ORO UPDATE AND COMMON FINDINGS IN ROUTINE REVIEWS

1
ORO UPDATE AND COMMON FINDINGS IN ROUTINE REVIEWS

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

2
OUTLINE

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

3
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,..Pu
blic law 108 (170) signed by President 12/6/2003
4
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

5
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

6
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

7
Q2-CY05 OROCompliance Activities

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

8
Q2-CY05 OROCompliance 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)

9
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

10
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)

11
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

12
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.

13
Routine On-Site Reviews

• Review Assess CA 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

14
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

15
Where Do Questions Asked in a Routine Review Come
From?Partial Listing Follows
16
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

17
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 (RD) Program Chapter
  2, RD Organizational Structure Chapter 3, RD
  Function

18
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

19
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 OROs
  mission

20
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.

21
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

22
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

23
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

24
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

25
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

26
WHAT TO REPORT TO OROMEMORANDOM

• Identifies issues VHA facilities must report to
  ORO as required by various Federal regulations
  and VHA policies.
• http//www.va.gov/oro/
• September 8, 2005

27
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.

28
Pre-Site Visit

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

29
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

30
Post-Site Visit

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

31
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

32
Routine Review Findings
33
HRP Findings RD Committee

• 1. Terms of RD 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.

34
HRP Findings RD Committee

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

35
HRP Findings RD Committee

• 3. RD 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

36
HRP FindingsInvestigational 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

37
HRP Findings IRB RD Minutes

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

38
HRP Findings IRB RD 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

39
HRP Findings SOPs

• 1. The SOPs for the IRB, RD, 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

40
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

41
HRP FindingsStaff Responsibilities

• 1. Chairpersons of RD 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

42
HRP FindingsInformed 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

43
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.htmq2, item 8, and at
  http//grants1.nih.gov/grants/olaw/references/laba
  00v29n3.htm

44
AW FindingsPolicies 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

45
AW FindingsPolicies 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

46
AW FindingsPolicies Procedures

• 3. Continuing review of protocols not receiving
  timely review by IACUC or RD 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

47
RS FindingsPolicies 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 RD Committee member

48
RS FindingsPolicies 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

49
Examples of For-Cause Review Findings
50
HRP COMPLIANCE FINDINGS2003-04

• -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

51
HRP COMPLIANCE FINDINGS2003-04

• Failure to obtain RD 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

52
HRP COMPLIANCE FINDINGS2003-04

• 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 RD and IRB not documented
• IRB 21CFR56.101(a), 21CFR.108, and 21CFR56.111

53
(No Transcript)