Reporting Noncompliance In Va Human Research

VA New Jersey Health Care System

RESEARCH COMPLIANCE AUDITING SOP

TABLE OF CONTENTS

PURPOSE PAGE 2 SCOPE PAGE 2 POLICY PAGE 2 DEFINITIONS PAGE 2 RESPONSIBILITY PAGE 4 PROCEDURES PAGE 5 ROUTINE AUDITS OF RESEARCH PAGE 5 INFORMED CONSENT DOCUMENTATION PAGE 5 RESEARCH RELATED COMPLAINTS AND ALLEGATIONS OF PAGE 6 NONCOMPLIANCE WITH REGULATIONS AND ETHICAL PRACTICES HUMAN RESEARCH SCOPE OF PRACTICE AND PRIVILEGES PAGE 7 REVIEW AUDIT OF IRB MINUTES PAGE 7 INSTITUTIONAL RESPONSIBILITIES, HUMAN RESEARCH PAGE 7 PROTECTION REVIEW IRB FILE AUDIT PAGE 7 RESEARCH PARTICIPANT OUTREACH PROGRAM AUDIT PAGE 8 TRIENNIAL/REGULATORY AUDITS PAGE 8 FOR-CAUSE PAGE 9 REPORTING PAGE10 APPARENT SERIOUS NONCOMPLIANCE PAGE 10 REPORTING DOCUMENT APPROVAL PAGE 11 REVISION HISTORY PAGE 11 REFERENCES PAGE 11 ABBREVIATIONS PAGE 12 ATTACHMENTS (AUDIT METHODOLOGIES) PAGE 13

0e5236b1341d2f576017e1081d6e213e.doc Page 1 of 73 Research Compliance Auditing SOP 1. PURPOSE: To describe the type of audits and methods used to audit research conducted at the VA New Jersey Health Care System (VANJHCS) by the Office of Research Compliance in fulfillment of VHA Directive 2008-064.

2. SCOPE: All employees of the VANJHCS that are involved in or conduct research (human or animal) as part of the research program. 2.1.1. Principal Investigators (PI) 2.1.2. Investigators 2.1.3. Study Staff 2.1.4. Facility Director 2.1.5. Chief of Staff (COS) 2.1.6. Associate Chief of Staff Research & Development (ACOS R&D) 2.1.7. Information Security Officer 2.1.8. Privacy Officer 2.1.9. Research Service 2.1.10. Research & Development Committee 2.1.11. IACUC 2.1.12. Institutional Review Board (IRB) 2.1.13. Subcommittee Research Safety (SRS)

3. POLICY: It is the policy of the VANJHCS to ensure that audits are conducted as part of the research compliance program to assess compliance with applicable laws, statutes, regulations and policies including those related to privacy, confidentiality and information security requirements and that audits be conducted to assess the adequacy of the HRPP processes such as communication with applicable committees, persons and officials and documentation of compliance with VA and other requirements.

4. DEFINITIONS: 4.1.1. ACOS/R: Associate Chief of Staff for Research & Development

4.1.2. Amendment: Changes or clarifications made in writing to the original protocol

4.1.3. Audit: An evaluation of a system or process to determine compliance with applicable laws, statutes, regulations and policies

4.1.4. CPRS: Computerized Patient Record System (VHA Electronic Medical Record)

4.1.5. Data Analysis: Practice in which raw data is ordered and organized so that useful information can be extracted from it

4.1.6. Freedom of Information Act (FOIA): This act allows for the full or partial disclosure of previously unreleased information and documents controlled by the United States Government

4.1.7. HIPAA: The Health Insurance Portability and Accountability Act of 1996 (HIPAA) Privacy and Security Rules protects the privacy of individually identifiable health information; the HIPAA Security Rule, which sets national standards for the security of electronic protected health information; and the confidentiality provisions of the Patient Safety Rule, which protect identifiable information being used to analyze patient safety events and improve patient safety

0e5236b1341d2f576017e1081d6e213e.doc Page 2 of 73 4.1.8. Human Subjects Research: As defined in the Common Rule (38 CFR 16) and VHA Handbook 1200.5, a human subject is a living individual about whom an investigator conducting research obtains:

4.1.9. Data through intervention or interaction with the individual

4.1.9.1.1. Intervention: An intervention includes both physical procedures by which data are gathered and all manipulations (physical, psychological, or environmental) of the human subject, or the subject’s environment that are performed for research purposes

4.1.9.1.2. Interaction includes communication or interpersonal contact between the investigator and the human subject

4.1.10. Identifiable private information

4.1.11. Indicator: Measureable objective

4.1.12. Informed consent: The knowing consent which is obtained without undue inducement or element of force, fraud, duress or coercion. Informed consent is not simply a form or signature, but an on- going process of information exchange that includes:

4.1.12.1.1. subject recruitment material 4.1.12.1.2. verbal instructions 4.1.12.1.3. written material 4.1.12.1.4. question/answer session 4.1.12.1.5. documented agreement (signed/dated)

4.1.13. Institutional Review Board (IRB): The IRB is a board established in accordance with, and for the purposes expressed in, the Common Rule (Title 38 Code of Federal Regulations (CFR) 16.102(g)). The IRB is an administrative body established to protect the rights and welfare of human research subjects recruited to participate in research activities conducted under its jurisdiction

4.1.13.1. The IRB must be and must be perceived to be fair and impartial, immune from pressure either by the institution's administration, the investigators whose protocols are brought before it, or other professional and nonprofessional sources

4.1.13.2. The IRB has the authority to approve, require modifications in, or disapprove all human studies research activities as specified by both the Federal regulations and local policy. Research that has been reviewed and approved by an IRB is subject to review and disapproval by the R&D Committee, however, the R&D Committee may not approve research if it has been disapproved by the IRB

4.1.13.3. The IRB must comply with the requirements of all relevant regulatory and compliance enforcement agencies or offices, including VHA Office of Research Oversight (ORO), DHHS Office of Human Research Protection (OHRP), and Food and Drug Administration (FDA).

0e5236b1341d2f576017e1081d6e213e.doc Page 3 of 73 4.1.14. Non-Compliance: Failure to follow the regulations; institutional policies governing human subject research

4.1.15. Principal Investigator (PI): The PI is 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 a PI and an investigator to be synonymous

4.1.16. Regulatory Audit Reporting Period: The regulatory reporting period extends from June 1 – May 31 of any given reporting year culminating with the Directors Certification of Research Oversight report

4.1.17. Research: Common Rule: (38 CFR 16.102(d)) defines research as a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalized knowledge

4.1.18. Research: FDA definition of research: any experiment that involves a test article and one or more human subjects and that either is subject to requirements for prior submission to the Food and Drug Administration under section 505(i) or 520(g) of the act, or is not subject to requirements for prior submission to the Food and Drug Administration under these sections of the act, but the results of which are intended to be submitted later to, or held for inspection by, the Food and Drug Administration as part of an application for a research or marketing permit

END OF DEFINITIONS

5. RESPONSIBILITIES: The Research Compliance Officer has the responsibility to audit all research conducted within the NJVAHCS as required by VHA Directive 2008-064. It is the responsibility of the Office of Research Compliance and the Research Compliance Officer or designee to conduct the audits

5.1. The Research Compliance Officer is responsible for: 5.1.1. Writing and updating this standard operating procedure and establishing content, implementation and oversight for the auditing program

5.1.2. Developing the methodologies for the audit

5.1.3. Conducting audits (including but not limited to: related training, corrective action plans and recommendations

5.1.4. Assuring that individuals assisting in conducting audits have sufficient training to carry out their duties

5.1.5. Documenting and reporting results to the Research and Development Committee, IRB, ACOS/R

5.1.6. Report annually to the R&D Committee regarding the effectiveness of the auditing program:

5.1.6.1.1. Audits Conducted

5.1.6.1.2. Corrective Actions Taken

0e5236b1341d2f576017e1081d6e213e.doc Page 4 of 73 5.1.6.1.3. Strength and weaknesses of the audit program and areas for improvement

6. PROCEDURES: There are three (3) types of audits conducted by the Office of Research Compliance at the VANJHCS: Routine -- Triennial/Regulatory -- For Cause

6.1. ROUTINE AUDITS OF RESEARCH

6.1.1. Informed Consent Documentation (ICD): Along with an application for continuing review submitted to the IRB office, the PI submits a list of all consented subjects for the study. The list will include names and social security numbers of consented subjects (see attachment A for the indicators used for this audit)

6.1.1.1. Copies of the ICD or a notation that the ICD is scanned into the medical record (CPRS) is included

6.1.1.2. RCO or designee will check medical records in CPRS to verify the scanned document is the correct version/date

6.1.1.3. Completed consent forms and related documents are reviewed for all studies at the time of each study’s continuing review. A sample of 5 consent forms and related documents (or all if less than 5) are reviewed for compliance with the indicators

6.1.1.4. Prior to completion of a report, the Principal Investigator (PI) is provided with the findings and an opportunity to comment or provide corrective actions. The PI’s response is reflected in the final report

6.1.1.5. Findings of serious noncompliance must be reported by the PI to the IRB, as they become known (within 5 business days after discovery)

6.1.1.6. If serious non-compliance is found, the PI is advised to promptly provide the IRB with a report of the non-compliance and relevant information

6.1.1.7. A quarterly report of the informed consent audit is provided to the IRB, R&D Committee, and the ACOS/R

6.1.2. Research Related Complaints and Allegations of Noncompliance with Regulations and Ethical Practices

6.1.2.1. The RCO receives reports of research related complaints and allegations of noncompliance with regulations and ethical practices as they occur.

6.1.2.2. The research community (Research Service, investigators, study staff, IRB and R&D Committees) is advised to forward the report to the ACOS/R or the RCO

6.1.2.3. The RCO is responsible to assure that:

6.1.2.4. All issues are resolved 6.1.2.5. All identifiable complainants receive a personal response 6.1.2.6. Service Chiefs have been apprised of the incidents (as appropriate)

0e5236b1341d2f576017e1081d6e213e.doc Page 5 of 73 6.1.2.7. Any serious and continuing non-compliance with human research protection regulations are reported to the IRB 6.1.2.8. A quarterly report of Research Related Complaints and Allegations of Noncompliance is prepared and submitted to the R&D Committee and its subcommittees. Prior to completing the report, the RCO confirms that all incidents have been received from the following:

6.1.2.8.1.1. ACOS/R 6.1.2.8.1.2. AO R&D 6.1.2.8.1.3. IRB Coordinator 6.1.2.8.1.4. Patient Safety Officer 6.1.2.8.1.5. Risk Manager 6.1.2.8.1.6. Compliance Officer 6.1.2.8.1.7. Patient Representative, East Orange 6.1.2.8.1.8. Patient Representative, Lyons, Outpatient 6.1.2.8.1.9. Patient Representative, East Orange Inpatient 6.1.2.8.1.10. Ethics Advisory Committee

6.1.3. Human Research Scope of Practice and Privileges Audit

6.1.3.1.1. An audit is conducted of all research study staff to determine that they are working within their clinical privileges or research scope of practice for each study on continuing review

6.1.3.1.2. The Research Compliance Officer provides a quarterly report of the results to the R&D committee. (see Attachment B for a description of the methodology for this audit)

6.1.3.1.3. This audit is conducted for the ACOS R&D. VHA Handbook 1200.01 states that the ACOS R&D is responsible for “providing an annual quality assurance review of research employees involved in human subject research to ensure the employees are working within their scopes of practice and their privileges allowed by the facility’s by- laws and granted to them by the facility”.

6.1.4. Audit of IRB Minutes

6.1.4.1. The IRB is responsible to review and approve research based on ethical principles and regulatory criteria which must be documented

6.1.4.2. Audits of IRB minutes are conducted by the RCO and reported to the ACOS/R, IRB and R&D Committee on a quarterly basis

6.1.4.3. Feedback, education and recommendations are provided to the IRB based on the findings of the audit. (see Attachment C for a description of the methodology and indicators for this audit)

6.1.5. Institutional Responsibilities, Human Research Protection Review

6.1.5.1. The VANJHCS is responsible to assure that human subjects of research are protected. The broad areas covered in this review have been identified as critical to the institution’s

0e5236b1341d2f576017e1081d6e213e.doc Page 6 of 73 compliance with regulations, accreditation standards and ethical principles for protection of subjects

6.1.5.2. This audit is conducted annually by the RCO. The RCO works with the process owners to continually pursue corrective actions until issues found to be out of compliance are fully addressed. (see Attachment D for a description of the methodology and indicators for this audit)

6.1.6. IRB File Audit

6.1.6.1. IRB file audit is conducted quarterly to assure all necessary documents are maintained within the IRB file

6.1.6.2. The indicators are intended to identify the required contents of IRB files, including: 6.1.6.2.1. Submission documents 6.1.6.2.2. Information needed for the IRB to evaluate the project 6.1.6.2.3. Information required to conduct continuing review 6.1.6.2.4. Documentation regarding: 6.1.6.2.5. Expedited review 6.1.6.2.6. Exemption 6.1.6.2.7. Device studies 6.1.6.2.8. (see attachment E for a description of the indicator used in the IRB file review)

6.1.7. Research Participant Outreach Program Audit

6.1.7.1. Each VHA facility conducting human research must establish a Research Participant Outreach Program for current, prospective, or past research participants or their designated representatives.

6.1.7.2. The RCO is responsible to oversee and evaluate the Facility Research Participant Outreach Program within the VHA Directive 2008-079.

6.1.7.3. The Volunteering in Research - Here are some things you need to know brochure is available in patient waiting areas.

6.1.7.4. The brochure is given to all subjects at the time of consent and documented in the CPRS progress note.

6.1.7.5. Adequate supply of the brochure is on hand by each investigator

6.1.7.6. At least one educational activity is conducted per 12 month calendar year and includes members of the community. (see attachment F for a description of the indicator used in the Outreach Program Audit)

6.2. TRIENNIAL / REGULATORY AUDITS : Audits of research studies (human, animal, and safety-related) initiated after January 1, 2008, must be performed at least every 3 years (i.e., triennially) and require review of case records and regulatory files, in anticipation of satisfying the triennial audit requirement.

0e5236b1341d2f576017e1081d6e213e.doc Page 7 of 73 6.2.1. Protocols selected for audit will be scheduled at a time that is mutually convenient for both the RCO and research staff.

6.2.2. Audits of investigator study records are conducted at the investigators’ areas.

6.2.3. Indicators are related to complete research records and information security.

6.2.4. Investigators are asked to undertake correction of non-compliance and provide a description of corrective actions.

6.2.5. Regulatory audit components may include, but are not limited to:

6.2.5.1. Interview with principal investigator (PI) and/or key study personnel regarding recruitment and enrollment procedures 6.2.5.2. Inclusion /exclusion criteria, informed consent process 6.2.5.3. Staff training and responsibilities 6.2.5.4. Institutional Review Board (IRB), Institutional Animal Care and Use Committee (IACUC), and Subcommittee for Research Safety correspondence 6.2.5.5. Data and safety monitoring

6.2.6. Review study files and informed consent documents for adherence to the IRB or IACUC approved protocol and appropriate documentation.

6.2.7. Review study regulatory file/binder for completeness. (see attachment G for a description of the indicator used in the Triennial/Regulatory Audit)

6.2.7.1. Triennial / Regulatory audits of the following studies are not required:

6.2.7.1.1. Any human study determined to be exempt from IRB review.

6.2.7.1.2. Any study (human, animal, or safety-related) approved prior to January 1, 2008. (ORO, Memo to Clarify RCO Audit requirements for 2009 and 2010 (06/09/09).

6.3. FOR CAUSE AUDIT:

6.3.1. For-Cause Audits occur only as the need arises.

6.3.2. For-Cause Audit content and procedures are determined by the Research Compliance Officer (RCO) when the need for the audit is determined. Planning is coordinated with the appropriate referring authority.

6.3.3. For-Cause Audit referrals come from authorities including:

6.3.3.1. Associate Chief of Staff Research & Development Committee 6.3.3.2. (ACOS/R) 6.3.3.3. IRB 6.3.3.4. R&D Committee 6.3.3.5. Chief of Staff (COS)

0e5236b1341d2f576017e1081d6e213e.doc Page 8 of 73 6.3.4. For-Cause Audit may be precipitated by such occurrences:

6.3.4.1. Complaints 6.3.4.2. Serious Adverse Events 6.3.4.3. Allegations of impropriety 6.3.4.4. Serious or Continued noncompliance 6.3.4.4.1. Studies with inexperienced investigators or investigators who are new to the VANJHCS may be referred to the RCO for an audit of early episodes of the informed consent process.

