SAEs, AEs, Unexpected Problems

Question 1

What is an Unanticipated Problem?

Answer 1

Per OHRP guidance, it must be ALL of the following:
1. unexpected (in terms of nature, severity, or frequency)
2. related or possibly related to participation in the research
3. places subjects OR others at greater risk of harm than previously known

Referenced in Common Rule 46.108(a)(4) but not defined there.

Question 2

What kind of event is defined as “unexpected, related, and greater risk of harm”?

Answer 2

An Unanticipated Problem (see OHRP guidance)

Question 3

When does an Adverse Event need to be reported to the IRB?

Answer 3

When that Adverse Event is ALSO an Unanticipated Problem (unexpected, related, and greater risk of harm).

Question 4

What is an Adverse Event?

Answer 4

Per OHRP guidance, any untoward/unfavorable medical occurrence in a human subject (any abnormal sign, symptom, or disease) temporally associated with participation in research - whether or not it is related to the research.

Question 5

What are the main differences between Adverse Events and Unanticipated Problems?

Answer 5

1. Unanticipated Problems must be related to research - doesn’t matter for AEs.
2. Unanticipated Problems must be unexpected - doesn’t matter for AEs.
3. AEs must affect the research subject - Unexpected Problems can affect the subject OR others.
4. AEs definitionally cause harm to subjects. Unanticipated Problems increase RISK of harm, but haven’t necessarily caused harm already.

Question 6

What is an unanticipated adverse device effect?

Answer 6

Per 21 CFR 812,

any serious adverse effect on health/safety or life-threatening problem or death caused by/associated with a device - if that effect/problem/death was not previously identified,

OR any other unanticipated serious problem associated with a device that relates to subject rights/safety/welfare.

Question 7

Per federal regulations: How quickly must a RESEARCHER report unanticipated adverse device effects, and to whom?

Answer 7

Per 21 CFR 812.150(a)(1), ASAP within 10 working days after learning of the effect, to the IRB and the sponsor.

Question 8

Per federal regulations: How quickly must a SPONSOR report unanticipated adverse device effects, and to whom?

Answer 8

Per 21 CFR 812.150(b)(1), ASAP within 10 working days after learning of the effect, to the FDA, to all reviewing IRBs, and to all investigators.

Question 9

According to OHRP, to whom must a RESEARCHER report unanticipated problems?

Answer 9

The IRB. Note that the FDA requires the researcher to report to the sponsor AND the IRB.

Question 10

According to the FDA, to whom must a RESEARCHER report unanticipated problems?

Answer 10

The IRB AND the Sponsor. Note that the OHRP only requires the researcher to report to the IRB.

Question 11

According to OHRP, to whom must the IRB report unanticipated problems?

Answer 11

To OHRP, other federal agencies, and other organizational offices as directed by written procedures.

Question 12

According to the FDA, to whom must the IRB report unanticipated problems?

Answer 12

To the FDA, OHRP if appropriate, and other organizational offices as directed by written procedures

Question 13

According to the FDA, to whom must Multicenter trial sponsors report unanticipated problems?

Answer 13

To researchers, IRBs, and the FDA. Note that OHRP does not include reporting requirements for Multicenter Trial Sponsors

Question 14

According to OHRP, how quickly must a RESEARCHER report unanticipated problems?

Answer 14

Per the Common Rule (45 CFR 46.108(a)(4)), reporting must be “prompt” but no timeframe is specified. In general, reporting of more serious problems should occur sooner.

Question 15

Grades of an AE

Answer 15

• None
• Mild
• Moderate
• Severe
• Life-Threatening or disabling
• Fatal

Question 16

Categories of AE causality

Answer 16

-Definitely related
- Probably related
- Possibly related
- Unlikely related
- Unrelated

Question 17

When is an AE considered “life-threatening”?

Answer 17

In the view of the investigator or sponsor, the occurrence places the subject at immediate risk of death. It does not include an AE or suspected adverse reaction that, had it occurred in a more severe form, might have caused death.

Question 18

When does an AE qualify as an SAE?

Answer 18

When the event results in the following outcomes:
- Death
- Life-threatening adverse drug experience
- Inpatient hospitalization or prolongation of existing hospitalization
- Persistent or significant disability/incapacity
- Congenital anomaly/birth defect
- Important medical event that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgement, that may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed above.

Question 19

What makes an AE or SAE unexpected?

Answer 19

It is not listed in the Investigator’s Brochure, the protocol or consent form, or elsewhere in the current IND application, or is not listed at the specificity or severity observed.

Question 20

Per ICH, what are the reporting timelines a SPONSOR should follow for fatal or life threatening, unexpected adverse drug reactions?

Answer 20

Notification to regulatory agencies as soon as possible but w/in 7 calendar days after the sponsor knows a case qualifies, followed by a complete report within 8 calendar days.

Question 21

Per ICH, what are the reporting timelines a SPONSOR should follow for serious, but not fatal or life-threatening, unexpected adverse drug reactions?

Answer 21

As soon as possible but no later than 15 calendar days of first knowledge by the sponsor that the case meets the criteria for expedited reporting.

Question 22

What does ICH E6 say about the reporting timelines from Investigators to sponsors for SAEs?

Answer 22

SAEs should be reported immediately to sponsors except for SAEs the protocol (or other documents) identify as not needing immediate reporting. A detailed, written report should promptly follow. Industry standard for “immediately” is w/in 24 hours.

Question 23

The sponsor must submit an IND Safety Report to the FDA if an adverse event is:

Answer 23

• Serious
• Unexpected
• There is a reasonable possibility that the drug caused the event

Question 24

Per the FDA, how soon must an investigator report Unanticipated Adverse Device Effects (and to whom)?

Answer 24

Investigators are required to report UADEs to the sponsor and the reviewing IRB/IEC within ten (10) working days after becoming aware of the event.