These include: the record keeping requirements of 21 CFR 312.57, and prompt reporting as required in 21 CFR 312.55(b) to the FDA and all participating investigators of significant new adverse effects or risks with respect to the drug or biologic.
(2.) Sponsor Assurance that IRBs Operate in Compliance with 21 CFR Part 56 FDA regulations [21 CFR 312.23(a)(1)(iv)] require that a sponsor assure the FDA that a study will be conducted in compliance with the informed consent and IRB regulations [21 CFR parts 50 and 56]. This requirement has been misinterpreted to mean that it is a sponsor's obligation to determine IRB compliance with the regulations. This is not the case. Sponsors should rely on the clinical investigator, who assures the sponsor on form FDA-1572 for drugs and biologics or the investigator agreement for devices that the study will be reviewed by an IRB. Because clinical investigators work directly with IRBs, it is appropriate that they assure the sponsor that the IRB is functioning in compliance with the regulations. An IRB must notify an investigator in writing of its decision to approve, disapprove or request modifications in a proposed research activity [21 CFR 56.109(e)]. This correspondence should be made available to the sponsor by the clinical investigator. In the Agency's view, this required documentation provides the sponsor with reasonable assurance that an IRB complies with 21 CFR part 56 and that it will be responsible for initial and continuing review of the study. Also, the sponsor and, in fact, anyone who is interested, may obtain an Establishment Inspection Report from an FDA inspection of an IRB. These reports summarize the conditions observed during the IRB inspection. FDA, however, does not certify IRBs. (3.) Sponsor Access to Medical Records The IRB is responsible for ensuring that informed consent documents include the extent to which the confidentiality of medical records will be maintained [21 CFR 50.25(a)(5)]. FDA requires sponsors (or research monitors hired by them) to monitor the accuracy of the data submitted to FDA in accordance with regulatory requirements. These data are generally in the possession of the clinical 162
investigator. Each subject must be advised during the informed consent process of the extent to which confidentiality of records identifying the subject will be maintained and of the possibility that the FDA may inspect the records. While FDA access to medical records is a regulatory requirement, subject names are not usually requested by FDA 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 cases studied or actual results obtained. The consent document should list all other entities (e.g., the sponsor) who will have access to records identifying the subject. The extent to which confidentiality will be maintained may affect a subject's decision to participate in a clinical investigation. (4.) Confidentiality of Sponsor Information The IRB's primary responsibility with respect to protecting confidentiality is to the research subject. IRBs should, however, respect the sponsor's need to maintain confidentiality of certain information about products under development. IRB members and staff should be aware that information submitted for review may be confidential, trade secret, and of commercial interest and should recognize the need for maintaining the confidentiality of the review materials and IRB records. It is advisable for IRBs to have policies that address this issue. (5.) Nonsignificant Risk Device Studies "A sponsor's preliminary determination that a medical device study presents an NSR is subject to IRB approval." The effect of the IRB's NSR decision is important to research sponsors and investigators because significant risk (SR) studies require sponsors to file an Investigational Device Exemption (IDE) with FDA before they may begin. NSR studies, however, may begin as soon as the IRB approves the study. The sponsor, usually through the clinical investigator, provides the IRB with information necessary to make a judgment on the risk of a device study. While the investigational plan and supporting materials usually contain sufficient information to make a determination, the IRB can request additional information if needed [21 CFR 812.150(b)(10)]. If the IRB believes that additional information is needed, it may contact the sponsor directly, but it should keep the clinical investigator apprised of the request. While making the SR/NSR determination, any of the three parties may ask FDA to provide a risk assessment. The IRB procedures for the review of Medical devices are described in section RR 408. (6.) Disagreements The sponsor may choose not to conduct, to terminate, or to discontinue studies that do not conform with the sponsor's wishes. For example, the sponsor, clinical investigator, and IRB may reach an impasse about study procedures or specific wording in an informed consent document. The FDA will not mediate such disagreements. The Agency's policy of decentralized ethical review of clinical investigations allows such decisions to be made by local IRBs, and any disagreements between a sponsor, IRB, and clinical investigator should be resolved through appropriate communication among those parties. 163
b) Sponsors-Investigator Sponsor-Investigators assume all of the responsibilities and requirements described above for Sponsors as well as the duties and Responsibilities of Investigators. These include: The general responsibilities of Investigators described in section (i) above. The general responsibilities of Sponsors described in section (iv) above. The additional responsibilities of investigators described in section (ii) above if the investigation involves the use of either and investigational drug or device. The additional investigator responsibilities described in section (iii) above if the investigation involves the use of an investigational drug. The additional investigator responsibilities described in section (iv) above if the investigation involves the use of an investigational device. Additional unique responsibilities of a Sponsor-Investigator as described below. Sponsor-Investigators who submit protocols to the IRB involving FDA test articles Assume all of the responsibilities that are described in section (v.) item (b) above. Additionally, if the IND or IDE product will be manufactured at VALBHS, the investigator-sponsor must submit documentation that: The product preparation and manufacture meets the standards for current good Manufacturing Practice (GMP), or any modification to those standards approved by the FDA in issuing the IND or IDE. o The GMP plan has been approved by the Chief of Staff. o The GMP plan has been reviewed and accepted by the Chief of Staff, Health Support Services Healthcare Group and the ACOS R&D. The investigator-sponsor shall select a monitor, qualified by training and experience, to monitor the progress of the investigation. o The investigator can hire a Contract Research Organization (CRO) o Or the investigator can use a R&D Committee approved compliance group within the organization 2. APPLICABLE REGULATIONS AND GUIDELINES 21 CFR 56.108(a)(4) 21 CFR 56.109(f) 21 CFR 56. 108 (a) (3) 21 CFR 56.108 (b) 45 CFR 46. 103 (b) (4) (iii) 45 CFR 46. 103 (b) (5) 38 CFR 16.103 (b)(4)(iii) VA Handbook 1200.5 21 CFR 312.60-62 38 CFR 16, 17 38 CFR 16.103 (B)(5) 21 CFR 812 21 CFR 312 ICH 3.3.7 ICH 3.3.8 ICH 4.4 ICH 4.10-12 21 CFR 50.20 to 24 21 CFR 812.20, 25, 27, 30, 150.