6.3.5. For-Cause Audits may be coordinated with or deferred to another entity when circumstances involve other entities or processes within the VANJHCS. Examples include:

6.3.5.1.1. Institutional Risk Assessment 6.3.5.1.2. Patient Safety 6.3.5.1.3. Compliance and Business Integrity 6.3.5.1.4. Administrative Board of Investigation 6.3.5.1.5. Misconduct Investigation

6.3.6. In cases where the review is deferred to another authority, the RCO, ACOS R&D, IRB Chair and R&D Committee Chair will be apprised of the findings and conclusions as necessary

6.3.7. For-Cause Audit results are provided in writing to: The PI, IRB, R&D Committee, and other referring authorities (if applicable).

6.4. Reporting:

6.4.1. For-Cause audit (see above section on For-Cause Audits).

6.4.2. Results of routine and regulatory audits are reported to the R&D Committee and all applicable subcommittees on a quarterly basis with the exception of audits conducted annually or when there is a finding of apparent serious noncompliance

6.4.3. Regulatory Audit report summaries are recorded in the annual Facility Director’s Certification of Research Oversight report

6.4.4. Apparent Serious or Continuing Noncompliance Reporting:

6.4.4.1. RCO is responsible for reporting to the Facility Director, ACOS R&D, R&D Committee, and IRB as soon as possible but no later than 5 business days after becoming aware of a problem during a regulatory audit when the problem:

6.4.4.1.1. Involves possible serious or continuing noncompliance

6.4.4.1.2. Involves or suggests risks to subjects or others, is determined to be serious, is unanticipated, and is related or possibly related to the research (see attachment H for the Reporting Noncompliance in VA Human Research decision flow chart)

6.4.5. Issues requiring immediate action

0e5236b1341d2f576017e1081d6e213e.doc Page 9 of 73 6.4.5.1. If an issue is identified that requires immediate action, prompt reporting to the appropriate authority will be made (Examples: ACOS R&D, R&D Chairperson, IRB Chairperson, IRB Coordinator, Research AO, Privacy Officer, Information Security Officer).

6.4.6. Corrective Actions

6.4.6.1. Corrective actions are pursued by the RCO when required by the R&D Committee (or its subcommittees or other appropriate entities) in response to findings in Research Compliance Officer Audit reports.

6.4.6.1.1. A report regarding compliance with the required corrective actions will be presented to the R&D Committee, its subcommittee or other appropriate entity.

6.4.6.2. Corrective actions provided by the PI in response RCO audit findings (that are not indicative of serious or continuing noncompliance and do not involve or suggest increased risk to subjects or others) are evaluated by the RCO and reported in compiled reports to the R&D Committee, applicable subcommittees and the ACOS R&D.

6.4.6.2.1. The audit remains open until all corrective actions have been implemented by the PI.

6.4.6.2.2. Example: document in IRB file but not is PI study file; lapse in training.

7. DOCUMENT APPROVAL: Approved by Lead Research Compliance Officer, 10/3/10. Preparation and review of this SOP are the responsibility of the Research Compliance Officer.

8. REVISION HISTORY: None

9. REFERENCES: 9.1. VHA Directive 2008-014 Auditing Of VHA Human Subjects Research to Determine Compliance With Applicable Laws, Regulations, and Policies 9.2. VHA Regulations for Human Subjects Protection Title 38 CFR 16 9.3. VHA Handbook 1200.5 Requirements for the Protection Of Human Subjects In Research 9.4. VANJHCS Research SOP Human Research Protection Program (HRPP) 9.5. VANJHCS Research SOP Research Related Complaints and Allegations of Non-Compliance 9.6. VANJHCS POLICY MANAGEMENT POLICY LD–01-0706 (003) Expiration Date: July 31, 2011 9.7. ATTACHMENTS: Six (6)

10. ABBREVIATIONS AAALAC = Association for Assessment and Accreditation of Laboratory Animal Care, International AAHRPP = Association for the Accreditation of Human Research Protection Programs AALAS= American Association for Laboratory Animal Science AAMC = Association of American Medical Colleges ACOS for R&D = Associate Chief of Staff for Research & Development AO for R&D = Administrative Officer for Research & Development CDC = Centers for Disease Control and Prevention CDRH = Center for Devices and Radiological Health 0e5236b1341d2f576017e1081d6e213e.doc Page 10 of 73 CFR = Code of Federal Regulations CIO = Conflict of Interest CPRS = Computerized Patient Record System COS = Chief of Staff CRADO = Chief Research and Development Officer CRC = Clinical Research Center CSP = Cooperative Studies Program CSPCC = Cooperative Studies Program Coordinating Center DHHS = Dept. of Health & Human Services (DHHS regs. Enforced by OHRP) DoD = Department of Defense DSMB = Data and Safety Monitoring Board DVA = Department of Veterans Affairs EPA = Environmental Protection Agency FOIA = Freedom of Information Act FWA = Federal Wide Assurance HIPAA = Health Insurance Portability and Accountability Act HRPP = Human Research Protection Program HSR&D = Health Sciences Research & Development HUD = Humanitarian Use Device IACUC = Institutional Animal Care and Use Committee ICD = Informed Consent Document IDE = Investigational Device Exemption IND = Investigational New Drug IO = Institutional Official/Medical Center Director JCAHO = Joint Commission on Accreditation of Hospitals Organization ICVAMC = Iowa City Veterans Affairs Medical Center ISO = Information Security Officer LOI = Letter of Intent MCD = Medical Center Director MOU = Memorandum of Understanding NCI = National Cancer Institute NIDA = National Institute on Drug Abuse NIH = National Institutes of Health NRC = Nuclear Regulatory Commission NSF = National Science Foundation OBA = Office of Biotechnology Activities OHRP = Office of Human Research Protection ORD = Office of Research and Development ORO = Office of Research Oversight OSHA = Occupation Safety and Health Administration PHI = Protected Health Information 0e5236b1341d2f576017e1081d6e213e.doc Page 11 of 73 PO = Privacy Officer PRIM&R = Public Responsibility in Medicine and Research RCO = Research Compliance Officer RFP = Request for Proposal R&D = Research and Development RIO = Research Integrity Officer RR&D = Rehabilitation Research & Development RSC = Radiation Safety Committee SAE = Serious Adverse Event SOP = Standard Operating Procedures SRS = Subcommittee on Research Safety USH = Undersecretary for Health VERA = Veterans Equitable Resource Allocation VISN = Veterans Integrated Service Networks WOC = Without Compensation

11. ATTACHMENTS: A Consent (Documentation of Research Informed Consent) B Human Research Scope of Practice and Privileges Review C Audit of IRB Minutes D Institutional Responsibilities for Human Research Protection E IRB File Audit F Research Participant Outreach Program G Regulatory/Triennial Audit H Reporting Noncompliance in VA Human Research flowchart

0e5236b1341d2f576017e1081d6e213e.doc Page 12 of 73 ATTACHMENT A Documentation of Research Informed Consent Indicator/ Measurement Methodology

VA NJ HEALTH CARE SYSTEM

Performance Improvement - Indicator/ Measurement Methodology

1/16/09 version Process being measured: Consent (Documentation of Research Informed Consent)

Indicator statement or measure: 1. Correct ICD used (date/version) 2. Subject’s signature & date (subject’s legally authorized representative’s signature & date) 3. Witness’ signature & date 4. Person obtaining consent signature & date 5. Investigator’s signature 6. Consent is documented in a CPRS progress note (Computerized Patient Record System) 7. CPRS template used for all progress notes 8. All 11 points of required information are included in progress note I Name of protocol II Name of PI III What investigational drug is involved IV Instructions for breaking the blind of blinded investigational drug (if applicable) V How to contact the PI in case of emergency or under what conditions VI Any information that providers should know VII Date that written consent was obtained VIII The name of the person obtaining the subject’s consent IX A statement that the subject or the subject’s legally-authorized representative was capable of understanding the consent process X A statement that the study was explained to the subject XI A statement that the subject was given the opportunity to ask questions 9. Person obtaining consent completes an IDMC screening tool for each subject 10. HIPAA authorization form completed by subject 11. Authorized person obtained consent

Is the connection between the indicator statement and the process that is being measured self-explanatory? yes no If no, please describe: Signing and dating of the HIPAA Authorization and Consent form indicates that the research subject has been fully informed and has entered the research study with full knowledge and freely volunteered to participate.

Definition of Key Terms (Please see attachment for text): (1) The person obtaining consent has been formally delegated this role. (2) HIPPA Authorization Form

0e5236b1341d2f576017e1081d6e213e.doc Page 13 of 73 Consent Form Subject Legally authorized representative IRB

Data collection method:

Copies of executed consent forms, logs of research subjects and CPRS will serve as the data sources.

Continuing reviews are done on all human studies at least annually. In preparation for continuing review of research by the IRB, principle investigators submit a continuing review packet to the Research Service office. This packet contains a log of subjects who have been enrolled in the study. The packet also contains a copy of all the executed consent forms for each study subject enrolled since the last continuing review. The IRB file will be used to confirm formal delegation of the person obtaining consent. The log of subjects and the copies of the consent forms are provided to the reviewer by the IRB Program Assistant. CPRS will be used to confirm that consent has been documented in a research progress note, that the consent progress template has been used and that all 11 points of required information have been recorded in the progress note.

100% of consent forms submitted on continuing review will be audited for each protocol with completed consent forms during their continuing review period. The IRB protocol file will be examined to confirm that the person obtaining consent has been so designated on the Application to Undertake Research or on an Amendment. Research Scopes of Practice will also be used to confirm that obtaining consent is a delegated duty.

The results of the reviews are compiled and reported on a quarterly basis.

Sample size: (minimum: 5% or 30 cases whichever is greater; if there are less than 30 cases per quarter, 100% review is required) 100% per: quarter

Statistics to be tracked: mean or average median mode standard deviation rate other: ______

Calculations/Formula for rate:

Numerator: 2. The number of cases meeting the indicator

Denominator: 3. The number of cases reviewed for the indicator

Please Note: If issues regarding consent or patient rights are identified through the course of this review, those findings will be reported as comments or other findings.

0e5236b1341d2f576017e1081d6e213e.doc Page 14 of 73 In addition to tracking your results on a data aggregate, how do you plan to display this data? run chart histogram other chart control chart bar graph undecided May use Run Chart and Bar Graph

Comparative Data Source (if any): None

Trigger for More Extensive Evaluation Method of Extensive Evaluation pre-established threshold of ______case review sentinel event focused study statistical control limits peer review significant deviation from comparative data CQI process review other: Individual cases of non- other (TBA) compliance will be communicated to PI’s.

Reference(s): The Common Rule: Title 38 Code Of Federal Regulations Part 16--Protection Of Human Subjects (The Common Rule Is Identical To Subpart A Of 45 CFR 46 HHA regulations). Department Of Veterans Affairs, VHA Handbook 1200.5, Veterans Health Administration, Requirements For The Protection Of Human Subjects In Research HHS' Research Guidance (April 17, 2003) for HIPAA http://privacyruleandresearch.nih.gov/pdf/HIPAA_Privacy_Rule_Booklet.pdf Memorandum: HIPAA Privacy Rule Compliance Steps, April 4, 2003, from Chief Research and Development Officer (12)

a) Guidance from the DHHS Office of Civil Rights (OCR) HIPAA Privacy, December 3, 2002, Revised April 3, 200, Standards For Privacy Of Individually Identifiable Health Information [45 CFR Parts 160 and 164] DHHS HIPAA Q&A http://answers.hhs.gov/cgi-bin/hhs.cfg/php/enduser/std_alp.php

Attachment Key Definitions The person obtaining consent has been formally delegated this role: The name of person designated to obtain consent must be on the Application to Undertake Research or on an amendment to the protocol. Obtaining Consent must be delegated on the Research Scope of Practice if applicable.

HIPPA Authorization Form: Health Insurance Portability and Accountability Act of 1996 (“HIPAA”) Privacy of Individually Identifiable Health Information 45 CFR Parts 160 and 164 (“Privacy Rule”). By signing this document, the subject authorizes the Veterans Health Administration (VHA) to provide the Principal Investigator and his or her research team to use and disclosure the individually identifiable health information about the subject. The subject is informed of the use of the information. The subject is informed of their rights and potential risks 0e5236b1341d2f576017e1081d6e213e.doc Page 15 of 73 related to the disclosure of this information. Consent Form: Documents that an informed consent process has taken place that includes the following Basic Elements of Informed Consent For Research. (a) Consent for Research Will Contain The Following Basic 8 Elements (1) 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; (2) A description of any reasonably foreseeable risks or discomforts to the subject; (3) A description of any benefits to the subject or to others which may reasonably be expected from the research; (4) A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject; (5) A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained; (6) 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; (7) 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 research-related injury to the subject; and (8) A statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled. (b) Additional elements of informed consent. When appropriate, one or more of the following elements of information shall also be provided to each subject: (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) which 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; (3) Any additional costs to the subject that may result from participation in the research; (4) The consequences of a subject's decision to withdraw from the research and procedures for orderly termination of participation by the subject; (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; and (6) The approximate number of subjects involved in the study. If someone other than the investigator conducts the interview and obtains consent from a subject, the investigator needs to formally delegate this responsibility, and the person so delegated must have received appropriate training to perform this activity. The person so delegated must be knowledgeable about the research to be conducted and the consenting process, and must be able to answer questions about the study. a. An investigator must seek such consent only under circumstances that: (1) Provide the prospective subject or the subject’s legally-authorized representative sufficient opportunity to consider whether or not to participate, and (2) Minimize the possibility of coercion or undue influence. b. The information that is given to the subject or the subject’s representative must be in language understandable to the subject or the subject’s representative. c. No informed consent, whether oral or written, may include any exculpatory language through which the subject or the subject’s 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, or its agents from liability for negligence. d. Department of Veterans Affairs (VA) Form 10-1086, Research Consent Form, or an electronic version of VA Form 10-1086, must be used as the consent form, and all required elements must be completed. Subject: A living human 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. Legally authorized representative: An individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject's participation in the procedure(s) involved in the research.

0e5236b1341d2f576017e1081d6e213e.doc Page 16 of 73 IRB: Institutional Review Board (IRB). An IRB is a board established in accordance with and for the purposes expressed in the Common Rule (38 CFR 16.102), (the federal and VA policy for protection of human subjects). Within VHA, an IRB was formerly known as the Subcommittee on Human Studies. At VA medical centers, the IRB is a subcommittee of the Research and Development (R&D) Committee. IRB approval is required for Research HIPAA Authorization forms and Research Consent forms.

0e5236b1341d2f576017e1081d6e213e.doc Page 17 of 73 ATTACHMENT B Human Research Scope of Practice and Privileges Review Indicator/ Measurement Methodology VA NJ HEALTHCARE SYSTEM Research Compliance Performance Improvement Indicator/ Measurement Methodology Reviewed and Current May 9, 2008 (No change from Version # 1, Date: October 2, 2007) Process being measured: Human Research Scope of Practice and Privileges Review

Indicator statement or measure: Type: Each human research study staff person is confirmed to be working PROCESS within their Research Scope of Practice or Clinical Privileges

Is the connection between the indicator statement and the process that is being measured self- explanatory? yes no

Definition of Key Terms: Research Scope of Practice: Duties requested by research staff person, assigned by principal investigator and approved by Service Chief and ACOS R&D as a required part of research credentialing. This is documented on a Research Scope of Practice form. A research scope of practice is required for all human research study staff who conduct study procedures with human subjects or who have access to research data (except for the PI and medical staff who are credentialed and privileged through the VetPro program (MD, DO, Podiatrist, Optometrist, Dentist, Clinical Psychologist). Clinical Privileges: Medical procedures that may be performed by a medical staff person as formally assigned by a professional standards board. (MD, DO, Podiatrist, Optometrist, Dentist, Clinical Psychologist)

Data collection method: (briefly describe in narrative format how data will be collected and what sources will be used such as service logs, the patient record, the DHCP) PI’s complete form: Human Research Scope of Practice and Privileges Review with IRB continuing review requests. 1) The form first asks PI’s to  Review the duties of each member of the study staff,  Review each staff persons research scope of practice or clinical privileges and  Update the research scope of practice or revise duties as necessary. 2) The PI is then instructed to list all members of the research staff and indicate whether or not they are working within their research scope of practice or clinical privileges.

0e5236b1341d2f576017e1081d6e213e.doc Page 18 of 73 3) If not, the form asks for an explanation and remedial action. The Human Research Scope of Practice and Privileges Review forms are submitted by the PI to the IRB office and forwarded to the Research Compliance Officer by the IRB intake staff person. The Research Compliance Officer provides a report to help fulfill R&D Committee oversight responsibilities.

