# Presentation: 305326

## ORO UPDATE AND COMMON FINDINGS IN ROUTINE REVIEWS

**David A. Weber, PhD, FACNP**
**Office of Research Oversight**
**October 18, 2005**

## OUTLINE

**ORO-2005**
**Compliance Activities**
**Conduct of Routine Reviews**
**Compliance Findings**

##               ORO LEGISLATION*¶ 7307. Office of Research Oversight“(a) Requirement for Office.-(1) There is in the Veterans Health Administration an Office of Research Oversight (hereinafter in this section referred to as the ‘Office’).  The Office shall advise the Under Secretary for Health on matters of compliance and assurance in human subjects protection,...........”*Public law 108 (170) signed by President 12/6/2003

## ORO MISSION

**Advise Under Secretary for Health on matters of regulatory compliance and assurance in research involving human subjects, animal welfare, research safety, and research misconduct**

## OVERSIGHT RESPONSIBILITIES

**Monitor, review, and investigate regulatory compliance and assurance in research involving human subjects, animal welfare, research safety and research misconduct.**
**Advise USH based on these findings**

## ORO COMPLIANCE ACTIVITIES

**For-Cause Reviews**
_**Routine Reviews**_
**BSL-3 Laboratory Inspections**
**Research Misconduct Oversight**
**Management of Assurance Program**
**Adverse Event Oversight, HB 1058.1**
**Compliance Information via Bimonthly Teleconferences, Meetings, etc.**
**Routine Monitoring and Follow-up of Compliance Issues**

## Q2-CY05 OROCompliance Activities

-  For Cause On-Site Reviews
- 3 Human Subject
**2 Follow-up**
**1 New**
- 2 Animal Welfare
**1 Follow-up**
**1 New****	****	****	****	****	**

## Q2-CY05 OROCompliance Activities

- Routine On-Site Reviews (6N/7FU)
- 10 Human Subject
- 1 Animal Welfare
- 1 Animal Welfare & Research Safety
- 1 Animal Welfare & Physical Security
- BSL-3 Laboratory Inspections
- 2 BSL-3 (1N/1FU)

## Q2-CY05 ORO Compliance Activities

- Research Misconduct (HB 1058.2)
- 8 cases under review
- Adverse Events in Research (HB 1058.1)
- oversight of AEs (IRB substantive actions/death)
- Management of Assurance Program
- ~115 FWAs and related MOUs with affiliates

## Q2-CY05 ORO Compliance Activities

- Other Compliance Cases (w/o site visit)
- 46 Human Subject
- 10 Animal Welfare
- 3 Research Safety
- (27 new cases in Q2-CY05)

## IN PROGRESS

- What to Report to ORO (9/8/05)
- Assurance Handbook
- Guidance and Policy Planning with ORD
- International Research
- Multi-site IRBs
- Data & Tissue Repositories

## ROUTINE REVIEW PROGRAM

**Systematic and prospective review of research programs to assist facilities fulfill their responsibilities to conduct research with adequate protection** **of human subjects and support for laboratory animal welfare, research safety, and laboratory security. **

## Routine On-Site Reviews

**Review & Assess C&A with laws, regulations, policies, and procedures governing research**
**Review all VHA facilities with research programs**
**Systematic & prospective**
**May result in action plan**
**Follow-up if action plan required**
**Not an: Audit, a For-Cause Review, an Investigation**

## ROUTINE REVIEWS

**4 to 6 RRs conducted by each RO/yr **
**Teams of 2-5 members for 1-5 days**
**Site visit reports**
**Facility action plans**
**ORO follow-up**

## Where Do Questions Asked in a Routine Review Come From?Partial Listing Follows

## Human Subject Protections

*The Belmont Report*, *Ethical Principles and Guidelines for the Protection of Human **Subjects of Research*
- 38 CFR Part 16, *Protection of Human Subjects*
*38 CFR 17.33, Patients’ Rights*
*38 CFR 17.85, Treatment of Research-Related Injuries to Human Subjects*

