Section VI: General Functions of the VCU IRB		WPP #: VI-3
Title 3: Investigations and Reporting of Unanticipated Problems, Serious or Contiuning Non-Compliance, Suspensions, and Terminations
Effective Date: 01-30-08	Revision History: 06-20-00; 07-26-00; 09-20-01; 06-07-04; 04-30-06; 06-21-06

Objective

To describe the circumstances resulting in reporting noncompliance and unanticipated problems to the VCU IRB; the process for evaluating, investigating, determining serious or continuing noncompliance or unanticipated problems; preparing, and distributing reportable IRB determinations.  The convened IRB Panel makes determinations of serious or continuing noncompliance and unanticipated problems involving risk to subjects or others, which are reportable to federal agencies and sponsors.  IRB actions such as suspensions or terminations of previously-approved research are also reportable.  The Director of the Office of Research Compliance and Education (ORCE) facilitates IRB review and determination of the above findings. 

All unanticipated problems reported to Western IRB (WIRB) by VCU investigators should also be sent to the VCU Office for Research Subject Protections (ORSP).  All determinations made by WIRB that are reportable findings according to the regulations, will also be reported to VCU.  The ORCE coordinates with WIRB relative to any determinations WIRB makes regarding unanticipated problems involving risk to subjects or others, serious or continuing noncompliance, or suspensions or terminations. The Office of Research Compliance and Education (ORCE) determines the extent to which the VCU IRB becomes involved in deliberations about occurrences reportable to WIRB. 

Description

1.  Definitions
1. Noncompliance: failure on the part of the PI or any member of the research team to:
1. adhere to the terms of the VCU IRB approval and/or
2. abide by applicable laws, regulations, or VCU policies.

Noncompliance varies in severity (based upon the overall risk potential of the noncompliance and its frequency).  All noncompliance is evaluated by the convened IRB to in order to determine seriousness and whether it is a continuing offense.

2. Serious or Continuing Noncompliance: 
1. “Serious Noncompliance” is defined as failure to adhere to the terms of the VCU IRB approval and/or abide by applicable laws, regulation, or VCU policies when that failure increases risk to participants or adversely affects the rights and welfare of the participants. (Examples may include:  conducting a research protocol without oversight of a functional investigator; utilizing improper consent procedures; a protocol violation that adversely affects the integrity of the research data).  Serious noncompliance is a finding that is determined by the convened IRB Panel.  The finding of serious noncompliance must be reported to regulatory authorities and the sponsor.
2. “Continuing Noncompliance” is defined as a pattern of reports of noncompliance (as defined above) that if unaddressed, may compromise the integrity of the human research protection program.  The pattern may reflect a lack of knowledge on the part of the investigator or research staff, inadequate time for oversight, etc.  Continuing noncompliance is a finding that is determined by the convened IRB Panel.  The finding of continuing noncompliance must be reported to regulatory authorities and the sponsor.
3. "General Noncompliance" is defined as any non-compliance not determined to be serious or continuing.  Reports of non-compliance are referred to the convened IRB Panel, wherein the Panel determines whether the non-compliance is ‘serious’ or ‘continuing.’ General noncompliance is dealt with by the IRB with assistance from the Director of ORCE.  The finding of general noncompliance is not reportable to federal oversight agencies.


4. Unanticipated Problem (UP) Involving Risks to Subjects or Others:  An unanticipated problem involving risk to participants or others is defined by meeting ALL 3 of the following criteria:
1. Was not anticipated or foreseen;
2. Involves risk or harm to participants or others; AND
3. Was probably or definitely related to, or caused by, the research activity in the judgment of the investigator.

See VCU IRB VIII-7 for the organizational policy on “unanticipated problems involving risk to subjects or others,” including the reporting requirements of the VCU IRB.

NOTE:  In some cases, a reported UP Involving Risks to Subjects or Others (whether or not the IRB determines such designation) may also involve alleged noncompliance.  If so, the IRB follows the process described in Section B below.

