NHLBI Adverse Event and Unanticipated Problem Reporting Policy

The purpose is to describe the National Heart, Lung, and Blood Institute (NHLBI) extramural programs’ policy and procedures for adverse event (AE) and unanticipated problem (UP) reporting.

This policy applies to all human subjects research funded in whole or in part by NHLBI extramural programs.

Adverse event (AE): OHRP guidance defines AEs as any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject’s participation in the research, whether or not considered related to the subject’s participation in the research (modified from the definition of adverse events in the 1996 International Conference on Harmonization E-6 Guidelines for Good Clinical Practice).  Adverse events encompass both physical and psychological harms.  They occur most commonly in the context of biomedical research, although on occasion, they can occur in the context of social and behavioral research.

Serious adverse event (SAE): OHRP guidance defines SAEs as any adverse event temporally associated with the subject’s participation in research that meets any of the following criteria:

1. Results in death;
2. Is life-threatening (places the subject at immediate risk of death from the event as it occurred);
3. Requires inpatient hospitalization or prolongation of existing hospitalization;
4. Results in a persistent or significant disability/incapacity;
5. Results in a congenital anomaly/birth defect; or
6. Any other adverse event that, based upon appropriate medical judgment, may jeopardize the subject’s health and may require medical or surgical intervention to prevent one of the other outcomes listed in this definition (examples of such events include allergic bronchospasm requiring intensive treatment in the emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse).

(Modified from the definition of serious adverse drug experience in FDA regulations at 21 CFR 312.32(a).)

Unanticipated Problem (UP): OHRP guidance defines UPs as any incident, experience, or outcome that meets all of the following criteria:

1. Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document; and (b) the characteristics of the subject population being studied;
2. Related or possibly related to participation in the research (in this guidance document, possibly related means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and
3. Suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.

4.1 Policy

All human subjects research supported by NHLBI must include procedures for identifying, monitoring, and reporting all AEs, including both serious (SAE) and non-serious events, and UPs. All NHLBI human subjects research will follow a uniform policy, which is based on the FDA/Office for Human Research Protections (OHRP) regulations and guidance including definitions and timelines, as outlined in Sections 4.2 and 4.3.

4.2 Reporting Procedures and Requirements

Procedures for identifying, monitoring, and reporting AEs and UPs must be described in the study's Institutional Review Board (IRB)-approved data and safety monitoring (DSM) plan that is submitted to the NHLBI (see NHLBI Data and Safety Monitoring Policy). AE and UP reporting should include at a minimum:

• Expedited reporting of serious and unexpected, suspected adverse reactions to the NHLBI based on the definitions and timelines in FDA regulations and/or OHRP guidance. For multi-center studies, this includes procedures for notifying all participating IRBs through the local investigator.
• For all AEs and UPs, individual and summary reporting to local IRBs on a schedule consistent with IRB-written procedures and consistent with FDA/OHRP regulations and guidance.

A monitoring person or body, such as a Data and Safety Monitoring Board (DSMB), may require additional expedited reporting. The program official will confirm with the principal investigator that any UP has been reported to the appropriate IRBs and that all corrective action/preventative action plans have been adequately implemented.

4.3 Reporting Timelines and Guidance

• Refer to the table below for SAE and UP safety reporting requirements and timelines for clinical research funded in whole or in part by NHLBI extramural programs.
  • Note that in some cases, more than one set of regulations/guidance may apply to a specific event. For example, in a study with FDA-regulated products, an UP that is also an SAE would require compliance with both FDA regulations and OHRP guidance.
  • Reporting timelines for all non-serious AEs should follow the IRB-approved Data and Safety Monitoring Plan for the study.

