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1.0 General Requirements for Adverse Event (AE) and Unanticipated Problems (UP) Reporting
1.1 All studies that involve human subjects must adequately address safety reporting procedures as part of their DSM Plan in their IRB-approved clinical protocol that is commensurate with the risk level of the clinical study. (Note: See also NHLBI Data and Safety Monitoring Plan Policy, http://public.nhlbi.nih.gov/ocr/home/GetPolicy.aspx?id=7)
1.2 Safety reporting plans includes both AE (including SAEs) and UP.
1.3 AE and UP reporting procedures will depend on the nature and complexity of the study.
1.4 AE and UP reporting procedures must be in the DSM Plan of the IRB-approved clinical protocol.
1.5 AE and UP reporting compliance with the IRB-approved DSM Plan will be monitored by NHLBI program staff
1.6 AE and UP reporting recipients must include the IRB(s), NHLBI and OHRP
1.7 AE and UP reporting recipients may also include:
- Study specific or independent medical monitor
- Monitoring board or committee (DSMB, OSMB, DMC, institutional-based advisory board)
- FDA for studies with investigational and marketed products
- NIH Office of Biotechnology Activities (OBA) for studies with gene and cell-based therapies
2.0 Classifying Adverse Events
2.1 Adequate monitoring and assessment of adverse events requires that they be classified as to severity, expectedness, and potential relatedness to the study intervention and participation. Clinical protocols must include a description of how adverse events will be classified in these terms. These classifications determine reporting requirements. When applicable, the protocol may also state what expected events will not be reported as single events but will be reported as aggregated data.
· 1 Mild adverse event; did not require treatment
· 2 Moderate adverse event; resolved with treatment
· 3 Severe adverse event; inability to carry on normal activities; required professional medical attention
· 4 Life-threatening or permanently disabling adverse event
· 5 Fatal adverse event
In this grading system, severity is not equivalent to seriousness.
A serious adverse event (SAE) would be any event in category 4 or 5, and any event in category 3 that required or prolonged hospitalization.
2.3 Expectedness
AEs must be assessed as to whether they were expected to occur or unexpected, meaning not anticipated based on current knowledge found in the protocol, investigator brochure, product insert, or label.
Unexpected: event is one for which the nature or severity is not consistent with information about the condition under study or intervention in the protocol, consent form, product brochure (PI), or investigator brochure (IB)s.
Expected: event is one known to be associated with the intervention or condition under study.
2.4 Relatedness
The potential event relationship to the study intervention and/or participation
A comprehensive scale in common use is:
· Definite: The event is clearly related to the intervention
· Probable: The event is likely related to the intervention
· Possible: The event may be related to the intervention
· Unlikely: The event is doubtfully related to the intervention
· Unrelated: The event is clearly not related to the intervention
Some studies may use fewer categories (e.g., unrelated, possibly related, probably related)
3.0 Unanticipated Problems (UP)
3.1 Institutions engaged in human subjects research conducted or supported by Department of Health and Human Services (DHHS) must have written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and any supporting department or agency head or designee, of any unanticipated problem involving risks to subjects or others (45 CFR 46.103(b)(5)).
3.2 For NHLBI sponsored studies, the agency head or designee is the NHLBI program official.
3.3 Unanticipated problems reporting must include corrective action plan/measures to prevent recurrence.
3.4 Reports may be forwarded to OHRP using ohrp@osophs.dhhs.gov .
4.0 Reporting Process and Timelines
4.1 Reporting of AEs and UPs to NHLBI is required in addition to any other reporting requirements reflected in the study’s DSM Plan.
4.2 NHLBI does not specify a reporting format; investigators may forward copies of AE/UP reports provided to other regulatory entities.
4.3 The following timeline(s) represent the minimum requirements set forth by NHLBI, OHRP and FDA; IRB(s) and any collaborating entities may impose more stringent reporting timelines.
4.4 If a follow-up action is requested by the IRB, Monitoring Board, FDA, or OBA, it is the responsibility of the investigator to include NHLBI on all follow-up reports and communications.
4.5 Expedited reporting is required for SAEs that are unexpected and deemed to be possibly, probably, or definitely related to participation in the clinical research study or resulting from protocol violations and UPs (meeting all 3 of the OHRP criteria). The timelines below are adapted from January 2007 OHRP Guidance and include the local or internal IRB, participating sites’ or external IRBs, NHLBI, OHRP, and FDA.
5.0 Serious and unanticipated adverse events that are fatal or life-threatening must be reported within 7 days to the local/internal IRB, NHLBI, and (if applicable) FDA (when the study is under an IND/IDE (IND Safety Report))
6.0 All serious adverse events that also are unanticipated problems must be reported within 7 days to the local/internal IRB
7.0 Events that are either unanticipated problems or serious adverse events must be reported within two weeks to NHLBI and (if applicable) within 15 days to FDA—when the study includes an investigational product (IND Safety Report) or marketed product (MedWatch report)
8.0 Any unanticipated problem that is not a serious adverse event must be reported within 30 days to OHRP, NHLBI and other participating sites for their IRB notification (external IRBs)
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OHRP
Unanticipated Problem
January 2007 OHRP Guidance |
FDA IND
Adverse Events
[21 CFR 312.32] |
FDA Marketed
Adverse Event
[21 CFR 310.305, 21 CFR 314.80] |
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Unexpected based on protocol related documents or natural progression of disease or condition |
Unexpected based on investigator’s brochure or protocol |
Unexpected based on approved package insert and/or label |
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Possibly, probably or definitely related |
Associated with the use of an investigational product |
N/A |
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Greater risk of harm than was previously known or recognized |
Serious |
Serious |
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To internal/local IRB
If UP also SAE- w/in 7 days, and to NHLBI is fatal or life-threatening
Other UPs/SAEs- w/in 2 weeks to NHLBI and FDA
UPs that are not SAE To OHRP, NHLBI, other IRBs -w/in 30 days |
To FDA, NHLBI and all participating investigators and IRBs
Fatal or life threatening- w/in 7 days
Other-w/in15 days |
To FDA and others named in product label, NHLBI and IRB for a clinical study
W/in 15 days |
8.1 Routine reporting requirements apply to all other categories of adverse events, and will be dictated by the DSM Plan of the IRB-approved protocol and include:
· Routine reporting of all adverse events to the designated study monitor
· Annual routine reporting to NHLBI, in summary form with the annual progress report
· More frequent reporting, such as quarterly, may be required at the discretion of NHLBI program staff, depending on the risks of the research
9.0 Internal Review of SAE(s) and UP(s) by NHLBI
9.1 Each Division is responsible for reviewing SAE and UP reports from its own funded studies and determining whether further follow-up is warranted.
9.2 A reviewer with the appropriate clinical background and expertise will be designated for each study.
9.3 The designated reviewers will use their judgment in evaluating whether a reported SAE/UP requires further follow-up, and each Division may determine the process for further review.
9.4 For all UPs, the corrective action plan will be reviewed for adequacy and implementation.
9.5 Follow-up actions will vary by the nature of the concern and may include: convening a DSMB call to discuss options, having a site call or site visit, increasing the frequency or content of monitoring, modifications of the study protocol. | 
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