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PROCEDURE 164
IRB Coordinator IRB Chair IRB Members
Contact investigators whose reports have not been received on schedule. Review Interim, Continuing Review, and Completion Reports, Modifications, and serious Adverse Events
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IR 802 EDUCATIONAL AND CREDENTIALING REQUIREMENTS FOR INVESTIGATORS, RESEARCH PERSONNEL AND STUDY MONITORS 1. POLICY A. Training: All principal investigators, investigators, research coordinators and assistants involved in human studies research and all members of the Research Office, all members of the R&D committee, and all members and staff of the IRB, exclusive of secretarial support, will complete an educational course or complete a web-based course on both the protection of human research subjects, as well as Good Clinical Practice (GCP). All individuals subject to this policy will be required to update their training annually. The investigator must provide documentation of satisfactory completion of all members of the study team to the IRB prior to performing any study procedures. New applications may be submitted and reviewed while such training is in process, but training must be completed and documented before final approval is granted. The investigator will maintain documentation of this training. The required training is described in the Research Education Plan, which is updated annually. Special training requirements also apply to external study monitors from the sponsors of research projects. External monitors are required to complete: A VA approved HIPAA training course. VA approved training in Cyber Security Awareness (if computer access is deemed necessary) Certificates that document the successful completion of this training must be presented to the Research Office prior to the scheduling of any monitor visit. The HRPP Officer will track all training and copies of training and maintain copies of training certificates on file in the Research Office. Requests for new studies will only be approved once the HRPP Officer confirms that the training requirement has been met. The IRB also has the authority to require additional training for individual investigators or staff members where noncompliance has been identified during review or during audits. B. Credentialing: Any research personnel who perform independent clinical activities (judgment based independent of the research protocol) as part of their research activities will be allowed to conduct such activities only if they are credentialed and privileged to provide those activities on patients by the standard credentialing and privileging process of the VALBHS (e.g., doctors, clinical psychologists). All such individuals whether compensated or on a WOC appointment will be credentialed through VetPro. All other individuals involved in human studies research (whether a licensed Title 5 employee; and whether the individual receives VA compensation or is without compensation) will have their credentials confirmed, a scope of work established and a record of such maintained for review. 166
All staff that by virtue of their education and training is eligible to obtain licensure, registration, or certification is required to be credentialed through VetPro even if they do not hold an active license, registration, or certification at the time they are appointed. Unlicensed nurses, physicians, pharmacists, clinical psychologists, and others requiring licenses, registration, or certifications for clinical practice cannot be hired into those occupations unless they obtain an active license, registration, or certification for the occupation and qualify under VA qualification standards. If they do not obtain the license, registration, or certification they must be hired under some other occupational category for which they qualify. If this and other occupational category allows a scope of practice to perform procedures AND there is no requirement for licensure or certification, then they may be allowed to perform these procedures which a duly exercised scope of practice after the appropriate credentialing is processed. Staff that must be credentialed in VetPro: All health care professionals who claim licensure, certification, or registration as applicable to their position within VHA. All research staff that hold a degree that may make them eligible for licensure, registration or certification. Such persons would include, but is not limited to: nurses, physicians, foreign medical graduates, clinical psychologists, and pharmacists that do not have a current active license. Note: See VHA Directive 2006-067 for a more complete list. All research staff including research administrative personnel, who by the nature of their position have the potential to assume patient care-related duties, or oversee the quality or safety of the patient care delivered, e.g. Research Assistants, Project Officers, etc. Trainees from our academic affiliates must have a Resident/Trainee Credentials Verification Letter (RCVL) prior to any interactions with research subjects. VHA Handbook 1400.1 contains further information regarding residents and trainees.
PROCEDURES: 1. All Employees: All employees involved in human subjects research will be checked against: (1) the Health and Human Services exclusion list, (2) the FDA debarment list, (3) the FDA disqualifications and restrictions list, and (4) the Public Health Service administrative actions list on a yearly basis. 2. Licensed staff: Licensed individuals will have their license(s) confirmed yearly. This requirement is separate from the Medical Center requirement for this confirmation to occur every two years.
