IRB Guidelines - Reporting of Unanticipated Problems Involving Risks to Participants or Others

Federal regulations [45CFR46.103(b)(5) and 21CFR56.108(b)(1)] require the IRB to ensure that investigators promptly report "any unanticipated problems in involving risk to subjects or others."

A. Definitions

1. Adverse Event: Any untoward physical or psychological occurrence or undesirable and unintended effect for a participant that may present itself during interventions and interactions used in the research or the collection of identifiable private information under the research, regardless of whether there may or may not be a relationship with the research intervention.

2. Expected adverse event: An adverse event that is not an unexpected adverse event.

3. Unexpected adverse event: Any adverse event, the specificity, frequency or severity of which is not consistent with either:

a. the known or foreseeable risk of adverse events associated with the procedures involved in the research that are described in the protocol-related documents, such as the IRB-approved research protocol, any applicable investigator brochure, the current IRB-approved informed consent document, and other relevant sources of information, such as product labeling and package inserts; or

b. the expected natural progression of any underlying disease or condition of the participant(s) experiencing the adverse event.

4. Related to the research: An event is related to the research if, in the opinion of the University of Massachusetts (UMASS) investigator, it was more likely than not to be the result of the interventions and interactions used in the research or the collection of identifiable private information in the research (i.e., there is a reasonable possibility that the event may have been caused by participation in the research).

5. Unrelated to the research: An adverse event is unrelated to the research if, in the opinion of the UMASS investigator, the adverse event is not related to the research.

6. Internal events: Adverse events experienced by participants enrolled at the site(s) under the IRB's jurisdiction for either multicenter or single-center research projects.

7. External events: Adverse events experienced by participants enrolled in multicenter clinical trials at sites other than the site(s) over which the IRB has jurisdiction.

8. Unanticipated problems involving risks to participants or others (unanticipated problems): Problems that are (1) unexpected (in terms of nature, severity or frequency) given the research procedures and the participant population being studied; and (2) suggest that the research places participants or others at a greater risk of harm or discomfort related to the research than was previously known or recognized including physical, psychological, economic or social harm.

B. IRB Reporting Requirements

1. Investigators are required to promptly report the following problems to the IRB:

a. Adverse events that are (1) unexpected and (2) related or likely related to the research as determined by the UMASS principal investigator;

b. Information that indicates a change to the risks or potential benefits of the research. For example:

•  An interim analysis or safety monitoring report indicates that frequency or magnitude of harms or benefits may be different than initially presented to the IRB

•  A paper is published from another study that shows that the risks or potential benefits of the research may be different than initially presented to the IRB;

c. Breach of confidentiality;

d. Change in FDA labeling or withdrawal from marketing of a drug, device, or biologic used in a research protocol;

e. Incarceration of a participant in a protocol not approved to enroll prisoners;

f. Specific protocol-defined events that requires prompt reporting to the sponsor;

g. Sponsor imposed suspension for risk;

h. Accidental or unintentional deviations to the IRB-approved protocol that involved risks;

i. Emergency protocol deviations taken without prior IRB review to eliminate apparent immediate hazard to research participants;

j. Complaints of participants that indicate unanticipated risk or which cannot be resolved by the research staff.

2. Investigators must report problems to the IRB in accordance with the following timelines:

a. Internal problems that require prompt reporting and are fatal or life-threatening must be reported to the IRB within one weekday of the principal investigator becoming aware of the problem.

b. All other internal problems that require prompt reporting must be reported within 5 weekdays of the principal investigator becoming aware of the event or problem.

c. External problems that require prompt reporting are to be reported within 30 days of their receipt by the UMASS principal investigator.

3. Reports must include the following:

a. An Unanticipated Problem Report Form, which includes identifying information (title of the research, name of principal investigator, and name of the sponsor), and a description of the event;

b. Any associated materials, if any, such as medical record notations, forms sent to a sponsor or the sponsor's safety report forms.

4. Records for problems and adverse events that do not require prompt reporting:

a. For internal adverse events that are expected and related and are consistent with the frequency and severity listed in the informed consent document, the principal investigator keeps a summary of the events that have occurred within the last approval period and submits the summary at the time of continuing review using the Event Tracking Log.

b. Accidental or unintentional deviations to the IRB-approved protocol that do not involve risks to participants may be submitted to the IRB using the Protocol Deviation/Violation Report Form if required by the sponsor.

c. External adverse event reports that do not require prompt reporting to the IRB, are reviewed, initialed and dated by the principal investigator and filed with the research regulatory documents. This record is to be made available to the IRB upon request.

C. IRB Process for Handling Reported Problems

1. All reports are provided to an IRB Administrator for review within five working days of their receipt.

2. The IRB Administrator reviews the materials to determine if the report includes the necessary information and for an initial evaluation.

a. If the report is incomplete, it is returned to the investigator with a request for the additional information.