Sample size: 100% PER QUARTER

Statistics to be tracked: MEAN OR AVERAGE

By Individual Staff Person - Numerator: The number of study staff persons working within their Research Scopes of Practice or Clinical Privileges as reported on Human Research Scope of Practice and Privileges Review forms ______

Denominator: The number of study staff persons as reported on Human Research Scope of Practice and Privileges Review forms ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

By Study - Numerator: The number of studies where all study staff persons are working within their Research Scopes of Practice or Clinical Privileges as reported on Human Research Scope of Practice and Privileges Review forms ______

Denominator: The number studies with study staff on Human Research Scope of Practice and Privileges Review forms

In addition to tracking your results on a data aggregate, how do you plan to display this data? UNDECIDED

Comparative Data Source (if any): None Trigger for More Extensive Evaluation Method of Extensive Evaluation Cases where the PI indicates that any study staff are not Case Review working within their Research Scope of Practice or Clinical Privileges Reference(s): The Research and Development (R&D) Committee Handbook 1200.1

0e5236b1341d2f576017e1081d6e213e.doc Page 19 of 73 ATTACHMENT C IRB Minutes Indicator/ Measurement Methodology

VA NJ HEALTH CARE SYSTEM Research Compliance Performance Improvement - Indicator/ Measurement Methodology Process being measured: IRB Minutes Version 10a. Reviewed and Current 5/9/08 IRB Minutes Process Improvement Indicators

For Initial Reviews, are indicators (1 – 30) addressed? For Continuing Reviews, are indicators (1 – 38) addressed? For Expedited Reviews, are indicators (39 – 40) addressed?

INITIAL REVIEWS 1. Summary of the study Vulnerable Subjects 2. Will some or all subjects likely to be vulnerable to coercion or undue influence? 3. Reasons for including vulnerable subjects (prisoners, pregnant women, fetuses, children, mentally disabled, economically or educationally disadvantage and those likely to be vulnerable to coercion or undue influence) 4. Additional safeguards to protect the rights and welfare of vulnerable subjects 5. Presence of IRB member or consultant knowledgeable or experienced with the vulnerable population 6. Three criteria for approval of subjects with IDMC (separate IRB Primary Reviewer Worksheet) 7. Selection of subjects is equitable (inclusion and exclusion, recruitments, purpose, setting) 8. Anticipated benefits and importance of knowledge 9. Risks of research 10. When appropriate, adequate provisions for monitoring the data collected to ensure safety of subjects Minimizing Risks 11. Risks have been minimized by using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk 12. Risks have been minimized, whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes 13. Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result (“Risk/Benefit Ratio”) 14. Risk level 15. Continuing review interval based on risk Privacy 16. The Setting, Methods and Circumstances for identifying subjects, obtaining information and conducting research Respect The Individual’s Privacy 17. Methods to obtain data 18. The research plan makes adequate provisions to protect the privacy interests of subjects Confidentiality 19. Protecting confidentiality (anonymous, coding, link destruction, etc.) 20. The research plan makes adequate provisions to maintain the confidentiality of data 21. Adequacy of Resources for human protection, care of subjects & safety during conduct of the research Consent/Waiver/Waiver of Documentation of Consent and HIPAA Authorization/Waiver 0e5236b1341d2f576017e1081d6e213e.doc Page 20 of 73 22. Consent form Basic Elements are present OR Waiver of Documentation of Consent criteria are met 23. Consent form Applicable Additional Elements are present 24. Consent Process Is Appropriate OR criteria for Waiver Of Consent are met 25. Is research FDA regulated? (Applicable when waiver of consent or waiver of documentation of consent are being considered) 26. HIPAA authorization is present and complete OR HIPAA Waiver criteria are met Devices 27. Is a research device being used? 28. Risk level of investigational DEVICES (SR/ NSR) (Significant Risk/ Non-Significant Risk) 29. Chair summarizes discussion: controverted & resolution; basis for requiring changes or disapproving research 30. Action: A) Approve, B) Approve with Modifications to Full IRB, C) Approve with Modifications via Administrative Review, D) Table, E) Disapprove CONTINUING REVIEWS (additional review items) 31. Review of AE’s 32. Investigator’s Brochure amended or updated 33. Research findings to date, including subject experiences 34. Summary of safety monitoring 35. Enumeration of subjects withdrawn and reasons 36. Review of unanticipated problems involving risks to subjects 37. New information that may change the risk/benefit ratio 38. Does project needs verification from sources other than the investigator that no material changes (serious non-compliance) have occurred since the previous IRB review? If YES: A) Internal inconsistency and resolution to be requested of investigator OR B) Instructions for obtaining verification (other source). EXPEDITED REVIEWS (additional review items) 39. The regulatory basis for approval of expedited review is cited 40. The study specific characteristics, that qualify the study to be expedited, are described

Review of Consent form basic and additional elements may be documented in the minutes as general statements or may (no requirement) specifically address any of the following: A. Consent Forms—Basic Elements 1. a statement that the study involves research 2. an explanation of the purposes of the research 3. the expected duration of the subject’s participation 4. a description of the procedures to be followed 5. identification of any experimental procedures 6. a description of any reasonably foreseeable risks or discomforts to the subject 7. a description of any benefits to the subject or to others, which may reasonably be expected from research 8. a disclosure of appropriate alternative procedures or courses of treatment (if any) that might be advantageous to the subject 9. a statement describing the extent (if any) to which confidentiality of records identifying the subject will be maintained 10. a statement that the FDA may inspect the records 11. for research involving more than minimal risk, an explanation as to whether any compensation exists if injury occurs 12. for research involving more than minimal risk, 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 and an explanation of whom to contact in the event of a research-related injury to the subject 13. an explanation of whom to contact for answers to pertinent questions about research and research subjects’ rights 14. a statement that participation is voluntary 15. a statement that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled 16. a statement that the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled. B. Consent Forms—Additional Elements, When appropriate 1. risks which are currently unforeseeable (a) a statement that the particular treatment or procedure may involve risks to the subjects which are currently unforeseeable 0e5236b1341d2f576017e1081d6e213e.doc Page 21 of 73 (b) a statement that the particular treatment or procedure may involve risks to the embryo or fetus, (if the subject is or may become pregnant) which 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 3. any additional costs to the subject that may result from participation in the research, consistent with the 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 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 6. the approximate number of subjects involved in the study C. Consent Forms—Payment and Exculpatory Language 1. include information concerning the amount of payment to subjects 2. include information concerning the schedule of payments to subjects 3. do not include any exculpatory language through which the subject or the subject’s legally authorized representative is made to waive or to appear to waive any of the subject’s legal rights, or releases or appears to release the investigator, the sponsor, the institution or its agents from liability for negligence. The following types of studies require additional elements of informed consent: 1. any study that involves currently unforeseeable risks to the subject (or to an embryo or fetus, if the subject is or may become pregnant) should include information about these risks in the informed consent document stating these risks. This is especially true with studies conducted under an Investigational New Drug Application (IND) or Investigational Device Exemption (IDE). 2. any study in which the protocol outlines circumstances under which the subject’s participation may be terminated by the investigator, without regard to the subject’s consent, requires a statement identifying these anticipated circumstances under which the investigator may terminate the subject’s participation. An unexplained statement that the investigator and/or the sponsor may withdraw subjects at any time does not adequately inform the subject of anticipated circumstances of withdrawal. 3. if subjects may incur additional costs because they are participating in research, the costs should be explained. Some insurance and/or other reimbursement mechanisms may not fund care that is delivered in a research context. 4. when withdrawal from a research study may have deleterious effects on the subject’s health or welfare, the informed consent must explain any withdrawal procedures necessary for the subject’s safety and state why they are important to the subject’s welfare. 5. any study in which the subject’s participation is expected to continue over a period of time during which new findings may become available requires a statement that significant new findings developed during the course of the research that may relate to the subject’s willingness to continue participation will be provided to the subject. 6. if the IRB determines that the number of subjects in a study is material to the subject’s decision to participate, the informed consent document must state the approximate number subjects involved in the study. This is particularly true in studies involving small numbers of subjects, as in Phase 1 and 2 studies.

What is the rationale for this performance improvement review? The intent of this performance improvement activity is to continually improve the IRB’s ethical consideration of issues for approval of research and the documentation of these issues in the minutes. There are regulatory and accreditation requirements that the basis for IRB approval be documented in minutes. As stated in our IRB Records and Retention SOP: IRB Meetings will be documented through Minutes for each meeting: 1. IRB actions are documented (including separate deliberations for each action and the basis for requiring modifications and for disapproving research) 2. Discussions are documented and findings and determinations noted (including risk level and requirements for the approval of research [per Title 38 CFR 16] and a summary of the discussion of controverted issues and their resolution) 3. The minutes document IRB determinations required by the regulations, and protocol-specific findings justifying those determinations (including: exemption, qualification for expedited review, waiver of HIPAA Authorization, waiver of consent and waiver of documentation of consent). 4. Statements of significant new findings provided to participants when reviewed at an IRB meeting, must be documented in the minutes. [VHA Handbook 1200.5 7.i(6)]

Is the connection between the indicator statement and the process that is being measured self-explanatory? yes no If no, please describe: 0e5236b1341d2f576017e1081d6e213e.doc Page 22 of 73 Definition of Key Terms: IRB: Institutional Review Board (Human Studies Sub-Committee of the Research and Development Committee)

Data collection method: IRB Minutes will be reviewed.

Sample size: (minimum: 5% or 30 cases whichever is greater; if there are less than 30 cases per quarter, 100% review is required) the IRB minutes from at least two meetings will be reviewed per: quarter

Statistics to be tracked: rate

Calculations/Formula for rate: Numerator: Number times that the indicator was met in the minutes reviewed Denominator: Number times that the indicator was applicable in the minutes reviewed In addition to tracking your results on a data aggregate, how do you plan to display this data? table

Trigger for More Extensive Evaluation Method of Extensive Evaluation other: Patterns of non-compliance, opportunities other: Research Service and the IRB will be for process improvement and education will be consulted regarding non-compliance and process pursued. improvement.

Reference(s): 1. VHA Handbook 1200.5 Requirements for the Protection of Human Subjects Of Research 2. Title 38 CFR 16 IRB Records and Retention, VA New Jersey Health Care System Research SOP

Orval Gautier, M.Ed., CIP, Research Compliance Officer

0e5236b1341d2f576017e1081d6e213e.doc Page 23 of 73 Attachment D VA NJ HEALTHCARE SYSTEM Research Compliance Performance Improvement Indicator/ Measurement Methodology

Version # 10.a Date: 8/28/10 Institutional Responsibilities for Human Research Protection

INDICATOR STATEMENT OR MEASURE: Indicators from 2009 Institutional Responsibilities for Human Research Protection Audit 1. The R&DC determines the extent to which the R&D Program has met its annual objectives for the research program. 2. Instructions on IRB modification letter no longer tell PI to address the stipulations by a date that is after expiration of approval. Referred to: IRB Coordinator

FWA and IRB Registration 3. FWA is current, accurate and complete 4. The membership rosters the facility’s IRBs of record are current. 5. All changes in IRB membership have been reported to OHRP through ORO. 6. IRB records contain a resume or CV for each member

Training and Credentialing 7. Records (file and database) document that all human research staff (including WOC appointees) are appropriately credentialed (including research scopes of practice where applicable). 8. All individuals involved in the conduct of human research have received appropriate human research protection training on an annual basis. (CITI or approved alternative) [Also above - Issue from 2009 Audit] a. ACOS/R (or C/R&D) b. Administrative Officer/Research (AO/R) c. R&DC d. IRB e. All research investigators and study coordinators, f. All relevant administrative staff, and relevant support staff g. Research Compliance Officers h. All persons administering, working in, or (as warranted) visiting research areas 9. All individuals involved in research have completed Information Security 201 for Research and Development Personnel (one time training). [Also above - Issue from 2009 0e5236b1341d2f576017e1081d6e213e.doc Page 24 of 73 Audit] a. ACOS/R (or C/R&D) b. Administrative Officer/Research (AO/R) c. R&DC d. IRB e. All research investigators and study coordinators, f. All relevant administrative staff, and relevant support staff g. Research Compliance Officers h. All persons administering, working in, or (as warranted) visiting research areas 10. Credentialing procedures are consistent with VANJHCS Research Credentialing Policy

Directors Research Oversight Certification 11. The Human Research Protection Program (HRPP) has sufficient resources and administrative support to perform their responsibilities satisfactorily, including sufficient personnel, space, equipment, engineering support, and technical assistance 12. Cooperative R&D Agreements (CRADAs) and other written agreement(s) for collaborative research projects or research oversight arrangements are current, accurate, and complete 13. MOU(s) and System Interconnection Agreement(s) approved by the facility ISO and Office of Information and Technology (OI&T) management for any interconnections with information systems outside VA, including those of the facility’s academic affiliate(s) are current, accurate, and complete. 14. Data Transfer Agreements are current, accurate, and complete 15. All required reports to oversight and accreditation bodies (AAHRPP submissions) are current, accurate, and complete 16. Facility maintains policies, and SOPs that are current, accurate, and complete a. Human Research Protection Program (HRPP) b. SOPs for the R&DC c. SOPs for the IRB 17. Required program assessment has been performed, and the Facility Director received and reviewed the report: Verification that all research involving human subjects has been reviewed by the PO and the ISO 18. Required program assessment has been performed, and the Facility Director received and reviewed the report: Review and recommendations regarding budgetary and resource needs 19. Required program assessment has been performed, and the Facility Director received and reviewed the report: Review of the HRPP 20. Required program assessment has been performed, and the Facility Director received and reviewed the report: Review of all R&DC Subcommittees 21. Required program assessment has been performed, and the Facility Director received and reviewed the report: Quality Assurance (QA) review of publications listing VA support and affiliation 22. Required program assessment has been performed, and the Facility Director received and reviewed the report: QA review of CRADAs Pending Issues in Research 8/19/10 23. Procedure for developing and managing SOPs and Forms including annual review (HRPP SOP. Long standing practice) 24. Written procedure for ACOS to notify IRB and R&D Committee of potential institutional conflict of interest (AAHRPP – Instructions from ORD. 11/12/09)

0e5236b1341d2f576017e1081d6e213e.doc Page 25 of 73 25. Reporting SOPs per Handbook 1058.01) 26. Written procedures describe review of each protocol by the ISO to ensure compliance with all VA and VHA requirements for use, disclosure, storage, transfer, and security of research information. Referred to: IRB Coordinator(Regulatory – Directive 2007-040) 27. Revise policy and procedures to require PIs who are not credentialed and privileged through VetPro to have a Research Scope of Practice 28. Process to screen and track unlicensed clinical staff for credentialing through VetPro per Directive 2009-054. (Regulatory. Directive 2009-054. 11/2/09) 29. Survey on the operation of the IRB (Annual Report to R&D Committee) (Accreditation and SOP. Long standing requirements) 30. Evaluation and Revision of the Outreach efforts (Annual Report to R&D Committee) (Accreditation and SOP. Long standing requirement)

Posted On The VBRI Website, Accessible To All Research Personnel: Federal Regulatory Reference Materials 31. DVA regulations codified in 38 CFR 16, 17.33 & 17.85 32. FDA regulations codified in 21 CFR 50, 56, 312, 600 & 812 33. DHHS regulations codified in 45 CFR 46 VHA Handbooks 34. VHA Handbook 1108.04 Investigational Drugs and Supplies 35. VHA Handbook 1200.5 Requirements for the Protection of Human Subjects In Research 36. VHA R&D Handbook 1200.1 March 2007 37. VHA Handbook 1058.01 Research Compliance Reporting Requirements Historical Reference Documents 38. Nuremberg Code 39. Declaration of Helsinki 40. Belmont Report

Is the connection between the indicator statement and the process that is being measured self-explanatory? yes no If no, please describe: There are a number of aspects of human research protection that the institution is responsible for in order to maintain a foundation for protection of subjects. This audit is designed to examine the institution’s compliance with some of the key responsibilities. Indicators have been drawn from the following sources: 1. Previously identified issues from earlier audits 2. FWA and IRB registration which represent an agreement between the facility and the DHHS Office of Human Research Protection for maintaining procedures and compliance with regulations and ethics for human research protection. 3. Training and credentialing of staff working in human research 4. Responsibilities for supporting and overseeing the human research program identified in the annual Director’s Research Oversight Certification 5. Pending issues in research (at the VA NJ HCS) as of 8/18/10 6. Regulatory and historical references

Definition of Key Terms: 1. R&DC Research and Development Committee. The R&D Committee is responsible, through the Chief of Staff (COS) to the medical center Director for: (1) Advising and assisting the medical center Director in providing oversight, planning, and execution of the local research Program; and 0e5236b1341d2f576017e1081d6e213e.doc Page 26 of 73 (2) Assisting the medical center Director in maintaining high standards throughout the R&D Program. 2. FWA Federal Wide Assurance. Signed by the Director; this is an agreement to protect human subjects and comply with regulatory requirements. 3. IRB IRB (Institutional Review Board) The IRB is an administrative body established to protect the rights and welfare of human research subjects recruited to participate in research activities conducted under its jurisdiction. The IRB is a subcommittee of the R&D Committee. Research under the IRB’s jurisdiction includes all research involving human subjects that is conducted completely or partially in VA NJ Health Care System facilities, approved off-site locations, and/or conducted by VA NJ HCS employees while on official VA duty time. The IRB must be and must be perceived to be fair and impartial, immune from pressure either by the institution's administration, the investigators whose protocols are brought before it, or other professional and nonprofessional sources. The IRB has the authority to approve, require modifications in, or disapprove all human studies research activities as specified by both the Federal regulations and local policy. Research that has been reviewed and approved by an IRB is subject to review and disapproval by the R&D Committee, however, the R&D Committee may not approve research if it has been disapproved by the IRB. The IRB must comply with the requirements of all relevant regulatory and compliance enforcement agencies or offices, including VHA Office of Research Oversight (ORO), DHHS Office of Human Research Protection (OHRP), and Food and Drug Administration (FDA). 4. OHRP Office for Human Research Protection. The Office for Human Research Protections (OHRP) provides leadership in the protection of the rights, welfare, and wellbeing of subjects involved in research conducted or supported by the U.S. Department of Health and Human Services (HHS). OHRP helps ensure this by providing clarification and guidance, developing educational programs and materials, maintaining regulatory oversight, and providing advice on ethical and regulatory issues in biomedical and behavioral research. 5. ORO Office of Research Oversight ORO serves as the primary VHA office in advising the Under Secretary for Health and exercising oversight concerning all matters of research compliance and assurance, including human subject protections, laboratory animal welfare, research safety, research laboratory security, research information security, research misconduct, debarment for research impropriety, and other matters that the Under Secretary for Health may assign.ORO is also responsible for developing and conducting research compliance officer education programs as directed by the Under Secretary for Health.

