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

Office of Research OversightOffice 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



Thank you to everyone here for helping to ensure compliant research contributing to quality research for the health and

welfare of our veterans!


PART I

ORO’s Mission Areas of Concern Common Problems in Compliance Case Studies



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



• 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


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 IRBsORO and ORD directed to:

• review accreditation standards and findings for VA use of university IRBs• review effectiveness of oversight by VA Research and Development

CommitteesORD directed to develop and implement education programs addressing

VA use of university IRBs. ORO will help.

ORO’s Mission:Areas of Concern


• 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


• 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…


ORO ChecklistsAvailable 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


Director’s Certification


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


• 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


Common ResearchNon-Compliance Problems

Human Subjects

Animal Welfare

Research Safety

Research Security


Some Case Examples of Systemic Compliance Failures

What went wrong?

Why?


CommonCompliance 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



• 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



• 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



• 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


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



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


• 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


• 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


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


• 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


• 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



• 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



• 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



• 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



• 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


• 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



• 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



• 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


• 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


• 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


• 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


• 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


• 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


PART II

Assurances

“Engagement in Research”

Reporting to ORO: AEs and UPRs* *Unanticipated problems involving risks to subjects or others.


• 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


Intellectual contributions meriting publication authorship

—VHA Handbook 1058.03 §8a

Assurances Needed by a Non-VA Entity


Entities operated under a contract from a VA (eg, Contract CBOC)

—VHA Handbook 1058.03 §4i(1)

Assurances Needed by a Non-VA Entity


Engagement of VA FacilitiesIn 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


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))


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



(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



(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



(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…)


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

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?

NO YES

NO YES

NO

YES

YES

NO

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



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



• 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



• 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



• 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)



• 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



• 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



• 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


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


Substantive IRB Action

Deaths

Anticipated Deaths

REPORTING TO OROReporting to the IRB vs

Adverse Events


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


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.


Laboratory Animal WelfareRequirements 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


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


Research MisconductRequirements 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


ORO Regional Offices

Northeastern Bedford, MAVISNs 1, 2, 3

MidwesternHines, ILVISNs 11, 12, 15, 19, 23

WesternLoma Linda, CAVISNs 18, 20, 21, 22

Southern

Duluth, GA

VISNs 7, 8, 16, 17

•AK

•HI

•WA

•OR •ID

•MT •ND•MN

•CA

•NV

•WY•SD

•WI•MI

•UT

•NE•IA

•IL •IN

•CO•KS •MO

•AZ •NM

•TX

•OK •AR

•LA

•MS •AL •GA

•SC

•FL

•OH•PA

•NY

•ME

•KY•WV•VA

•TN•NC

•V•T•NH •MA

•RI•CT

•NJ•DE

•MD

Mid-Atlantic

Washington, DC

VISNs 4, 5, 6, 9, 10


Office of Research Oversighthttp://www1.va.gov/oro/

ORO (Central Office)Department of Veterans Affairs811 Vermont Ave, NW, Suite 574 (10R)Washington, DC 20420202.565.5184 fax: 202.565.9194

ORO Mid-Atlantic Regional OfficeDistrict of Columbia VAMC50 Irving Street, N.W. (10R)Washington, DC 20422202.745.8110 fax: 202.745-8538

ORO Midwestern Regional OfficeHines VAMCBuilding 1 (10R), Room B-1035th & Roosevelt AvenuesHines, IL 60141708. 202.7254 fax: 708.202.7250

ORO Northeastern Regional OfficeBedford VAMC200 Springs Road (10R)Bedford, MA 01730781.687.3850 fax: 781.687-3858

ORO Southern Regional Office3700 Crestwood Pkwy, NWSuite210 (10R)Duluth, GA 30096678.924.5762 fax: 678.924.5708

ORO Western Regional OfficeP.O. Box 7360Moreno Valley, CA 92552-7360Express Delivery:14560 2nd Street , Bldg. 2641, Suite B Riverside, CA 92518909.801.5164 fax: 909.801.5176

Documents

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