1. Office of Research Oversight Office of Research Oversight 1 ORD Local Accountability Meetings 2007 – 2008 Tom Puglisi, PhD, CIP Joan P. Porter, MSc, DPA, MPH, CIP, CIPP/G Office of Research Oversight

2. Office of Research Oversight Office of Research Oversight 2 Office of Research Oversight Thank you to everyone here for helping to ensure compliant research contributing to quality research for the health and welfare of our veterans!

3. Office of Research Oversight Office of Research Oversight 3 PART I ORO’s Mission Areas of Concern Common Problems in Compliance Case Studies Office of Research Oversight

4. Office of Research Oversight Office of Research Oversight 4 PART II Engagement in Human Research VHA Handbook 1058.03: Assurance Requirements What Constitutes Engagement Reporting AEs & UPRs in Human Research To the IRB To ORO Other Reporting to ORO Office of Research Oversight

5. Office of Research Oversight Office of Research Oversight 5 Advise Under Secretary for Health Monitor / Review / Investigate Compliance – Protection of Human Subjects – Laboratory Animal Welfare – Research Safety & Security – Research Misconduct – Research Information Security – Governmentwide Debarment & Suspension (VHA Handbook 1058.04) ORO’s Mission

6. Office of Research Oversight Office of Research Oversight 6 Use of Affiliate IRBs ORO directed to: review VA use of university IRBs conduct targeted on-site reviews of effectiveness of university IRBs for VA research programs strengthen facility research program assessments and Facility Director certification of research oversight to include use of university IRBs ORO and ORD directed to: review accreditation standards and findings for VA use of university IRBs review effectiveness of oversight by VA Research and Development Committees ORD directed to develop and implement education programs addressing VA use of university IRBs. ORO will help. ORO’s Mission: Areas of Concern

7. Office of Research Oversight Office of Research Oversight 7 Privacy, Confidentiality, & Information Security ─ ORO responsibilities under VHA Directive 1058 (revised February 2008) ─ Information Security Routine On-site Reviews ─ Checklists on ORO website Effectiveness of Facility Oversight – Roles of Director, R&D Committee, and ACOS/R ─ Facility Director Certification of Research Oversight ─ Facility Director Checklist ─ R&D Committee Annual Program Evaluations ─ Implementation of ACOS/R Responsibilities ORO’s Mission: Areas of Concern

8. Office of Research Oversight Office of Research Oversight 8 Access to Protected Health Information (PHI) for recruitment of research subjects ─ VHA is more restrictive than HIPAA, HHS, and NIH ─ VHA requires ─ Prospective IRB Review and Approval ─ Documented Waiver of HIPAA Authorization ─ Documented Waiver of Informed Consent under Common Rule ─ Approval of R&D Committee * see ORO’s website at http://vaww1.va.gov/oro/ ORO’s Mission: Areas of Concern – Just a reminder…

9. Office of Research Oversight Office of Research Oversight 9 ORO Checklists Available on ORO Website Facility Director Research Oversight Certification & Checklist Human Research Protection Program Checklist Institutional Review Board (IRB) Checklist Research & Development Committee Checklist Laboratory Animal Welfare Checklist  Research Laboratory Safety Checklist Security Checklist for BSL-1 & BSL-2 Research Laboratories Security Checklist for BSL-3 Research Laboratories Research Data Security Checklist Research Privacy Checklist  Checklists for Memoranda of Understanding

10. Office of Research Oversight Office of Research Oversight 10 Director’s Certification

11. Office of Research Oversight Office of Research Oversight 11 Facility Director Research Oversight Certification and Checklist Detailed Checklist of Facility Director’s Specific Responsibilities (4 pages, single spaced) Provided Annually Action Plans with Timelines Monitoring of Action Plan Implementation by ORO Regional Offices ─ 43% No Action Plan Required ─ 57% Action Plan in Progress  Annual Assessment or Reports  Written Operating Procedures

12. Office of Research Oversight Office of Research Oversight 12 For Cause Reviews Off and On-site Routine (Not for Cause) Reviews ─ Frequency  50 Annually (previously 25-30) ─ End of 2007  67 onsite visits to review 97 programs for compliance ─ Focus ─ Research Information Security ─ Research Safety & Security ─ Human Research Protection Program ─ Laboratory Animal Welfare Technical Assistance ─ Research Misconduct ─ Federal-wide Assurances ORO’s Activities

13. Office of Research Oversight Office of Research Oversight 13 Common Research Non-Compliance Problems Human Subjects Animal Welfare Research Safety Research Security

14. Office of Research Oversight Office of Research Oversight 14 Some Case Examples of Systemic Compliance Failures What went wrong? Why?

