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Chapter XXII - Reporting Unanticipated Problems, Adverse Events, Deviations, Noncompliance, and Suspensions and Terminations

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OVERVIEW
Health and Human Services (HHS) Office of Human Research Protections (OHRP)—regulations require IRBs “have written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the department or agency head of (i) any unanticipated problems involving risks to participants or others, or any serious or continuing non-compliance with this policy or the requirements or determinations of the IRB and (ii) any suspension or termination of IRB approval.” 45 CFR 46.103(b)(5).

HHS Food and Drug Administration—regulations require “written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the Food and Drug Administration of: (1) Any unanticipated problems involving risks to human participants or others; (2) any instance of serious or continuing non-compliance with these regulations or the requirements or determinations of the IRB; or (3) any suspension or termination of IRB approval.” 21 CFR 56.108 (b).

EXAMPLES – UNANTICIPATED PROBLEMS INVOLVING RISK TO PARTICIPANTS OR OTHERS AND NON-COMPLIANCE
Unanticipated problems which meet the following definition of “any accident, experience or outcome” that meets the following criteria must be reported:

  • Unexpected in terms of nature, severity, or frequency;
  • Related, or possibly related, to a participant’s participation in the research;
  • Places participants or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.

Examples of types of unanticipated problems that must be reported to the IRB include:

  • Any accidental or intentional deviation from the IRB-approved protocol that involves risks (e.g., missed safety labs, incorrect dosing or labeling);
  • Any deviation from the protocol taken without prior IRB review to eliminate apparent immediate hazard to a given research participant;
  • Any publication in the literature, safety monitoring report, interim result, or other finding that indicates an unexpected increase in the risk to benefit ratio of the research;
  • Any complaint of a participant that indicates an unanticipated risk or which cannot be resolved by the research staff;
  • Any other untoward event that affects the welfare or the privacy, confidentiality or other rights of research participants or members of their family (e.g. lost or stolen research data);
  • Any other untoward event that presents a risk to investigators and research staff involved in the conduct of the research.

Examples of non-compliance that must be reported to the IRB include:

  • Performing non-exempt human participant research without obtaining prospective IRB approval;
  • Implementing protocol modifications without obtaining prospective IRB approval;
  • Altering from the informed consent process as described in the IRB approved protocol;
  • Obtaining consent using an outdated consent form;
  • Conducting research during a lapse in IRB approval;
  • Failing to adhere to the IRB approved protocol due to action (or inaction) of the investigator or staff (i.e., protocol deviations);
  • Not -adhering to inclusion/exclusion criteria;
  • Enrolling more participants than approved in the protocol;
  • Performing research procedures outside the protocol specified window.

Examples of non-compliance that are considered to meet the definition of serious noncompliance include, but are not limited to:

  • Performing non-exempt human participant research without obtaining prospective IRB approval;
  • Implementing substantial modifications to a research study without obtaining prospective IRB approval;
  • Failing to systematically obtain research participants’ informed consent as required by the IRB approved protocol;
  • Failing to comply with federal regulations governing human participant protections.

APPLICATION
This policy applies to the reporting of AEs, SAEs, Unanticipated Problems, protocol violations/deviations), serious/continuing non-compliance, and suspensions and terminations for clinical research. The investigator or any member of the study team must follow the terms of the IRB approval and must abide by applicable laws/ regulations/IRB policies, such as 32 CFR 219.103 (5), which requires written procedures for ensuring prompt reporting to the IRB of (i) any unanticipated problems involving risks to participants or others or any serious or continuing noncompliance with this policy or the requirements or determinations of the IRB and (ii) any suspension or termination of IRB approval.

The events that must be reported to the IRB are specified in the federal regulations at 21 CFR 56.104(c), 21 CFR 56.108(a)(3), 21 CFR 56.108(b)(1), and 21 CFR 56.108(b)(2). Further, as a criterion for its approval of research, an IRB may require, when appropriate, that the research plan makes adequate provision for monitoring the data collected to ensure the safety of participants (32 CFR 219.111(a)(6) and 21 CFR56.111(a)(6)).