0e5236b1341d2f576017e1081d6e213e.doc Page 27 of 73 6. WOC Without Compensation

7. CITI The Collaborative Institutional Training Initiative (CITI) was founded in March 2000 as a collaboration between the University of Miami and the Fred Hutchinson Cancer Research Center to develop a web based training program in human research subjects protections. 8. Cooperative Cooperative Research and Development Agreement R&D The Federal Technology Transfer Act of 1986, Public Law (Pub. L.) Agreements 99-502 created CRADAs to serve as a flexible form of agreement (CRADAs) between Federal and non-Federal organizations for establishing the terms of collaborative research efforts. CRADAs were specifically designed to respect both government and non-governmental organizations’ rights to intellectual property in order to foster translation of research results into commercial products. CRADAs, which are legally binding on all parties, allow the VA to establish ownership and licensing rights to inventions in advance. 9. MOU Memorandum of Understanding

10 Data Agreements for release or exchange of data between VA and outside . Transfer agency or within VA. Agreement 11 AAHRPP Association for the Accreditation of Human Research Protection . Programs.

12 SOP Standard Operating Procedure .

13 ACOS Associate Chief of Staff .

14 ISO Information Security Officer .

15 VetPro VetPro . Federal Credentialing Program for Healthcare Providers The NIH Computer Center hosts VetPro—a Web-based physician credentialing system for federal agencies that employ healthcare providers. VetPro increases the efficiency and accuracy of the credentialing process—it allows for accurate and complete credentials to be obtained once, electronically banked, and retrieved for review and updating in a secure Web-based environment. VetPro was created by the Federal Credentialing Program (FCP), which is responsible for developing a uniform healthcare credentialing process. 16 VBRI Veterans Biomedical Research Institute New Jersey . Mission: To support all medical research and education programs for veterans in the New Jersey VBRI is a nonprofit organization incorporated in the State of NJ.

0e5236b1341d2f576017e1081d6e213e.doc Page 28 of 73 The VBRI websites provides access to the VA New Jersey Health Care System Research announcements, procedures, forms and links

Data collection method: (briefly describe in narrative format how data will be collected and what sources will be used such as service logs, the patient record, the DHCP)

DATA COLLECTION METHOD

Indicators from 2009 Institutional Responsibilities for Human Research Protection Audit 1. The R&DC determines the extent to which the Review of R&DC minutes. R&D Program has met its annual objectives 2. Instructions on IRB modification letter no Review of IRB modification letters in longer tell PI to address the stipulations by a IRB file. date that is after expiration of approval.

FWA and IRB Registration 3. FWA is current, accurate and complete Review of FWA (obtain from AO R&D or ACOS R&D) 4. The membership rosters the facility’s IRBs of Review of FWA (obtain from IRB record are current. Coordinator) 5. All changes in IRB membership have been Interview IRB Coordinator reported to OHRP through ORO. 6. IRB records contain a resume or CV for each Review IRB records maintained by member IRB Coordinator

Training and Credentialing Review Research Service Indicators 7-10 Credentialing Database

DATA COLLECTION METHOD

Directors Research Oversight Certification 11. The Human Research Protection Program R&DC minutes. Alternatively, (HRPP) has sufficient resources interview: IRB Chair, IRB Coordinator, ACOS R&D 12. Cooperative R&D Agreements (CRADAs) are R&DC minutes. Alternatively, current, accurate, and complete interview: Executive Director VBRI 13. MOU(s) are current, accurate, and complete. Interview: ISO and Review MOUs 14. Data Transfer Agreements are current, accurate, Interview: ISO and and complete Review Data Transfer Agreements 15. All required reports to oversight and Interview: AO Research and accreditation bodies (AAHRPP submissions) Development are current, accurate, and complete 16. Facility maintains policies, and SOPs that are Review a sample of 10 SOPs current, accurate, and complete Program assessment has been performed, and the R&DC Minutes Facility Director received and reviewed the report: 0e5236b1341d2f576017e1081d6e213e.doc Page 29 of 73 Indicators 17 - 22

Pending Issues in Research 8/18/10 23. Procedure for developing and managing SOPs Interview: IRB Coordinator and Forms including annual review 24. Written procedure for ACOS to notify IRB and Review Research Conflict of Interest R&D Committee of potential institutional SOP conflict of interest 25. Reporting SOPs per Handbook 1058.01) Review Reporting SOPs 26. Written procedures describe review of each Review SOP. Consult with IRB protocol by the ISO Coordinator 27. Revise policy and procedures to require PIs who Review VA New Jersey Health Care are not credentialed and privileged through System Research Credentialing VetPro to have a Research Scope of Practice Policy. Consult with AO Research Service 28. Process to screen and track unlicensed clinical Interview AO Research Service and staff for credentialing through VetPro or ACOS R&D. Review tracking records 29. Survey on the operation of the IRB (Annual R&D Committee Minutes. Consult Report to R&D Committee) with Research Service AO 30. Evaluation and Revision of the Outreach efforts R&D Committee Minutes. Consult (Annual Report to R&D Committee) with Research Service AO

Posted On The VBRI Website, Accessible To All Research Personnel: Federal Regulatory Reference Materials Review VBRI Website Indicators 31 - 40

Sample size: (minimum: 5% or 30 cases whichever is greater; if there are less than 30 cases per quarter, 100% review is required) Compliance with each indicator will be evaluated. For training and credentialing, all applicable cases in the credentialing database will be reviewed.

Statistics to be tracked:  mean or average  median  mode  standard deviation  rate other: Not determined

Numerator: The number of indicators where compliance is demonstrated ______

Denominator: The number of applicable indicators

In addition to tracking your results on a data aggregate, how do you plan to display this data?  run chart  histogram  other chart  control chart  bar graph undecided

Comparative Data Source (if any): 0e5236b1341d2f576017e1081d6e213e.doc Page 30 of 73 None

Trigger for More Extensive Evaluation Method of Extensive Evaluation  pre-established threshold of ______ case review  sentinel event focused study  statistical control limits  peer review  significant deviation from comparative data CQI process review x other: issues out of compliance will be pursued  other (TBA)

Reference(s):

2009 Institutional Responsibilities for Human Research Protection Process Improvement Report Veterans Health Administration (VHA) 2010 Facility Director’s Certification Of Research Oversight

0e5236b1341d2f576017e1081d6e213e.doc Page 31 of 73 Attachment E

VA NJ HEALTH CARE SYSTEM Research Compliance

Performance Improvement - Indicator/ Measurement Methodology (IMM) Version 1. August 29, 2010 IRB File Audit

This audit utilizes indicators from the Institutional Responsibilities Audit Version 9., July 24, 2009

Indicators are in 4 sections: A – D

A. Exempt [3 Indicators] B. Device Research [1 Indicator] C. Full Board Reviews [52 Indictors] D. Expedited Reviews [55 Indictors]

Indicator statement or measure: A. Exempt [3 Indicators] 1. Did the research meet the regulatory requirements for use of exempt allowable categories of research? 2. Did an authorized individual (IRB Chairperson or designate, institutional official) conduct the exempt review action? 3. For review of exempt research, IRB records contain a statement explaining under which category listed in the regulations the study qualifies as exempt.

B. Device Research [1 Indicator] 1. Copy of the sponsor's risk assessment and rationale used in making its risk determination for investigational devices.

C. Full Board Reviews [52 Indictors] IRB Project Files include: 1. Study protocol with abstract. 2. Grant application (for federally funded research). 3. Clinical Investigator’s brochure. 4. Study advertising material. 5. Approved informed consent (VA Form 10-1086). 6. Copy of Investigational Drug Information Record VA Form 10-9012. 7. Copy of Report of Subcommittee on Human Studies VA Form 10-1223. INITIAL REVIEW GENERAL EVALUATION 8. Do the new protocol application materials describe where the research (setting) is to be conducted? 9. Do the new protocol application materials contain information concerning the reasons for including vulnerable subjects in the research? 0e5236b1341d2f576017e1081d6e213e.doc Page 32 of 73 10. Do the new protocol application materials contain information addressing additional safeguards included to protect the rights and welfare of vulnerable subjects? RISK/BENEFIT EVALUATION 11. Do the new protocol application materials contain information about the anticipated benefits of the research to research subjects? 12. Do the new protocol application materials contain information about the importance of the knowledge that may be reasonably expected to result from research? 13. Do the new protocol application materials contain information about the purpose of the study? 14. Do the new protocol application materials contain information about the study design? 15. Do the new protocol application materials contain information about provisions for safety monitoring? 16. Do the new protocol application materials identify physical, psychological, social, and/or economic risks that may result from participation in the research? 17. Do the new protocol application materials describe steps that are taken to minimize physical, psychological, social, and/or economic risks that may result from participation in the research? SUBJECT SELECTION AND RECRUITMENT 18. Do the new protocol application materials contain information that describes the methods used to identify and recruit potential subjects? 19. Do the new protocol application materials contain information about scientific and ethical justification for excluding classes of persons who might benefit from the research? 20. Do new protocol application materials contain subject inclusion criteria? 21. Do the new protocol application materials contain subject exclusion criteria? 22. Do the new protocol application materials contain information about the nature of compensation offered to subjects for participation in the research? 23. Do the new protocol application materials contain information about proposed advertisements and other recruitment methods for subjects? CONFIDENTIALITY 24. Do the new protocol application materials describe methods used to obtain information about participants? 25. Do the new protocol application materials describe provisions for protecting the confidentiality of research data? IRB DECISIONS 26. If the proposed research protocol was approved, did the IRB document in correspondence the continuing review interval? CONTINUING REVIEW In Addition to Initial Review 27. The IRB review took place prior to expiration of the continuing review period or evidence that the IRB did not allow the study to continue if continuing review expired 28. Brief summary of the research methodology and procedures 29. Number of subjects entered for the review period and since the inception of the research project 30. Number of subjects withdrawn (including the reasons for withdrawal) for the review period and since the inception of the research project 31. The gender and minority status of those entered into the protocol 32. Number of subjects considered as members of specific vulnerable populations 33. A copy of the proposal and all approved amendments 34. A copy of the current approved informed consent form 35. A copy of the current HIPAA Authorization document

0e5236b1341d2f576017e1081d6e213e.doc Page 33 of 73 36. Information that may impact on the risk/benefit 37. Research findings to date, if available. 38. Research findings to date, including summary of subject experiences (benefits, adverse reactions) 39. Subject complaints 40. New scientific findings in the literature, or other relevant finds, that may impact on the research. 41. Statements of significant new findings provided to the subjects. 42. A summary of the DSMB or DMC meetings (if applicable) or findings based on information collected by the data and safety monitoring plan submitted in the initial proposal. 43. Assurance that all SAEs and UAEs have been reported. 44. Summary of unexpected and serious adverse events, as well as injuries to subjects 45. Requests to change and/or amend protocol after study initiation and IRB actions on each. 46. Amended or updated Investigator’s Brochures 47. All written communications regarding the study to and from the PI and IRB including approval letters. 48. Approved HIPAA Authorization 49. Documentation of protocol violations 50. Documentation of non-compliance with the applicable regulations 51. Protocol Abstract 52. Final report IRB determination for continuing review

D. Expedited Reviews [55 Indictors] IRB Project Files include:

1. Study protocol with abstract. 2. Grant application (for federally funded research). 3. Clinical Investigator’s brochure. 4. Study advertising material. 5. Approved informed consent (VA Form 10-1086). 6. Copy of Investigational Drug Information Record VA Form 10-9012. 7. Copy of Report of Subcommittee on Human Studies VA Form 10-1223. INITIAL REVIEW GENERAL EVALUATION 8. Do the new protocol application materials describe where the research (setting) is to be conducted? 9. Do the new protocol application materials contain information concerning the reasons for including vulnerable subjects in the research? 10. Do the new protocol application materials contain information addressing additional safeguards included to protect the rights and welfare of vulnerable subjects? RISK/BENEFIT EVALUATION 11. Do the new protocol application materials contain information about the anticipated benefits of the research to research subjects? 12. Do the new protocol application materials contain information about the importance of the knowledge that may be reasonably expected to result from research? 13. Do the new protocol application materials contain information about the purpose of the study? 14. Do the new protocol application materials contain information about the study design? 15. Do the new protocol application materials contain information about provisions for safety

0e5236b1341d2f576017e1081d6e213e.doc Page 34 of 73 monitoring? 16. Do the new protocol application materials identify physical, psychological, social, and/or economic risks that may result from participation in the research? 17. Do the new protocol application materials describe steps that are taken to minimize physical, psychological, social, and/or economic risks that may result from participation in the research? SUBJECT SELECTION AND RECRUITMENT 18. Do the new protocol application materials contain information that describes the methods used to identify and recruit potential subjects? 19. Do the new protocol application materials contain information about scientific and ethical justification for excluding classes of persons who might benefit from the research? 20. Do new protocol application materials contain subject inclusion criteria? 21. Do the new protocol application materials contain subject exclusion criteria? 22. Do the new protocol application materials contain information about the nature of compensation offered to subjects for participation in the research? 23. Do the new protocol application materials contain information about proposed advertisements and other recruitment methods for subjects? CONFIDENTIALITY 24. Do the new protocol application materials describe methods used to obtain information about participants? 25. Do the new protocol application materials describe provisions for protecting the confidentiality of research data? IRB DECISIONS 26. If the proposed research protocol was approved, did the IRB document in correspondence the continuing review interval? CONTINUING REVIEW In Addition to Initial Review 27. The IRB review took place prior to expiration of the continuing review period or evidence that the IRB did not allow the study to continue if continuing review expired 28. Brief summary of the research methodology and procedures 29. Number of subjects entered for the review period and since the inception of the research project 30. Number of subjects withdrawn (including the reasons for withdrawal) for the review period and since the inception of the research project 31. The gender and minority status of those entered into the protocol 32. Number of subjects considered as members of specific vulnerable populations 33. A copy of the proposal and all approved amendments 34. A copy of the current approved informed consent form 35. A copy of the current HIPAA Authorization document 36. Information that may impact on the risk/benefit 37. Research findings to date, if available. 38. Research findings to date, including summary of subject experiences (benefits, adverse reactions) 39. Subject complaints 40. New scientific findings in the literature, or other relevant finds, that may impact on the research. 41. Statements of significant new findings provided to the subjects. 42. A summary of the DSMB or DMC meetings (if applicable) or findings based on information collected by the data and safety monitoring plan submitted in the initial proposal. 43. Assurance that all SAEs and UAEs have been reported.

0e5236b1341d2f576017e1081d6e213e.doc Page 35 of 73 44. Summary of unexpected and serious adverse events, as well as injuries to subjects 45. Requests to change and/or amend protocol after study initiation and IRB actions on each. 46. Amended or updated Investigator’s Brochures 47. All written communications regarding the study to and from the PI and IRB including approval letters. 48. Approved HIPAA Authorization 49. Documentation of protocol violations 50. Documentation of non-compliance with the applicable regulations 51. Protocol Abstract 52. Final report IRB determination for continuing review EXPEDITED REVIEW 53. The IRB Chairperson or designee conducted the expedited review 54. The expedited action met the regulatory requirements for use of expedited procedures 55. The IRB documented the basis for allowing the expedited review procedures

Is the connection between the indicator statement and the process that is being measured self-explanatory? yes no If no, please describe:

The indicators are intended to identify the required contents of IRB files, including: Submission documents Information needed in order for the IRB to evaluate the project Information required to conduct continuing review Documentation regarding: Expedited review Exemption Device studies ______Definitions: IRB: Institutional Review Board. In the VA also known as the Human Subjects Sub-Committee (HSS) of the Research and Development Committee Exempt: Human Subjects Research that is exempt from IRB review and requirements of the common rule. The categories of exempt research and relevant procedures are described in the VA NJ HCS SOP, Exempt Research. Exempt research is subject to R&D Committee review Expedited: Under an expedited review procedure, the IRB Chairperson, or one or more experienced reviewers designated by the Chairperson from among the members of the IRB, reviews the research protocol. The IRB shall adopt a method for keeping all IRB members advised of research proposals that have been approved under the expedited review procedure. In conducting expedited review, the IRB reviewers may exercise all of the authorities of the IRB except that they may not disapprove the research. A research activity may be disapproved only after review by the convened IRB in accordance with the nonexpedited procedure set forth in 45 CFR 46.108(b). Device: A medical device is an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is—  recognized in the official National Formulary, or the United States Pharmacopeia, or any supplement to them,  intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or  intended to affect the structure or any function of the body of man or other animals, and  which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes (21 U.S.C. 321(h)).