15. Office of Research Oversight Office of Research Oversight 15 Common Compliance Concerns Oversight of Research Program ─ Lack of Program Oversight by Facility Director ─ Lack of Program Oversight by R&D Committee ─ Role Confusion / Inappropriate Reliance on ACOS/R or AO/R ─ Lack of R&D Committee Knowledge about VA and Federal Research Requirements ─ Lack of R&D Committee Knowledge about Subcommittee Responsibilities, Procedures, and Current Issues of Concern ─ Uncritical R&D Committee Reliance on Subcommittees ─ Lag in Meeting Information Security Requirements

16. Office of Research Oversight Office of Research Oversight 16 Common Compliance Concerns Human Research Protection Program ─ Initiating Research without IRB and/or R&D Committee Approval ─ Enrolling Subjects with Absent or Deficient Informed Consent ─ Implementing Unapproved Protocol Changes / Deviations ─ Inadequate Procedures for Reporting to IRB and/or ORO: ─ Serious / Related / Unexpected Adverse Events ─ Unanticipated Problems Involving Risks to Subjects/Others ─ Inadequate Procedures for Reporting to Privacy Officer and/or ISO ─ Unauthorized Use / Disclosure / Loss of Identifiable Patient Info ─ Violations of VA Information Security Requirements ─ Inappropriate “Contingent Approval” Requiring Substantive Changes ─ Lack of Procedures for Conducting Protocol and IRB Audits

17. Office of Research Oversight Office of Research Oversight 17 Common Compliance Concerns Animal Care and Use Program ─ Failure to Conduct Semi-Annual Program and Facility Review ─ Failure to Implement Occupational Health and Safety Program ─ Inadequate Review of Category D and E Protocols ─ Inadequate Post-Surgical Care and Monitoring ─ Use of Inappropriate Anesthesia Techniques ─ Use of Outdated and/or Non-Pharmaceutical Grade Drugs ─ Inadequate Tracking and Securing of Controlled Substance ─ Inadequate Population Management and Animal Tracking ─ Inadequate Training: IACUC Members, Investigators, Caretakers ─ Implementation of Unapproved Protocol Changes ─ Inadequate Facility Maintenance and Temperature Control Testing

18. Office of Research Oversight Office of Research Oversight 18 Common Compliance Concerns Research Safety Program ─ Failure to Conduct Annual Reviews of the Research Areas and of the Chemical Hygiene Plan ─ Failure to Conduct Semi-Annual Reviews of Personnel Access, Hazardous Agent Inventory, Select Agent / Toxin Exempt Quantity Logs ─ Failure to Implement VHA Handbook 1200.06 (October 2005) ─ Failure to Appoint a Research Safety Coordinator ─ Failure to Ensure Annual Research-Specific Safety Training ─ Failure to Comply with NIH rDNA and IBC Requirements ─ Failure to Comply with National Standards for Eyewash Stations, Storage of Flammable Chemicals, Labeling and Containment of Hazardous Chemical Wastes

19. Office of Research Oversight Office of Research Oversight 19 ORO Suspensions Since April 30, 2006 Smoking Cessation Study Animal Care and Use Program Research Safety Program Research Information Security (Birmingham) Use of Affiliate IRB Office of Research Oversight

20. Office of Research Oversight Office of Research Oversight 20 Collaborative HSR&D Project to: Increase use of care for smoking cessation Ensure that a “best practice” (telephone care coordination for smoking cessation) becomes routine care throughout two VISNs Concerns brought to ORO by one IRB Smoking Cessation Study