Events that the Principal Investigator must report promptly or immediately are detailed in the following sections. For the purposes of this policy, prompt reporting means providing initial notification of an event as quickly as possible after it has been identified. It is acknowledged that although circumstances may prevent immediate notification of reportable events, all required reporting must occur without delay. Investigators should contact the IRB office with any questions about the interpretation of what events require reporting to theIRB.

BACKGROUND
For federally sponsored research, regulations require that institutions and IRBs report the following determinations to investigators, the IRBs, institutional officials, and federal agencies:

  • Unanticipated problems involving risks to participants or others;
  • Serious noncompliance;
  • Continuing noncompliance;
  • Suspensions of IRB approval;
  • Terminations of IRB approval.

For all other research involving human participants, reports of these determinations are provided to investigators, the IRBs, and appropriate institutional officials. The content, timing, and communication of these reports are described in further detail below.

Unanticipated problems are those problems that may arise and are not described in the protocol or other study documents.

“Unanticipated Problems Involving Risks to Participants or Others” (UPIRTSOs) is a broader category than Serious Adverse Events (SAEs), and may include issues other than adverse drug reactions, such as problems with overdosing or drug abuse, loss of control of research agents, patient data, or hazardous materials, psychological reactions, breach of confidentiality, economic risks, less than ideal results of treatment, etc. The criteria for whether such occurrences need to be acted on and perhaps reported to the department or other authorities are the same as for any SAEs or traditional safety report (32 CFR 219.103(b)(5)(i)), (21 CFR 56.108(b)(i)). The GA IRB will decide if these reported events are truly part of the risks of daily living or routine medical care and thus implicitly anticipated. Risks to others must also be reported. For example, an inadvertent exposure of a household contact in a smallpox vaccine trial would be a reportable event. Problems resulting in risks to members of the research team are also reportable.

The only regulatory citation regarding reporting of AEs to the IRB is given at 21 CFR 812.150(a)(1). It states that an investigator shall submit to the Sponsor and to the reviewing IRB a report of any unanticipated adverse device effect occurring during an investigationas soon as possible, but in no event later than 10 working days after the investigator first learns of the effect.

Theoretically, the IRB is not required to receive AE reports other than those that are UPIRTSOs as per 32 CFR 219.103(b)(5)(i) and 21 CFR56.108(b)(1).

As a criterion for its approval of research, an IRB may require when appropriate, that the research plan makes adequate provision for monitoring the data collected to ensure the safety of participants (32 CFR 219.111(a)(6) and 21 CFR 56.111(a)(6)). What this means is that the IRB may require the investigator to evaluate all AEs to ensure the safety of the participants.

The events that are required to be reported to the IRB are given at 32 CFR 219.103(b)(4)(iii), 32 CFR 219.103(b)(5)(i), 21 CFR 56.104(c), 21 CFR 56.108(a)(3), 21 CFR 56.108(b)(1), and 21 CFR 56.108(b)(2). These citations contain no mention ofAEs.

REPORT CONTENT AND REVIEW
Reports of IRB actions/determinations are initially drafted by a staff member at the site with assistance from the IRB office, Office of Research Compliance and/or Office of Legal Affairs, as required or as applicable.

Each report includes (but is not limited to) the following information:

  • Institution conducting the research (e.g., the site);
  • Title of the research protocol and grant proposal (as applicable) in which the problem, noncompliance, and/or suspension or termination occurred;
  • Principal investigator of the research protocol and award, as applicable;
  • Protocol number assigned to the study by the IRB and number (internal and sponsordefined) of any applicable federal award(s) (grant, contract, or cooperative agreement);
  • Number of participants enrolled in the study;
  • Detailed description of the problem or noncompliance (if applicable);
  • Reason(s) for IRB suspension or termination (if applicable);
  • Plans for continued investigation (if applicable);
  • Action(s) taken or plans for action to address the problem, noncompliance, and/or suspension or termination.

Reports may be accompanied by supplemental materials (e.g., redacted IRB minutes) to provide additional background and details as needed.

Internal reports (for research not Federally sponsored) are based upon meeting minutes and are drafted by study staff and reviewed and approved by the applicable IRB Chair or Vice Chair.

Federally sponsored research reports are sent to the Institutional Official for approval and signature.