5. Suspensions and Terminations:  See VCU IRB WPP VI-2 for the VCU IRB policy on suspensions and terminations of VCU IRB approval.  Related investigations which may result in suspensions or terminations and reporting procedures are referenced within this WPP.
2. Evaluations and Investigations of Allegations of Noncompliance and/or Unanticipated Problems

1. Incoming allegation of noncompliance: When a report (by the PI or the IRB) or allegation (by anyone other than the PI or IRB) is received by the VCU IRB, ORCE, ORSP, or Institutional Official, the recipient informs the Director of the ORCE in order to initiate an inquiry and gather pertinent information.  Noncompliance may be found or alleged in a number of ways, including:  1) as an Unanticipated Problem involving risks to subjects or others, i.e. protocol violation, 2) may be found during post-approval monitoring (IRB Support) visits, or 3) may be reported by a concerned individual.   Reasonable efforts should be taken to protect the confidentiality of any persons who allege non-compliance or file reports or grievances, as well as the confidentiality of the investigator and those interviewed during the investigative process.

2. Initial evaluation by ORCE and IRB Chair/designee:   The IRB Chair/designee, with the assistance of ORCE, evaluate the severity of the allegation or report to determine if immediate actions are necessary to ensure the ongoing protection of research participants.  The IRB chair/designee, with the assistance of ORCE, will also evaluate whether the report/allegation of noncompliance warrants further evaluation.  The ORCE obtains file information and other documentation from ORSP.  IRB Coordinators may also be able to supply relevant information related to the protocol application and submissions.  The ORCE or IRB Chair/designee may or may not be able to gather information from the principal investigator and/or other relevant members of the research team prior to evaluating whether the report warrants further review.

3. Fact Finding Inquiry:   The ORCE initiates a fact-finding inquiry with the principal investigator and/or other relevant members of the research team to determine the scope of the problem and status of any resolution.  The IRB Chair/ IRB reviewer(s) may participate with the ORCE. Investigative activities may include any of the following:  interviews with research personnel; audits of research records and/or IRB records; and interviews with research participants (who grant their permission to be interviewed). If an interview is held, the IRB Chair, other IRB members, ORSP Director, or other relevant individuals may be asked to attend.  The ORCE should document any actions and decisions, including a timeline of events and actions taken during the course of the investigation and retain these documents.

4. Forwarding to IRB Reviewer(s):  The allegation of noncompliance is forwarded to the assigned reviewer(s) on the protocol, and/or the Chair or Chair designee.  If the relevant protocol was originally reviewed as Expedited, the allegation is forwarded to the one assigned reviewer.  If initially reviewed as Full Board, the allegation and accompanying material is forwarded to both primary and secondary reviewers.  The Chair/designee may substitute as a reviewer, as needed.  The reviewer(s) of the allegation will receive a copy of:  1) the protocol, 2) consent documents, and 3) any other applicable materials pertinent to the allegation.  In addition, if available, IRB reviewers receive:  1) a summary report of the allegation, 2) immediate actions taken by the PI or imposed by the IRB Chair/designee or ORCE, 3) status of the inquiry thus far, including recommendations for IRB consideration (#1-3 may be contained within the same document).

5. Forwarding to the IRB:  For reports of noncompliance forward to IRB reviewer(s), the convened IRB Panel will also review the allegation of noncompliance.  Panel members receive copies of the following materials:  1) a summary report of the allegation, 2) immediate actions taken by the PI or imposed by the IRB Chair/designee or ORCE, 3) status of the investigation thus far, including recommendations for IRB consideration (#1-3 may be contained within the same document), 4) the protocol and 5) consent document(s), in addition to other materials pertinent to the allegation.  At the meeting, ORCE and the IRB Chair/reviewer(s) will provide information about the noncompliance (to the extent that it has been gathered), so that the IRB may consider the disposition of the noncompliance.

