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# Department of

# Veterans Affairs

Date: September 8, 2005

From: Chief Officer, Office of Research Oversight (ORO) (10R)

To: Institutional Officials of VHA Facilities Conducting or Supporting
Research

What to Report to the Office of Research Oversight

This memorandum identifies issues that VHA facilities must report to ORO
as required by applicable Federal regulations and VHA policies.

The memorandum addresses reporting requirements to ORO only. VHA
facilities may also be required to report information to other entities
such as the VHA Office of Research and Development (ORD), the relevant
VHA Network Director, the Food and Drug Administration (FDA), the
Department of Health and Human Services (DHHS) Office for Human Research
Protections (OHRP), the DHHS Office of Research Integrity (ORI), and/or
the National Institutes of Health (NIH) Office of Laboratory Animal
Welfare (OLAW).

Guiding Principles

1.  **Report in Writing.** Although ORO staff are available for
    consultation regarding the content and scope of reports, each VA
    facility must provide the required information to ORO in a **written
    report from the facility Director. Reports should first be sent by
    FAX or e-mail [and]{.underline} then promptly forwarded in hard
    copy.**

2.  **Report Promptly.** Reports should be provided to ORO as soon as
    possible, but no later than 10 working days after the issue has come
    before the responsible facility official or oversight committee
    (e.g., Institutional Review Board, Institutional Animal Care and Use
    Committee), unless otherwise indicated in the following material. If
    the facility has not made a final determination as to disposition of
    the issue within this 10 day period, the facility Director should
    provide ORO with a preliminary report and with followup reports as
    needed until the issue is resolved.

3.  **Report to ORO Regional Office.** Reports should be addressed to
    the ORO Regional Office Director for the region in which the
    facility is located, unless otherwise indicated (see contact
    information attached).

4.  **Report Descriptive Information and Actions.** Reports should
    include:

    a.  The name and any relevant Assurance number of the reporting VA
        facility.

    b.  The title of the research project(s) involved.

    c.  The name of the principal investigator(s) involved (except for
        animal research).

    d.  The number(s) used by the facility's Institutional Review Board
        (IRB), Institutional Animal Care and Use Committee (IACUC),
        and/or Research Service to identify the project(s) involved.

    e.  The name of any external sponsor(s) of the project(s) involved.

    f.  The funding source(s) for the project(s) involved.

    g.  A detailed description of the issue being reported.

    h.  A detailed description of the actions the facility is taking, or
        plans to take, to address the issue.

What to Report to ORO: Protection of Human Subjects in VA Research

1.  Any adverse event (i.e., an untoward physical, psychological,
    social, or economic occurrence) in a human subject, or an imminent
    threat of an adverse event, that results in a substantive action by
    the Institutional Review Board (IRB) under VHA Handbook 1058.1 on
    *Reporting Adverse Events in Research* (attached).

2.  Any unexpected death of a human subject under VHA Handbook 1058.1
    NOTE: Such deaths must be reported within 24 hours of the IRB's
    determination that the death was unexpected or within 10 working
    days if the IRB has not yet made a determination about whether the
    death was unexpected.

3.  Any unanticipated problem involving risks to subjects or others that
    results in a substantive action by the IRB.

4.  Any for-cause suspension or termination of VA human subject research
    by the IRB, the VA facility, or a VA affiliate institution. NOTE:
    This does NOT include suspensions or terminations resulting solely
    from the expiration of the IRB approval period.

5.  Any serious or continuing noncompliance with federal regulations or
    VHA policies for the protection of human subjects (including 38 CFR
    Part 16; 45 CFR Part 46; 21 CFR Parts 50, 56, 312 or 812; and VHA
    Handbook 1200.5).

6.  Any serious or continuing noncompliance with IRB requirements or
    determinations.

7.  Any findings of noncompliance in human research protections from the
    VHA Office of Research and Development (ORD) or other VA office.
    NOTE: The report to ORO should include a copy of the official
    findings. The facility should promptly provide ORO with copies of
    all subsequent correspondence between the office and the facility
    until the issue is resolved.