REPORT DISTRIBUTION AND TIMING
Reports of unanticipated problems, serious and/or continuing noncompliance, suspensions, and terminations will be distributed promptly after IRB review and determination, as described below.

FEDERALLY SPONSORED RESEARCH
Study staff will distribute copies of the signed report (with applicable attachments) to the following as required by regulations:

  • OHRP, for DHHS-regulated research;
  • FDA, for FDA-regulated research (except as described below)
  • Other federal agencies when the research is overseen by the agency and separate reporting is required;
  • Sponsor of the research (if other than above);
  • IRBs;
  • Principal investigator;
  • Principal investigator’s Department and/or Division Chair (or Signatory Official) if applicable;
  • Director of Sponsored Programs;
  • Principal investigator’s College Research Officer and/or Dean, if applicable;
  • Director of the Office of Responsible Research Practices.

Copies of the report will also be sent to the following, as appropriate, based on the nature of the report and at the discretion of the IRB Chair or Vice-Chair and Institutional Official:

  • Co-investigator(s);
  • Office of Research Compliance;
  • Other institutional officials (e.g., Privacy Officer for issues involving PHI, etc.), if applicable;
  • Other site(s) involved in the research.

RESEARCH NOT FEDERALLY SPONSORED
Study staff will distribute copies of the signed report (with applicable attachments) to the following for unfunded or non-federally funded research:

  • FDA, for FDA-regulated research (except as described below)
  • IRBs;
  • Institutional Official;
  • Principal investigator;
  • Principal investigator’s Department and/or Division Chair (or Signatory Official);
  • Principal investigator’s College Research Officer and/or Dean if applicable;
  • Director of the Office of Responsible Research Practices.

Copies of the report will also be distributed to the following, as appropriate, based on the sponsor (if any), nature of the report, and at the discretion of the IRB Chair or Vice-Chair:

  • Co-investigator(s);
  • Office of Research Compliance;
  • Other institutional officials (e.g., Privacy Officer for issues involving PHI);
  • Director of Sponsored Programs (for funded research, etc.);
  • Sponsor and/or contract research organization.

APPLICABLE REGULATIONS/GUIDANCE
21 CFR 56.108, 45 CFR 46.103, OHRP “Guidance on Reporting Incidents to OHRP” (06/20/2011).

RESPONSIBILITIES OF THE PRINCIPAL INVESTIGATOR TO THE IRB
Timely reporting of significant research events to the GA IRB is necessary for the appropriate oversight of the protection of the rights and welfare of participants in funded research. Reportable events include (AEs); (SAEs); Unanticipated Problems Involving Risks to Participants or Others; Deviations, Noncompliance or suspensions or terminations.

Prompt reporting means providing initial notification of an event as quickly as possible after it has been identified. It is acknowledged that although circumstances may prevent immediate notification of reportable events, all required reporting must occur without delay. Investigators should contact the IRB office with any questions about the interpretation of what events require reporting to theIRB.

Serious Adverse Events, and UPIRTSOs. The principal investigator is responsible for the clinical management of the participant and accurate written documentation, investigation, and follow-up of all possible study-related events. The investigator is also responsible for describing and adhering to the procedures for identifying, monitoring, and reporting reportable events.

If there is a medical monitor assigned to the protocol, the medical monitor is required to review reports of serious adverse events/UPIRTSOs and provide an unbiased written report of the event. At a minimum, the medical monitor should comment on the outcomes of the event or problem and, in the case of an AE or death, comment on the relationship to participation in the study. The medical monitor should also indicate whether s/he concurs with the details of the report provided by the study investigator.

Any information regarding SAEs or unanticipated problems received from other sites on multi-site protocols should also be provided to the GA IRB forreview.

Findings and recommendations by the GA IRB related to UPIRTSOs will be promptly reported to the FDA, asrequired.

In addition to prompt reporting, all AEs (expected or unexpected), all participant deaths, and all unexpected problems occurring during the reporting period should be described in the continuing review report submitted to the GA IRB and should also be summarized in the final report after the study.

Outlined below are the requirements for reporting to the IRB. Note that investigators may have additional reporting obligations as specified by the study sponsor or oversight agency.

