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Events Requiring Prompt Reporting to the IRB including Unanticipated Problem Involving Risks to Subjects or Others Reporting Requirements

 

Federal Regulation 21CFR §56.108(b)(1) and 45 CFR 46.103(b)(5) require the IRB to "follow written procedures for ensuring prompt reporting to the IRB…any unanticipated problems involving risk to human subjects or others."  

 

In alignment with 21 CFR 312, investigators are required to promptly report to the IRB:

 

(1) Unanticipated problems including suspected adverse reactions and adverse reactions.

 

An event is considered a “suspected adverse reaction” when there is reasonable possibility that the drug/investigational product caused the adverse event.  For these reporting purposes, reasonable possibility means there is evidence to suggest a causal relationship between the drug/investigational product and the event.

 

For University of Pennsylvania IRB reporting, this means an event should be considered probably or definitely related to the research procedures.

 

Examples:

1.       A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure (e.g. angioedema, hepatic injury, Stevens - Johnson syndrome).

2.       One or more occurrences of an event that is not commonly associated with drug exposure, but is otherwise uncommon in the population exposed to the drug (eg. tendon rupture).

3.       An aggregate analysis of specific events observed in a clinical trial (such as known consequences of the underlying disease or condition under investigation or other events that commonly occur in the study population independent of drug therapy) that indicates those events occur more frequently in the drug treatment group than in a concurrent or historical control group.

 

An event is “unexpected” if it is not listed in the investigator’s brochure/package insert, or, is not listed at the specificity or severity that has previously been observed with the specific drug/investigational product; if an investigator’s brochure/package insert is not available, is not consistent with the risk information described in the general investigational plan.)

 

“Unexpected” also refers to events that are mentioned in the investigator’s brochure/package insert as occurring with a class of drugs or as anticipated, but, are not mentioned as to have been occurring (have been seen) with the particular drug/investigational product under study. 

 

Examples:

4.       Hepatic necrosis would be “unexpected” (by virtue of greater severity) if the investigator’s brochure/package insert referred only to elevated hepatic enzymes or hepatitis.

5.       Cerebral thromboembolism and cerebral vasculitis would be “unexpected” (by virtue of greater specificity) if the investigator’s brochure/package insert listed only cerebral vascular accidents.

 

(2) Unanticipated adverse device reaction. 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.

 

For drug/investigational product and device events, “serious” is defined as any death, life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect.  Other events that may be considered “serious” but not meet the prior criteria include: those events that may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes noted above.

 

(3) In addition to unanticipated problems, the IRB also requires prompt reporting of the following events:

 

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

 

Violation or deviation (meaning an accidental or unintentional change to the IRB approved protocol) only when: one or more participants were placed at increased risk of harm, or, the event has the potential to occur again, the event represents serious or continuing noncompliance. 

 

Breach of confidentiality.

 

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.

 

 

Reporting Process 

 

REPORTS MUST BE SUBMITTED ELECTRONICALLY at this link: https:\\medley.isc-seo.upenn.edu\hsProtocol\jsp\fast.do

 

The IRB requires investigators to submit reports within 10 working days (with one exception) of events that meet the definition of an unanticipated problem involving risks to subjects or others.  Exception: If the adverse event involved a death and indicates that participants or others are at increased risk of harm, investigators are required to submit a report to the IRB within 3 days.

 

Submit a narrative summary of adverse events at the time of continuing review. Submit routine, periodic reports (e.g. DMC reports that indicate no changes, sponsor annual progress reports) to the IRB at Continuing Review.

 

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.

 

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.

 

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 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.

 

Policy Reference

Penn IRB Policy RR 404 , Section 3.2

Reportable Events Process Flow Chart


 

 
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