8.  Any findings of noncompliance in human subject protections from
    external oversight agencies such as the Office for Human Research
    Protections (OHRP), the Food and Drug Administration (FDA), etc.
    NOTE: The report to ORO should include a copy of the official
    findings (e.g., FDA Form 483, *Inspectional Observations)*. The
    facility should promptly provide ORO with copies of all subsequent
    correspondence between the agency and the facility until the issue
    is resolved.

9.  Any change in the facility's accreditation status from a
    VA-recognized accreditation organization for human research
    protections, or in the accreditation status of an affiliate
    institution or other VA facility upon which the facility relies.

10. Any change in the facility\'s Federalwide Assurance (FWA) or
    designated IRB(s) as filed with OHRP. NOTE: Report such changes
    directly to ORO Central Office and simultaneously copy the ORO
    Regional Office.

11. Any significant change in the facility\'s Memorandum of
    Understanding (MOU) with an affiliate institution or other VA
    facility regarding the designation of IRB(s) or other human research
    protection function. NOTE: Report such changes directly to ORO
    Central Office and simultaneously copy the ORO Regional Office.

What to Report to ORO: Laboratory Animal Welfare in VA Research

> NOTE: Reports regarding VA animal research should NOT include the
> name(s) of the investigator(s) unless this information has been
> specifically requested by ORO.

1.  Any incident that seriously affects the health or safety of
    laboratory animals.

2.  Any loss of animal life due to physical plant deficiencies and/or
    engineering failures or mishaps.

3.  Any work related injury to personnel working within an animal
    facility that requires more than minor medical intervention or leads
    to serious complications or death.

4.  Any for-cause suspension or termination of VA animal research by the
    Institutional Animal Care and Use Committee (IACUC).

5.  Any serious or continuing noncompliance with the *Public Health
    Service (PHS) Policy on Humane Care and Use of Laboratory Animals*
    or VHA Handbook 1200.7 on *Use of Animals in Research*.

6.  Any serious deviation from the requirements of the Animal Welfare
    Act under 9 CFR Parts 1, 2, and 3.

7.  Any serious deviation from the *Guide for the Care and Use of
    Laboratory Animals.*

8.  Any findings of noncompliance in laboratory animal care from the VHA
    Office of Research and Development (ORD) or other VA office. NOTE:
    The report to ORO should include a copy of the official findings.
    The facility should promptly provide ORO with copies of all
    subsequent correspondence between the office and the facility until
    the issue is resolved.

9.  Any findings of noncompliance in laboratory animal care from
    external oversight agencies such as the US Department of Agriculture
    (USDA) Animal and Plant Health Inspection Service (APHIS), the
    National Institutes of Health (NIH) Office for Laboratory Animal
    Welfare (OLAW), etc. NOTE: The report to ORO should include a copy
    of the official findings. The facility should promptly provide ORO
    with copies of all subsequent correspondence between the agency and
    the facility until the issue is resolved.

10. Any change in the facility's accreditation status from a
    VA-recognized accreditation organization for laboratory animal
    welfare, such as the Association for Assessment and Accreditation of
    Laboratory Animal Care International (AAALAC), or in the
    accreditation status of an affiliate institution or other VA
    facility upon which the facility relies.

11. Any change in the facility\'s Animal Welfare Assurance status as
    filed with OLAW, or in the Animal Welfare Assurance status of an
    affiliate institution or other VA facility upon which the facility
    relies.

12. Any significant change in the facility\'s Memorandum of
    Understanding (MOU) with an affiliate institution or other VA
    facility regarding animal care and use arrangements. NOTE: Report
    such changes directly to ORO Central Office and simultaneously copy
    the ORO Regional Office.

What to Report to ORO: Safety and Security in VA Research

# 

1.  Any work-related occupational injury to personnel working within a
    research facility that requires more than minor medical intervention
    or leads to serious complications or death.