0e5236b1341d2f576017e1081d6e213e.doc Page 36 of 73 MIRB: MIRB™ is "Software to Manage Your IRB and Other Committees." MIRB™ was initially developed specifically for Veterans Affairs Medical Centers, in conjunction with VA research administrators. Now MIRB™ is available outside the VA! MIRB is used to track all research studies submitted (initial review, continuing review, amendments, etc.) for approval at the VA NJ HCS.

Data collection method: (briefly describe in narrative format how data will be collected and what sources will be used such as service logs, the patient record, the DHCP)

I. – L. IRB PROJECT FILES The MIRB will be utilized Five (hard copy) IRB Study files will be checked in each of the following categories for a total of 20: 1. Exempt 2. Device (only 1 device study exists for review at the time of this version) 3. Full Board (Initial & Continuing Reviews) 4. Expedited (Initial & Continuing Reviews)

Sample size: 20 IRB study files or less will be reviewed (5 or all available for each of the 4 categories) per: Quarterly review Statistics to be tracked: mean or average median mode standard deviation rate other: undetermined Calculations/Formula for rate:

(i) Not Applicable In addition to tracking your results on a data aggregate, how do you plan to display this data? run chart histogram other chart control chart bar graph table Comparative Data Source (if any): None

Trigger for More Extensive Evaluation Method of Extensive Evaluation other: each incidence of non-compliance will case review be pursued for corrective action Reference(s): Office of Research Oversight (ORO), Institutional Review Board (IRB) Checklist, July 3, 2007

0e5236b1341d2f576017e1081d6e213e.doc Page 37 of 73 ATTACHMENT F

VA NJ HEALTHCARE SYSTEM Research Compliance

Performance Improvement Indicator/ Measurement Methodology

Version 1: 7/13/10

Process being measured: RESEARCH PARTICIPANT OUTREACH PROGRAM

Rationale: X mandated measure VHA Directive 2008-079 X new process

Involved Disciplines: All disciplines involved in Human Subjects Research at the VANJHCS

Purpose: The RCO is responsible to oversee and evaluate the facility Research Participant Outreach Program within the VHA Directive 2008-079 that each VHA facility conducting human research establishes a Research Participant Outreach Program for current, prospective, or past research participants or their designated representatives. This performance improvement review is designed to examine compliance with requirements described in Directive 2008-079. Two of the requirements are addressed by the locally established and required informed consent form template. Data for these two items will not be collected through this review because they are consistently addressed through the informed consent form: 1. The directive requires “A reliable mechanism for research participants to communicate with research project investigator, and with an informed VA representative who is independent of the research project in question (e.g., providing contact information in the informed consent form).” Our informed consent form requires that contact information be provided for the investigator and for the VA Patient Representative, who is independent of the research project. 2. The directive requires “Venues for participants and their designated representatives to obtain information and discuss their questions and concerns and offer their input.” Our informed consent process involves providing subjects with a survey and contact information for the VA Patient Representative and the Research Compliance Officer. The VA Patient Representative’s contact information is also provided for this purpose in the informed consent form (as stated in 1 above).

0e5236b1341d2f576017e1081d6e213e.doc Page 38 of 73 Indicator statement : Type: 1. For studies that consent subjects: One or more brochures  outcome “Volunteering in Research” is available in places where potential × process participants may be recruited and has contact information for  rate based participants to discuss their questions and concerns (clinic waiting  sentinel event areas). This only applies to studies that have a waiting area. 2. For studies that consent subjects: The investigator has at least one copy of the brochure on hand (in addition to the brochures posted in patient waiting areas) 3. A progress note in CPRS confirms that each subject is given a copy of the brochure during the consent process. (This will be evaluated for progress notes entered as of 10/1/2009.) 4. At least one educational activity is conducted per 12 month calendar year and includes members of the community.

Is the connection between the indicator statement and the process that is being measured self- explanatory? yes no If no, please describe:

1. During the conduct of the Regulatory Audit, pose the question, ”where are the brochures located” --Area walk through, an exception will be made for investigators that do not have patient waiting areas 2. The requirement that brochures be available (displayed) will be assessed as of 7/12/10 for the purposes of this audit. 3. Research Consent & Contact CPRS progress notes will be used to confirm issuance of the Brochure to consented subjects. (This will be evaluated for progress notes entered as of 10/1/2009.) 4. Annual Research Day held within the 12 month calendar year

Definition of Key Terms:

IRB- Institutional Review Board CPRS- Computerized Patient Record System Research Subject/Participant – A patient or healthy individual consented to participate in a research study. Brochure/“Volunteering in Research – Here are some things you need to know”: An informational brochure made available through the VA Office of Research and Development’s Center On Advice and Compliance Help (COACH) at http://www.research.va.gov/programs/pride/resources/order.cfm

Data collection method: (briefly describe in narrative format how data will be collected and what sources will be used such as service logs, the patient record, the DHCP)  During the conduct of regulatory audits, the investigator will be asked to show the supply of brochures on hand  During regulatory audit, the investigator will be asked to point out the area the brochure is available (Required as of 7/12/10). This applies to studies that have patient waiting areas only.  CPRS progress notes will serve as data sources that brochures are given to subjects during the 0e5236b1341d2f576017e1081d6e213e.doc Page 39 of 73 consent process. This data will be collected during informed consent audits (for progress notes entered after the date (10/1/2009) a check off item for the brochure was established.)  Note that Research Day (or other educational activity for research subjects and the community) held within a 12 month period

Sample size: (minimum: 5% or 30 cases whichever is greater; if there are less than 30 cases per quarter, 100% review is required) 100% per quarter of CPRS Research Consent & Contact progress notes to confirm that brochure was given to subjects during the consent process. 100% of applicable studies per quarter from studies receiving regulatory audits (applies to having Brochure available [displayed] and on supply on hand0.

Statistics to be tracked: mean or average  median  mode  standard deviation  rate other: to be determined

By Investigator:

# studies w/brochures # studies w/brochures # CPRS progress Numerator: available on hand notes confirming issuance of Brochure # studies that had reg. # studies that had reg. # CPRS progress Denominator: audit audit notes reviewed

Overall data collected for period: # studies w/brochures # studies w/brochures # CPRS progress Numerator: available on hand notes confirming issuance of Brochure # studies that had reg. # studies that had reg. # CPRS progress Denominator: audit audit notes reviewed

In addition to tracking your results on a data aggregate, how do you plan to display this data?  run chart  histogram  other chart  control chart bar graph undecided ~descriptive narrative

Comparative Data Source (if any): None

Trigger for More Extensive Evaluation Method of Extensive Evaluation other: Individual cases of non-compliance will CQI process review be communicated to the investigator  (case by case basis) 0e5236b1341d2f576017e1081d6e213e.doc Page 40 of 73 Reference(s): Dept. of Veterans Affairs VHA Directive 2008-079 – Research Participant Outreach Program Dept. of Veterans Affairs VHA Directive 2008-064 – Research Compliance Officer and the Auditing of VHA Human Subjects Research to Determine Compliance with Applicable Laws, Regulations, and Policies

0e5236b1341d2f576017e1081d6e213e.doc Page 41 of 73 Attachment G VA NJ HEALTH CARE SYSTEM Research Compliance Performance Improvement - Indicator/ Measurement Methodology (IMM) Version 1. September 3, 2010 REGULATORY AUDIT

CONTENTS PAGE I. Indicator Statements Or Measures 2 I.A. Indicators For Human Studies 2 I.B. Indicators for studies involving safety hazards subject to 4 SRS review I.C. Indicators for Animal Research studies and Science-Only 5 Studies with Hazards (as applicable) II. The connection between the indicator statement and the 6 process that is being measured III. Definitions 7 IV. Data collection method 10 IV.1) How the audit plan is created 10 IV.1)b) Requirements for regulatory audits 10 IV.2) System to assure that all studies are audited as required 11 IV.3) How the audit plan is monitored 11 IV.4) How the results are reported 11 IV.5) Where the audit results are maintained 12 IV.6) Data Collection 12 IV.7) Preparation (Prior to Audit) 12 IV.8) Following the audit 13 IV.9) Sources to locate necessary information and specifications 14 V. Sample size 19 VI. Statistics to be tracked 20 VII. Comparative Data Source 20 VIII. Trigger for More Extensive Evaluation 21 IX. Method of Extensive Evaluation 21 X. References 21 XI. Appendices 22 1. VHA Triennial Regulatory Compliance Audit, Good Clinical 23 Practice & Human Research Protection Program Optional Audit Tools, VA NJ HCS version 9/5/10 2. VHA Triennial Regulatory Compliance Audit, Research Safety 36 Audit Tool 3. VHA Triennial Regulatory Compliance Audit, Animal Welfare 39 Audit Tool 4. June 9, 2009 Memorandum: Clarification of RCO Research 41 Audit Requirements for 2009 and 2010, from Chief Officer ORO

0e5236b1341d2f576017e1081d6e213e.doc Page 42 of 73 1. Institutional Responsibilities I. Indicator Statements or Measures I.A. Indicators for Human Studies Audit worksheet Attachment 1 1. Total enrollment is within the total number of subjects approved for enrollment by the IRB 2. Investigator record contain copies of IRB Submissions, Approvals, And Other Actions 3. No research was conducted without IRB approval (possible serious noncompliance) 4. No research was conducted prior to IRB approval (possible serious noncompliance) 5. Suspension or Termination (Data collected for audit but not an indicator) 6. There was no Unapproved Activity During Lapse of Approval (following expired continuing review) (possible serious noncompliance) 7. Research & Development Committee Approval is documented (as applicable) 8. Each version of submitted informed consent forms is in the investigator record 9. Each version of stamped informed consent forms is in the investigator record 10. If Re-Consent was required: the re-consenting was conducted as required (possible serious noncompliance) Local Unanticipated Serious Adverse Events (SAEs), Unanticipated Problems Involving Risks To Subjects Or Others (UPRS) And Significant Safety Reports / Data Monitoring Committee (DMC) Reports (SAEs, UPRS And Significant Safety Reports / Data Monitoring Committee (DMC) Reports) 11. SAEs, UPRS And Significant Safety Reports / Data Monitoring Committee (DMC) Reports Reported to IRB within required time period (from the date the event was first recognized to have occurred by any member of the research staff, or the RCO) 12. SAEs, UPRS And Significant Safety Reports / Data Monitoring Committee (DMC) Reports Reviewed & categorized within required time period (from the date the event was reported to the IRB) 13. SAEs, UPRS And Significant Safety Reports / Data Monitoring Committee (DMC) Reports Reported to ORO within required time frame (as applicable) (from the date the event was determined to be reportable) 14. Deviations, if any, reported to IRB per IRB rules 15. Deviations, if any, recorded in compliance with protocol requirements 16. CITI Study Staff Training completed as required (at time of audit or study closure) 17. Documented study specific SAFETY training (at time of audit or study closure) 18. FDA Form 1572 signed by responsible individual (PI) 19. Scope of Practice or equivalent Documented for each staff person (at time of audit or study closure) 20. No staff member was found by the IRB to be working outside scope of practice 21. Documentation that consent obtained prior to initiation of study procedures for each subject (possible serious noncompliance) 22. Documentation Found Verifying Inclusion Criteria Met for each subject 23. Documentation Found Verifying Serious Adverse Events/UPRS for each applicable subject

0e5236b1341d2f576017e1081d6e213e.doc Page 43 of 73 24. Is at least one copy of the Brochure “VOLUNTEERING IN RESEARCH” available/displayed for potential subjects 25. Is at least one additional copy of the Brochure (above) on-hand for future distribution 26. Does the investigator record include pertinent sponsor correspondence 27. No cases of Possible Serious Noncompliance were found during the regulatory audit 28. Reporting to the Director and ORO, etc. was made consistent with reporting HB 1058.01 29. The IRB reviewed and made a determination regarding the case of possible serious noncompliance found during the RCO regulatory audit

I.B. Indicators for Studies Involving Safety Hazards Subject To SRS Review Audit worksheet Attachment 2 1. Annual reviews were conducted within required time frame (as applicable) 2. No research activities took place during SRS suspension (or following termination) of research for safety concerns (as applicable) 3. Stipulations of the SRS were met for reinstatement following suspension of research for safety concerns (as applicable for studies with chemical hazards) 4. The laboratory chemical inventory was reviewed by a safety representative prior to SRS approval? (as applicable) 5. The laboratory chemical/hazard inventory was reviewed semi-annually by a safety representative following SRS approval (as applicable for studies with chemical hazards) 6. If the SRS determined that the study involves non-exempt rDNA, the protocol underwent a review consistent with NIH Guidelines (as applicable) 7. All personnel responsible for packing, shipping or transporting infectious materials have been appropriately trained for these duties (as applicable) 8. The safety containment level is clearly stated in the protocol (as applicable for studies with Biological Hazards) 9. Security Risk Assessments have been completed for all study personnel (as applicable for studies with select agents or select toxins) 10. The protocol has been reviewed by the RSO or the RSC (as applicable for studies that involve radioisotopes or a radiation source) 11. All controlled substances are obtained through the VA Pharmacy (as applicable for studies with controlled substances. Also a separate indicator in Animal Welfare audit worksheet) 12. Logs of inventory and usage of controlled substances are maintained (where controlled substances are being held at the time of the audit for use in the study. Also a separate indicator in Animal Welfare audit worksheet) 13. Evaluated in Animal and Science-Only audit: All personnel involved in the research have been offered the opportunity to enroll in an approved Occupational Safety and Health Program? (This applies to annual survey and offer of health services to Animal research staff. This will be considered in the Animal Welfare Audit. Other research staff are considered to be enrolled.) 0e5236b1341d2f576017e1081d6e213e.doc Page 44 of 73 14. Study staff have received documented study specific safety training and or general safety training (as applicable) 15. Science-Only studies with hazards are not begun prior to R&D Committee approval 16. Science-Only studies with hazards do not proceed during suspension of R&D Committee approval

I.C. Indicators for Animal Research studies and Science-Only Studies with Hazards (as applicable) Audit worksheet Attachment 3 1. No research was conducted prior to IACUC approval 2. The protocol received the required initial and annual IACUC approval – with a completely new review conducted every 3 years (as applicable) 3. No research activity took place during periods of lapsed IACUC annual reviews (as applicable) 4. No research activity took place during periods of IACUC suspension or following termination of IACUC approval (as applicable) 5. The protocol clearly specifies the animal species to be used (as applicable) 6. The protocol indicates the maximum number of animals to be used during the approval period (as applicable) 7. There is a completed Animal Component of Research Protocol (ACORP) (as applicable) 8. There is evidence that the PI searched for alternatives to animal use that would minimize pain or distress to animals (as applicable) 9. The U.S. Department of Agriculture (USDA) pain and distress category has been determined (as applicable) 10. If the study includes a Category E pain and distress level, a justification is provided (and reviewed by the IACUC) for not relieving pain or distress (as applicable) 11. All animal housing and procedure locations are specified in the ACORP (as applicable) 12. All personnel involved in animal research have been offered the opportunity to enroll in an approved Occupational Safety and Health Program (This applies to annual survey and offer of health services to Animal research staff.) 13. Euthanasia is performed in accordance with AVMA Guidelines (as applicable) 14. Staff Training is in investigator’s records (as applicable – ACORP and Safety specific) (as applicable) 15. The investigator maintains records and provides storage for Controlled Substances (double locked with log of drugs currently held by investigator) (as applicable) 16. A log of study procedures conducted is in the investigator’s records (as applicable) 17. If the ACORP defined training for individuals – The training for those individuals is recorded in the investigator records (as applicable) 18. All animal research staff completed CITI training (as applicable) 19. The PI and all research staff have Research Scopes of Practice or equivalent (as applicable. All animal research staff including the PI need Research Scopes of Practice)

0e5236b1341d2f576017e1081d6e213e.doc Page 45 of 73 II. The Connection Between The Indicator Statement And The Process That Is Being Measured Is the connection between the indicator statement and the process that is being measured self- explanatory? yes no If no, please describe: The indicators for the regulatory audits are drawn from regulatory audit tools and instructions provided by the VHA Office of Research Oversight (ORO).  VHA Triennial Regulatory Compliance Audit, Good Clinical Practice & Human Research Protection Program Optional Audit Tools, VA NJ HCS version 9/5/10  VHA Triennial Regulatory Compliance Audit, Research Safety Audit Tool  VHA Triennial Regulatory Compliance Audit, Animal Welfare Audit Tool The indicators represent documentation requirements for research investigators and or the research program (managed by Research Service) that research compliance officers are required to audit.