6. IRB determination and disposition of alleged noncompliance.

1. Every effort should be made to allow a mechanism for due process for the investigator.  The PI should be informed that the allegation of noncompliance being presented to the IRB is subject to a determination of “serious” or “continuing noncompliance” which must be reported to regulatory agencies and sponsors. At a minimum, the investigative report to be given to the IRB should first be shared with the investigator to ensure accuracy of information to be reported to the IRB.  The investigator should also be involved in the development of a corrective action plan.  The IRB (or PI) may request the PI’s presence at the convened Panel meeting in order to provide clarifications.  The Chair of the IRB Leadership and Enhancement Committee (ILEC) will be apprised of matters related to alleged non-compliance as necessary and may call the ILEC to consider the matter.
2. The IRB should first determine if the report constitutes noncompliance, and if it does, determine if the occurrence is serious noncompliance or continuing noncompliance (see both definitions above).  A first-time offense may be determined to be “serious noncompliance” if risk to participants was significantly increased or if subjects’ rights or welfare were seriously compromised.  It is important to note that the convened IRB must make the determination of serious or continuing non-compliance.  The convened IRB may make the determination at the first report of the occurrence, or the final determination may be made after the completion of an inquiry or investigation.  The IRB’s initial and/or final determination may trigger the required report preparation and procedure as described in Sections C-H below. 
3. The IRB will evaluate reports of noncompliance that are not determined to be serious by asking the following question:  ‘Does this noncompliance demonstrate a continuation of issues that have been repeatedly noted by the IRB and communicated to the investigator over time (without evidence of correction or improvement)?’ Answering ‘yes’ to the above question, may constitute a finding of ‘continuing noncompliance.’  If the answer is ‘no’, the IRB should not make a determination of ‘continuing noncompliance.’  Continuing noncompliance should not be determined upon a first time offense by an investigator. 
4. Possible actions imposed by the IRB in response to a determination of serious or continuing noncompliance include, but are not limited to: 1) suspension of the research, 2) termination of the research, and/or 3) notification of research participants about the serious or continuing noncompliance when such information may impact their willingness to participate.  Further actions that may be required include: 4) a corrective action plan to be designed by the PI, IRB, and/or ORCE, and approved by the IRB, 5) compliance audit, 6) letter of reprimand to the investigator that may also be copied to supervisors, and 7) restrictions on serving as an investigator for human subjects research.  As a courtesy, the investigator is notified that a reportable finding has been made by the IRB prior to the report being sent to regulatory authorities and sponsors. The investigator may contact the IRB Chair and/or Director of ORCE to offer further information, request further discussion, and/or request appearance before the convened IRB.
5. If the IRB determines that serious or continuing noncompliance has occurred, a formal report to OHRP and other oversight entities is required.  See Sections C-H below.
6. If the noncompliance is determined to be neither ‘serious’ or ‘continuing,’ the IRB, assisted by the ORCE, should develop a corrective action plan for general noncompliance, with the cooperation of the PI.  Possible additional actions taken by the IRB and/or the ORCE include, but are not limited to: 1) a compliance audit, 2) a letter of reprimand with a copy to the department Chair, and 3) restrictions on serving as an investigator for human subjects research. 
   
   The IRB should take steps to ensure that the noncompliance does not recur.  Such a plan may involve the ORCE. Measures to ensure non-recurrence may include:  targeted education, more frequent continuing review, progress reports from the investigator, and post-approval monitoring site visits.


7. If the report or allegation is determined to not represent general noncompliance, the convened IRB will consider if it is an unanticipated problem involving risk to subjects or others (and recommend reporting as such).  If the report or allegation does not represent an unanticipated problem, the IRB will recommend that the issue be handled as a complaint and/or concern in accordance with VCU IRB WPP XVII-10.
   