21. Office of Research Oversight Office of Research Oversight 21 Veteran subjects and their local, referring VA providers not informed adequately that the program involved:  Research comparing four separate approaches to intervention (intervention groups)  Assignment of participants to intervention groups based on geographic location rather than clinical factors. Smoking Cessation Study – ORO’s Concerns

22. Office of Research Oversight Office of Research Oversight 22 Local VA providers not given adequate information regarding medications prescribed to their patients  Nicotine  Bupropion (entails risks)  Serious contraindication: MAO inhibitors  Dose-related seizures in a small number of patients, especially patients suddenly stopping regular use of sedatives (e.g., benzodiazepines) or alcohol Smoking Cessation Study: ORO’s Concerns

23. Office of Research Oversight Office of Research Oversight 23  Suspension of New Enrollments June 15, 2006 Notification of all referring providers Evaluation of risks to each subject by referring provider  Resumption of Research VISN A: December 13, 2006 Local investigator at each site Local IRB & R&D Committee approval VISN B: January 22, 2007 No local site investigators Permission of Facility Director and COS at each site Smoking Cessation Study: ORO Suspension

24. Office of Research Oversight Office of Research Oversight 24 Relatively new Facility Director had delegated all oversight of ACUP to long-time ACOS/R IACUC meeting tapes demonstrated that former ACOS/R had inappropriately:  Influenced IACUC deliberations  Made IACUC decisions without IACUC input IACUC members uninformed about:  Specific regulatory and policy requirements  Program oversight responsibilities Animal Care and Use Program: ORO’s Findings

25. Office of Research Oversight Office of Research Oversight 25 Breakdown of communications and respect between research community and VMO  Semi-Annual Program Review and Facility Self-Assessment still not completed as of ORO site visit  Investigators perceived VMO to be; ─ Unavailable for consultation pre/post IACUC meetings ─ Arbitrary in enforcing regulatory compliance ─ Disrespectful in investigator communications  VMO perceived investigators to be: ─ Disrespectful of regulatory requirements ─ Subjecting animals to danger and harm Animal Care and Use Program: ORO’s Findings

26. Office of Research Oversight Office of Research Oversight 26 VMO lacked:  Access to copies of approved protocols  Access to certain animal research labs  Control over animal procurement  Any input into budgetary decisions, including per diem charges ACUP lacked:  Comprehensive Occupational Safety & Health Program  Mechanisms to ensure proper training prior to handling animals  Mechanisms for tracking animal census and linking to protocols  Population management mechanisms Animal Care and Use Program: ORO’s Findings

27. Office of Research Oversight Office of Research Oversight 27 ORO inspections revealed:  OSH and training requirements for access to animals not enforced  Controlled substances obtained outside VA pharmacy  Controlled substances not properly locked and tracked  Widespread use of expired drugs  Widespread use on non-pharmaceutical grade drugs  Lack of investigator and IACUC awareness of above requirements  Investigator failure to obtain IACUC approval for protocol changes  Widespread violations of veterinary standards, especially surgical  Lack of periodic HVAC temperature testing  Lack of monitoring of cage wash temperatures Animal Care and Use Program: ORO’s Findings

28. Office of Research Oversight Office of Research Oversight 28 ORO inspections revealed:  Lack of primate technician and primate enrichment program  Lack of security for back entrance to animal facility  Chronic problems with mouse hepatitis virus (MHV), pinworms, and mouse parvovirus (MPV) such that affiliate would not accept animals transfers from VA facility  Multiple safety deficiencies in both animal and non-animal laboratories Systemic lack of R&D Committee oversight Complex remedial action plan in multiple areas Resumption of ACUP: January 19, 2007 Animal Care and Use Program: ORO’s Findings

29. Office of Research Oversight Office of Research Oversight 29 Unsafe storage of chemicals  Improper containers  Co-storage of incompatible chemicals  Flammable chemicals in unsafe cabinets  Outdated chemicals ─ Crystallized picric acid ─ Perchloric acid Inoperable eyewash stations Use of Bunsen burners in unsuited biosafety cabinets  Often placed adjacent to warning label on cabinet Research Safety Program: ORO’s Findings