•  The UMASS principal investigator's assessment of external events must be provided or the report will be considered incomplete and will be returned to the investigator.

b. If in the judgment of the reviewer, the report is definitely not an unanticipated problem involving risks to participants or others, the following procedures are followed:

•  If the report is for an external adverse event, the report is returned to the investigator with an explanation for why it is being returned.

•  If the report is for an internal event, the report is accepted, signed by the reviewer and filed in the IRB study file. A correction to the log will be requested.

•  If the report is for a publication, safety monitoring report, interim results, or other findings, the report is accepted, signed by the reviewer and filed in the IRB study file.

c. All other reports are referred to the full IRB for further action with the following exceptions.

d. If, in the judgment of the reviewer, participants may be at immediate risk of harm and there is insufficient time to wait for review by the convened IRB, an IRB Chair, or the Director of the Human Research Protection Office is consulted. If the Chair or a Director determines that participants are at immediate risk of harm, the principal investigator will be required to suspend the study according to IRB policy for suspension or termination of research. 

3. For reports that are sent to the full IRB for review, the report is added to an IRB meeting agenda and is assigned to a primary reviewer by the IRB staff on the basis of the scientific expertise of the review. The primary reviewer and all other board members receive the following information:

a. A copy of the report;

b. A copy of all supplemental material attached to the report;

c. A copy of all tracking logs, if applicable;

d. A copy of the sponsor adverse event report form, if applicable;

e. A copy of the DSMB or safety report, if applicable;

f. A summary of the study;

g. Copies of the current, IRB-approved informed consent document(s) and revised informed consent document(s); and

h. Any other relevant materials.

4. The primary reviewer summarizes the report at the convened IRB meeting and the full IRB will determine if the report meets the definition of an unanticipated problem involving risks to participants or others by deciding if the event meets the following criteria:

a. Unexpected, i.e., not anticipated (in terms of nature, severity or frequency) given the research procedures and the participant population being studied; and

b. Places participants or others at a greater risk of harm or discomfort related to the research than was previously known or recognized including physical, psychological, economic or social harm.

5. The IRB may decide to postpone a decision while awaiting additional information. If, in the judgment of the IRB, participants may be at immediate risk of harm while waiting for this information, the principal investigator may be required to suspend the study according to IRB policy for suspension or termination of research. 

6. If the IRB determines that the event meets both criteria, then the event will be considered an unanticipated problem involving risk to participants or others and will be processed as follows:

a. The IRB will consider the following actions:

•  No action necessary;

•  Modification to the protocol;

•  Modification to the informed consent document(s) for future participants;

•  Notification of current or past participants by phone, letter or addendum to the informed consent document;

•  Modification of the continuing review schedule;

•  Monitoring of the research or consent process;

•  Referral to legal counsel, risk management or the institutional official; or

•  Other appropriate action as determined by the IRB.

b. For a report of an accidental or unintentional deviation to the IRB-approved protocol that involved risks or has the potential to recur, the IRB will also consider if the event represents serious or continuing non-compliance. 

c. For a report of an emergency protocol deviation taken without prior IRB review, the IRB will consider if the changes were consistent with the rights and welfare of participants.

d. The IRB decision and required actions are documented using the appropriate template and this documentation is sent to the principal investigator.

e. The IRB submits a report of the unanticipated problem involving risk to participants or others to appropriate institutional officials and entities.

7. If the IRB determines that the reported event or information does not meet one of the two criteria, then the event or information will not be considered an unanticipated problem involving risk to participants or others; therefore, no further action is required. The IRB decision is documented using the appropriate template and this documentation is sent to the principal investigator.

8. Investigators may appeal the IRB determinations regarding the report of an unanticipated problem involving risks to participants or others. In order to appeal an IRB decision, the investigator must submit his/her rationale or that of the sponsor and any supporting information. An appeal must be reviewed by the IRB that made the original decision.

D. IRB Process for Handling Non-Reported Events

1. Internal events submitted on the Event Tracking Log will be reviewed at the time of continuing review.

2. Accidental or unintentional deviations to the IRB-approved protocol that do not involve risks are reviewed by an IRB Administrator.

a. If the report is incomplete, it is returned to the investigator with a request for the additional information.

b. If the investigator indicates that the deviation involved risks, the IRB Administrator contacts the investigator to request that the investigator complete the Unanticipated Problem Report Form.

c. Otherwise, the IRB Administrator stamps the form acknowledging receipt by the IRB office, signs, dates the form and returns a copy of the form to the investigator.

3. External events submitted to the IRB are reviewed by an IRB Administrator.

a. If the report is incomplete, it is returned to the investigator with a request for the additional information.

b. If the investigator indicates that any event meets the definition of a reportable problem, the IRB Administrator contacts the investigator to request that the investigator complete the Unanticipated Problem Report Form.

c. Otherwise, the IRB Administrator stamps the form acknowledging receipt by the IRB office, signs, dates the form and returns a copy of the form to the investigator.