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3. For all staff engaged in human subjects research and not covered by VetPro, their credentials must also be verified. All such staff will complete an appropriate application(s). Nurses may use VA Form 10-2850a, Optional Application for Federal Employment OF612 in conjunction with the Declaration for Federal Employment OF306. 4. Staff engaged in human research and not covered by VetPro, including foreign medical graduates without US licensure, will provide research service the following: Dated copy of CV/Resume Copy of current professional license (if applicable) Education verification forms Completed SF 85 Questionnaire for Non-Sensitive Positions
5. The Principal Investigator will provide for each research staff under their administrative or project supervision (some staff may "report" to one supervisor for purposes of timekeeping, performance, etc, but might also be named under several protocols under different PIs): A Scope of Practice
6. All VA employees who conduct research that involves human subjects will complete and submit the following documents to the Research Office: Cirriculum Vitae Form SF 85 And either Form 10-2850a (Nurses only) or Form OF 612 and Form OF 306 (others) 7. The Credentialing Coordinator in Research Service will verify the following for each research staff member: Education (that resulted in a degree, certification or license) Current licenses and certifications Create and compile a list of all research employees, check names against exclusionary lists 8. Verification of Education, Certifications and Licenses: All education that leads to a degree or certification, and any education or training that is relevant to the activities performed by the employee (such as survey methods, interview skills, etc.) must be documented and verified. If the search for documents is unsuccessful or primary source documents are not received after a minimum of two requests, full written documentation of these efforts, in the form of a report of contact will be placed in the credentialing folder in lieu of the documents sought. If certificates are presented, the original should be presented and copied and noted as an authentic copy, initialed and dated by the individual making the copy. In addition, verification by an individual who can substantiate the individual's participation in the school/program should be considered and could be obtained through something comparable to a reference letter verifying participation. This individual could be a professor, supervisor, or peer whose own current position can be verified. 168
If written verification of education is not possible in the time permitted the employee/applicant's education and degree may be verified over the telephone. It is very important that all the information requested be completed along with the date of the institutional contact. The person contacting the institution should sign the Report. Every effort to get written verification of education/degrees should be made. The written confirmation of education/degree should be placed in the credentialing file when it is received. If written confirmation of education/degree is not possible, this should be explained in the space provided. If the primary source verification(s) of credentials for an individual are on file (paper or electronic database) at a VA facility, those credentials that were verified at the time of initial appointment, can be considered verified. If neither written nor verbal confirmation for licenses, education, or certifications can be obtained, the candidate must be disqualified from participation in the research. The PI has the option of not hiring the candidate or assignment of duties other than human subjects research. 9. Documentation: A copy of all documents, forms, certifications, resumes, and Scope of Practice should be maintained and be retrievable in the Research Office. All current certifications and licenses should be updated and verified at the time of expiration or annually. Any new educational degrees, licenses or certifications obtained since the last verification should also be confirmed during the next annual review. 10. Coordination of Information: Credentials should only be verified by the employee's home VA site. Copies of materials collected and verified by the home VA site should be shared with other VA sites requiring this information. The other VA sites do not have to do primary verification of credentials. The HRPP Officer will be the point of contact for providing verification of credentialing to other VAs who may inquire. RESPONSIBILITIES: 1. Human Resource Management (HRM) at VALBHS has the primary responsibility for verifications of a candidate's qualifications including education, relevant training and experience, and current competence to hold the position. HRM is also responsible for checking US citizenship or visa status. 2. The ACOS/R&D has delegated to the HRPP Officer responsibility to ensure that all research staff: Have been credentialed prior to appointment Have a Scope of Practice or Functional Statement that is consistent with their education, licensure, or certification, and Have been granted the appropriate privileges, if applicable under the facility's bylaws, Annually ascertain compliance with these requirements Maintain records that will adequately show these responsibilities have been fulfilled
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3. Principal Investigators are responsible for the overall conduct of their research protocols ensuring that all research staff for the protocol are working within their Scope of Work or Functional Statement. 4. Individuals must not practice beyond the occupation they are hired/appointed into and their Scope of Practice or Functional Statement.
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APPLICABLE REGULATIONS AND GUIDELINES ORD Memorandum (8-15-2000) and attachment 1. VA Memorandum (3-14-2001). NIH OD-00-039, NOT-OD-01-06 PHS Policy On Instruction In The Responsible Conduct Of Research 12/01 VA Stand down memorandum dated 3/6/2003. VHA Directive 2006-067 December 22, 2006 "Credentialing of Health Care Professionals" VHA Handbook 1100.19 March 6, 2001 "Credentialing and Privileging" VHA Handbook 1400.1 July 27, 2005 "Resident Supervisions" VA Handbook and Directive 0710, September 10, 2004 "Personnel Suitability and Security" VA Handbook 5005 April 15, 2002 "Staffing"
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PROCEDURE Research personnel HRPP Officer Provide evidence of the completion of training Provide evidence of Credentials from a primary source Maintain records of completion of investigator education Maintain list of educational programs meeting these requirements Maintain records of the credentialing of persons who perform human subjects research
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QA 901 QUALITY IMPROVEMENT PROCEDURES 1. POLICY The day-to-day operations of the IRB and its staff are subject to periodic selfassessment for purposes of quality improvement. Such self-assessments will determine the extent to which the IRB complies with VA, Federal, and state regulations and its own SOPs, and the adequacy of its processes and documentation. Quality Assurance reviews will be performed by the Research Compliance Officer on a quarterly basis. Areas to be reviewed fall into three general categories: a.) review of recurring IRB processes to be sure that all standard operating procedures are followed, b.) review of IRB files for compliance with standard operating procedures and applicable regulations, and c.) monitoring of the informed consent process. Quarterly reviews will also include new developments such as changes in regulatory requirements and the results of external audits. Quality Improvement Assessments will be performed by the IRB. In conducting these assessments the IRB will review the results of Quality Assurance reports, will identify areas that require improvement or corrective action, and will determine a plan for corrective action. Areas for improvement will include, but will not be restricted to regulatory compliance. Additional criteria will be based upon the efficacy of the policies and procedures and their relevance to the needs of the Human Research Protection Program. The ACOS R&D and the Human Research Protection Officer will implement the plan. The Research Compliance Officer will monitor the progress and efficacy of corrective measures and assessments will be tracked in subsequent quarterly reports. The IRB will establish goals, re-evaluate the effectiveness of corrective actions, judge whether further improvement is needed, and will repeat the cycle until the goals are achieved. In evaluating, or re-evaluating, the efficacy of quality improvement, the IRB has the authority to conduct its own independent audits that may include: Recurring processes Research records and case histories The informed consent process Guidelines and procedures for these activities are described in detail in the SOP for Human Research Compliance and Quality Assurance.