Investigators who serve as sponsor-investigators of an IND or IDE also have additional reporting obligations to the FDA.

Unless subject to different IRB reporting requirements by a federal agency, investigators must report to the IRB:

  • Internal Adverse Events that are (i) Unexpected, (ii) Related or Possibly Related to the Research Intervention, and (iii) serious or otherwise suggests that the research places the participant or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously know or recognized;
  • External Adverse Events that are (i) Unexpected, (ii) Related to the Research Intervention, and (iii) Serious or otherwise suggests that the research places participants or others at a greater risk than was previously recognized.

Note: the clear majority of Adverse Events will not meet the definition of an Unanticipated Problem Involving Risk to Participants or Others, and need not be reported to the IRB. Expected Adverse Events or Adverse Events which are determined by the investigator to be unrelated to the Research Intervention will not be reviewed by the IRB.

MAJOR DEVIATIONS AND VIOLATIONS
Deviations that meet the definition of a major deviation, and all protocol violations, mustbe reported to the GA IRB promptly following the Investigator’s knowledge of the event, no matter how the deviation or violation was discovered (e.g. discovered by the sponsor during a monitoring visit, discovered by the Principal Investigator,etc.).

The Principal Investigator must submit to the GA IRB a report that includes a description of the major protocol deviation(s), the plan to mitigate its negative effects, if any, and the plan to minimize or eliminate future occurrences.

Serious or continuing noncompliance. In addition to the above federal regulations requires written procedures for ensuring prompt reporting to the IRB of “any serious or continuing noncompliance with this [32 CFR 219.103] policy or the requirements or determinations of the IRB”.

GENERAL IRB REPORTING TIMELINES
All events (AE, SAE, UPIRTSO, Deviations) that meet the IRB’s reporting requirements must be reported to the IRB office as follows:

Internal Adverse Events which are unexpected, fatal or life-threatening, AND Possibly or Definitely Related to the Research Intervention must be reported to the IRB within 24 hours of learning of the event.

To fulfill the GA IRB’s responsibility for monitoring and oversight of research, all UPIRTSOs, SAEs and all participant deaths must be promptly reported by telephone: Genetic Alliance Institutional Review Board at +01 (202) 966-5557.

A complete written report must follow the initial notification. (Note: It is recognized that the information available during this 24-hour period may not be sufficient to permit accurate completion of the required adverse event reporting forms. However, the IRB should, at a minimum, be notified of the fatal or life-threatening internal adverse event during this time frame, with subsequent follow-up submission of a more detailed written report.)

All other internal Adverse Events (inclusive of all Unanticipated Problems Involving Risks to Human Participants or Others) which are unexpected, serious AND Possibly or Definitely Related to the Research Intervention will be reported to the IRB within 10 working days of the investigator learning of the event.

External Adverse Events which are Unexpected, Serious AND Possibly or Definitely Related to the Research Intervention will be reported to the IRB within 30 working days of their receipt by the principal investigator. (Note: only sponsor-generated safety reports that meet the Adverse Event reporting of the IRB should be submitted to the IRB.)

Investigators are to submit all Unanticipated Problems Involving Risks to Human Participants or Others that are Possibly or Definitely Related to the research within 10 working days of the investigator becoming aware of the event.

Noncompliance that meet the IRB’s reporting requirements must be reported to the IRB office within 10 working days of the investigator becoming aware of the event.

PROCEDURE FOR SUBMISSION OF REPORTS
To report any adverse events, unanticipated problems, or incidents of non-compliance, please submit to Genetic Alliance Institutional Review Board at +01 (202) 966-5557. Report must include:

  • Site information, including name and contact information of the Principal Investigator;
  • Study information;
  • Report summary inclusive of dates, times, events, and personnel.

To fulfill the GA IRB’s responsibility for monitoring and oversight of research, all UPIRTSOs, SAEs and all participant deaths must be promptly reported by telephone: Genetic Alliance Institutional Review Board at +01 (202) 966-5557. A complete written report must follow the initial notification.

REVIEW PROCESS
Event reports and accompanying information will be screened for completeness by the GA IRB staff members, additional clarifications will be requested from the investigator as necessary.