## Human Subject Protections

- Veterans Health Administration (VHA) Handbook 1058.1, *Reporting Adverse Events to the ORO*
- VHA Handbook 1200.5, *Requirements for the Protection of Human Subjects in Research*
- VHA Handbook 1200.16,* Off-Site Research Handbook*
- Additional VHA Memoranda and Directives related to HRP
- VA Manual, M-3, Part 1, Chapter 1, *Introduction, Research and Development (R&D) Program; *Chapter 2, *R&D Organizational Structure; *Chapter 3,* R&D Function*

## Human Subject Protections

- VA Office of Research and Development, Cooperative Studies Program Guidelines for the Planning and Conduct of Cooperative Studies
- 21 CFR Part 50, Protection of Human Subjects;  Part 54, Financial Disclosure by Clinical Investigators; Part 56, Institutional Review Boards; Part 312, Investigational New Drug Application; Part 600, Biological Products; Part 812, Investigational Device Exemptions;    and Part 814, Premarket Approval of Medical Devices. Food and Drug Administration (FDA).
- FDA Information Sheets: Guidance for Institutional Review Boards and Clinical  Investigators
- 62 FR 25692, International Conference on Harmonization (ICH), Good Clinical Practice Guidelines. FDA

## Human Subject Protections

- 45 CFR Part 46 Subpart A* Protection of Human Subjects; *Subpart B, *Additional Protections for Pregnant Women, Fetuses, and Neonates; *Subpart C, *Additional Protections for Prisoners; *Subpart D, *Additional Protections for Children. *Department of Health and Human Services (DHHS).
*Federalwide Assurance (FWA), Terms of Assurance,* Office for Human Research Protections (OHRP), DHHS
*Engagement of Institutions in Research*, OHRP
*OHRP Compliance Activities: Common Findings and Guidance*
- Additional OHRP guidance as related to ORO’s mission

## LABORATORY ANIMAL WELFARE

- Veterans Health Administration (VHA) Handbook 1200.7, *Use of Animals in Research*
- PL 99-158, *Health Research Extension Act of 1985, *Section 495:* Animals in Research*
- 7 USC, 2131-2159, 7 CFR 2.22, 2.80, and 371.2(g), *Animal Welfare Act, As Amended.*
- 9 CFR Parts 1, 2, 3, and 4, *Procedures under the Animal Welfare Act, *Department of Agriculture.

## LABORATORY ANIMAL WELFARE

*Guide for the Care and Use of Laboratory Animals. *National Research Council
*Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals. Office of Laboratory Animal Welfare, *National Institutes of Health (NIH), 2002)
*US Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research and Training, *as found in* PHS Policy on Humane Care and Use of Laboratory Animals*

## Research Safety and Security

- VHA Handbook 1200.6, *Control of Hazardous Materials in VA Research Laboratories, *2004
- VHA Handbook 1200.8, *Safety of Personnel Engaged in Research*, 2002
- VHA Directive 2003-030,* Management of Hazardous Chemicals, *2003
- VHA Directive 2005-003. *Requirements for Submittal and Approval of Biosafety Level-3 (BSL-3) Research Laboratory Construction and Renovation, *2005

## Research Safety and Security

- 7 CFR Part 331 and 9 CFR Part 121, *Agricultural Bioterrorism Protection Action of 2002: Possession, Use, and Transfer of Biological Agents and Toxins. *Department of Agriculture
- 29 CFR Part 1910, *Occupational Safety and Health (OSHA) Standards*; Section 1910.1030, *Bloodborne Pathogens*; Section 1910.1200, *Hazard Communication*; and Section 1910.1450, *Occupational Exposure to Hazardous Chemicals in Laboratories*
- 29 CFR Part 1960, *Basic Program Elements for Federal Employee Occupational Safety and Health Programs and Related Matters.* OSHA

## Research Safety and Security

- 42 CFR Part 73, *Possession, Use, and Transfer of Select Agents and Toxins (Final Rule), HHS*
*Biosafety in Microbiological and Biomedical Laboratories (4th Edition). CDC, NIH, *1999
*Guidance Document for Application for Laboratory Registration for Possession, Use, and Transfer of Select Agents and Toxins.* HHS and DOA, OMB Nos. 0579-0213 & 0920-0576.
*NIH Guidelines for Research Involving Recombinant DNA Molecules, *NIH,* *2002