30. Office of Research Oversight Office of Research Oversight 30 Chemical fume hoods with clutter impeding air flow Improper inspection of biosafety cabinets and fume hoods Outdated chemical inventories Fire code violations:  Obstruction of exits  Exposed electrical wiring  Blocked sprinklers  Use of extension cords Inconsistent temperature regulation and ventilation Research Safety Program: ORO’s Findings

31. Office of Research Oversight Office of Research Oversight 31 Failure to label equipment, supplies, and waste as radioactive Failure to decontaminate abandoned labs Lack of coordination with Occupational Safety and Health Program Laboratory personnel poorly trained/supervised about standard and specific safety precautions  “Shorts and flip flops” Systemic failure of SRS and R&D Committee Oversight  Failure to correct chronic observed deficiencies Research Safety Program: ORO’s Findings

32. Office of Research Oversight Office of Research Oversight 32 ORO involvement began with FDA termination 3 collaborative studies involving VA, affiliate, and FDA VA facility audits identified serious deficiencies in a number of studies University IRBs:  Not cognizant of VA requirements  Failed to inform facility systemically of SAEs / noncompliance  Unresponsive to audit reports Facility R&D Committee:  Inadequate review of individual protocols  Inadequate oversight of research program Use of Affiliate IRB: ORO’s Findings

33. Office of Research Oversight Office of Research Oversight 33 Facility Research Service:  Extreme reliance on affiliate  Inadequate written policies and procedures  Absence of infrastructure and internal controls for research ─ Lack of complete protocol records in Research Service ─ Deficient protocol inventory and tracking ─ Failure to identify VA research vs Affiliate research ─ Lack of COI monitoring and management procedures ─ Lack research credentialing procedures ─ Lack of enforcement of training requirements Use of Affiliate IRB: ORO’s Findings

34. Office of Research Oversight Office of Research Oversight 34 Under Secretary for Health:  Cease use of Affiliate IRBs  Establish VA IRB ORO:  Cease initiation of new studies  Cease enrollment of subjects in existing research unless necessary for health of individual subject and approved by COS Restriction of Research: August 30, 2007

35. Office of Research Oversight Office of Research Oversight 35 ORO:  Continue already enrolled subjects in ongoing research where necessary for health of individual  Transfer oversight to another VA IRB ASAP  Negotiate procedures with affiliate for transfer of ongoing research to VA IRB  Establish appropriate R&D Committee review and oversight procedures Restriction of Research: August 30, 2007

36. Office of Research Oversight Office of Research Oversight 36 Facility amended FWA to permit use of another VA’s IRB In Fall 2007, 10-12 high priority protocols were reviewed and approved by this IRB Facility established its own IRB, including: ─ IRB and R&D Committee member training ─ Individual and group investigator training program ─ COI review mechanisms ─ IRB administration and protocol tracking systems ─ Training and COI tracking systems Status as of Jan 29, 2008

37. Office of Research Oversight Office of Research Oversight 37 Facility amended FWA to include its own IRB Facility IRB began reviewing protocols in priority order in late December 2007 Facility IRB has reviewed 20-25 protocols with 10-12 fully approved A few low priority protocols halted when approval period lapsed Other protocols remain suspended to new enrollments pending IRB review and approval Status as of Jan 29, 2008

38. Office of Research Oversight Office of Research Oversight 38 PART II Assurances “Engagement in Research” Reporting to ORO: AEs and UPRs* *Unanticipated problems involving risks to subjects or others.