III. Definitions: Terms for which definitions are to be provided are listed here. The full definitions appear below. 1) Active study 2) Adverse Event (AE) 3) Completed study 4) Continuing Noncompliance 5) Human Subjects Research 6) Institutional Review Board (IRB) 7) Investigator 8) MIRB 9) Principal Investigator (PI) 10) RCO audit 11) Research 12) Research Review Committee 13) Serious Adverse Event (SAE) 14) Serious Noncompliance 15) Subcommittee on Research Safety (SRS) 16) Suspension or Termination of Research

Full Definitions 1) Active study: An “active” study is a study approved by and under continuing oversight from the Research and Development Committee (R&DC), Institutional Review Board (IRB), Institutional Animal Care and Use Committee (IACUC), Subcommittee on Research Safety (SRS), or other VA or VA-designated research oversight committee, regardless of whether the study is “open” or “closed” to accrual.

0e5236b1341d2f576017e1081d6e213e.doc Page 46 of 73 2) Adverse Event (AE): An AE is any untoward physical or psychological occurrence in a human subject participating in research. An AE can be an unfavorable and unintended event, including an abnormal laboratory finding, symptom, or disease associated with the research or the use of a medical investigational test article. An AE does not necessarily have to have a causal relationship with the research. NOTE: AEs are discussed in VHA Handbook 1200.05. 3) Completed study: A “completed” study is a study for which oversight by all relevant research oversight committees (see Item 1b above) has been concluded. 4) Continuing Noncompliance: Continuing noncompliance is a persistent failure to adhere to the laws, regulations, or policies governing human research 5) Human Subjects Research: Human subjects research is research that involves human subjects. a) As defined in the Common Rule (38 CFR 16) and VHA Handbook 1200.5, a human subject is a living individual about whom an investigator conducting research obtains: i) Data through intervention or interaction with the individual, or ii) Identifiable private information (1) An intervention includes both physical procedures by which data are gathered and all manipulations (physical, psychological, or environmental) of the human subject, or the subject’s environment, which are performed for research purposes. (2) Interaction includes communication or interpersonal contact between the investigator and the human subject. 6) Institutional Review Board (IRB): The IRB is a board established in accordance with, and for the purposes expressed in, the Federal Policy (Common Rule) for the Protection of Human Subjects (Title 38 Code of Federal Regulations (CFR) 16.102(g)). It is responsible for the review of, approval or disapproval of, and continuing oversight of research involving human subjects. 7) Investigator: An investigator is an individual 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 must 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 (IPA) of 1970. The FDA considers an investigator and a PI to be synonymous. 8) MIRB: MIRB™ is "Software to Manage Your IRB and Other Committees." MIRB™ was initially developed specifically for Veterans Affairs Medical Centers, in conjunction with VA research administrators. Now MIRB™ is available outside the VA! MIRB is used to track all research studies submitted (initial review, continuing review, amendments, etc.) for approval at the VA NJ HCS. 9) Principal Investigator (PI): Within VA, a PI is 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 a PI and an investigator to be synonymous. 0e5236b1341d2f576017e1081d6e213e.doc Page 47 of 73 10) RCO audit: RCO audits are audits conducted, supervised, or verified by the facility’s lead RCO. 11) Research: As defined by the Common Rule (38 CFR 16.102(d)) research means a systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge. 12) Research Review Committee: A research review committee is any committee or subcommittee designated by a VA research facility to ensure compliance with Federal, VA, or facility requirements for the conduct of research (e.g., R&D Committee, IRB, IACUC, SRS). 13) Serious AE (SAE): An SAE is an AE in human research that results in death, a life-threatening experience, inpatient hospitalization, prolongation of hospitalization, persistent or significant disability or incapacity, congenital anomaly, or birth defect. An AE is also considered serious when medical, surgical, behavioral, social, or other intervention is needed to prevent such an outcome. NOTE: SAE’s are also discussed at 21 CFR 312.32(a). 14) Serious Noncompliance: Serious noncompliance is a failure to adhere to the laws, regulations, or policies governing human research that may reasonably be regarded as: a) Involving substantive harm, or a genuine risk of substantive harm, to the safety, rights, or welfare of human research subjects, research staff, or others; or b) Substantively compromising the effectiveness of a facility’s human research protection or human research oversight programs 15) Subcommittee on Research Safety (SRS): An SRS is a committee formally designated by a VA facility to review the safety and security of VA research laboratories in accordance with VA and other Federal requirements. NOTE: SRS responsibilities are discussed in VHA Handbook 1200.01 and related VHA Handbooks. 16) Suspension or Termination of Research, relative to VA research: a) Suspension refers to a temporary interruption in the enrollment of new subjects, activities involving previously enrolled subjects, or other research activities. b) Termination refers to a permanent halt in the enrollment of new subjects, activities involving previously enrolled subjects, or other research activities. c) The terms “suspension” and “termination” apply to interruptions related to concerns regarding: i) The safety, rights, or welfare of human subjects, research investigators, research staff, or others; or ii) The safety, health, or welfare of laboratory animals d) Suspension and termination do not include: i) Interruptions in research resulting solely from the expiration of a project approval period ii) “Administrative holds” or other actions initiated voluntarily by an appropriate facility official, research investigator, or sponsor for reasons other than those described in preceding subparagraph 4aa(3).

0e5236b1341d2f576017e1081d6e213e.doc Page 48 of 73 IV. Data Collection Method 1) How the audit plan is created: a) The requirement for regulatory audits is described in VHA DIRECTIVE 2008-064 Research Compliance Officers And The Auditing Of VHA Human Subjects Research To Determine Compliance With Applicable Laws, Regulations, And Policies as well as written instructions from the VHA Office of Research Oversight (ORO). b) Requirements for regulatory audits i) Regulatory audits of human, animal, and safety-related research studies initiated after January 1, 2008, must be performed at least every 3 years (i.e., triennially) and require review of case records and regulatory files. Animal studies receiving IACUC triennial review after 1/1/08 must receive an RCO regulatory audit within three years following the triennial review. ii) When a study that is subject to regulatory audit closes, it must receive a regulatory audit during the reporting period in which it closes (June 1 – May 31) iii) Regulatory audits for the June 1, through May 31 reporting period must be completed in time to be included in the annual Facility Director Certification of Research Oversight, which must be submitted to ORO Regional Offices through the Network Director and received by ORO no later than July 15. iv) Regulatory audits are not required for: (1) Any human study determined to be exempt from IRB review (2) Any study (human, animal, or safety-related) initiated (i.e., approved for implementation as a VA study) prior to January 1, 2008 (except Animal studies receiving IACUC triennial review after 1/1/08 must receive an RCO regulatory audit within three years following the triennial review). (3) Any study (human, animal, or safety-related) completed prior to June 1, 2009 (4) Protocols that involve no human subjects, no laboratory animals, and no hazardous agents or safety concerns do not require a triennial regulatory audit. Protocols involving human subjects that have been ruled exempt from IRB review do not require a triennial regulatory audit. v) If an approved research study using human subjects has closed without enrolling any subjects at the local facility, then an abbreviated audit including only the information on the first page of the GCP/HRPP audit tool is sufficient. vi) If an approved human subjects study closes during this audit period, and has already had one or more regulatory audits since it was initially approved, then an abbreviated audit including only the information on this first page is sufficient. 2) System to assure that all studies are audited as required a) In order to plan for and record regulatory audits, a system has been established: i) A database is maintained with a listing of all studies that are required to have regulatory audits ii) Scheduling and priority setting is conducted using this database. iii) Study closure is tracked using research committee agendas and minutes 3) How the audit plan is monitored

0e5236b1341d2f576017e1081d6e213e.doc Page 49 of 73 a) A program of regulatory audits is managed by the Research Compliance Officers. This involves maintaining records of studies, approval dates and audit results. Records include scheduling, findings and tracking pending issues. 4) How the results are reported a) Findings of possible serious or continuing noncompliance are reported as per the requirements of VHA Handbook 1058.01. b) Investigators are provided with preliminary audit results on exit interview and in writing prior to completion. Investigators are asked for their corrections and comments as well as proposed corrective actions for any findings. c) Quarterly reports of regulatory audits are compiled and presented to the applicable review committees. d) An annual report of regulatory audits (for the June 1 to May 31 yearly period) is prepared for inclusion in the Annual Facility Director Certification of Research Oversight that is submitted to ORO. 5) Where the audit results are maintained a) Audit records are maintained electronically on the VHA RCO shared network folder \\Vhaeasclu1\groupshares$\Res_Compliance and in hard copy binders locked in the RCO office. b) Audit reports presented to the research review committees will be maintained with the hard copy records of the meeting minutes. 6) Data Collection a) A printed protocol history will be used to record presence of submitted and received documents (where applicable). b) The applicable audit tools (customized for the VA NJ HCS) will be completed for each regulatory audit: i) VHA Triennial Regulatory Compliance Audit, Good Clinical Practice & Human Research Protection Program Optional Audit Tools ii) VHA Triennial Regulatory Compliance Audit, Research Safety Audit Tool iii) VHA Triennial Regulatory Compliance Audit, Animal Welfare Audit Tool 7) Preparation (Prior to Audit) a) For routine audits, coordination will take place with the PI and the study staff regarding: the schedule, time, place, person, contact information, general description of records to be audited b) The MIRB protocol history will be examined to identify issues for audit. The issues will vary from study to study. (Examples: study specific training, serious adverse events, lapses in approval) c) The Research Service study records will be examined to identify issues for audit. d) Study staff will be identified and training records will be examined. e) For human studies, the MIRB protocol history will be used to identify all submissions to the IRB, IRB modification letters and approval letters with dates of IRB action. These documents must be in the IRB study file as well as the investigator’s records. Among documents identified in this manner (partial list) are: i) Informed Consent Form versions ii) Stamped copies of Informed Consent Forms iii) HIPAA Authorizations

0e5236b1341d2f576017e1081d6e213e.doc Page 50 of 73 iv) Waivers of HIPAA Authorization v) Advertisements vi) Questionnaires/Surveys vii) Forms 10-9012 viii) Financial Disclosure Forms ix) Investigator Agreement x) Continuing Reviews xi) Continuing Review dates indicating possible lapse in approval xii) Amendments xiii) Serious Local Adverse Events xiv) Local Unanticipated Problems Involving Risks to Subjects or Others xv) DSMB/DMC reports xvi) Notifications xvii) Study Closure xviii) R&D Committee Approval with date 8) Following the audit a) An exit interview will be conducted with the PI and or study staff to review the results and any findings of noncompliance. A preliminary discussion will be held regarding the implications and need for follow-up. b) A preliminary written report will be provided to the PI (and study staff, if applicable) for comment, correction and appropriate corrective action. Investigators may be advised to self report deviations and possible serious or continuing noncompliance. c) Audit data is entered in tracking database. d) Findings are recorded for compilation report and for tracking of corrective actions e) Pending issues will be tracked until resolved. Communications with the PI and or study staff will continue until resolution of pending issues is confirmed. f) Reporting will be conducted per item in this methodology: How Results Are Reported

9) Sources to locate necessary information and specifications (see table below) Indicators For human studies Sources to locate necessary information and specifications Audit worksheet Attachment 1 1. Total enrollment is within the total number of subjects IRB records (protocol hx) and 0e5236b1341d2f576017e1081d6e213e.doc Page 51 of 73 approved for enrollment by the IRB Investigator records 2. Investigator record contain copies of IRB Submissions, Investigator records Approvals, And Other Actions 3. No research was conducted without IRB approval IRB records (protocol hx) and (possible serious noncompliance) Investigator records 4. No research was conducted prior to IRB approval IRB records (protocol hx) and (possible serious noncompliance) Investigator records 5. Suspension or Termination (Data collected for audit but IRB records not an indicator) 6. There was no Unapproved Activity During Lapse of IRB records (protocol hx) and Approval (following expired continuing review) Investigator records (possible serious noncompliance) 7. Research & Development Committee Approval is IRB/R&D Committee records documented (as applicable) (protocol hx) and Investigator records 8. Each version of submitted informed consent forms is in IRB records (protocol hx) and the investigator record Investigator records 9. Each version of stamped informed consent forms is in IRB records (protocol hx) and the investigator record Investigator records 10. If Re-Consent was required: the re-consenting was IRB records (protocol hx) and conducted as required (possible serious noncompliance) Investigator records

Indicators For human studies Sources to locate necessary information and specifications Local Unanticipated Serious Adverse Events (SAEs), Unanticipated Problems Involving Risks To Subjects Or Others (UPRS) And Significant Safety Reports / Data Monitoring Committee (DMC) Reports (SAEs, UPRS And Significant Safety Reports / Data Monitoring Committee (DMC) Reports) 11. SAEs, UPRS And Significant Safety Reports / Data IRB records (protocol hx) and Monitoring Committee (DMC) Reports Reported to Investigator records IRB within required time period (from the date the event was first recognized to have occurred by any member of the research staff, or the RCO) 12. SAEs, UPRS And Significant Safety Reports / Data IRB records (protocol hx) and Monitoring Committee (DMC) Reports Reviewed & Investigator records categorized within required time period (from the date the event was reported to the IRB) 13. SAEs, UPRS And Significant Safety Reports / Data IRB records (protocol hx) and Monitoring Committee (DMC) Reports Reported to Investigator records. Consult ORO within required time frame (as applicable) (from with IRB Coordinator if the date the event was determined to be reportable) necessary 14. Deviations, if any, reported to IRB per IRB rules IRB records (protocol hx) and Investigator records 15. Deviations, if any, recorded in compliance with IRB records (protocol hx) and protocol requirements Investigator records

0e5236b1341d2f576017e1081d6e213e.doc Page 52 of 73 16. CITI Study Staff Training completed as required Research Service credentialing (at time of audit or study closure) database 17. Documented study specific SAFETY training (at EES TEMPO and Investigator time of audit or study closure) records 18. FDA Form 1572 signed by responsible individual Investigator records (PI) 19. Scope of Practice or equivalent Documented for Research Service files and each staff person (at time of audit or study closure) credentialing database 20. No staff member was found by the IRB to be Protocol history working outside scope of practice

Indicators For human studies Sources to locate necessary information and specifications 21. Documentation that consent obtained prior to Investigator records initiation of study procedures for each subject (possible serious noncompliance) 22. Documentation Found Verifying Inclusion Criteria IRB Study file (Application and Met for each subject or protocol) and Investigator records 23. Documentation Found Verifying Serious Adverse IRB records (protocol hx) and Events/UPRS for each applicable subject Investigator records 24. Is at least one copy of the Brochure Study staff interview and available/displayed for potential subjects observation 25. Is at least one additional copy of Brochure on- Study staff interview and hand for future distribution observation 26. Does the investigator record include pertinent Investigator records sponsor correspondence 27. No cases of Possible Serious Noncompliance were Any pertinent findings during found during the regulatory audit audit 28. Reporting to the Director and ORO, etc. was made RCO records consistent with reporting HB 1058.01 29. The IRB reviewed and made a determination IRB meeting minutes regarding the case of possible serious noncompliance found during the RCO regulatory audit

Indicators for studies involving safety hazards Sources to locate necessary subject to SRS review information and specifications Audit worksheet Attachment 2

1. No research was conducted prior to SRS approval Protocol history and investigator record 2. Annual reviews were conducted within required time Protocol history frame (as applicable) 3. No research activities took place during SRS Protocol history and suspension (or following termination) of research for investigator records

