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Reporting of Unanticipated Problems

Reporting Protocol Deviations

Minor Deviations

A minor deviation is an unintentional change to or noncompliance with the research protocol that does not have a significant effect on the subject's rights, safety or welfare, and/or on the integrity of the data. Deviations may result from the action of the participant, researcher, or research staff. Examples of deviations include:

  • Follow up visits occurring outside the protocol required time frame because of the participant’s schedule
  • Blood samples being obtained at times close to but not precisely at the time points specified in the protocol
  • Failure to collect an ancillary self-report questionnaire
  • Failure to use the IRB stamped Consent Form when consenting a subject
  • Over-enrollment of subjects on minimal risk studies
  • Use of translated consent documents without first submitting to the HRP for review and approval

The UCI IRB does not require a report of minor deviations. However, if the Sponsor requires the submission of a report to the IRB, a Deviation Tracking Log may be submitted at the time of annual renewal via the Continuing Protocol Application (CPA).

Major Deviations

There are two types of major deviations that can occur: 1) emergency deviations and 2) non-emergency deviations. All major deviations must be promptly reported to the UCI IRB as follows:

Emergency deviations involve a departure from the approved protocol to avoid an immediate hazard to the participant. Emergency deviations may occur without time for prospective IRB review and approval. However, a report of the event must be submitted within 5 business days of the Lead Researcher (LR) learning of the event. If the emergency deviation meets the definition of an Unanticipated Problem, submit an Unanticipated Problem (UP) Report; otherwise, submit a Modification Application (MOD).

Non-emergency deviations are planned (non-emergent) and represent a major change in the approved protocol. Major, non-emergency deviations should be submitted to the UCI IRB for prospective review (in advance of the event). If the deviation will occur within 48 hours, submit a Prospective Deviation Request; otherwise, submit a MOD.

Prospective Deviation Request

A prospective deviation is an anticipated and/or intentional and known deviation to the protocol for no more than 3 subjects before they occur.  Examples of prospective deviations to a research study include but are not limited to, the following:

  • Continuation of research activities during lapse in IRB approval
  • Inclusion/exclusion criteria deviation
  • Allowing subject to remain in study despite reaching an endpoint or progression of disease
  • Dosing variance

If the deviation will occur within 48 hours, submit a Prospective Deviation Request; otherwise, submit a MOD.

Reporting Noncompliance

Noncompliance

Noncompliance is when a research team fails to comply with the requirements of an applicable law, regulation, or institutional policy pertaining to the protection of human subjects, and/or with the requirements or determinations of an IRB. Often noncompliance that is not serious or continuing is considered a minor deviation.

The UCI IRB does not require a report of noncompliance; unless it constitutes an unanticipated problem and/or serious and/or continuing noncompliance. However, if the Sponsor requires the submission of a noncompliance report to the IRB, a Deviation Tracking Log may be submitted at the time of annual renewal via the Continuing Protocol Application (CPA).

Serious and/or Continuing Noncompliance

Serious noncompliance is noncompliance that has a significant adverse impact on the rights or welfare of participants or on the integrity of the data.

Continuing noncompliance is a pattern of noncompliance that indicates an inability or unwillingness to comply with applicable laws, regulations, or institutional policies pertaining to the protection of human subjects and/or with the requirements or determinations of an IRB.

Possible examples of serious and/or noncompliance may include:

  • Failure to obtain prospective IRB approval for an additional research related activity not currently listed on the IRB approved protocol
  • Failure to obtain signed informed consent or HIPAA from subjects as required from the IRB
  • Failure to collect screening labs before initiation of study procedures.
  • Enrolling a participant who does not meet the inclusion criteria

All incidents of serious and/or continuing noncompliance and must be reported to the IRB within 5 business days of the occurrence or within 5 business days from the date in which the LR learned of the occurrence. If the serious and/or continuing noncompliance meets the definition of an unanticipated problem, submit an Unanticipated Problem (UP) Report; otherwise, submit a New Information Report (NIR).

Reporting Unanticipated Problems

UCI considers both OHRP and FDA guidance when assessing whether an event constitutes an unanticipated problem. In accordance with Federal regulations and HRP policies, an Unanticipated Problem is defined as:

  1. Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document; and (b) the characteristics of the subject population being studied; and
  2. Related or possibly related to participation in the research (possibly related means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and
  3. Suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.