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APPLICABLE REGULATIONS AND GUIDELINES VA Handbook 1200.5 FDA Self-Evaluation Checklist for IRBs VA Human Research Protection Accreditation Program SOPs Accreditation Standards 171
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PROCEDURE Research Compliance Officer Perform quality reviews of recurring processes and files for compliance Compile benchmark data IRB Chair IRB Members ACOS/R&D HRPP Officer Analyze results of quality reviews Make changes in policies and/or procedures as needed Implement plan for corrective action
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QA 902 MAINTENANCE OF DOCUMENTATION AND RECORD RETENTION 1. POLICY The Coordinator of the IRB will prepare and maintain adequate documentation of its activities, including: 1. Copies of all institutional assurances (MPA and/or FWA) 2. A roster of regular and alternate IRB members identified by name; earned degrees; representative capacity; affiliation or non-affiliation status; indications of experience such as, board certifications, licenses, etc., sufficient to describe each regular and alternate member's chief anticipated contribution to the IRBs deliberations; any employment or other relationship between each member and the IRB and/or institution (e.g., full-time employee, part-time employee, member of governing panel or board, stockholder, paid or unpaid consultant); status as a scientist or non-scientist; voting status; alternate status; and status as a chairperson. A resume for each IRB member will be maintained by the IRB Coordinator. The HRPP Officer will ensure that current IRB Membership rosters are maintained and that any changes in IRB membership are reported promptly to OHRP with a copy to ORD. 3. Education and Training Records. All IRB members, staff, investigators, and study monitors will comply with all IRB, VA, and institutional educational requirements. The HRPP Officer will ensure that accurate records are maintained listing research investigators, IRB members, IRB staff, and study monitors who have fulfilled the facilitys human subject protection initial and continuing training requirements. 4. Copies of the Standard Operating Policies and Procedures Manual. 5. Copies of all minutes of IRB meetings in sufficient detail to show the following: The presence of a quorum throughout the meeting including the presence of at least one member whose primary concern is in a non-scientific area and at least one member who is not otherwise affiliated with this institution. Attendance at the meetings including those members who are participating through video or teleconference (and documentation that those attending through videoconferencing or teleconferencing received all pertinent material prior to the meeting and were able to actively and equally participate in all discussions); Alternate members attending the meeting and who they are substituting for; Members participating by video or teleconference have received and reviewed all required information; The approval of previous meeting minutes; Notification (and discussion if applicable) of expedited reviews and exemptions from review and the eligibility category serving as justification for exemption or expedited review; 173
All actions taken by the IRB; The vote on actions including the number of members voting for, against, abstaining and recused (due to possible conflict of interest), and the names of members recused; A determination of the risk level, that the risk/benefit ratio is appropriate, and that steps have been taken to minimize risk to subjects; Separate deliberations, actions, and votes for each protocol undergoing initial review, continuing review, and review of modifications. That the research meets all required criteria for approval as described in Section 403, specifically that: 1. Risks to subjects are minimized; 2. Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and in relation to the importance of the knowledge that may be expected to result; 3. Selection of subjects is equitable; 4. Informed consent will be sought from each prospective subject or the subject's legally authorized representative; 5. Informed consent will be appropriately documented; 6. There is adequate provision for monitoring the data collected, to ensure the safety of subjects; 7. There are adequate provisions to protect the privacy of subjects, and to maintain the confidentiality of data. That the informed consent document was reviewed in accordance with the criteria in Section 701 and contains all of the required elements and all applicable optional elements; Documentation of the four required findings when waiving the requirement to obtain an informed consent Documentation of the four required findings when approving a consent procedure that does not include or that alters some or all of the required elements of informed consent A determination of risk level of investigational devices and rationale for significant risk/nonsignificant risk and subsequent approval or disapproval decisions for the clinical investigation That any IRB member who has a real or potential conflict of interest relative to the proposal under consideration recused him/herself (physically leaves the meeting room) prior to discussion and voting on the proposal (and that the quorum was maintained); The basis for requiring changes in or disapproving research (and documentation of resolution of these issues when resolution occurs); A written summary of the discussion of controverted issues and their resolution; Review of additional safeguards to protect vulnerable populations if entered as study subjects; and For protocols involving the use of placebos or that involve symptom provocation, a written summary of the discussion regarding the need for these and the safeguards that are in place, plus the resolution of the discussion of these issues. 174
The frequency of continuing review of each proposal as determined by the IRB For initial and continuing review, documentation of the degree of risk and the approval period (review interval), to reflect the determination of which protocols require continuing review more often than annually, as appropriate to the degree of risk Documentation indicating the approval of a waiver or alteration of the HIPAA Authorization Statements of significant new findings provided to subjects when reviewed at an IRB meeting Protocol specific findings for research involving pregnant women, human fetuses, and neonates. Protocol specific findings for research involving prisoners as subjects Protocol specific findings for research involving children as subjects Justification of any deletion or substantive modification of information concerning risks or alternative procedures contained I the informed consent document that was approved by the IRB When an alternate member replaced a primary member The rationale for significant risk/non-significant risk device determinations The approval of research contingent on specific minor conditions by the Chair or designee, to be documented in the minutes of the first IRB meeting that took place after the date of the approval Attendance at the meetings including those members or alternate members who participated through videoconference or teleconference, and documentation that those members received all pertinent material prior to the meeting and were able to actively and equally participate in all discussions