SAE and UP Event Reporting Timelines

1. The Food and Drug Administration (FDA) regulations define the sponsor of a clinical trial (21 CFR 50.3) as the person or entity who initiated the trial. NIH guidance elaborates on the definition and provides examples. Designee is appointed by the sponsor; for example, DCC, CRO.
2. Per OHRP guidance: only when a particular AE or series of AEs is determined to meet the criteria for an UP should a report of the AE(s) be submitted to the IRB at each institution under the HHS regulations at 45 CFR part 46. Typically, such reports to the IRBs are submitted by investigators.
3. Investigators should also take into account local IRB guidance if reporting timelines for UPs are shorter than OHRP guidance

• OHRP Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events, 2007
• HHS regulations for the protection of human subjects (45 CFR part 46)
• FDA Final Rule: Investigational New Drug Safety Reporting Requirements for Human Drug and Biological Products and Safety Reporting Requirements for Bioavailability and Bioequivalence Studies in Humans
• FDA Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies
• 21 CFR 312.32 IND Safety Reporting
• 21 CFR 312.64 Investigator Reports
• 21 CFR 314.80 Postmarketing Reporting of Adverse Drug Experiences
• New FDA Regulation to Improve Safety Reporting in Clinical Trials (NEJM 2011; 365(1):3-5)
• NHLBI Data and Safety Monitoring Policy, 2011
• NIH Guidance on Reporting Adverse Events to Institutional Review Boards for NIH-Supported Multicenter Clinical Trials, 6/11/1999
• FDA Investigational Device Exemptions
• 21 CFR 812 Investigational Device Exemptions (see 812.46(b), 812.150)
• 21 CFR 50 Protection of Human Subjects
• 21 CFR 50.3 Protection of Human Subjects Definitions
• 21 CFR 56 Institutional Review Boards
• 21 CFR 56.108 Institutional Review Boards (Unanticipated Problem Reporting)
• Guidance for Clinical Investigators, Sponsors, and IRBs Adverse Event Reporting to IRBs- Improving Human Subject Protection.
• Draft Guidance: Elaboration of Definitions of Responsible Party and Applicable Clinical Trial

For additional information contact the NHLBI Program or Program Official associated with your study. Questions and comments regarding this policy may be directed to Office of Clinical Research, NHLBI.

1. Q: Does this NHLBI policy only apply to clinical trials?
A: This policy applies to all human subjects research funded in whole or in part by NHLBI extramural programs.

2. Q: What is the difference between an adverse event and an unanticipated problem?
A: The key question regarding a particular adverse event is whether it meets the three criteria described below and therefore represents an unanticipated problem.  To determine whether an adverse event is an unanticipated problem, the following questions should be asked:

• Is the adverse event unexpected?
• Is the adverse event related or possibly related to participation in the research?
• Does the adverse event suggest that the research places subjects or others at a greater risk of harm than was previously known or recognized?
• If the answer to all three questions is yes, then the adverse event is an unanticipated problem.

3. Q: What is the difference between an adverse event and a suspected adverse reaction?
A: A suspected adverse reaction is any adverse event for which there is a reasonable possibility that study participation caused the adverse event (21 CFR 312.32).

4. Q:  Is this policy for all trials or just FDA-regulated trials?
A: All NHLBI human subjects research will follow this uniform policy, which is based on the FDA/Office for Human Research Protections (OHRP) regulations and guidance including definitions and timelines, as outlined in Sections 4.2 and 4.3 of the policy.

5. Q: How should non-serious adverse events be reported?
A: Reporting timelines for all non-serious AEs should follow the IRB-approved Data and Safety Monitoring Plan for the study.

6. Q: What regulations should be followed to report an SAE that is also a UP?
A: In some cases, more than one set of regulations/guidance may apply to a specific event. For example, in a study with FDA-regulated products, an unexpected problem that is also an SAE would require compliance with both FDA regulations (21 CFR 312.32) and OHRP guidance for a UP.

7. Q: Who makes the final determination of “relatedness?”
A:  The sponsor makes the final determination of AE relatedness to a drug. Under the new regulation (21 CFR 312.32), PIs are now required to report all serious adverse events to the sponsor, whether or not they are considered drug-related.  But it’s difficult for an investigator to attribute a serious adverse event to a drug on the basis of an isolated incident, and individual investigators may not have timely access to the entire safety database. Therefore, causality of adverse events is best evaluated in the aggregate by the sponsor.