39. Office of Research Oversight Office of Research Oversight 39 Each entity engaged in human research conducted or supported by VA must provide a written Assurance to comply with the Federal Policy for the Protection of Human Subjects (38 CFR Part 16) ─ VA Facilities / VA Investigators ─ Non-VA Institutions — VHA Handbook 1058.03 §2b(1)&(2) When an Assurance is Needed for the Protection of Human Subjects

40. Office of Research Oversight Office of Research Oversight 40 Intellectual contributions meriting publication authorship — VHA Handbook 1058.03 §8a Assurances Needed by a Non-VA Entity

41. Office of Research Oversight Office of Research Oversight 41 Entities operated under a contract from a VA (eg, Contract CBOC) —VHA Handbook 1058.03 §4i(1) Assurances Needed by a Non-VA Entity

42. Office of Research Oversight Office of Research Oversight 42 Engagement of VA Facilities In Human Research VA is guided by, but does not completely follow, Office for Human Research Protections Guidance (January 1999) If a VHA Facility is engaged in human research, the research needs review and approval from: The Facility’s IRB of Record The Facility’s R&D Committee

43. Office of Research Oversight Office of Research Oversight 43 Engagement in Human Research A VA facility is engaged in human subject research (and needs an Assurance) whenever its employees or agents: Intervene or interact with living individuals for research purposes, or Obtain, release, or access individually-identifiable private information (or individually-identifiable specimens) for research purposes — VHA Handbook 1200.5§3.b. (See also 38 CFR 16.102(f))

44. Office of Research Oversight Office of Research Oversight 44 Examples of Engagement OHRP Guidance January 1999 (A)(1) Employees or Agents Intervene with Living Individuals for Research: ◦ Collecting biological specimens for research ◦ Administering interventions for research ◦ Dispensing drugs for research ◦ Using invasive or non-invasive tests for research

45. Office of Research Oversight Office of Research Oversight 45 Examples of Engagement OHRP Guidance January 1999 (A)(2) Employees or Agents Intervene with Living Individuals by Manipulating the Environment for Research: ◦ Manipulating light, sound, or temperature for research ◦ Presenting sensory stimuli for research ◦ Orchestrating environmental events or social interactions for research ◦ Making voice, digital, or image recordings for research

46. Office of Research Oversight Office of Research Oversight 46 Examples of Engagement OHRP Guidance January 1999 (A)(3) Employees or Agents Interact with Living Individuals for Research: ◦ Protocol-specified communication ◦ Interpersonal contact for research ◦ Surveys and interviews for research ◦ Obtaining informed consent for research

47. Office of Research Oversight Office of Research Oversight 47 Examples of Engagement OHRP Guidance January 1999 (A)(4)Institutions whose employees/agents release individually identifiable private information, or permit investigators to obtain individually identifiable private information, for research without subjects' explicit written permission ◦ Releasing patient names to investigators for solicitation as research subjects ◦ Permitting investigators to record private information from medical records in individually identifiable form (VA departs from this guidance under certain circumstances…)

48. Office of Research Oversight Office of Research Oversight 48 Reporting to the IRB: AEs vs Unanticipated Problems (UPRs) 38 CFR 16.103(b)(5); 21 CFR 56.108(b)(1); 21 CFR 812.150(a)(1) VHA Handbook 1058.1 requires detailed SOPs. ◦ ORO has provided guidance (see ORO website). ◦ Problems reportable to IRB should ensure that all UPRs are reported promptly to the IRB. ◦ AEs that do not qualify as UPRs and to do not require prompt reporting to the IRB should at least be reported as part of the continuing review process. Facilities have flexibilities in ensuring the required reporting ◦ Algorithm for reporting to the IRB ◦ Over-reporting may be desirable at the facility level to ensure that IRB is informed of all reportable UPRs

49. Is the problem or event RELATED or POSSIBLY RELATED to the research? Does the problem or event involve RISKS to ANYONE ELSE (e.g., subjects’ family members, research personnel, others)? ≈≈≈ Facilities have flexibility in setting IRB reporting requirements. Does the problem or event involve RISKS to SUBJECTS? Was the problem or event ANTICIPATED as to NATURE, SEVERITY, and FREQUENCY as described in the protocol, consent document, or other materials approved by the IRB? Is the AE “SERIOUS” as defined by FDA? i.e., did the AE result in (or need medical or surgical intervention to prevent) death, a life-threatening experience, inpatient hospitalization, prolongation of hospitalization, persistent or significant disability or incapacity, congenital anomaly or birth defect, or jeopardy to a subject rights, safety, or welfare? NOYES NOYES NO YES NO  The problem or event MUST BE REPORTED PROMPTLY to the IRB. YES A problem occurs during a research project. An Adverse Event (AE) occurs during a research project. Algorithm for Reporting AEs & UPRs to the IRB