IRB proceedings must be written and available fro review within 3 weeks of the meeting date. Once approved by the members at a subsequent IRB meeting, the minutes must not be altered by anyone including a higher authority. Complete (non-redacted) minutes must be submitted to the Research and Development Committee and maintained in the research office. 6. Any meeting worksheets or reviewer worksheets used to document required elements of the review process and related discussion during the meeting. 7. Copies of all logs, audit reports and continuing review activities. 8. Copies of all correspondence between the IRB and the investigators or research staff. The IRB Coordinator will ensure that accurate records are maintained of all correspondence to or from the IRB. This correspondence shall include communications related to review of research by the convened IRB meeting, communications related to review of research by the expedited procedure, and oversight of ongoing research. All correspondence concerning a study will be filed in the research study files. 9. Statements of significant new findings provided to subjects. 175
10. Reports of any complaints by subjects that have been received. 11. Documentation of Device approvals and the assignment of risk to investigational devices. 12. Documentation of exemptions and exceptions (including citation of the specific category justifying the exemption) 13. Documentation of all expedited reviews (including the specific permissible category; a description of the review; description of the action taken by the reviewer; any findings required under the DHHS regulation; and protocol specific findings pertaiing to waiver of alteration for informed consent; waiver of consent documentation; research that includes pregnant women or fetuses, prisoners or children as subjects) 14. Research Tracking System. The IRB Coordinator will ensure the maintenance of reliable, computerized research (protocol) tracking systems, including the VA PROMISE system and other programs that may be used. 15. Human Subjects Research Study Files. The study file for each protocol will contain all items reviewed, including the following materials: VA Form 10-1436 Abstract Application for IRB Review Form Narrative Summary of Research A complete copy of the protocol, research plan, or investigational plan The IRB-approved informed consent document, with the approval date DHHS-approved sample consent forms (when available) Any other supporting material: Advertising, informational or recruiting materials, if any. Investigator's Brochure, if applicable For devices, IDE Information and a report of prior investigations VA Form 10-9012 Proposed subject instructions, if applicable Continuing review progress reports and related information. Applications for protocol amendments or modifications. Applications for Federal support, if any. Reports of unanticipated problems involving risks to subjects or others. Reports of serious or unexpected adverse events occurring within the VAMC (or involving employees or agents of the VAMC) and reported to any regulatory agency. Date of original IRB approval Date of original R&D Committee approval Date of most recent IRB approval Date by which next IRB Continuing Review must occur Reports of external adverse events received from sponsors or cooperative groups. 176
Data and Safety Monitoring Board (DSMB) reports, if any. Results of any external monitoring activities, including reviews provided to the investigator by sponsors, cooperative groups, or Federal agencies. Letters of IRB approval from outside institutions where the investigator is conducting the study. All other IRB correspondence related to the research. Clear documentation of all IRB review and approval actions, including initial and continuing convened (full) IRB review. Documentation of project completion. All correspondence Scientific evaluations (if any) that accompany the proposals Approved HIPAA authorization document Reports of injuries to subjects Documentation of protocol violations Copies of all correspondence with the Research and Development Committee Documentation of non-compliance and applicable regulations and investigator records Determination required by the regulations along with protocol-specific findings justifying those determinations for initial and continuing review by the expedited procedure.
All IRB records will be retained for at least five years. Records relating to research that is conducted will be retained for five years after the completion of the study at the sites. Investigators should always contact the sponsor prior to the disposal of records. IRB All IRB records should be kept secure in locked filing cabinets or locked storage rooms in order to protect the privacy and confidentiality of subjects and sponsor data. Access to IRB records is generally limited to the ACOS/R&D, the HRPP Officer, the IRB Chairperson and IRB members, R&D Committee Chairperson and R&D Committee members, IRB Coordinator, IRB staff, members of other R&D subcommittees, the RCO, and authorized VA representatives. Records will be made accessible for inspection and copying by authorized representatives of the FDA, VA, ORD, OHRP, or other appropriate federal departments or agencies at reasonable times and in a reasonable manner. Research investigators will be provided reasonable access to files related to their research. All other access to IRB records is limited to those who have legitimate need for them, as determined by the Medical Center Director, the ACOS/R&D, the R&D Committee, and VA Central Office. Appropriate accreditation bodies will be provided access and may recommend additional procedures for maintaining security of IRB records. Records are the property and responsibility of the research office. The medical center must designate where the records will be maintained and stored. If the investigator leaves the VA Long Beach Healthcare System, the original research records must be retained at the institution.
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APPLICABLE REGULATIONS AND GUIDELINES VA Handbook 1200.5 21 CFR 56.103(a) 177
21 CFR 56.108(a-b) 45 CFR 46. 108 (a) 45 CFR 46. 103 (b)(4-5) 45 CFR 46. 115 45 CFR 164 (i)(2) 38 CFR 16. 108 (a) 38 CFR 16. 103 (b)(4-5) 38 CFR 16. 115 ICH 3.2.2 21 CFR 56. 115 VHA Record Control Schedule 10-1
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PROCEDURE IRB Coordinator Maintain full and complete files for all research studies Maintain roster of regular and alternate IRB members. Establish archive method for files that are not in current use but must still be retained Become familiar with FDA IRB inspection procedures Ensure accurate training records are maintained Maintain copy of FWA
HRPP Officer
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QA 903 PROBLEMS, ADVERSE EVENTS, AND NON-COMPLIANCE 1. Policy A. This organization ensures prompt reporting of unanticipated problems that involve risks to participants, or others, and serious or continuing noncompliance to the IRB, regulatory agencies, and appropriate institutional officials. B. Allegations of Scientific Misconduct, while unexpected, are covered by the Ethical Standards and Misconduct in Research SOP rather than this policy. 2. Policy A. Unexpected Problems are defined as problems that are unforeseen. Unforeseen problems include those that 1) are not expected on the basis of common side-effects listed on product inserts, and 2) are not listed as being anticipated in section 5 of the Application for IRB Review; or 3) have a greater severity or frequency than may have been foreseen on the basis of descriptions in the protocol, consent form, or other material provided to the IRB; or 4) may not be expected on the basis of normal staff turnover. B. Unanticipated Problems Involving Risks To Participants Or Others are defined as problems that are 1) unexpected; 2) indicate that participants or others are at increased risk of harm. C. Increased risk means the potential to do harm. Risks include problems that may not have occurred, but could reasonably occur, as well as those that have already occurred D. An allegation is an assertion made by a party that must be proven or supported with evidence. E. Non-compliance means a failure to follow the regulations, or the policies and procedures of the VALBHS Human Research Protection Program, or the requirements of the VALBHS IRB, or the requirements of VHA handbook 1200.5. F. Continuing non-compliance means a repeated pattern of noncompliance that is likely to continue without intervention. Examples of continuing non-compliance are: Consistently late submissions of deviations. Failure to sign last 10 application forms. Continuing to conduct exempt research after IRB orders a stop. 10% of consents missing on 5 protocols. 2 previous actions by the IRB to address the same problem. 180