## Research Misconduct

- Veterans Health Administration (VHA) Handbook 1058.2, *Research Misconduct, *2005
- 38 CFR Part 44, *Governmentwide Debarment and Suspension (Nonprocurement).*
- 65 FR 76260, *Federal Policy on Research Misconduct,* Office of Science and Technology Policy (OSTP), 2000

## WHAT TO REPORT TO OROMEMORANDOM

**Identifies issues VHA facilities must report to ORO as required by various Federal regulations and VHA policies. **
**	****	**
**	**_[http://www.va.gov/oro/](http://www.va.gov/oro/)_
**September 8, 2005**

## WHEN IS A ROUTINE REVIEW DONE?

**RRs are routinely initiated by ORO ROs. The ORO RO Director will select the VHA facilities to be reviewed.  Requests for review from facilities are also considered.**

## Pre-Site Visit

**Scheduling**
**Initial Contact**
**Letter of Notification**
**Pre-Site Visit Preparation**

## Site Visit

**Entrance Briefing **
**Review Processes**
**Interview of key personnel**
**Group Meetings**
**Record/Document Review**
**Process Observation**
**Facility Inspection**
**Executive Session**
**Briefing and Exit Interview**

## Post-Site Visit

**Drafting the Report**
**Finalizing the Review**
**Follow-up **

## ORO Regional Offices

**Northeastern**
**	****Bedford, MA**
**	****VISNs 1, 2, 3**
**Mid-Atlantic**
**	****Washington, DC**
**	****VISNs 4, 5, 6, 9, 10**
**Southern**
**	****Decatur, GA**
**	****VISNs 7, 8, 16, 17**

**Midwestern**
**	****Hines, IL**
**	****VISNs 11, 12, 15, 19, 23**
**Western**
**	****March ARB, CA**
**	****VISNs 18, 20, 21, 22**

## Routine Review Findings

## HRP Findings: R&D Committee

- 1.  **Terms of R&D Committee members often found to exceed three years**
- M-3, Part I, Chapter 2.02 b. (5) (c) members serve terms of not more than 3 years with not less than 1 year between terms (does not apply to ex officio members).  The terms shall be staggered to provide partial change in membership annually.

## HRP Findings: R&D Committee

**2.  ****R&D Committee reports to Director through ACOS/R&D**
- VA Manual, M-3, P-I, Chapter 2.02.b(1) the R&D Committee reports to the facility Director through COS (Chapter 2.02b(2)(e) the ACOS/R&D serves as an ex officio member of the R&D Committee with a vote and functions as R&D Executive Secretary)

## HRP Findings: R&D Committee

**3.  R&D Committee meets when issues arise and time allows**
- M-3, Part 1, Ch 3.01(c) requires the committee to meet monthly with exception of one month in the summer

## HRP Findings:Investigational Drug Logs 

**1.  Research pharmacy files incomplete, lack VA Forms 10-9012, Investigational Drug Record and 10-1223, Report of Subcommittee on Human Studies, or lack required signatures on forms**
- VHA HB 1200.5.14c; M-2, Part VII, Chapter 6 maintain log of all transactions involving receipt, dispensing and disposition of investigational drugs and other study related information

## HRP Findings: IRB & R&D Minutes

**1.  IRB and R&D minutes not appropriately processed and signed off**
- M-3, Part I, Chapter 3.01e requires R&D Committee to review IRB minutes and to append them to the minutes of the R&D Committee.
- M-3, Part I, Chapter 3.01d(3)The R&D Committee minutes should be signed by the Chair and the Executive Secretary (i.e., ACOS/R&D) and copies submitted to the facility Director and COS for review and signature

## HRP Findings: IRB & R&D Minutes

**2. IRB minutes do not distinguish between recusal and abstention**
- 38 CFR 16.107 (e) and VHA Handbook 1200.5, ¶6.g, lacking VA Form 10-1223, Report of Subcommittee on Human Studies

## HRP Findings: SOPs

**1.  The SOPs for the IRB, R&D, and investigators are out of date and do not comply with relevant regulations and policies**
- Should update to include requirements from HB 1200.5., 38 CFR 16, 45 CFR 16, 38 CFR 17 (treatment of research injuries), 21 CFR 50, and 21 CFR 312 and 812