0e5236b1341d2f576017e1081d6e213e.doc Page 53 of 73 safety concerns (as applicable) 4. Stipulations of the SRS were met for reinstatement Protocol history and following suspension of research for safety concerns investigator records (as applicable for studies with chemical hazards) Indicators for studies involving safety hazards Sources to locate necessary subject to SRS review information and specifications 5. The laboratory chemical inventory was reviewed by a Research service records (initial safety representative prior to SRS approval? (as submission) applicable) 6. The laboratory chemical/hazard inventory was Not clear how this will be reviewed semi-annually by a safety representative audited as of 9/10/10. following SRS approval (as applicable for studies Possibilities: with chemical hazards) SRS minutes, Research Service records or request to Safety Officer or Industrial Hygienist 7. If the SRS determined that the study involves non- Protocol history exempt rDNA, the protocol underwent a review consistent with NIH Guidelines (as applicable) 8. All personnel responsible for packing, shipping or Study staff interview and transporting infectious materials have been Investigator training records appropriately trained for these duties (as applicable) 9. The safety containment level is clearly stated in the Research Service records protocol (as applicable for studies with Biological Hazards) 10. Security Risk Assessments have been completed for Not Applicable at the time that all study personnel? (as applicable for studies with this methodology is being select agents or select toxins) developed 9/10/10 Investigator records, Inquiry with Police and or Human Resources 11. The protocol has been reviewed by the RSO or the Research Service records RSC (as applicable for studies that involve radioisotopes or a radiation source) 12. All controlled substances are obtained through the VA Site visit interview Pharmacy? (as applicable for studies with controlled substances. Also a separate indicator in Animal Welfare audit worksheet) 13. Logs of inventory and usage of controlled substances Site visit interview and are maintained (where controlled substances are being observation held at the time of the audit for use in the study. Also a separate indicator in Animal Welfare audit worksheet) 14. Evaluated in Animal and Science-Only audit: All Staff list from Research Service personnel involved in the research been offered the records and Lead Animal opportunity to enroll in an approved Occupational Technician’s records Safety and Health Program? (This applies to annual survey and offer of health services to Animal

0e5236b1341d2f576017e1081d6e213e.doc Page 54 of 73 research staff. This will be considered in the Animal Welfare Audit. Other research staff are considered to be enrolled.) 15. Study staff have received documented study specific Research Service records and safety training and or general safety training (as investigator records applicable) 16. Science-Only studies with hazards are not begun prior Protocol history and to R&D Committee approval investigator records 17. Science-Only studies with hazards do not proceed Protocol history and during suspension of R&D Committee approval investigator records

Indicators for Animal Research studies and Sources to locate necessary Science-Only Studies with Hazards information and specifications Audit worksheet Attachment 3

1. The protocol received the required initial and annual Protocol history IACUC approval – with a completely new review conducted every 3 years (as applicable) 2. No research activity took place during periods of Protocol history and lapsed IACUC annual reviews (as applicable) Investigator records 3. No research activity took place during periods of Protocol history and IACUC suspension or following termination of Investigator records IACUC approval (as applicable) 4. The protocol clearly specifies the animal species to be ACORP reviewed in Research used (as applicable) Svc and or Investigator records 5. The protocol indicates the maximum number of ACORP reviewed in Research animals to be used during the approval period (as Service and or Investigator applicable) records 6. There is a completed Animal Component of Research ACORP reviewed in Research Protocol (ACORP) (as applicable) Svc and or Investigator records 7. There evidence that the PI searched for alternatives to ACORP reviewed in Research animal use that would minimize pain or distress to Service and or Investigator animals (as applicable) records 8. A US Department of Agriculture (USDA) pain and ACORP reviewed in Research distress category has been determined (as applicable) Svc and or Investigator records

Indicators for Animal Research studies and Sources to locate necessary Science-Only Studies with Hazards information and specifications 9. If the study includes a Category E pain and distress ACORP reviewed in Research level, a justification is provided (and reviewed by the Service and or Investigator IACUC) for not relieving pain or distress (as records applicable) 10. All animal housing and procedure locations are ACORP reviewed in Research specified in the ACORP (as applicable) Service and or Investigator records 11. All personnel involved in animal research have been Staff list from Research Service 0e5236b1341d2f576017e1081d6e213e.doc Page 55 of 73 offered the opportunity to enroll in an approved records and Lead Animal Occupational Safety and Health Program? (This Technician’s records applies to annual survey and offer of health services to Animal research staff.) 12. Euthanasia is performed in accordance with AVMA ACORP reviewed in Research Guidelines (as applicable) Service and or Investigator records 13. The investigator maintains records and provides Site visit interview and storage for Controlled Substances (double locked inspection with log of drugs currently held by investigator) (as applicable) 14. A log of study procedures conducted is in the Site visit interview and investigator’s records (as applicable) Investigator records 15. Staff Training in Safety is in investigator’s records Research Service records, (as applicable – ACORP and Safety specific) (as protocol history, ACORP and applicable) Investigator records 16. If the ACORP Defined Training for Individuals – The ACORP and Investigator training for those individuals is recorded in the records investigator records (as applicable) 17. All animal research staff completed CITI training (as Research Service credentialing applicable) database, Investigator interview 18. The PI and all research staff have Research Scopes of Research Service records of Practice or equivalent (as applicable. All animal credentialing for individual staff research staff including the PI need Research Scopes persons of Practice)

Indicators for Animal Research studies and Sources to locate necessary Science-Only Studies with Hazards information and specifications V. Sample size Sample size: (minimum: 5% or 30 cases whichever is greater; if there are less than 30 cases per quarter, 100% review is required) _30 CASES PER QUARTER OR 100%______per: month quarter Please Note regarding sample size: In fulfilling the requirements for regulatory audits, sampling is not pertinent for most aspects of the audits. Sampling is applied to human research subject indicators. 10 or 10% of subject records will be audited. VI. Statistics To Be Tracked: Statistics to be tracked:  mean or average  median  mode  standard deviation  rate other: results will be recorded on a spread sheet Calculations/Formula for rate: (Calculation of rate of compliance will not be done) Numerator: ______Denominator: In addition to tracking your results on a data aggregate, how do you plan to display this data? 0e5236b1341d2f576017e1081d6e213e.doc Page 56 of 73  run chart  histogram  other chart  control chart  bar graph  undecided

Please Note regarding statistics to be tracked: The regulatory audits do not lend themselves immediately to statistical analysis. The data will be recorded in a spread sheet. It may be possible to discern trends; however, the audit plan does not include tracking the data statistically. Over time, statistical analysis will be added if feasible. Process Improvements will be pursued whenever the findings lend themselves to process improvement. VII. Comparative Data Source Comparative Data Source (if any): None

VIII. Trigger for More Extensive IX. Method of Extensive Evaluation Evaluation Trigger for More Extensive Evaluation Method of Extensive Evaluation  pre-established threshold of ______ case review  focused study  sentinel event  peer review  statistical control limits  CQI process review  significant deviation from comparative data  other. The method of evaluation will generally involve other: Individual findings will be pursued on a case by case basis individual follow up by the RCOs with the PI; however, consultation with ORO, the ACOS R&D, the pertinent review committee Chairs and institutional officials are all possible. X. References References: VHA Directive 2008-064 Research Compliance Officers And The Auditing Of VHA Human Subjects Research To Determine Compliance With Applicable Laws, Regulations, And Policies VHA Triennial Regulatory Compliance Audit, Good Clinical Practice & Human Research Protection Program Optional Audit Tools, VA NJ HCS version 9/5/10 Veterans Health Administration (VHA), Facility Director’s Certification Of Research Oversight June 9, 2009 Memorandum: Clarification of RCO Research Audit Requirements for 2009 and 2010, from Chief Officer ORO

XI. APPENDICES APPENDICES: 1. June 9, 2009 Memorandum: Clarification of RCO Research Audit Requirements for 2009 and 2010, from Chief Officer ORO 2. VHA Triennial Regulatory Compliance Audit, Good Clinical Practice & Human Research Protection Program Optional Audit Tools, VA NJ HCS version 9/5/10

0e5236b1341d2f576017e1081d6e213e.doc Page 57 of 73 3. VHA Triennial Regulatory Compliance Audit, Research Safety Audit Tool 4. VHA Triennial Regulatory Compliance Audit, Animal Welfare Audit Tool

2. Institutional Responsibilities

0e5236b1341d2f576017e1081d6e213e.doc Page 58 of 73 Department of Memorandum Veterans Affairs

Date: June 9, 2009 From: Chief Officer, Office of Research Oversight (ORO)(10R) Subj: Clarification of RCO Research Audit Requirements for 2009 and 2010 To: Network Directors Facility Directors Associate Chiefs of Staff for Research (ACOS/Rs) Research Compliance Officers (RCOs)

1. RCO audit requirements. This memo clarifies and supersedes previous guidance on the requirements for RCO informed consent and regulatory audits during (i) the January 1, 2009, through May 31, 2009, reporting period and (ii) the June 1, 2009, through May 31, 2010, reporting period. a. Definition of RCO audit. RCO audits are audits conducted, supervised, or verified by the facility’s lead RCO. b. Definition of active study. An “active” study is a study approved by and under continuing oversight from the Research and Development Committee (R&DC), Institutional Review Board (IRB), Institutional Animal Care and Use Committee (IACUC), Subcommittee on Research Safety (SRS), or other VA or VA-designated research oversight committee, regardless of whether the study is “open” or “closed” to accrual. c. Definition of completed study. A “completed” study is a study for which oversight by all relevant research oversight committees (see Item 1b above) has been concluded. 2. Informed consent audits. Informed consent audits of all active human research studies must be performed each year (i.e., annually) and require a review of subjects’ signed VA informed consent documents (where applicable). a. IRB-exempt studies. The annual informed consent audit requirement includes human studies determined to be exempt from IRB review. The audit requirement is fulfilled by completing the “Protocol Information” section and the “Protocol Exempt” checkbox on the ORO informed consent audit template (or equivalent) for any active IRB-exempt study. b. Template. The template for informed consent audits is posted on the ORO website at: http://www1.va.gov/oro/docs/RCO_InformedConsent_SampleAuditTemplate_01_09_09.doc 3. Informed consent audits for the January 1, 2009 – May 31, 2009, reporting period. a. Studies to be audited. All human research studies active at any time between January 1, 2009, and May 31, 2009, must receive an informed consent audit. b. Informed consent documents to be audited. The informed consent audit must include all informed consent documents (where applicable) obtained within 12 months prior to the date of the audit. .Studies completed during the reporting period. A final informed consent audit must be conducted for any study completed between January 1, 2009, and May 31, 2009. Note: A study audited during the reporting period will require a supplemental audit if the study was completed before the end of the reporting period (i.e., before May 31, 2009) and additional informed consent documents were obtained after the audit. d. Deadline. Informed consent audits for the January 1 through May 31, 2009, audit period must be completed in time to be included on page 6 of the 2009 Facility Director Certification of Research Oversight, which must be submitted to ORO Regional Offices through the Network Director and received by ORO no later than July 15, 2009. e. Templates. i. The full 2009 Facility Director Certification template is posted on the ORO website at:

0e5236b1341d2f576017e1081d6e213e.doc Page 59 of 73 http://www1.va.gov/oro/docs/RCO_2009AnnualFacilityDirectorsCertification_052809.doc ii. A stand-alone copy of the Facility Director Certification Audit Summary (i.e., Certification page 6) is posted on the ORO website at: http://www1.va.gov/oro/docs/RCO_AnnualCertification_RequiredAudits_FirstReportingPeriod_052809.d oc 4. Informed consent audits for the June 1, 2009 – May 31, 2010, reporting period. a. Studies to be audited. All human research studies active at any time between June 1, 2009, and May 31, 2010, must receive an informed consent audit. b. Informed consent documents to be audited. For the this reporting period: i. Studies that were not audited previously must include all informed consent documents obtained within 12 months prior to the date of the audit. ii. Studies that were audited previously must include all informed consent documents obtained since the previous audit. c. Studies completed during the reporting period. A final informed consent audit must be conducted for any study completed between June 1, 2009, and May 31, 2010. Note: A study audited during the reporting period will require a supplemental audit if the study is completed before the end of the reporting period (i.e., before May 31, 2010) and additional informed consent documents are obtained after the audit. b. Deadline. Informed consent audits for the June 1, 2009, through May 31, 2010, reporting period must be completed in time to be included in the 2010 Facility Director Certification of Research Oversight, which must be submitted to ORO Regional Offices through the Network Director and received by ORO no later than July 15, 2010. c. Template. The 2010 Facility Director Certification template will be posted on the ORO website as soon as it is finalized. 5. Regulatory audits. Except as noted in Item 5b (below), regulatory audits of human, animal, and safety-related research studies initiated after January 1, 2008, must be performed at least every 3 years (i.e., triennially) and require review of case records and regulatory files. a. Examples: i. A study initiated (i.e., approved for implementation as a VA study) on January 15, 2008, must receive a regulatory audit no later than January 14, 2011 (or if closed earlier, during the reporting period in which it closed). ii. A study receiving a regulatory audit on July 2, 2009, must receive another regulatory audit no later then July 1, 2012 (or if closed earlier, during the reporting period in which it closed). b. Audits not required. Regulatory audits of the following studies are not required. i. Any human study determined to be exempt from IRB review. Note: Informed consent audits of IRB-exempt studies are required per Item 2a. ii. Any study (human, animal, or safety-related) initiated (i.e., approved for implementation as a VA study) prior to January 1, 2008. iii. Any study (human, animal, or safety-related) completed prior to June 1, 2009.* * PLEASE NOTE: ORO recognizes that practical constraints have precluded most facilities from performing regulatory audits during the January 1 through May 31, 2009, reporting period. The Deputy Under Secretary for Health for Operations and Management (DUSHOM) has directed that RCO and Facility Director performance goals and evaluations be adjusted accordingly. Thus, no regulatory audits of studies completed prior to June 1, 2009, are, or will be, required. c. Templates. i. The template for human research regulatory audits is posted on the ORO website at: http://www1.va.gov/oro/docs/RCO_AuditTriennialWorksheet_GCP_HRPP_011209.doc

0e5236b1341d2f576017e1081d6e213e.doc Page 60 of 73 ii. The templates for animal and safety research audits are posted on the ORO website at: http://www1.va.gov/oro/docs/RCO_AnimalBiosafetyTriennialAudit_Comments_Draft_052809.doc 6. Regulatory audits for the January 1 – May 31, 2009, reporting period. a. Studies to be audited. No regulatory audits are required for the January 1, 2009, through May 31, 2009, reporting period. b. Deadline. Any regulatory audits performed during the January 1 through May 31, 2009, reporting period should be included in the 2009 Facility Director Certification of Research Oversight, which must be submitted to ORO Regional Offices through the Network Director and received by ORO no later than July 15, 2009. c. Templates. i. The full 2009 Facility Director Certification template is posted on the ORO website at: http://www1.va.gov/oro/docs/RCO_2009AnnualFacilityDirectorsCertification_052809.doc ii. A stand-alone copy of the Facility Director Certification Audit Summary (i.e., Certification page 6) is posted on the ORO website at: http://www1.va.gov/oro/docs/RCO_AnnualCertification_RequiredAudits_FirstReportingPeriod_052809.d oc 7. Regulatory audits for the June 1, 2009 – May 31, 2010, reporting period. a. Studies to be audited. Except as noted in Item 5b (above): i. All human, animal, and safety-related research studies completed between June 1, 2009, and May 31, 2010, must receive a regulatory audit during the June 1, 2009, through May 31, 2010 reporting period. ii. Approximately 33% of human, animal, and safety-related studies initiated after January 1, 2008, should receive a regulatory audit in the June 1, 2009, through May 31, 2010 reporting period, and in each future reporting period, in anticipation of satisfying the triennial audit requirement. b. Deadline. Regulatory audits for the June 1, 2009, through May 31, 2010, reporting period must be completed in time to be included in the 2010 Facility Director Certification of Research Oversight, which must be submitted to ORO Regional Offices through the Network Director and received by ORO no later than July 15, 2010. c. Template. The 2010 Facility Director Certification template will be posted on the ORO website as soon as it is finalized.

Please do not hesitate to contact me should you have any questions.

J. Thomas Puglisi, PhD cc: Deputy Under Secretary for Health for Operations and Management (DUSHOM)(10N) Chief Research and Development Officer (12)

0e5236b1341d2f576017e1081d6e213e.doc Page 61 of 73 VHA Triennial Regulatory Compliance Audit Good Clinical Practice & Human Research Protection Program Optional Audit Tools To be used for audits conducted 1 June 2010 – 31 May 2011 ADMINISTRATIVE INFORMATION

Principal Investigator: Study Coordinator:

Protocol Title:

Current Audit Date: Research Compliance Officer (RCO) or Designated Auditor(s):

Local VA VA ORD VA CSP NIH Other federal: Sponsor Protocol Number / Study acronym: Sponsor / Support: Industry/Pharma NA Other:

Date of Initial IRB Approval: Regulatory Status: IND IDE None IRB of Record: Affiliate IRB Number: Local VA Central VA Academic VA Study Site(s): (check all that apply Local facility CBOC(s) specify Academic Affiliate Other:

Study Type: (check all that apply) Multicenter Trial Single Center Trial International Trial: ORD approval letter on file? Y N

Does this study involve children? Y N If yes, is the ORD approval letter on file? Y N

Category: (check all that apply) Biomedical Behavioral Educational Other:

Actively enrolling new subjects Temporarily closed to new enrollments Current IRB Status: Active only for long-term observation Permanently closed to enrollments Active only for long-term data analysis Closed / Terminated Date:

Number approved Approved enrollment has not been Number of Subjects: Total Enrollment to Date: by IRB for enrollment: exceeded:

Research closed – NO subjects enrolled Y N If YES, complete this page only

Research closed – previous HRPP regulatory audit(s) done Y N If YES, date(s) of previous HRPP audit(s) , and complete this page only

Investigator and Study 0e5236b1341d2f576017e1081d6e213e.doc 62 of 73 VHA Triennial Regulatory Compliance Audit Good Clinical Practice & Human Research Protection Program Optional Audit Tools To be used for audits conducted 1 June 2010 – 31 May 2011

IRB SUBMISSIONS, APPROVALS, AND OTHER ACTIONSi RESEARCH & SUBMISSION & DEVELOPMENT APPROVAL PROTOCOL, Research Research Lapse in IRB Continuing Review IRB DATESII COMMITTEE LETTERS ON AMENDMENTS without prior to Suspension or APPROVAL FILE?IV , CONTINUING IRB IRB Termination DATE OR N/AIII Y/N/ N/A APPROVAL approval approval Date Date of Activity ETC. approval reinstate- During APPROVAL EXPIRATION lapsed ment Lapse

See Protocol History

NOTE: Informed Consent Document approvals and SAE/UPR submissions are recorded on the following pages. (A) Comments may be used, for example, to note any lapse in required research approval, suspensions, terminations, or significant IRB determinations about the protocol or the research staff. The auditor may elect to add addition fields or columns for specific information as desired.