50. Office of Research Oversight Office of Research Oversight 50

51. Office of Research Oversight Office of Research Oversight 51 Reporting to ORO In Human Research: Adverse Events: VHA Handbook 1058.1 An Adverse Event (AE) in research is ◦ Any untoward occurrence in a human subject participating in research ◦ (IRB of record for VA at affiliate does not report to ORO directly, but should have SOPs) ◦ Physical, psychological, social, economic ◦ Any unfavorable or unintended events, eg, abnormal laboratory findings, symptoms, disease, death ◦ Not necessarily due to error or protocol deviation ◦ Not necessarily caused by the research

52. Office of Research Oversight Office of Research Oversight 52 Reporting to ORO In Human Research: Adverse Events: VHA Handbook 1058.1 VHA facility must report to its ORO Regional Office All AEs and imminent threats of AEs in on-site research that result in ◦ An IRB taking substantive action(s) or ◦ An unexpected death, regardless of IRB action

53. Office of Research Oversight Office of Research Oversight 53 Reporting to ORO In Human Research: Adverse Events: VHA Handbook 1058.1 The death of a research subject must be reported to ORO ◦ Within 24 hours after IRB determines that it is unexpected, or ◦ Within 10 working days if a determination has not yet been made

54. Office of Research Oversight Office of Research Oversight 54 Reporting to ORO In Human Research: Adverse Events: VHA Handbook 1058.1 Reporting of AEs to ORO must be ◦ Separate for each AE ◦ In writing ◦ Initialed by the Facility Director ◦ Sent by express mail and e-mail or fax ◦ Accompanied by all relevant IRB meeting minutes (when available but no more than 4 weeks after the meeting)

55. Office of Research Oversight Office of Research Oversight 55 Reporting to ORO In Human Research: Adverse Events: VHA Handbook 1058.1 An Imminent Threat of an Adverse Event (AE) in research is ◦ Any situation in which an AE has not yet occurred but is likely to occur without preventive measures ◦ As determined by ◦ An IRB member, ◦ Research team member, or ◦ Clinical team member

56. Office of Research Oversight Office of Research Oversight 56 Reporting to ORO In Human Research: Adverse Events: VHA Handbook 1058.1 An unexpected death ◦ Is one where a high risk of death is not projected as indicated by ◦ The protocol, or ◦ Informed consent document, or ◦ The clinical investigator’s brochure, or ◦ Does not include deaths, ◦ Associated with a terminal condition unless the research hastened the subject’s death ◦ Determined not to be associated with the research

57. Office of Research Oversight Office of Research Oversight 57 Reporting to ORO In Human Research: Adverse Events: VHA Handbook 1058.1 A substantive IRB action ◦ Is an action taken by the IRB that materially affects the substance and meaning of ◦ The protocol, or ◦ The informed consent document or process, or ◦ Investigator status ◦ Includes, but is not limited to, ◦ Restriction, suspension, or termination of a study ◦ Restriction, suspension, or termination of investigator participation ◦ Actions taken to prevent future occurrence of the AE

58. Office of Research Oversight Office of Research Oversight 58 Reporting to the IRB: AEs vs Unanticipated Problems (UPRs) 38 CFR 16.103(b)(5); 21 CFR 56.108(b)(1); 21 CFR 812.150(a)(1) Adverse Events

59. Office of Research Oversight Office of Research Oversight 59 Substantive IRB Action Deaths Anticipated Deaths REPORTING TO ORO Reporting to the IRB vs Adverse Events

60. Office of Research Oversight Office of Research Oversight 60 Reporting to ORO In Human Research: Other Requirements Any for-cause suspension or termination of human research by the IRB, VHA Facility, or VHA Affiliate Any serious or continuing noncompliance with federal regulations or VA requirements Any serious or continuing noncompliance with IRB requirements Any finding of noncompliance by ORD, another VHA Office, OHRP, or FDA Any change in accreditation status of VHA facility or affiliate Any change in the VHA Facility’s FWA or designated IRB(s) Any significant change in an MOU governing IRB oversight

61. Office of Research Oversight Office of Research Oversight 61 Reporting to ORO In Human Research: Other Requirements Calling a suspension an “Administrative Hold” is no excuse for not reporting non-compliance to ORO. In other words – An “Administrative Hold” based on or involving research noncompliance must be reported to ORO.