   When a report of an unanticipated problem is received, and/or an incident of ‘noncompliance’ is instead being considered as an Unanticipated Problem, it is processed in accordance with the VCU IRB VIII-7.  It should be noted that an Unanticipated Problem Involving Risks to Subjects or Others is a specific finding by a convened IRB, subject to federal reporting.  An Unanticipated Problem Involving Risk may be accompanied by serious or continuing noncompliance, findings which are also reportable to federal authorities

8. Every effort is made to work directly with investigators or research staff who self-report all forms of non-compliance and/or with the management of unanticipated problems.  Resources may be made available to assist with corrective actions, when necessary, through the self-reporting process.
3. Required IRB Reporting (To Regulatory Officials):

The VCU IRB will promptly report the following to relevant regulatory and oversight agencies (in accordance with DHHS and FDA regulations), regardless of funding source:

1. unanticipated problems involving risks to subjects or others.
2. serious or continuing noncompliance with the requirements or determinations of the IRB.
3. suspension or termination of previously approved research (as per WPP VI-2, Suspensions and Terminations of Previously Approved Research).

4. Report Preparation:

Official written reports for official reporting to oversight agencies of 1) unanticipated problems involving risk to subjects or others, 2) serious or continuing noncompliance, or 3) suspension or termination of IRB-approved activities  are to be prepared as follows:

1. Drafted by the Director of the ORCE (with the cooperation of the Chairperson of the IRB Panel, and others as necessary). 
2. Reviewed for comments by the ORSP Director, Director of OSP, as appropriate, and the Institutional Official (IO) or designee (as deemed appropriate by the Director of the ORCE).  If the report is related to a WIRB-approved protocol, the ORCE Director coordinates the drafting and review of the report with the WIRB counterpart.
3. Approved by the IRB Panel Chair, ORCE Director, and the IO.
4. Signed by the Director of the ORCE or the IO or designee.
5. Elements of the Report:

The following elements must be included in the report, which should be kept concise and include only detail which directly supports the actions taken:

1. The nature of the event or events.
2. The findings of the organization.
3. Actions taken by the organization, including any IRB actions taken related to this matter.
4. Specific reasons for the actions identified.
5. Clear identification that the issue is resolved or specific plans for continued investigation or action.
6. Distribution of the Report:

The distribution of the written report begins with federal agencies that have oversight due to funding, conduct, or an assurance of compliance.  A report is always sent to OHRP, the FDA if FDA-regulated research, and other “Common Rule Signatories” that require reporting separate from OHRP.  A VCU report may not be sent to federal agencies already made aware of the event by way of the investigator, sponsor, or another organization, as determined by the ORCE Director and/or IRB Chair.

1. The report must be drafted as soon as information is available that confirms or clarifies the issue to be reported.  The timing for official distribution of the report to oversight agencies should be as soon as practicable, with the primary attention first given to taking any actions (if necessary) to ensure the ongoing protection of human research participants.
2. Copies of the report are directed to:
   1. The VCU IRB Panel Chairperson (or the Western IRB Chairperson, if appropriate)
   2. The VPR (the VCU FWA Signatory Official)
   3. The OSP or OIP, as appropriate (for reporting to any sponsoring organization)
   4. The Signatory Official on the VCU FWA and, as appropriate, the VCU Health System FWA.
   5. The Principal Investigator and/or supervisor of the Principal Investigator
7. Distribution of the Report to the DHHS Office for Human Research Protections (OHRP):

   An official written report (regarding the circumstances outlined in Section A of this WPP) must be submitted to the OHRP for NON-EXEMPT research that is:           

   1. conducted or supported by HHS;
   2. conducted or supported by any non-HHS federal department or agency that has adopted the Common Rule and is covered by a Federalwide Assurance (FWA) determined to be appropriate for such research; or
   3. covered by an FWA, regardless of funding source.

The appropriate OHRP address for sending these reports is available on the OHRP webpage.  It should be noted that the reporting timeline for the OHRP is "promptly."  For more serious incidents, the report will be filed as soon as practicable (maybe even within days).  It may be necessary to telephone OHRP in order to alert the agency to a very serious problem.  Subsequent written reports should reference the date and time of the initial telephone call.  In the case of an urgent written or phone report, indicate the nature of the report, the investigation on the part of the institution, and a pending follow-up report with more information as it becomes known. 