## HRP Findings: SOPs

**2.  IRB does not consistently follow SOPs and VA regulations for expedited review procedure & waiving documentation of informed consent**
- 38 CFR 16.117 (c), must document findings for waiver of informed consent

## HRP Findings:Staff Responsibilities

**1. Chairpersons of R&D and IRB Committees do not show working knowledge of duties and responsibilities of their positions**
- Training and resource support is recommended, consult PRIDE
**2. Approval of protocols without quorum and use of e-mail voting outside of convened meeting shows IRB Committee lacks knowledge of federal regulations, VHA policies, and directives governing HRP**
- 38 CFR 16.108 (b) and VHA Handbook 1200.5, paragraph 7.f, consult PRIDE

## HRP Findings:Informed Consent Form

** **
- 1. **Review and approval of ICF do not follow SOP and VA regulations**
- 38 CFR 16.116 (a), VHA HB 1200.5, Appendix C

## AW Findings: IACUC

- 1. IACUC Permits extension of protocol approvals beyond 3 yr term without completion of re-review or re-approval
- Not in compliance with PHS Policy on Humane Care and Use of Laboratory Animals, see guidance at http://grants1.nih.gov/grants/olaw/references/lab_animal2003v32n9_wolff.htm#q2, item #8, and at http://grants1.nih.gov/grants/olaw/references/laba00v29n3.htm

## AW Findings:Policies & Procedures

- 1. VAMC policies and procedures have not been revised to include requirements of VHA HB 1200.7
- 	e.g.
- Recorded votes must show number for, against, and abstentions
- Annual review of SOPs by VMO and IACUC
- Annual training of all persons involved in animal use
- PI must consult VMO prior to submitting new protocol
- Annual medical exam of employees that handle animals

## AW Findings:Policies & Procedures

- 2. Annual tuberculin testing is not conducted in personnel working with primates
- VHA HB 1200.7, App. C, ¶10.b.(2)(b) requires testing at time of employment and at least annually; latest CDC guidelines for testing to be followed

## AW Findings:Policies & Procedures

- 3. Continuing review of protocols not receiving timely review by IACUC or R&D Committee, some exceeding 12 months beyond IACUC annual renewal date
- VHA HB 1200.7, ¶8.d.2, and ¶8.e. The IACUC must review the conduct of animal protocols annually or studies must be suspended

## RS Findings:Policies & Procedures

- 1. Policies and procedures do not follow requirements of VHA HB 1200.8
- SRS annual review of all research protocols
- Union representative must serve on the SRS
- SRS minutes must show number for, against, and abstentions
- SRS membership must include R&D Committee member

## RS Findings:Policies & Procedures

- 2. Initial and annual security vulnerability assessment of research laboratories not conducted
- VHA HB 1200.6.7.h.5(j) required to identify high-risk areas, sensitive materials, and physical security issues

## Examples of For-Cause Review Findings

## HRP COMPLIANCE FINDINGS2003-04

- -**Failure to obtain written informed consent**
- 38CFR16.116 and 117a; VHA 1200.5, App. C; CFG31, 32
- -**Failure to follow IRB approved protocol**
- 38CFR16.103.b.4.iii; VHA 1200.5, 7.c.1; CFG23

## HRP COMPLIANCE FINDINGS2003-04

**Failure to obtain R&D Committee approval prior to conducting research**
- 	M-3, P-1, Ch 3.01.e; VHA HB 1200.5, 7.b
**Resources and staff not adequate to support HRPP program.  Inadequate protocol/records tracking system**
- 		38CFR16.103.b.2; CFG 52

## HRP COMPLIANCE FINDINGS2003-04

**Failure to maintain records for at least 3 years after completion of study**
- 3 yrs in 38CFR115(b), 5 yrs in VHA HB 1200.5.8.j
**Inconsistent documentation in IRB minutes and IRB files**
- 38CFR16.115.a.1,3,4,7, and 116d
**Reviews of SAE by R&D and IRB not documented**
- IRB: 21CFR56.101(a), 21CFR.108, and 21CFR56.111

## Slide 53