2.  Any significant, work-related exposure to hazardous materials of
    personnel working within a research facility.

3.  Any for-cause suspension or termination of VA research by the
    Subcommittee on Research Safety (SRS) or other institutional safety
    committee.

4.  Any serious or continuing noncompliance with federal regulations or
    VHA policies governing research safety and security, including 7 CFR
    Part 331; 9 CFR Part 121; 29 CFR Part 1910, Sections 1910.1030,
    1910.1200, 1910.1450; 29 CFR Part 1960; 42 CFR Part 73; VHA Handbook
    1200.6; VHA Handbook 1200.8; VHA Directive 2003-030; and VHA
    Directive 2005-003.

5.  Any exposure, release, loss, or theft of hazardous materials,
    including select agents and toxins.

6.  Any findings of noncompliance in research safety or security from
    the VHA Office of Research and Development (ORD), the VA National
    Health Physics Program Office, the VA Office of Inspector General
    (OIG), or other VA office. NOTE: The report to ORO should include a
    copy of the official findings. The facility should promptly provide
    ORO with copies of all subsequent correspondence between the office
    and the facility until the issue is resolved.

7.  Any findings of noncompliance in research safety or security from
    external oversight agencies such as the National Institutes for
    Health (NIH) regarding the use of recombinant DNA; the Centers for
    Disease Control and Prevention (CDC) regarding hazardous materials,
    including select agents and toxins in research areas; the United
    States Department of Agriculture (USDA) regarding hazardous
    materials including select agents and toxins in research areas; the
    Occupational Health and Safety Administration (OSHA); the Nuclear
    Regulatory Commission (NRC); etc. NOTE: The report to ORO should
    include a copy of the official findings. The facility should
    promptly provide ORO with copies of all subsequent correspondence
    between the agency and the facility until the issue is resolved.

What to Report to ORO: Misconduct in VA Research

# 

> NOTE: Report the following DIRECTLY to the ORO CENTRAL OFFICE. ORO
> Central Office will notify the appropriate ORO Regional Office.

1.  During the course of a research misconduct proceeding, ORO should be
    notified **immediately** of the following, and of any interim
    administrative actions taken to minimize resultant damage: any harm
    or threatened harm to research subjects; harm or threat of harm to
    those involved in an inquiry or investigation into research
    misconduct; serious violations of animal welfare requirements;
    research safety or security compromises; risks to public health or
    safety; loss or destruction of VA funds or property; possible
    violations of civil or criminal law associated with the alleged
    research misconduct. (VHA Handbook 1058.2 §12.e.1)

2.  Any requests for pre-approval of significant changes or departures
    from the procedures outlined in VHA Research Misconduct Handbook.
    NOTE: Pre-approval of such changes by ORO is REQUIRED. (VHA Handbook
    1058.2 §12.b & 12.d)

3.  Any opening of a research misconduct [inquiry]{.underline}. (VHA
    Handbook 1058.2 §14.c)

4.  Any requests for approval of extensions of the normal 30-day period
    for the inquiry review. NOTE: Requests for extension of the inquiry
    review period must be timely. (VHA Handbook 1058.2 §14.e.1)

5.  Any closure of a research misconduct [inquiry]{.underline} without
    further investigation. NOTE: The report to ORO must include a copy
    of the Inquiry Report and the concurrence of the Facility Director.
    (VHA Handbook 1058.2 §14.g)

6.  Any opening of a research misconduct [investigation]{.underline}.
    (VHA Handbook 1058.2 §15.c)

7.  Any requests for approval of extensions of the normal 90-day period
    for the investigation review. NOTE: Requests for extension of the
    investigation review period must be made at least 5 working days
    prior to the end of the initial investigation review period. (VHA
    Handbook 1058.2 §15.f.1)

8.  Closure of a research misconduct [investigation]{.underline}. NOTE:
    The report to ORO must include a copy of the final Investigation
    Report and the recommendations of the Facility Director. (VHA
    Handbook 1058.2 §15.h.3)