G. Serious non-compliance means non-compliance that affects the rights and welfare of subjects. 3. Procedures A. REPORTING TO THE IRB (i.) Problems to Report. Investigators must promptly report the following problems to the IRB: Any adverse event, which in the opinion of the principal investigator, was unexpected and was more likely than not to have been related to the research procedures, regardless of whether the adverse event was on-site (internal), off-site (external), serious, or not serious. Allegations or findings of non-compliance. These include the results of monitor visits and internal audits. Any change to the IRB-approved protocol (i.e., protocol deviation or protocol violation that involves risk(s) or has the potential to recur. This includes intentional measures taken to avoid immediate hazards to research participants as well as accidental or unintentional deviations from the approved procedures. Information that indicates a change to the risks or potential benefits of the research. For example: o An interim analysis or safety monitoring report indicates that frequency or magnitude of harms or benefits may be different than initially presented to the IRB. o A paper is published from another study that shows that the risks or potential benefits of the research may be different than initially presented to the IRB. o A safety monitoring report; interim result, or other finding that indicates an unexpected change to the risks or potential benefits of the research. A breach of confidentiality. Changes in FDA labeling or withdrawal from marketing of a drug, device, or biologic used in a research protocol. Any event that requires prompt reporting according to the protocol or sponsor. Any complaint of a participant that indicates an unanticipated risk or which cannot be resolved by the research staff. Unanticipated problems should be reported regardless of whether they occur during the study, after study completion or after participant withdrawal or completion. Summaries of communications from Data Safety Monitoring Boards (DSMBs) if a DSMB is used. Any other unanticipated problem that may involve a risk to participants or others. (ii.) Reporting Responsibility. The Principal Investigator is required to report all problems described in section 3.A(i) above. All problems that involve fatal or immediately life-threatening events must be reported in writing as soon as possible, 181
but not later than within 3 working days of when the investigator first learns of the event. Other problems or events must be reported within 10 working days after the investigator first learns of the situation. The RCO is required to report all problems that are described in section 3.A(i) that 1) are discovered in the course of project audits; and 2) have either been unreported, or misreported by the principal investigator. Such reports should be made within 10 working days of when the RCO first learns of the situation. The HRPPO is required to report all lapses of project approval. A lapse of approval is a failure to obtain re-approval of a study within the period of time that was approved by the IRB at the time that the study was last reviewed. External monitors are required to report all problems that are revealed in the course of auditing activities, as is described in section RR407. Any person may report 1) complaints about the conduct of research or the review process; 2) allegations of misconduct; 3) allegations of noncompliance. (iii.) How Reports are to be made. Problems, adverse events, or allegations, may be reported through the following mechanisms: Adverse Events. The investigator must report any adverse event that occurs at his/her own site on the Local Serious or Unexpected Adverse Event Notification Form. A separate report must be submitted for each incident. In the report the principal investigator will indicate the nature of the event, whether, in the investigators opinion, the adverse event was unexpected and more likely than not related to the research activity, why the investigator holds this opinion, and whether changes in the protocol and/or consent form are warranted. Reports of adverse events occurring at non-local sites will be submitted on the Non-Local Adverse Event Notification Form. Multiple events may be reported on a single Non-Local Adverse Event Notification Form. If the adverse event involved a fatality or immediately lifethreatening situation then the investigator must submit copies of any reports that have been sent, or that have been prepared to send, to the study sponsor or the FDA. Other Problems. The investigator should utilize the Deviation/ Unanticipated Problems Reporting Form to report all other problems or events. Complaints and Allegations. Any person may make a complaint or allegation. These may be submitted either in writing, or in person. Complaints and allegations may be made to the ACOS/ R&D, as indicated on consent documents. Complaints or allegations may also be submitted using the SCIRE web page (www.SCIRE-lb.org). 182
Complaints and allegations that are submitted to the ACOS/ R&D, or others will generally be directed to the HRPPO. Alternatively, persons that are making complaints or allegations have the option to submit these to other persons as is described on the SCIRE web page. Persons who are making complaints or allegations should provide: A description of the problem, complaint, or allegation. A description of when and where any events or problems may have taken place. A description of who was involved and who was present. A description of any other reasons as to why the reporting person may feel that the situation is real and/or requires corrective action. Contact information, if the reporting person does not desire to be remain anonymous. (iv.) Where reports are to be sent. All reports are to be directed to the HRPPO or the HRPPOs designee. The HRPPO, or designee, will distribute the reports to the appropriate primary reviewer as described below in section 3.B(i.a). B. Handling of Reports. A primary review process serves to screen reports. (i.) Primary Review Process. (a.) Selection of Primary Reviewer. Reports submitted to the HRPPO, or designee, are distributed to one of three primary reviewers. The 3 primary reviewers are: HRPPO IRB Chair Ad Hoc SAE Chair In determining the appropriate primary reviewer the HRPPO, or designee, will consider the following criteria (in order of precedence): 1) Has an unexpected death occurred? If yes, then the Chair of the IRB is the primary reviewer. 2) Does the matter involve a drug or device? If yes, then the Ad Hoc SAE Chair is the primary reviewer. 3) Does the matter involve research subjects? If yes, then the IRB Chair is the primary reviewer. 4) In all other cases the HRPPO is the primary reviewer. If any primary reviewer is unable to complete the functions of the primary review for any reason, then the primary reviewer will be the IRB Chair. If the IRB Chair is unable to complete the functions of the primary review for any reason, then the matter will be referred to the full IRB. (b) Determinations Made By The Primary Reviewer. The primary reviewer evaluates materials described in section 3.A (i.) above. Requests any additional material as may be required to clarify the evaluation and determines: 183
