Unanticipated Problem Increasing Risks to Subjects including Reportable Adverse Events

Reporting Requirements

The University of Pennsylvania IRB has recently revised its policy on the reporting of unanticipated problems posing risk to subjects or others, including adverse events (AEs). This policy is consistent with Department of Health and Human Services Office for Human Research Protections (OHRP), US Food and Drug Administration (FDA) and Association for the Accreditation of Human Research Protection Programs (AAHRPP) guidance.

The IRB strongly discourages submissions of IND safety reports and other adverse event information that does not meet the rubrics outlined in Penn policies. Unnecessary reporting of events or problems that do not potentially affect the rights, welfare or safety of subjects in the study may impair the IRB’s ability to review and respond in a timely manner to actual situations where subject rights, welfare or safety are threatened.

The IRB will not acknowledge safety reports or bulk AE submissions that do not meet the criteria outlined below. These submissions will be returned. Notify your sponsor of this policy.

The IRB encourages study teams to communicate this policy to sponsors and should use this document for verification as necessary.

Reporting Requirements

SOP 404, Section 3.2 Unanticipated Problems Increasing Risks to Subjects or Others and Other Reportable Events

Consistent with federal regulations, the University of Pennsylvania requires reporting to the IRB of unanticipated problems posing risks to subjects or others. Unanticipated problems are: (1) unforeseen; and (2) indicate that  participants are at increased risk of harm.

The IRB requires researchers to submit reports of the following problems within 10 working days with one exception.  The one exception for prompt reporting within 10 days applies to death of a research participant as noted below.

3.2.1 Adverse Event (regardless of whether the event is serious or non-serious, on-site or off-site) that occurs any time during or after the research study, which in the opinion of the principal investigator is both unexpected and related to research procedures.

An event is “unexpected” when its specificity and severity are not accurately reflected in the protocol-related documents, such as the IRB-approved research protocol, any applicable investigator brochure, and the current IRB-approved informed consent document, and (b) other relevant sources of information, such as product labeling and package inserts);

An event is “related to the research procedures” if the event is deemed probably or definitely related.

If the adverse event involved death as unforeseen and indicates participants or others are at increased risk of harm, report in three days.

3.2.2 Unanticipated adverse device effect. 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.

3.2.3 Information that indicates a change to the risks or potential benefits of the research, in terms of severity or frequency. For example:

• An interim analysis indicates that participants have a lower rate of response to treatment than initially expected.

• Safety monitoring indicates that a particular side effect is more severe, or more frequent than initially expected.

• A paper is published from another study that shows that an arm of your research study is of no therapeutic value.

3.2.4 Any adverse event that represents a serious unexpected problem that is rare in absence to drug exposure (agranulocytosis, hepatic necrosis, or Stevens-Johnson syndrome).

3.2.5 Withdrawal from marketing for safety of a drug, device, or biologic used in a research protocol.

3.2.6 Change to the protocol taken without prior IRB review to eliminate apparent immediate hazard to a research participant.

3.2.7 Event that requires prompt reporting to the sponsor.

3.2.8 Complaint of a participant when the complaint indicates unexpected risks or the complaint cannot be resolved by the research team.

3.2.9 Violation, meaning an accidental or unintentional change to the IRB approved protocol) that placed one or more participants at increased risk, or has the potential to occur again.

3.2.10 Breach of confidentiality.

3.2.11 Incarceration of a participant when the research was not previously approved under Subpart C and the investigator believes it is in the best interest of the subject to remain on the study.

The IRB will accept other reports when the investigator is unsure whether the event should be reported, and the IRB will review such reports to determine whether the event meets the threshold for an unanticipated event presenting risk to the participant.

Principal investigators will submit a written report of the above events. Initial reports may be accepted by other means such as e-mail, or phone with a follow up written report.

The IRB staff, when necessary in conjunction with the IRB chair, review reports and decide whether the event meets the definition of an unanticipated problem increasing risks to subjects or others. 

Events that meet these criteria will be considered unanticipated problems involving risks to participants or others, will be reviewed by the convened IRB, and will be reported according to CO 602.

The IRB Administrator selects the primary reviewer. When, possible the IRB member assigned to the initial primary review will review the event. Otherwise, reviewers will be selected based on their, education, experience, and areas of expertise.

Primary reviewers will receive the sponsor protocol, investigator brochure, original IRB application form, consent document, copy of the report form, any supplemental information

All other IRB members will receive the original application form, consent document, copy of the report form, any supplemental information.

The IRB may request a consultant opinion or engage the division or department chair to collect additional information on the event.

The IRB considers the following actions:

• Accept report or with no additional requirements.

• Approve investigator’s proposed changes.

• Administrative hold on the study pending IRB receipt of further information from the PI in a time period not to exceed 90 days.

• Modification of the protocol.

• Modification of the information disclosed during the consent process.

• Providing additional information to current participant the information may relate to the participant’s willingness to continue participation.

• Making arrangements for clinical care outside the research or additional follow-up for participants.

• Providing additional information to past participants.

• Requiring current participants to re-consent to participation.

• Alteration of the frequency of continuing review.

• Observation of the research or the consent process.

• Requiring additional training of the investigator.

• Notification of investigators at other sites.

• Obtaining additional information.

• Termination or suspension of the research.  If this action is taken, the IRB Director will notify the Institutional Official to initiate any reporting actions. If the IRB does not consider the event to represent an unanticipated problem involving risks to participants or others, no further action needs to be taken.