Reasonable judgment must be used when determining what constitutes an unanticipated problem. Researchers must consider the psychological, emotional, economic and social harms, not merely physical harms. When in doubt, it is best to err on the side of reporting the event or contact the Human Research Protections (HRP) staff for guidance.

External Unanticipated Problems

FDA guidance on Adverse Event Reporting to IRBs — Improving Human Subject Protection states that it is neither useful nor necessary for reports of individual adverse events occurring at other multi-center sites to be distributed routinely to investigators or IRBs at all institutions conducting the research.

The LR is expected to review any external unanticipated problem reports and determine whether the report indicates a change in the risk/benefit profile. If the report indicates a change in the risk/benefit profile, submit a Modification Application (MOD) with the appropriately revise IRB-approved documentation.

If UCI is the coordinating site and IRB of record, the LR will need assess if the change to the risk/benefit profile necessitates the submission of an Unanticipated Problem (UP) Report.

Responsibility to Report Unanticipated Problems

Unanticipated problems must be reported when:

  • The event occurred at a UCI site (UCI Main Campus, UCIMC, including UCIMC satellite clinics) where UCI is the IRB of record (the reviewing IRB) OR
  • The event occurred at a non UCI site, with a non-UCI researcher, where the UCI IRB is the IRB of record (the reviewing IRB)

Reporting Timeframe and Method

Submit an UP within 5 business days of the occurrence or within 5 business days from the date in which the LR learned of the occurrence. The UP Report is an online, electronic application, accessible 24 hours a day / 7 days a week. Only the LR or IRB approved Co-Researcher (Co-R) can officially submit the UP Report; however, any member of the study team can draft the UP Report.

A timely submission of follow-up UP is required if the unanticipated problem is unresolved at the time of the initial report or if the unanticipated problem results in a chronic condition or death.

Unanticipated Adverse Device Effect (UADE)

Devices may have an UADE to participants or others.  The investigational device exemption (IDE) regulations define an UADE as “any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects”.

UADEs must be reported by the clinical investigator to the sponsor and the IRB (via the UP), as described below:

  • For device studies, investigators are required to submit a report of a UADE to the sponsor and an UP to the UCI IRB as soon as possible, but in no event later than 5 business days after the investigator first learns of the event (§ 812.150(a)(1)).
  • Sponsors must immediately conduct an evaluation of a UADE and must report the results of the evaluation to FDA, all reviewing IRBs, and participating investigators within 10 working days after the sponsor first receives notice of the effect (§§ 812.46(b), 812.150(b)(1)).

Unanticipated Problems Related to a Humanitarian Use Device (HUD)

Whenever the physician or health care provider receives or otherwise becomes aware of information, from any source, that reasonably suggests that a HUD has or may have caused or contributed to the death or serious injury of a patient, the physician or health care provider must report such findings to the FDA and submit an UP to the UCI IRB as soon as possible, but no later than 5 business days after the physician first learns of the event/problem. This reporting is in addition to, not a substitute for, FDA and/or manufacturer reporting requirements in accordance with 21 CFR 803.30.

The physician or health care provider must promptly report any FDA action regarding the death or serious injury to the patient to the IRB.

Significant Findings Discovered from Unanticipated Problems

Federal regulations require that research participants be informed of all significant new findings identified during the course of the research.  A significant new finding may affect the willingness of subjects to continue to participate in the research.  

Significant findings almost always involve necessary changes to the Protocol Narrative and Consent Form (e.g., the addition of new risks posed to participants).  If the unanticipated problem involves significant findings, in addition to submitting an UP, submit a MOD with the appropriately revise IRB-approved documentation. It is helpful to reference the UP Report number when submitting the MOD.

Reporting Protocol Violations

A protocol violation is an accidental or unintentional change to or noncompliance with the IRB-approved protocol that increases risk or decreases benefit and/or affects the subject's rights, safety, welfare, and/or the integrity of the data. A protocol violation is generally either an unanticipated problem and/or serious noncompliance and must be reported within 5 business days of the occurrence or within 5 business days from the date in which the LR learned of the occurrence. If the protocol violation constitutes an unanticipated problem, submit an Unanticipated Problem (UP) Report; otherwise, submit a New Information Report (NIR).