9.  The final decision of the Director of the Veterans Integrated
    Services Network (VISN) on the merits of a research misconduct case.
    (VHA Handbook 1058.2 §16.f)

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David A. Weber, PhD, FACNP

Attachments:

> Office of Research Oversight (ORO). *Contacts for Reporting to ORO.*
>
> VHA Handbook 1058.1, *Reporting Adverse Events in Research to the
> Office of Research Oversight.* (November 19, 2004).
>
> Adverse Events (AEs) in VA Research AE -- Report Format. VA Form
> 10-0420.

+-----------------------------------------------------------------------+
| **OFFICE OF RESEARCH OVERSIGHT (ORO)**                                |
|                                                                       |
| **CONTACTS FOR REPORTING TO ORO**                                     |
|                                                                       |
| Send written report to the appropriate ORO Office first by FAX or     |
| e-mail                                                                |
|                                                                       |
| and then forward promptly in hard copy.                               |
|                                                                       |
| For additional resources, reference ORO's website:                    |
| <http://www1.va.gov/oro/>                                             |
+-----------------------------------------------------------------------+
| #### CENTRAL OFFICE                                                   |
|                                                                       |
| > 811 Vermont Avenue, N.W., Suite 574 (10R)                           |
|                                                                       |
| Washington, D.C. 20420                                                |
|                                                                       |
| PHONE: (202) 565-5184                                                 |
|                                                                       |
| FAX: (202) 565-9194                                                   |
+-----------------------------------------------------------------------+
| ###### NORTHEASTERN REGIONAL OFFICE (VISNs 1, 2, 3)                   |
|                                                                       |
| Bedford VAMC -- 200 Springs Road, Bldg 7, Room B-08 (10R)             |
|                                                                       |
| Bedford, MA 01730                                                     |
|                                                                       |
| PHONE: (781) 687-3850                                                 |
|                                                                       |
| FAX: (781) 687-3858                                                   |
+-----------------------------------------------------------------------+
| #### MID-ATLANTIC REGIONAL OFFICE (VISNs 4, 5, 6, 9, 10)              |
|                                                                       |
| 50 Irving Street, N.W. (10R)                                          |
|                                                                       |
| ###### Washington, D.C. 20422                                         |
|                                                                       |
| ##### PHONE: (202) 745-8110                                           |
|                                                                       |
| ##### FAX: (202) 745-8538                                             |
+-----------------------------------------------------------------------+
| #### SOUTHERN REGIONAL OFFICE (VISNs 7, 8, 16, 17)                    |
|                                                                       |
| 1670 Clairmont Road (10R)                                             |
|                                                                       |
| Decatur, GA 30033                                                     |
|                                                                       |
| ##### PHONE: (404) 417-2929                                           |
|                                                                       |
| ##### FAX: (404) 417-2935                                             |
+-----------------------------------------------------------------------+
| #### MIDWESTERN REGIONAL OFFICE (VISNs 11, 12, 15, 19, 23)            |
|                                                                       |
| PO Box 5000, Building 1, Room B-103 (10R)                             |
|                                                                       |
| 5^th^ Avenue & Roosevelt Road                                         |
|                                                                       |
| Hines, IL 60141                                                       |
|                                                                       |
| ##### PHONE: (708) 202-7254                                           |
|                                                                       |
| ##### FAX: (708) 202-7250                                             |
+-----------------------------------------------------------------------+
| #### WESTERN REGIONAL OFFICE (VISNs 18, 20, 21, 22)                   |
|                                                                       |
| P.O. Box 7360, Moreno Valley, CA 92552-7360                           |
|                                                                       |
| ###### *Express Delivery:* ORO Western Regional Office (10R)          |
|                                                                       |
| March Air Reserve Base -- 5029 4th Street, Bldg. 2641                 |
|                                                                       |
| March Air Reserve Base, CA 92518                                      |
|                                                                       |
| PHONE: (909) 801-5164                                                 |
|                                                                       |
| ##### FAX: (909) 801-5176                                             |
+-----------------------------------------------------------------------+