(1.) If special circumstances apply and the problem must be reviewed additionally by an alternative process. Special circumstances include: if the matter may possibly involve Scientific Misconduct. Scientific Misconduct is a serious deviation from accepted practice in carrying out research or in reporting the results of research, or material failure to comply with Federal requirements affecting specific aspects of the conduct of research, such as the protection of human subjects. This may include plagiarism, misrepresentation of authorship, fabrication falsification or destruction of data, or other serious deviations from accepted scientific practices, such as obstruction of anothers research, violation of confidentiality, intentional deception, omission, research dishonesty. If the matter may involve scientific misconduct then it will be referred immediately through the HRPPO to the Research Integrity Officer as well as being processed under this policy and procedure. If the matter may involve a compromise of privacy or data integrity. If this is the case, the matter will be referred immediately through the HRPPO to the Chair of the VALBHS Security Committee as well as being processed under this policy and procedure. If the matter involves the unexpected death of a research subject. If such circumstances apply then the primary reviewer must notify the HRPPO of this fact. The HRPPO will refer the matter to the IRB Chair. If the matter involves a subject who was treated with a device who has experienced an adverse event. If such circumstances apply then the primary reviewer must notify the HRPPO of this fact. The HRPPO will refer the matter to the IRB Chair.
(2.) The primary reviewer determines: If the matter is an Unanticipated Problem Involving Risks To Participants or Others. The matter is an unanticipated problem involving risks to participants or others if the problem: o Is unexpected; AND o Indicates that participants or others are at increased risk of harm.
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If the matter involves non-compliance or an allegation of noncompliance. If the primary reviewer determines that the matter does not involve an unanticipated problem involving risks to participants or others and does not involve non-compliance or an allegation of noncompliance, then: o The primary reviewer documents this finding. o No further action is taken under this policy.
2. Actions Made By The Primary Reviewer. If the primary reviewer is unable to determine whether the matter is an unanticipated problem involving risks to participants or others, it is referred to the convened IRB. If the primary reviewer determines that the matter involves an allegation of non-compliance, the primary reviewer determines and documents whether the non-compliance has a basis in fact. o If the allegation of non-compliance has no basis in fact, no further action is taken. o If the allegation on non-compliance has a basis in fact the matter is treated as non-compliance. o If the reviewer is unable to determine whether the noncompliance has a bsis in fact, the matter is referred to the convened IRB. If the primary reviewer determines that the matter involves noncompliance, the primary reviewer determines and documents whether the non-compliance is serious or continuing. o If the non-compliance is neither serious nor continuing, the primary reviewer manages the problem with the investigator. o If the non-compliance is either serious or continuing, the primary reviewer refers the matter to the convened IRB. o If the primary reviewer is unable to determine that the matter is neither serious no continuing, then the primary reviewer will refer the matter to the convened IRB. (ii.) Full IRB Review Process. The primary reviewer will present at a convened meeting of the IRB. 185
(a.) Materials Provided to IRB members In advance of the meeting all IRB members will be provided and are expected to review: A description of the matter. The original IRB application updated with any changes. The protocol. The consent. Other documents determined to be relevant by the primary reviewer. All problems determined by the primary reviewer to be unanticipated problems involving risks to participants or others, all problems determined by the primary reviewer to be serious or continuing non-compliance, and all matters that are not resolved by the primary review process will be reviewed by the convened IRB.
(b.)
Confirmation of findings or allegations. The IRB will establish whether the problem or event are true or took place. In making this determination, the IRB may: Accept reports of adverse events, deviations, or unanticipated problems from investigators. Accept the findings of any audits that have been performed. Consider determinations made during the course of the primary review. Contact the Investigator for information. Interview the investigator at a convened meeting. Conduct an investigative audit of the investigators records. Interview study personnel or research subjects.
If the problem or event involves an allegation that is contested by the investigator, or the investigators staff then the IRB will review all available information, including the audit report, administrative files, literature, source documents, requests for additional information from the investigator, interviews with the investigator, their research staff, and/or interviews with the complainant, and any other documents that could serve to validate or dismiss the allegation. If appropriate, the IRB will seek the opinion of regional counsel. The Convened IRB will consider the preponderance of evidence and will determine if the allegation is confirmed. (c.) Unanticipated Problem That Involves Risks To Subjects Or Others. The IRB will determine whether, or not, the matter represents an unanticipated problem that involves risk. If the IRB determines that the matter is an unanticipated problem involving risks to participants or others, the IRB considers the actions below and then 186
the HRPPO will report the unanticipated problem involving risks to participants or others following the organizations reporting policy (i.) If the IRB determines that the matter does not involve an unanticipated problem involving risks to participants or others and dos not involve noncompliance then: The IRB documents this finding. No further action is taken under this policy.
(ii.) Further actions for Non-compliance. If the IRB determines that the matter involves non-compliance, the IRB determines and documents whether the non-compliance is serious or continuing. o If the non-compliance is neither serious nor continuing, the IRB manages the problem with the investigator. o If the non-compliance is either serious or continuing, the IRB considers the actions below and then the HRPPO will report the serious or continuing non-compliance following the organizations reporting policy.