Reports of events determined during screening to represent possible unanticipated problems involving risks to participants or others and/or serious/continuing noncompliance will be forwarded to the IRB for convened review. Reports of events that do not meet the requirements for prompt reporting may be returned. All other event reports will be reviewed by the expedited procedure.

EXPEDITED REVIEW
The appropriate IRB Chairperson, Vice-Chair, or one of the experienced members with relevant expertise designated by the Chair will conduct expedited review. Reviewers will have access to the complete protocol file, including previously reported events, for review. The Chairperson or designee will determine if the report raises new concerns about risks and will recommend further review by the convened IRB, as necessary, for a final determination. The IRB Chair or Vice-Chair may suspend or terminate approval of an investigator’s research if necessary to assure the protection of research participants. The Chair or Vice-Chair will consider the rights and welfare of participants when suspending, terminating, or modifying research. If during expedited review the event is determined not to be an unanticipated
problem involving risks to participants or others, the reviewer will make any necessary recommendations for action (see below), which will be communicated to the principal investigator. Further actions proposed by the investigator or IRB reviewer that represent minor changes will also be reviewed by the expedited procedure. IRB members will be informed of these expedited reviews.

CONVENED REVIEW
Reports of events determined during screening or expedited IRB review to represent possible unanticipated problems involving risks to participants or others and/or serious/continuing noncompliance will be forwarded to the full IRB for convened review. The complete protocol file will be available to any IRB member upon request prior to or during the convened IRB meeting.

The IRB will consider the rights and welfare of participants when suspending, terminating, or modifying research.

IRB ACTIONS
The types of actions that the IRB may consider for any event include, but are not limited to:

  • Modification(s) of the research protocol or procedures;
  • Modification(s) of the consent process or consent form;
  • Providing additional information to current research participants (required when such information may relate to their willingness to continue in the research);
  • Providing additional information to past research participants;
  • Reconfirming consent of current research participants;
  • Requiring additional follow-up/monitoring for current and/or past research participants;
  • Monitoring of the research (including audits) or consent process;
  • Education or mentoring for the principal investigator and/or research staff;
  • Additional reporting, including modification of the continuing review schedule;
  • Requiring additional resources to support the investigator’s research activities;
  • Placing limitations (e.g., restriction to co-investigator status) on the investigator’s research activities or use of research data;
  • Suspending or terminating the research;
  • Referral to other appropriate university process (e.g., misconduct review).

The IRB’s determination and action(s), including votes taken, will be recorded in the meeting minutes. The requirements for quorum and majority apply.

Investigators will be notified in writing by IRB staff of IRB decisions regarding events determined not to represent unanticipated problems involving risks to participants or others and/or noncompliance following approval of the meeting minutes by the IRB Chair or ViceChair.

Suspended IRB approval may be reinstated, as appropriate, based on the outcome of the convened review. Investigators (and others) will be notified of IRB actions regarding events determined to be unanticipated problems involving risks to participants or others as described below.

INSTITUTIONAL REPORTING
If the IRB determines that an event represents an unanticipated problem involving risks to participants or others, serious and/or continuing noncompliance, or if the Board suspends or terminates approval of research that is associated with unexpected serious harm to participants, the appropriate internal and external persons and/or agencies will be notified in writing of the determination and reasons for the IRB’s action(s) in accordance with the PI’s Federalwide Assurance. The content of the report will conform to OHRP requirements for incident reporting.

RECORD RETENTION
Records of reports and reviews of events representing possible unanticipated problems involving risks to participants or others, including submission materials and communications, are retained by the study for at least three years, in keeping with federal regulations, applicable state and local laws, and, when relevant, university policies.

APPLICABLE REGULATIONS/GUIDANCE
21 CFR 50.25(b)(5), 21 CFR 56.108(b)(1), 21 CFR 812.150(a)(1), 45 CFR 46.103(b)(5)(i), 45 CFR 46.116(b)(5), OHRP “Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Participants or Others and Adverse Events” (01/15/2007), OHRP “Guidance on IRB Continuing Review of Research” (11/10/2010), OHRP “Guidance on Reporting Incidents to OHRP” (06/20/2011).

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