Section VIII: Review Types/Process		WPP #: VIII-7
Title 7: Required Reporting of Unanticipated Problems Involving Risk or Harm to Subjects or Others
Effective Date: 01-15-08	Revision History: 06-20-00; 1-25-01; 11-12-01; 06-07-04; 12-06-04; 6-21-06; 11-1-06

Objective

To describe the VCU IRB reporting requirements unanticipated problems involving risk or harm to the subjects or others. This policy applies to both behavioral research and biomedical research and includes (but is not limited to) the reporting of adverse events, protocol deviations/violations, and confidentiality breaches. All unanticipated problems reported to Western IRB (WIRB) by VCU investigators should also be sent to the VCU Office for Research Subject Protections. The Office of Research Compliance Education (ORCE determines the extent to which the VCU IRB becomes involved in deliberations about occurrences reportable to WIRB.

Description

1. Key Definitions:

While there are many unique terms to define a given type of reportable events (e.g., serious adverse event, adverse event, adverse experience, etc.), the VCU IRB uses the following single definition for an IRB-reportable event:

1. "Unanticipated Problem" (UP):  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.

   NOTE:  UPs are "unanticipated" and therefore are generally not previously identified in the consent document.  Anticipated problems occurring at a greater severity or frequency than previously expected may qualify as unanticipated problems reportable to the IRB. UPs that occur on-site or external to VCU IRB jurisdiction must be reported in the same way. Protocol deviations to minimize immediate risk or protocol violations involved in risk or harm to subjects or others are also considered unanticipated problems for reporting purposes (see definition below).

2. "Protocol Deviation":  Any change to the IRB-approved protocol taken without prior IRB review to eliminate an apparent immediate hazard to a research participant(s).
3. “Protocol Violation”:  An accidental or unintentional change to the IRB approved protocol that harmed participants or others or that indicates participants or others may be at increased risk of harm.
4. "Promptly":  Federal regulations state that all UPs (involving risks to research participants or others) must be reported promptly to the IRB.  The VCU IRB has provided a specific window of 5 working days (Monday-Friday) for reporting unanticipated problems involving risk or harm to subjects or others. Every effort should be made to report all UPs as soon as possible. The VCU IRB requests information in order to monitor compliance with the prompt reporting requirement. 
5. "Research Setting":  The research setting refers to the research site and the IRB responsible for that site.  The terms below specify the research setting in terms of IRB jurisdiction:
   1. Internal - An 'internal' UP involves a research site under the jurisdiction of the VCU IRB. 
   2. External - An 'external' UP involves a research site that is NOT under the jurisdiction of the VCU IRB. 

   NOTE:  In multicenter studies, the VCU IRB only has jurisdiction over the research activities carried out under the direct control of the VCU principal investigator.

• Scope of Unanticipated Problems:

The scope of what qualifies as an unanticipated problem for any given research study includes one or more of the following:

1. An adverse event (including on-site and off-site adverse events, injuries, side effects, deaths, or other problems), which in the opinion of the principal investigator meets the definition of UP (stated above). 
2. An unexpected increase in frequency or severity of an otherwise expected event.
3. New information from the literature, sponsor, lead site, and/or safety & monitoring board that increases the risk to participants
4. Sponsor-imposed protocol suspension for harm or increased risk to participants or other sponsor actions involving risk
5. Changes in labeling or withdrawal from marketing of a drug, device, or biologic used in the research.
6. Breach of confidentiality involving risk or harm to subjects or others (eg., lost, stolen, or missing data). 
7. Protocol deviation, such as any change to the protocol taken without prior IRB review to eliminate apparent immediate hazard to a research participant(s).
8. Protocol violation, such as any accidental or unintentional change to the IRB-approved protocol that involved harm to participants or indicates increased risk of harm.
9. Any complaint of a participant that indicates an unanticipated risk or which cannot be resolved by the research staff.
10. NOTE:  Incarceration of a participant in a protocol not approved to enroll prisoners may be viewed as an unanticipated problem, however reporting to the IRB is via a different form.  Refer to the PI Guidance-Prisoner form to submit this information to the IRB:  http://www.research.vcu.edu/forms/PIGuidance-Prisoner.doc

2.  PI UP Report Preparation: 

The report must be prepared using the VCU IRB PROMPT Reporting Form for UNANTICIPATED PROBLEMS,, found on the VCU IRB Forms Page.  The principal investigator is ultimately responsible for ensuring that the information provided (including relevant dates, event description, actions taken, next actions, etc.) is comprehensive, accurate, and complete.  The PI must sign the UP form. The VCU IRB Prompt Reporting Form is to be submitted to the VCU Office for Research Subjects Protection.

3. IRB Process for Reported Events:

Reportable events are received/opened/date stamped by the intake coordinator and sorted by category/class.

1. Unanticipated Problems that Involve Risk to Subjects or Others (UPs):  All UPs are promptly provided to the Panel Coordinator, who contacts/forwards forms/related information to the Chairperson of the panel (and/or designated reviewer).  (Documents distributed to the Chair/reviewer include at a minimum:  the report form, the protocol, the consent form, and if relevant, the sponsor proposal, the investigator brochure, or other materials).  The Chairperson (and/or designated reviewer of the protocol) evaluates the UP and may consult the investigator, other panel members, the ORCE Director, and others as appropriate.  If the IRB Chair/reviewer ascertains, after consultation, that the problem is NOT an unanticipated problem involving risks to participants or others, no further action is taken by the IRB.  In cases of extreme urgency, the Chairperson (and/or designated reviewer) may act independently in order to ensure the immediate safety of the research participants. 