Was Re-Consent Required: / If Re-Consent was required: Was Re-Consenting conducted as required?

INFORMED CONSENTv - IRB SUBMISSIONS, APPROVALS, & OTHER ACTIONS – INFORMED CONSENTvi Informed RE-CONSENT Informed Consent Consent DATE OF IRB VIII IRB STAMP OR Reason for Revision REQUIRED? IX Comments Date Version APPROVALVII EQUIVALENT Y/N Number

LOCAL UNANTICIPATED SERIOUS ADVERSE EVENTS (SAES) UNANTICIPATED PROBLEMS INVOLVING RISKS TO SUBJECTS OR OTHERS (UPRS) SIGNIFICANT SAFETY REPORTS / DATA MONITORING COMMITTEE (DMC) REPORTSX REPORTED EVENT B HOSPITAL TO IRB CATEGORIZED BY IRB INDICATE REVIEWED & DATE DATE OR DEATH DATE WITHIN B REPORTED SAE: CATEGORIZED WITHIN UPR/SAE LEARNED OF SUBJECT ID REPORTED REQUIRED TO OROXV UPR OR REQUIRED TIME PERIOD B B B CCURREDXI VENTXII TO IRB TIME U R S Y/N/NA O E XIVY/N/NA DSMB/DMC PERIODXIII Y/N Y/N Y/N Y/N/NA

B U – Unanticipated B R – Related to study participation B S – Serious B Event must be reviewed & categorized either by IRB or designated, qualified IRB member

PROTOCOL DEVIATIONS / VIOLATIONS

IRB rules for reporting protocol deviations/violations to IRB: Deviations, if any, reported to IRB per IRB rules: Yes No Deviations, if any, recorded in compliance with protocol requirements: Yes No

NOT WORKING OUTSIDE OF SCOPE OF PRACTICE ALL SCOPE OF PRACTICE OR OR EQUIVALENT TRAINING CITI Role in Study FDA Form 1572 EQUIVALENT CD XVI (IRB WOULD DETERMINE SITE PERSONNEL CURRENT Date PI/SC/SI Y/N/NA DOCUMENTED IF WORKINGOUTSIDE Y/N Y/N/NA SCOPE) Y/N

SUBJECT RECORD REVIEW ASSESS TIMING OF CONSENT, COMPLIANCE WITH ELIGIBILITY CRITERIA, ETC. IF FEWER THAN 10 SUBJECTS ENROLLED IN THIS PERIOD, AUDIT ALL OF THEM E WAS THERE EXPIRATION OF IRB APPROVAL? YES OR NO Investigator and Study 0e5236b1341d2f576017e1081d6e213e.doc 66 of 73 VHA Triennial Regulatory Compliance Audit Good Clinical Practice & Human Research Protection Program Optional Audit Tools To be used for audits conducted 1 June 2010 – 31 May 2011

HOW MANY SUBJECTS HAVE BEEN ENROLLED TO DATE OF AUDIT: ………………….

DOCUMENTATION Documentation Found THAT CONSENT SUBJECT WAS DOCUMENTATION FOUND DOCUMENTATION FOUND Verifying Serious SUBJECT OBTAINED PRIOR TO RECONSENTED IF VERIFYING INCLUSION VERIFYING EXCLUSION Other issues found, Adverse Events/UPRS STUDY ID INITIATION OF STUDY REQUIRED BY IRB CRITERIA MET F CRITERIA MET F specify on line below for this participant G PROCEDURESXVII Y/N/NA Y/N/NA Y/N/NA Y/N/NA Y/N/NA

Brochure/“Volunteering in Research – Here are some things you need to know”

IS AT LEAST ONE COPY OF THE BROCHURE AVAILABLE/DISPLAYED FOR POTENTIAL SUBJECTS? YES OR NO

IS AT LEAST ONE ADDITIONAL COPY OF BROCHURE ON-HAND FOR FUTURE DISTRIBUTION? YES OR NO

PROTOCOL DEVIATIONS / VIOLATIONS

Investigator and Study 0e5236b1341d2f576017e1081d6e213e.doc 67 of 73 VHA Triennial Regulatory Compliance Audit Good Clinical Practice & Human Research Protection Program Optional Audit Tools To be used for audits conducted 1 June 2010 – 31 May 2011 IRB rules for reporting protocol deviations/violations to IRB: Deviations, if any, reported to IRB per IRB rules: Yes No Deviations, if any, recorded in compliance with protocol requirements: Yes No

NA Drug INVESTIGATIONAL PRODUCT ACCOUNTABILITY IN INVESTIGATOR REGULATORY BINDER Device Product accountability records (storage, inventory, dispensing) maintained? Yes No NA Comments: VAF 10-9012 (Summary Drug Information) on file in the Site regulatory file? Yes No NA Comments: Investigator Brochure or Package Insert on File? Yes No NA Comments: Custody & Storage of investigational product (drug and/or device): N/A Pharmacy Investigator Other Complies with the facility requirements or as stipulated by the IRB/R&D Committee? Yes No Comment:

OTHER COMMENTS

If there is anything the RCO/auditor thinks should be noted about this audit, please note/comment here:

AUDIT PREPARATION TOOL Present Present Document – Investigator and Document – Investigator and Comments Comments Regulatory Files Reviewed Regulatory Files Reviewed Y/N/NA Y/N/NA Protocol & Amendments R&D Correspondence Approved Case Report Notes-to-File Forms IRB Approved Consent Site-Sponsor Forms Correspondence, if app. -Information Provided to -Conference call minutes Subjects -E-mails -HIPAA Forms -Newsletters -Advertisements -Conference calls -Record of Approved -Letters, memos, faxes Consent Form Versions Study Site Personnel Subject Log Signatures, Qualifications,

(current/accurate) Training, Scope of Practice, CVs, Delegation Signed Attestation or IRB Correspondence Investigator’s Agreement (Sponsor, Institution, FDA) IRB Submissions, Official Documents

Notifications, Approvals Letters, Memos, etc. Serious Adverse Signed PI Conflict of

Events/Safety Reports Interest/Disclosure Statement Investigational Products, if Investigator Brochure/VA applicable - Form 10-9012 Accountability, Handling, Pharmacy, Elsewhere Are there local IRB requirements for record keeping? Yes No NA Comments:

Investigator and Study 0e5236b1341d2f576017e1081d6e213e.doc 69 of 73 VHA Triennial Regulatory Compliance Audit Good Clinical Practice & Human Research Protection Program Optional Audit Tools To be used for audits conducted 1 June 2010 – 31 May 2011 GENERAL INSTRUCTIONS FOR PERFORMING AN AUDIT OF PROTOCOLS INVOLVING HUMAN SUBJECTS WITH THE GCP/HRPP AUDIT TOOL

All open research protocols that involve human subjects live animals or any safety concerns requiring review by an SRS must be audited at least once every 3 years. Protocols that involve no humans, no animals, and no safety concerns do not require a triennial regulatory audit. The only exceptions to this requirement are:

1) Protocols that were initially approved prior to January 1, 2008

2) Human subject protocols that have been ruled exempt from IRB oversight (Remember that such exempt human research will still require an ICD audit annually)

Beginning with the June 1, 2010, - May 31, 2011 auditing period, abbreviated audits have been approved for two special cases listed on the first page of the audit tool: protocols that close without enrolling any human subjects at the local facility, and protocols that close after undergoing a previous triennial regulatory audit. All other human subject protocols excluding the two exceptions above should receive a complete audit with the GCP/HRPP tool. However, for certain types of studies some of the data on the GCP/HRPP tool may be not applicable, and the auditor may simply note this as “n/a”. For example, human subjects research that only involves retrospective chart review commonly has the need for informed consent waived, in which case there are no informed consent documents to review. Therefore, on the subject record review page, the column entitled “Documentation that consent obtained prior to initiation of study procedures” would be “n/a” for these cases. However, the next column regarding inclusion and exclusion criteria might still be relevant for auditing. Every RCO can judge which columns are relevant and meaningful to the specific facts of every protocol, and enter “n/a” when indicated. Of course, RCOs are free to audit additional information if described in their standard operating procedures (SOPs) and helpful for monitoring the quality, safety and compliance of their facility’s research program.

In addition to the requirement that every protocol be audited no less frequently than every 3 years, research protocols must receive an audit with all relevant triennial regulatory audit tools during the audit period in which they close. Certain NO protocols, such as those that did not enroll any subjects at the facility, or those that have had a previous regulatory audit, are eligible for an abbreviated audit as described on page 1 of the GCP/HRPP audit tool. The RCO should review on a regular basis the number and types of open protocols in their research program in order to create an auditing plan that will ensure all open protocols of all types are audited in accordance with the 3-year requirements. The audit plan should realistically address the work time involved in accomplishing the required audits, both triennial regulatory audits as well as required annual audits of all newly-signed Informed Consent Documents (ICDs). Remember that the lead RCO may utilize other facility resources in accomplishing all required audits, as long as the audits are performed by the RCO, overseen by the RCO, or validated by the RCO.

The GCP.HRPP audit tool should be used to audit all open protocols that involve human subjects and are overseen by the IRB. Remember that certain protocols involving human subjects may have safety concerns as well, and if so the protocol should also be overseen by the SRS and the Safety audit tool should be used as well when such a protocol is audited. Examples of protocols involving human subjects that may have safety concerns requiring review by a SRS include any research use outside of normal clinical settings of hazardous chemicals, radioactive materials, controlled substances, and/or blood products, among others.

The shaded areas on the GCP/HRPP audit tool are optional fields to be used as the RCO desires, when applicable. The intent of most is described in the instructions below. In addition, three are optional pages to help ROCs (or other auditors) during the process. The optional page entitled “Audit Preparation Tool” is intended as a list of possible documents that may be useful as sources for information necessary to complete the GCP/HRPP audit tool. Some RCOs have found this list useful in preparing for an audit. Some RCOs have given this list, customized for their facility, to Principle Investigators and research staff and asked them to help assemble the documentation in advance in order to make the audit process more efficient.

Every RCO should have a SOP that describes how they create and monitor their triennial audit plan, and the sources they typically review to locate necessary information. This may vary from facility to facility. In addition, the RCO’s local SOP should describe how the results of audits are reported, and where the audit results are maintained. Audit results may be maintained on paper, electronically, or both. Some facilities store audit results in specific files in the RCO’s office, others in the protocol file. Each facility has discretion to customize tools and solutions that work best in their situation, however these solutions should be described in SOPs and then followed.

Investigator and Study 0e5236b1341d2f576017e1081d6e213e.doc 70 of 73 i The intent of this page is to document, usually in chronological order, actions of the IRB related to the audited protocol. This would include approval, changes, amendments, continuing review/approval, changes in staff, and any other action. The exceptions would be actions related to matters on the next few pages of the audit tool. IRB actions related to the informed consent document and actions related to local unanticipated serious adverse events or other unanticipated problems involving risks to subjects or others are recorded separately on the pages of the tool that follow. The auditor should note any possible compliance issues related to IRB actions on this page of the audit tool, using the comment section. Two examples would be possible lapses in IRB continuing review, and research occurring during a period of lapse of continuing review. The RCO may elect to add other fields or columns to this tool that they judge would help to make it more effective. ii The date should be audited for every IRB action. This will allow the auditor to determine, as relevant, the timeliness of the action and the timeliness of any further actions that may be required by regulation, such as continuing review of approved protocols within 365 days. Date of expiration of the action, if any should also be recorded by the auditor. iii Date of Research and Development Committee (RDC) approval of the IRB action should be entered, if RDC approval is required. Some IRB actions, for example minor amendments to protocol staffing, do not require RDC approval, and “N/A” may be recorded if no RDC approval is required or occurred. Lack of timely approval, when required, should be noted in the comments and appropriately reported by the auditor. iv In most cases the protocol file should include documentation of the submission of the request for an action, and a letter communicating the action to the PI by either the IRB, ACOS, or as designated by policy. Record whether appropriate documentation of required action notification is found during the audit, or “N/A” if no documentation is required for the action by policy. v This page of the GCP/HRPP audit tool is to be used to record sequentially the versions of the informed consent document that have been approved by the IRB for this protocol, the date of approval, and whether re-consent was required. The auditor should also check that the appropriate IRB stamp or equivalent was used. Other information used locally to identify the ICD version may be optionally tracked, and as always the RCO auditor may add other fields as needed. A clear chronology of approved ICDs is necessary for the auditor to ascertain that all enrolled subjects received the version of the ICD that was appropriate on the date of their enrollment in the research. vi This page of the GCP/HRPP audit tool is to be used to record sequentially the versions of the informed consent document that have been approved by the IRB for this protocol, the date of approval, and whether re-consent was required. The auditor should also check that the appropriate IRB stamp or equivalent was used. Other information used locally to identify the ICD version may be optionally tracked, and as always the RCO auditor may add other fields as needed. A clear chronology of approved ICDs is necessary for the auditor to ascertain that all enrolled subjects received the version of the ICD that was appropriate on the date of their enrollment in the research. vii The date of IRB approval of each version of the informed consent document (ICD) is necessary for the auditor to assure that every subject received the current version of the ICD on the date of his/her signature. The date of the writing or revision of the document is used by some facilities as an identifier to refer to the ICD version, other facilities use a version number or other method. These document identifiers may be recorded in the first, optional columns of this page of the tool, or the RCO may redesign this tool adding additional information that makes it more effective for their facility and local standard operating procedures. viii Each time an IRB approves a new version of an ICD, the IRB should make an explicit determination of whether the change is substantive enough to require re-consenting subjects that have agreed to and signed previous versions of the ICD. The determination of the IRB on this topic should be recorded in this column. If the auditor finds that no determination was made or documented, or that re-consent was required but did not occur, these findings should be noted in comments and reported appropriately. ix The presence of the appropriate IRB stamp (or equivalent) on the ICD should be audited and recorded. x It is very important for protection of human subjects that significant safety issues be addressed by the research oversight committees in a timely manner. VA policy requires that significant safety reports and unanticipated, local serious adverse events (SAEs) possibly related to research, as well as local unanticipated problems involving risks to subjects or others be reported to the IRB in an expedited manner, and reviewed by the IRB or a qualified member per policy in a timely manner. This page of the audit tool is intended to record all such events and notices for each audited human subject protocol and to ascertain that required review and determinations occurred in the manner and time required by VA policy. xi “Date event occurred” Record here the date the event actually occurred, according to the documentation available, regardless of when it was first recognized and/or reported. xii “Date learned of event” Record here the date the event was first recognized to have occurred by any member of the research staff, or the RCO. Under VA policy, such recognition begins a timeline for reporting, evaluation and possible action. xiii The time between the date the event was learned of and the date the report was made to the IRB should be checked for compliance with both local SOP and VHA Handbook 1058.01, whichever is the shorter time. Record whether the report was made in a manner compliant with time requirements here. xiv Once the IRB has received a report of a significant safety issue, local unanticipated problem involving risks to subjects or others, or possible local SAE, a review and evaluation must be performed by either the convened IRB or a qualified member within a time period that is the shorter of that in local SOP and that required by VHA Handbook 1200.05. xv If the result of the determination is a category of unanticipated, serious, and related or possibly related to the research, then reporting to ORO should occur as described in VHA Handbook 1058.01. Record here if reporting occurred in compliance with VA and local policy, or enter “n/a” if the determination did not require reporting. xvi For the 2010-2011 audit period RCOs are being asked to ascertain the presence of a scope of practice or equivalent at the time of the audit. No look-back period is expected. The RCO auditor is not expected to evaluate the content or appropriateness of any scope of practice. xvii The date the subject signed the ICD should be compared with the documented date that study procedures began for the subject, to ascertain that informed consent preceded beginning research.