# Presentation: 514334

## WHAT’S NEW IN COMPLIANCE?AN UPDATE FROM OROE23, 11:30 AM-1:45 PM

**David A. Weber, PhD, FACNP**
**Office of Research Oversight**
**Department of Veterans Affairs**
**December 6, 2005**

## OUTLINE

**ORO’s Oversight Responsibilities**
**Compliance Activities 2005**
**Routine Reviews**
**Compliance Findings**
**Routine/For Cause**

## OVERSIGHT RESPONSIBILITIES

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

##               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 COMPLIANCE ACTIVITIES2005

**For-Cause Reviews**
**Routine Reviews**
**BSL-3 Laboratory Inspections**
**Research Misconduct Oversight, HB 1058.2**
**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**

## Q3-CY05 OROCOMPLIANCE ACTIVITIES

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

## Q3-CY05 OROCOMPLIANCE ACTIVITIES 

- Routine On-Site Reviews (6N/10FU)*
- 10 Human Subject
- 2 Animal Welfare
- 2 Human Subject, Animal Welfare, Res Safety
- 1 Animal Welfare & Research Safety
- 1 Research Safety
- * involving 1-6 VAMCs/review

## Q3-CY05 OROCOMPLIANCE ACTIVITIES

- BSL-3 Laboratory Inspections
- 4 Laboratories
- 1 Annual Inspection Follow-Up
- 3 Annual Inspections

## Q3-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
- 116 FWAs and related MOUs with affiliates

## Q3-CY05 OROCOMPLIANCE ACTIVITIES

- Other Compliance Cases (w/o site visit)
- 41 Human Subject
- 8 Animal Welfare
- 2 Research Safety
- (21 new cases, 30 follow-up cases)

## ORO Q3-CY05 OROCOMPLIANCE DOCUMENTS 

- Recent Documents Issued
- VHA Handbook 1058.1 (11/18/2004)
- 		Reporting of Adverse Events to ORO
- VHA Handbook 1058.2 (5/4/2005)
- 		Research Misconduct
- What to Report to ORO Memorandum (9/8/2005)

## IN PROGRESS

- 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

_**Assessment**_** of compliance with laws, regulations, and policies governing research and **_**Remediation**_** of identified deficiencies**
_**Not an Audit, not a For-Cause Review, not an Investigation**_
**All VHA facilities with research programs**
**Findings may require an action plan**
**Follow-up if action plan required**

## 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**

## 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

## WHAT ARE THE SOURCES OF THE ROUTINE REVIEW QUESTIONS?Partial Listing Follows

## HUMAN SUBJECTS 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 SUBJECTS 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, 7/15/03***
**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 SUBJECTS 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).**

## HUMAN SUBJECTS 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).**
**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 SUBJECTS PROTECTIONS

***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**

## 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 selects 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 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 **

## HRP FINDINGS: R&D Committee

- 1.  **Terms of R&D Committee members often exceed three years**
- M-3, Part I, Chapter 2.02 b. (5) (c) members serve terms of not more than 3 years with at least 1 year between terms (does not apply to ex officio members).

## 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) requires the R&D Committee to report to 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, section 14c; M-2, Part VII, Chapter 6 requires log of all transactions be maintained for 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 show IRB member w COI remains in meeting and abstains from voting on project approval **
- 38 CFR 16.107 (e) and VHA Handbook 1200.5, section 6.g require individuals with a COI to recuse themselves and be absent from the deliberation and vote on project approvals.

## HRP FINDINGS: IRB & R&D Minutes

**3. IRB occasionally uses expedited review  to approve research requiring substantive modifications or clarifications**
-  38 CFR 16.111 requires that approval of the proposed research be deferred for review of responsive material by convened IRB

## 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: SOPs

**3. Lacks formal policy to inform staff, institutional officials, and regulatory agencies about unanticipated problems in research, serious or continuing noncompliance, SAEs, or suspensions or terminations of IRB approval**
- Develop written policies and procedures in accordance with 38 CFR 16.103(b)(5).

## HRP FINDINGS: SOPs

- 4. Investigational Drug Policies do not reflect current FDA requirements, especially regarding emergency, off-protocol and other special uses of investigational drugs
- Revise policies for pharmacy operation and use of investigational drugs to be in compliance with 21 CFR 50, 56 and 312 (see FDA Information Sheets(1998) at _[http://www.fda.gov/oc/ohrt/irbs/default.htm](http://www.fda.gov/oc/ohrt/irbs/default.htm)__)_

## 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 FORMS

** **
- 1. **Informed Consent forms do not follow SOP and VA regulations**
- 38 CFR 16.116 (a), VHA HB 1200.5, Appendix C requires consent form to include required elements

## HRP FINDINGS:INFORMED CONSENT FORMS

- 2. Consent forms do not contain signatures for individuals who witnessed the subject’s signature.
- VHA Handbook 1200.5, Appendix C, 3.a.(2) requires the signature of a witness.

## 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
**Failure to document SAE reviews by R&D and IRB**
- IRB: 21CFR56.101(a), 21CFR.108, and 21CFR56.111

## CONCLUSIONS

## Slide 48