IRB Review of Unanticipated Problems and Serious and/or Continuing Noncompliance

The UCI IRB will review the Unanticipated Problem or New Information Report in a timely manner and confirm whether the submission constitutes an unanticipated problem involving risk to participants or others. The IRB will consider a range of possible corrective actions such as:

  • Suspend or terminate the research
  • Notify current participants when such information might be related to their willingness to continue to take part in the research (e.g., reconsenting participants)
  • Require modifications to the protocol and/or consent documents
  • Provide additional information to past participants (e.g., long-term risks have been identified that could affect them)
  • Increase the frequency of continuing review
  • Impose additional monitoring requirements
  • Require additional training of the researcher and research team
  • Notify other UCI committees or departments

The UCI IRB will report any unanticipated problems to the LR, appropriate UCI officials, the funding agency or study sponsor, if applicable, the Office for Human Research Protections (OHRP), the Food and Drug Administration (FDA) and other applicable regulatory authorities.

The UCI IRB has the authority to suspend or terminate approval of research that has been associated with unexpected serious harm to participants. When an IRB Committee takes such action, it is required to provide a statement of reason for the action and to promptly report this action to the LR, appropriate UCI officials, the funding agency or study sponsor, if applicable, the Office for Human Research Protections (OHRP), the Food and Drug Administration (FDA) and other applicable regulatory authorities.

Additional Special Topics

Data Breaches

A data security breach (e.g., a stolen laptop or misplaced thumb drive) involving identifiable data almost always constitutes an unanticipated problem. If this occurs submit an Unanticipated Problem (UP) Report within 5 business days of the occurrence or within 5 business days from the date in which the LR learned of the occurrence.

For a data security breach that involves protected health information (PHI) under HIPAA, the LR must contact the UCI Health Privacy Compliance Officer at 714-456-3672 or hacompliance@uci.edu.

In addition, it is strongly advised that the LR contact the OIT Response Center at (949) 824-2222 to report that a potential security breach has occurred and request immediate notification of the OIT security staff and the Security Breach Lead Campus Authorities. Information may be sent via email to security@uci.edu with a copy to security-lca@uci.edu.

Data Safety Monitoring Board Reports

The LR is expected to review any Data and Safety Monitoring Board (DSMB) reports and determine whether the report indicates a change in the risk/benefit profile. If the report indicates a change in the risk/benefit profile, submit a Modification Application (MOD) with the appropriately revise IRB-approved documentation.

If UCI is the coordinating site and IRB of record, the LR will need to also assess if the change to the risk/benefit profile necessitates the submission of an UP. If the LR determines that an UP report is not necessary, the DSMB report should be submitted at the time of annual renewal via the Continuing Protocol Application (CPA).

Adverse Events and Safety Reports

Adverse events are untoward or unfavorable occurrences in a human subject, including any abnormal sign (e.g., abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject’s participation in the research, whether or not considered related to the subject’s participation in the research. Safety Reports are external adverse events.

Adverse events should only be reported to the IRB when the event changes the risk/benefit profile of the study and/or when the IRB-approved documents (e.g., protocol and consent form) must be revised. Submit a MOD with the appropriately revise IRB-approved documentation.

Serious Adverse Event Reporting Requirements for Human Gene Transfer Research

Human gene transfer (a.k.a. "gene therapy") protocols have additional adverse event reporting responsibilities. The NIH Guidelines require that any significant problems, violations, or any significant research-related accidents and illnesses” be reported to the NIH Office of Biotechnology Activities' (OBA) within 30 days.  If the gene transfer study is supported by an external sponsor, this reporting should be coordinated with the sponsor. In addition to submitting a serious adverse event (SAE) to the OBA, the LR must submit SAEs to the UCI Institutional Biosafety Committee (IBC), and any unanticipated problems to the UCI IRB via the UP.  

Failure to report gene transfer SAEs to the federal oversight bodies (FDA, NIH-OBA) may result in sanctions for the LR and for the institution. For more information regarding the additional reporting responsibilities for human gene transfer research, please refer to the OBA main webpage, the OBA FAQ page on incident reporting, or contact the UCI IBC.

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