62. Office of Research Oversight Office of Research Oversight 62 Laboratory Animal Welfare Requirements for Reporting to ORO Any incident that seriously affects the health or safety of lab animals Any loss of animal life due to physical plant or engineering deficiencies Any work related injury to personnel that requires more than minor medical intervention or leads to serious complications or death Any for-cause suspension or termination of research by the IACUC Any serious or continuing noncompliance with PHS Policy Any serious deviation from the Animal Welfare Act or the “Guide” Any finding of noncompliance by ORD, another VHA Office, USDA, or OLAW Any change in the Animal Welfare Assurance or Accreditation status of the VHA facility or the entity on which the facility relies Any significant change in an MOU governing Lab Animal Welfare

63. Office of Research Oversight Office of Research Oversight 63 Research Lab Safety and Security Requirements for Reporting to ORO Any work related occupational injury to personnel that requires more than minor medical intervention or leads to serious complications or death Any significant, work-related exposure to hazardous materials of personnel working with a research facility Any for-cause suspension or termination of research by a Facility safety committee Any exposure, release, loss, or theft of hazardous materials, including select agents and toxins Any finding of noncompliance in research safety or security by ORD, the VA National Health Physics Program (NHPP), VA OIG, or another VHA Office Any finding of noncompliance in research safety or security from external oversight agencies such as NIH OBA, CDC, USDA, OSHA, or the NRC

64. Office of Research Oversight Office of Research Oversight 64 Research Misconduct Requirements for Reporting to ORO ORO should be notified immediately of ◦ Any harm or threat of harm to research subjects ◦ Any harm or threat of harm to those involved in an Inquiry or Investigation ◦ Serious regulatory noncompliance ◦ Risks to public health or safety ◦ Loss or destruction of VA funds or property ◦ Possible civil or criminal violations Any request for pre-approval of significant changes or departures from the procedures or time frames required under VHA Handbook 1058.2 Any opening or closure of an research misconduct INQUIRY Any opening or closure of an research misconduct INVESTIGATION The Network (VISN) Director’s decision on the merits of a research misconduct case

65. Office of Research Oversight Office of Research Oversight 65 ORO Regional Offices Northeastern Bedford, MA VISNs 1, 2, 3 Midwestern Hines, IL VISNs 11, 12, 15, 19, 23 Western Loma Linda, CA VISNs 18, 20, 21, 22 Southern Duluth, GA VISNs 7, 8, 16, 17 Mid-Atlantic Washington, DC VISNs 4, 5, 6, 9, 10

66. Office of Research Oversight Office of Research Oversight 66 Office of Research Oversight http://www1.va.gov/oro/ ORO (Central Office) Department of Veterans Affairs 811 Vermont Ave, NW, Suite 574 (10R) Washington, DC 20420 202.565.5184  fax: 202.565.9194 ORO Mid-Atlantic Regional Office District of Columbia VAMC 50 Irving Street, N.W. (10R) Washington, DC 20422 202.745.8110  fax: 202.745-8538 ORO Midwestern Regional Office Hines VAMC Building 1 (10R), Room B-103 5th & Roosevelt Avenues Hines, IL 60141 708. 202.7254  fax: 708.202.7250 ORO Northeastern Regional Office Bedford VAMC 200 Springs Road (10R) Bedford, MA 01730 781.687.3850  fax: 781.687-3858 ORO Southern Regional Office 3700 Crestwood Pkwy, NW Suite210 (10R) Duluth, GA 30096 678.924.5762  fax: 678.924.5708 ORO Western Regional Office P.O. Box 7360 Moreno Valley, CA 92552-7360 Express Delivery: 14560 2nd Street, Bldg. 2641, Suite B Riverside, CA 92518 909.801.5164  fax: 909.801.5176