This official written report must include the following elements (in addition to those identified above):

1. For unanticipated problems involving risks to subjects or others:
   1. Name of institution conducting the research;
   2. Title of research project and/or grant proposal;
   3. Name of the principal investigator on the protocol;
   4. Number of research projects under the authority of the PI  (active IRB-approved protocols) and the number of any applicable federal award(s) (including grants, contracts, or cooperative agreements);
   5. A detailed description of the circumstance resulting in the reporting; and
   6. Actions the institution is taking or plans to take to address the problem (these corrective actions might include specific changes to consent materials or protocol, etc.).

2. For serious or continuing noncompliance:
   1. Name of institution conducting the research;
   2. Title of research project and/or grant proposal;
   3. Name of the principal investigator on the protocol;
   4. Number of research projects assigned by the IRB and the number of any applicable federal award(s) (including grants, contracts, or cooperative agreements);
   5. A detailed description of the noncompliance (serious and continuing issues described); and
   6. Actions the institution is taking or plans to take to address the problem (these corrective actions might include additional education requirements for the investigator, random audits, etc.).

3. For suspension or termination:
   1. Name of institution conducting the research;
   2. Title of research project and/or grant proposal;
   3. Name of the principal investigator on the protocol;
   4. Number of research projects assigned by the IRB and the number of any applicable federal award(s) (including grants, contracts, or cooperative agreements);
   5. A detailed description of the reason for the suspension or termination; and
   6. The actions the institution is taking or plans to take to address the suspension or termination (e.g., require additional monitoring of the investigator's research).

   NOTE:  When continuing review of a research protocol does not occur prior to the end of the approval period specified by the IRB, IRB approval expires automatically. Such expiration of IRB approval does not need to be reported to OHRP as a suspension of IRB approval under HHS regulations.

4. Distribution of the Report to the US Food and Drug Administration (FDA):

The FDA requires that a report be filed and sent to the appropriate division regarding all circumstances described in Section A above involving FDA regulated products, as per 21CFR56.108(b) and in accordance with the FDA Guidance for Required Reporting:  “Suspension or Termination of IRB Approval, Good Clinical Practice in FDA-Regulated Clinical Trials”

1. For Reports Involving Drug Products:
   • Division of Scientific Investigations (HFD-45)
   • Office of Medical Policy
   • Center for Drug Evaluation and Research
   • 7520 Standish Place
   • Rockville, MD 20855
   • Phone: 301-594-0020
   • Fax: 301-594-1204
2. For Biologic Products:
   • Bioresearch Monitoring Branch (HFM-664)
   • Division of Inspections and Surveillance
   • Office of Compliance and Biologics Quality
   • Center for Biologics Evaluation and Research/FDA
   • 1401 Rockville Pike, Room 400S
   • Rockville, MD 20852-1448
   • Phone: 301-827-6221
   • Fax: 301-827-6748
3. For Medical Devices:
   • Division of Bioresearch Monitoring (HFZ-310)
   • Office of Compliance
   • Center for Device and Radiological Health (CDRH)
   • 2094 Gaither Road
   • Rockville, MD 20850
   • Phone: 301-594-4718
   • Fax: 301-827-6748

Responsibility

It is the responsibility of the ORCE to plan for and coordinate all elements of the VCU IRB's determination of unanticipated problems involving risk, serious and continuing noncompliance, and reporting, on behalf of VCU (under the VCU FWA).  Western IRB retains the right and responsibility to follow its own procedures for determining findings for Serious and Continuing Non-Compliance and Unanticipated Problems Involving Risks to Subjects or Others.  However, ORCE coordinates with WIRB regarding those procedures for determinations and reporting.

References

DHHS OHRP Guidance:  Incident Reporting
FDA Guidance:  Suspension or Termination of IRB Approval
AAHRPP Tip Sheet:  Reporting of Unanticipated Problems
VCU IRB WPP VIII-7 Required Reporting of Unanticipated Problems Involving Risk or Harm to Subjects or Others
VCU IRBWPP VI-2 Suspensions and Terminations of Previously Approved Research