Revised: September 8, 2005

**November 19, 2004 VHA HANDBOOK 1058.1**

**REPORTING ADVERSE EVENTS IN RESEARCH**

**TO THE OFFICE OF RESEARCH OVERSIGHT**

**1. PURPOSE**

This Veterans Health Administration (VHA) Handbook sets forth the
requirements for reporting certain adverse events (AEs) in research to
the Office of Research Oversight (ORO) (10R) (formerly, ORCA).
***NOTE:** This Handbook does not preempt or otherwise alter any other
applicable adverse event reporting requirements, whether within the
Department of Veterans Affairs (VA) or to other Federal and state
agencies or commercial sponsors.*

**2. BACKGROUND**

a**.** ORO serves as the primary VHA office for advising the Under
Secretary for Health on all matters of compliance and assurance related
to human subjects' protections. As part of its mission, ORO is
responsible for overseeing compliance with the system-wide requirements
for reporting AEs in research.

b\. VA is committed to supporting high quality human research protection
programs (HRPPs) in all its facilities involved in research. Reporting
and management of AEs in research are important aspects of HRPPs. The
Institutional Review Boards (IRBs) are integral parts of institutions'
HRPPs and, as such, are responsible for reviewing and managing AEs in
research (Title 38 Code of Federal Regulations \[CFR\] 16).
Specifically, VA regulation requires prompt reporting of any
unanticipated problems involving risks to subjects and others to the
IRB, appropriate institutional officials, and the department or agency
head (see 38 CFR 16.103(b)\[5\]). ***NOTE:** Likewise, Food and Drug
Administration (FDA) regulations require investigators to report
promptly to the sponsor any adverse effect that may reasonably be
regarded as caused by, or probably caused by, an investigational new
drug (IND) (21 CFR 312.64(b)). Further investigators must submit to the
sponsor and reviewing IRB a report of any unanticipated adverse
investigational device effect occurring during an investigation as soon
as possible, but in no event later than 10 working days after the
investigator first learns of the effect (see 21 CFR 812.150\[a\]\[1\]).*

c\. Each IRB needs to develop Standard Operation Procedures (SOPs) that
provide detailed instructions on how to report and manage AEs consistent
with all relevant regulations and VHA policies, including the VHA
Handbook 1050.1.

d\. This VHA Handbook addresses only the reporting of certain AEs in
research to ORO. Since ORO serves as the primary VHA office for advising
the Under Secretary for Health on all matters of compliance and
assurance related to human subjects' protections, ORO is responsible for
overseeing compliance with the system-wide requirements for reporting
AEs in research.

e\. In the past, facilities were required to report all serious and
unexpected AEs in research to ORO. This Handbook replaces that reporting
requirement with a more narrowly defined reporting requirement. The new
procedure set forth in this Handbook allows ORO to focus on

**1**

**VHA HANDBOOK 1058.1 November 19, 2004**

the most serious AEs in research and better assess how such incidents
are being reported and managed by investigators and IRBs.

**3. SCOPE**

## a. This Handbook: 

## (1) Identifies the AEs in research that must be reported to the relevant ORO Regional Office (ORO RO); 

## (2) Provides the timelines for reporting such AEs; and 

## (3) Indicates what information must be provided in such reports. 

b\. In addition to following this Handbook's reporting requirements, VA
facilities must continue to follow all other relevant laws, regulations,
and policies related to AE reporting (see par. 7). For example, VHA
facilities must continue to report "unanticipated problems" and "adverse
events" to their IRBs of record and to other oversight agencies such as
the Office for Human Research Protections (OHRP), the FDA, and sponsors.
It is essential that principal investigators report all research-related
incidents to the IRB as required in the facility's IRB SOP, or any
Office of Research and Development (ORD) policies on reporting of
incidents. The definitions, procedures, and timelines contained in this
Handbook pertain solely to the reporting requirements of this Handbook.