For UPs associated with expedited or full board studies, the Chairperson (and/or designated reviewer) may take the following actions:

1. Verify that the 'UP' meets the defined criteria.
2. Require any actions necessary to ensure the ongoing safety of research participants, including the following which are in no particular order:
   1. Modification of the research protocol;
   2. Modification of the information disclosed during the consent process;
   3. Additional information provided to past participants;
   4. Notification of current participants (required when such information may relate to participants' willingness to continue to take part in the research);
   5. Requirement that current participants re-consent to participation;
   6. Modification of the continuing review schedule;
   7. Monitoring of the research;
   8. Monitoring of the consent;
   9. Suspension of a portion or all of the research;
   10. Termination of the research;
   11. Request involvement by the ORCE
   12. Request an emergency panel meeting to discuss
   13. Request more information from the principal investigator;
   14. Referral to other organizational entities (e.g., legal counsel, institutional official); and/or
   15. No action (if appropriate).
3. UPs for non-exempt protocols must be referred for review to the next meeting of the relevant IRB Panel, regardless of whether the protocol was initially approved via Full Board review.  (Documents distributed to the IRB members include at a minimum:  the report form, the protocol, the consent form, and if relevant, other sponsor-related materials)The Panel is to make the following determinations:
   1. confirm that the designation of UP applies,
   2. evaluate the adequacy of immediate actions taken by the investigator to protect the subject or others from further risk,
   3. determine the status of actions taken by the Chair/designee,
   4. determine whether other actions are indicated, including changes to the research and consent form, and
   5. indicate that for non-exempt research a UP report will be submitted to OHRP and other appropriate entities by the ORCE.  
4. For UPs that are accompanied by, or are the result of, a protocol deviation or violation, the IRB is also to determine whether the protocol deviation/variance describes Serious or Continuing  Non-Compliance.  If so, ORCE will also submit such a report to OHRP and the sponsor.  

2. Protocol Deviations and Violations - Protocol deviations and violations (that caused harm or increased risk) are Unanticipated Problems (as defined in this WPP).  Documents to be distributed to the IRB Chair/reviewer and IRB members are as mentioned in D1 above.  The action(s) taken by the IRB in review of the protocol deviation/violation are as outlined in 1(b)(i-xv), above.  If the IRB Chair/reviewer ascertains that the protocol deviation/violation does NOT constitute an unanticipated problem involving risks to participants or others, the IRB will still need to determine whether the protocol deviation/violation constituted Serious or Continuing Non-Compliance.

Protocol deviations and violations (as previously defined) for non-exempt protocols must be referred for review to the next meeting of the relevant IRB Panel, regardless of whether the protocol was initially approved via Full Board review.  The Panel is to make the following determinations:

1. confirm that a protocol deviation or violation occurred,
2. evaluate the adequacy of immediate actions taken to protect the subject or others from further risk, and
3. determine whether other or additional actions are indicated, including changes to the research and consent form,
4. determine if a corrective action plan is indicated for the protocol deviation or violation, and evaluate whether the protocol deviation or violation constitutes Serious or Continuing Non-Compliance.  If so, ORCE will also submit such a report to OHRP and other relevant oversight entities.

Documenting the Review of Reported Events:

Decisions of the Chairperson and designated reviewers of promptly reportable events concerning only exempt protocols will be documented in writing and reported to the appropriate IRB Panel each month.  This documentation will be stored as part of the official record with the minutes and agenda from that meeting.  The VCU ORCE reports unanticipated problems involving risks to participants or others and Serious or Contininuing Non-compliance in accordance with the requirements of federal oversight agencies. (see VCU IRB WPP#: VI-3 Investigations and Reporting of Unanticipated Problems, Serious or Continuing Non-Compliance, Suspensions, and Terminations).

PI Responsibility to Monitor ALL Problems:

As a reminder, anticipated problems should not be reported to the VCU IRB, unless they represent a trend or concerns involving risk that were NOT anticipated.  It is the responsibility of the principal investigator to monitor ALL PROBLEMS that involve risk to research participants or others, both unanticipated and anticipated. 

The investigator/research team is to maintain a log of anticipated problems, participant questions and complaints, as well as, other issues that arise within the conduct of the research that do not rise to the level of unanticipated problem requiring prompt reporting to the IRB. 

The investigator/research staff should:

1. Record the occurrence of the problem within their log;
2. Consider the need for clarification of the nature of the problem within the consent document (submitting any clarifications to the consent document to the VCU IRB for prior review and approval);
3. Consider the need to further review and analyze event trends (including the need to document new procedures for handling events and/or educate the research staff about new event procedures);
4. Consider the need to change research procedures (submitting any request for changes to the VCU IRB for prior review and approval);
5. Consider the option to consult with the IRB Chairperson and/or reviewer (as needed); and,
6. Recognize that the IRB may request some, or all, of the investigator's log and related documentation at the time of continuing review.

Responsibility

It is the responsibility of the Principal Investigators to follow the above reporting requirements and provide the IRB with additional information (follow-up reporting) as warranted. The IRB is responsible for assessing risk or harm to subjects or others and for confirming the presence of an Unanticipated Problem, as well as, Serious or Continuing Non-Compliance.

References

45 CFR 46.103(b)(5)
21 CFR 56.103(b)(5)
VCU IRB WPP#: VI-3 Investigations and Reporting of Unanticipated Problems, Serious or Continuing Non-Compliance, Suspensions, and Terminations
Guidance on Reporting and Reviewing Adverse Events and Unanticipated Problems Involving Risks to Subjects or Others [DRAFT - October 11, 2005]