Unanticipated Problems and Reporting to the IRB

Part of Human Subjects Protection for Clinical Research Staff: Risks, Adverse Events and Unanticipated Problems.

About 5 minutes. Free, in your language, no account needed.

Why this matters

An adverse event is a fact about a participant. An unanticipated problem is a judgment about what the event means for the study. Staff who treat the two as the same either over-report everything or under-report what matters. This lesson shows how to sort them and who decides.

ICH E6(R3) is the international baseline in this course. The US federal regulations (45 CFR 46, 21 CFR 56) are taught as the detailed worked example, and passages that name them are US law. Outside the United States, follow your national law and ethics committee requirements. State or local rules may add requirements, and your IRB's written procedures control the details.

What the regulations require

IRBs must have written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, the department or agency head and OHRP of any unanticipated problems involving risks to subjects or others, any serious or continuing noncompliance, and any suspension or termination of IRB approval (45 CFR 46.108(a)(4)). FDA's IRB rule has the same list, with reports to the IRB, institutional officials and FDA (21 CFR 56.108(b)).

The 2007 OHRP guidance cites the older section numbers, such as 46.103(b)(5). The corresponding current provision is 46.108(a)(4).

What counts as an unanticipated problem

The regulations use the phrase "unanticipated problems involving risks to subjects or others" but do not define it. OHRP considers an incident, experience or outcome to be one if it meets all three of these:

  1. It is unexpected, in nature, severity or frequency, given the protocol-related documents and the subject population.
  2. It is related or possibly related to participation in the research.
  3. It suggests that the research places subjects or others at greater risk of harm (physical, psychological, economic or social) than was previously known.

All three have to be present. A common, listed side effect is not unexpected, and an illness unconnected to the study is not related.

An unanticipated problem need not be an adverse event. OHRP gives the example of sensitive identifiable data on an unencrypted laptop stolen from a car, which is a confidentiality breach.

Who assesses, and what gets reported

OHRP says that when an investigator becomes aware of an internal adverse event, the investigator should assess whether it is an unanticipated problem. If so, it should be reported promptly to the IRB. Either way, the investigator must make sure the event goes to a monitoring entity, such as the sponsor, a coordinating center, a medical monitor or a data and safety monitoring board, if the protocol or institutional policy requires.

For multicenter studies, OHRP says individual external adverse events rarely meet the three criteria. Only external events identified as meeting all three need to be reported to the IRB as unanticipated problems.

The FDA guidance "Adverse Event Reporting to IRBs" covers reports of unanticipated problems, including certain adverse event reports, to IRBs under 21 CFR parts 56, 312 and 812. It helps sponsors and investigators of IND trials tell adverse events that are unanticipated problems from those that are not. This course did not review its full text, so follow your sponsor and IRB instructions.

Timing: recommendations, not rules

The regulations do not define "prompt." OHRP recommends that serious adverse events that are unanticipated problems be reported to the IRB within 1 week of the investigator becoming aware, other unanticipated problems within 2 weeks, and institutional reports to officials, the agency head and OHRP within one month of the IRB's receipt. These are recommendations. Your IRB's written procedures control.

Find your IRB's actual deadlines in its procedures and put them where your team will see them.

After the report

The IRB conducts continuing review at intervals appropriate to the degree of risk, and trial status summaries go to the IRB per local requirements or on request (ICH E6(R3) sections 1.2.4 and 2.4.5).

In practice

A site is part of a multicenter study. The sponsor sends a safety letter describing an event at another site. The coordinator does not forward it to the IRB automatically. She gives it to the investigator, who reads it against the protocol and the investigator's brochure, and asks whether it meets the three criteria. The assessment and decision are documented, and if a submission is required, the coordinator prepares it by the IRB's own deadline.

What this looks like when it goes wrong

A coordinator tells new staff, "Anything serious goes to the IRB within a week." One day a participant has a serious, expected event that the consent form lists. The coordinator files it with the IRB as an unanticipated problem anyway. On another day a stolen laptop with participant data is treated as "not a medical event, so not reportable." The first report overstates the event. The second may be a late report of an unanticipated problem. A rule of thumb replaced judgment and the IRB's procedures.

Key takeaways