C. Plan of Action (i.) Considerations in response to unanticipated problem involving risks to participants or others or serious continuing non-compliance. The convened IRB considers: No action. More information sought pending a final decision. Requiring additional training and education of the investigator and/or the research staff. Modification of the research protocol. Modification of the information disclosed during the consent process. Additional information provided to past participants. Notification of current participants (required when such information may relate to participants willingness to continue to take part in the research). Require that current participants re-consent to participation. Modification of the continuing review schedule. Limiting the number or type of research projects that the investigator may engage in. Embargo of publications. Research Privilege probation*. Monitoring of research*. Monitoring of Consent*. Letter of Censure* 187
Suspension of the research*. Termination of the research*. Referral to other organizational entities (e.g. regional counsel, risk management, institutional official*)
Items marked above with an asterisk(*) are considered to be substantive actions. Other actions may also be considered to be substantive depending upon the severity of the problem and the extent of the required action. These include actions taken by the IRB that materially alter the substance and meaning of a protocol, informed consent form or process, or the status of the investigator. If the IRB determines that an investigator may continue his/her project with corrective action, or approval is reinstated after appropriate corrective action, a plan for continuing review will be formulated. Continuing review in this situation may include, but is not limited to audits, Interim Reports, and third party verification, and will be carried out on a periodic basis until the IRB is satisfied that the problem has been adequately resolved. Procedures for the Suspension or Termination of IRB approval are described in section RA 601. (ii.) Reporting IRB actions will be communicated to the investigator as is described in section RA 602. The investigator may appeal or otherwise respond to IRB actions as described in that section. IRB actions will be communicated to Institutional Officials and external agencies as described in section RA 604. Substantive actions must be reported to ORO as described in section RA 604. Actions that are considered to be Substantive are described in section QA 903.
4. APPLICABLE REGULATIONS AND GUIDELINES VHA Handbook 1200.14 VHA Handbook 1200.5 VHA Handbook 1050.1 VHA Handbook 1058.1 21 CFR 56.113 21 CFR 46.113 36 CFR 16.113 5. PROCEDURE Investigators Report to the IRB all problems that 188
Primary Reviewers
IRB HRPPO
require prompt reporting to the IRB as defined in QA 903. Make initial evaluations, resolve minor problems with investigators, forward serious or continuing noncompliance and unanticipated problems that involve risks to subjects or others to IRB. Confirm findings of primary review, formulate plan for corrective action. Draft reports as required.
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Appendix A Timetable for Actions Described in This Manual Action Investigators must submit reapproval materials prior to the Continuing Review Deadline of the study, at least Investigators must submit interim reports prior to the date required, at least Investigators submit completion report after completion or termination of the study within Members should receive materials prior to regularly scheduled meetings at least Reporting of fatal or immediately life-threatening events to the IRB after discovery no later than Other types of adverse events after awareness of the problem no later than Investigator notified in writing of the IRBs decision after the meeting within Investigator must supply required modifications or appeal within Investigator reports study modifications to eliminate hazards to subjects to IRB within Investigator reports suspension or termination of study, IND, or IDE to IRB within Investigator notified in writing of results of IRB review of audit report within Deadline to submit relevant review documentation after emergency use of a test article outside of an approved study within Deadline to submit independent review after emergency use of a test article outside of an approved study within Complete Audit Report after completing the audit within The results of an IRB Review of an audit communicated in writing to the Investigator, after commencement of the review The investigator must respond to the notification of IRB review of an audit report within Telephone notification of IRB Review finding of serious noncompliance Written notification of IRB Review finding of serious noncompliance Response by investigator after notification of serious noncompliance Appeal by investigator of IRB finding of noncompliance Number of days prior to the Continuing Review Deadline during which IRB may re-approve research and still maintain the same date for the Continuing Review Deadline Maximum time permitted 60 days 14 days 60 days 3 working days 3 working days 10 days 5 working days 90 days 5 working days 5 working days 3 working days 5 working days 5 working days 5 working days 5 working days 30 days 24 hours 5 working days 10 working days 90 days 30 days
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Appendix B Chart 1 Determining Whether an Activity is Human Subjects Research
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Appendix B Chart 2 Waiver or Alteration of Informed Consent Decision Chart
WAIVER OR ALTERATION OF INFORMED CONSENT UNDER 45 CFR 46.116(d) DECISION CHART
Will the research in its entirety involve greater than minimal risk as defined in 45 CFR 46.102(i)? No
Yes
No waiver or alteration Is it practicable to conduct the research without the waiver/alteration?
No
Yes
No waiver or alteration
Will waiving/altering informed consent adversely affect subjects' rights & welfare?
No
Yes
No waiver or alteration Will pertinent information be provided to subjects later, if appropriate?
Yes
No
No waiver or alteration
Waiver or alteration is possible if the IRB documents these 4 findings and approves the waiver or alteration.
IMPORTANT: Is the research FDA- regulated? If yes, the exemption cannot be granted.
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INSTITUTIONAL REVIEW BOARD

Standard Operating Procedures Manual

VA Long Beach Healthcare System

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LISTING OF REFERENCED ATTACHMENTS AND FORMS

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IRB Chair (or delegated designee)

ATTACHMENTS VALBHS IRB MPA IRB Exempt Eligibility Determination Form

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GA 102 REVIEW OF POLICIES AND PROCEDURES

IRB Members IRB Coordinator

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HRPP Officer RCO

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IRB Chair HRPP Officer IRB Coordinator

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ATTACHMENTS IRB Roster

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Maintain roster of IRB membership

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3. PROCEDURE IRB Chair HRPP Officer

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PROCEDURE IRB Coordinator

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