**4. REPORTING REQUIREMENT GOALS**

> These reporting requirements are designed to:
>
> a\. Facilitate ORO's oversight of AEs in VA research;

b\. Specify which AEs are to be reported to ORO, the details to be
reported, and the timeline for reporting; and

c\. Collect information to provide better oversight, guidance, and
support for protecting research subjects and to assist IRBs in taking
appropriate actions.

**5. DEFINITIONS**

a\. **[Adverse Event (AE) in Research.]{.underline}** An AE in research
is defined for purposes of this Handbook as any untoward occurrence
(physical, psychological, social, or economic) in a human subject
participating in research. An AE in research can be any unfavorable or
unintended event including abnormal laboratory finding, symptom,
disease, or death associated with the research or the use of a medical
investigational test article. An AE in research may occur even in the
absence of any error or protocol deviation, and does not necessarily
have to be caused by any identifiable aspect of the research.

**2**

**November 19, 2004 VHA HANDBOOK 1058.1**

b\. **[Imminent Threat of an AE in Research]{.underline}.** Any issue in
which an AE in research has not yet occurred but is likely to occur, as
determined by an IRB, research, or clinical team member, without
preventative measures.

c\. **[Substantive Action.]{.underline}** An action taken by an IRB that
materially alters the substance and meaning of a protocol, informed
consent form or process, or investigator status, including, but not
limited to, restriction, suspension or termination of a study or
investigator participation, and actions taken to prevent future
occurrence(s) of the AE in research.

d\. **[Unexpected Death.]{.underline}** The death of a research subject
in which a high risk of death is not projected, as indicated by the
written protocol, informed consent form, or sponsor brochure. This
definition does not include deaths associated with a terminal condition
unless the research intervention clearly hastened the subject's death. A
subject's death that is determined to be clearly not associated with the
research is also not an "unexpected death" for purposes of the reporting
requirements of this Handbook.

**6. REPORTING REQUIREMENTS**

a\. Each VHA facility must report to the appropriate ORO RO (see sub.
6b) all AEs in research and imminent threats of AEs in research
conducted on site that result in either:

\(1\) An IRB taking substantive action(s) as defined in subparagraph 5c.
A written report of the AE in research (or an imminent threat thereof),
and the IRB action(s) to be taken, must be submitted to the ORO RO
within 10 working days of the IRB's determination to take such
action(s).

**Or**

\(2\) An unexpected death of a research subject, regardless of IRB
action. Such deaths must be reported to the ORO RO within 24 hours after
the IRB determines that the death was unexpected, as defined in
subparagraph 5d. If the IRB is unable to determine whether a research
subject's death was unexpected after 10 working days of being informed
of the death, the death must then be reported to the ORO RO. When a
final determination is made as to whether or not the death was
unexpected, a follow-up report must be made to the ORO RO.

b\. **Written Report.** The institutional official (VHA facility
Director), or designee, must:

\(1\) Prepare a separate report, for each AE in research (or imminent
threat thereof) required to be reported by this Handbook, following the
format indicated in Appendix A.

\(2\) Initial the completed report and facilitate its submission to the
Director of the ORO RO that oversees the VHA facility, using express
mail (e.g., Fed Ex) and either e-mail or fax. A copy of all IRB minutes
from meetings in which the AE in research and subsequent actions were
discussed, ratified, or summarized needs to accompany the report to the
ORO RO, or be sent when the IRB minutes become available, but in no case
no later than 4 weeks after the IRB meeting.

**3**

**November 19, 2004 VHA HANDBOOK 1058.1**

**7. REFERENCES**

a.  Title 38 CFR 16.

b.  Title 45 CFR 46.

c.  Title 21 CFR 56.

d.  Title 21 CFR 312.

e.  Title 21 CFR 812.

f.  VHA Handbook 1200.5.

g.  VHA Handbook 1050.1.

**4**

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