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Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events: OHRP Guidance (2007)

Date :  January 15, 2007

Scope: This document applies to non-exempt human subjects research conducted or supported by HHS.  It provides guidance on HHS regulations for the protection of human research subjects at 45 CFR part 46 related to the review and reporting of (a) unanticipated problems involving risks to subjects or others ( hereinafter referred to as unanticipated problems ); and (b) adverse events.  In particular, this guidance clarifies that only a small subset of adverse events occurring in human subjects participating in research are unanticipated problems that must be reported under 45 CFR part 46.  The guidance is intended to help ensure that the review and reporting of unanticipated problems and adverse events occur in a timely, meaningful way so that human subjects can be better protected from avoidable harms while reducing unnecessary burden. 

The guidance addresses the following topics:

I. What are unanticipated problems ?

II. What are adverse events ?

III. How do you determine which adverse events are unanticipated problems ?

IV. What are other important considerations regarding the reviewing and reporting of unanticipated problems and adverse events?

V. What is the appropriate time frame for reporting unanticipated problems to the institutional review board (IRB), appropriate institutional officials, the department or agency head (or designee), and OHRP?

VI. What should the IRB consider at the time of initial review with respect to adverse events?

VII. What should the IRB consider at the time of continuing review with respect to unanticipated problems and adverse events?

VIII. What should written IRB procedures include with respect to reporting unanticipated problems?

Appendix A: Glossary of Key Terms

Appendix B:  Examples of Unanticipated Problems that Do Not Involve Adverse Events and Need to be Reported Under the HHS Regulations at 45 CFR Part 46

Appendix C:  Examples of Adverse Events that Do Not Represent Unanticipated Problems and Do Not Need to be Reported under the HHS Regulations at 45 CFR Part 46

Appendix D: Examples of Adverse Events that Represent Unanticipated Problems and Need to be Reported under the HHS Regulations at 45 CFR Part 46

NOTE:  For some HHS-conducted or -supported research, the Food and Drug Administration (FDA) and the HHS agency conducting or supporting the research (e.g., the National Institutes of Health [NIH]) may have separate regulatory and policy requirements regarding the reporting of unanticipated problems and adverse events.  Anyone needing guidance on the reporting requirements of FDA or other HHS agencies should contact these agencies directly.  Furthermore, investigators and IRBs should be cognizant of any applicable state and local laws and regulations related to unanticipated problems and adverse events experienced by research subjects, as well as foreign requirements for research conducted outside the United States.  OHRP recommends that investigators and IRBs consult with their legal advisors for guidance regarding pertinent state, local, and international laws and regulations.

Target Audience : IRBs, investigators, and HHS funding agencies that may be responsible for review, conduct, or oversight of human subjects research conducted or supported by HHS.

Regulatory Background :

HHS regulations for the protection of human subjects ( 45 CFR part 46 ) contain five specific requirements relevant to the review and reporting of unanticipated problems and adverse events: 

• Institutions engaged in human subjects research conducted or supported by HHS must have written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and any supporting department or agency head of any unanticipated problem involving risks to subjects or others (45 CFR 46.103(b)(5)).
• For research covered by an assurance approved for federalwide use by OHRP, HHS regulations at 45 CFR 46.103(a) require that institutions promptly report any unanticipated problems to OHRP.
• Risks to subjects are minimized (i) by using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk, and (ii) whenever appropriate, by using procedures already being performed on the subject for diagnostic or treatment purposes (45 CFR 46.111(a)(1)).
• Risks to subjects are reasonable in relation to anticipated benefits, if any, to the subjects, and the importance of the knowledge that may reasonably be expected to result (45 CFR 46.111(a)(2)).
• When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects (45 CFR 46.111(a)(6)).
• An IRB must conduct continuing review of research conducted or supported by HHS at intervals appropriate to the degree of risk, but not less than once per year, and shall have authority to observe or have a third party observe the consent process and the research (45 CFR 46.109(e)).
• An IRB must have authority to suspend or terminate approval of research conducted or supported by HHS that is not being conducted in accordance with the IRB’s requirements or that has been associated with unexpected serious harm to subjects.  Any suspension or termination of approval must include a statement of the reasons for the IRB’s action and must be reported promptly to the investigator, appropriate institutional officials, and any supporting department or agency head (45 CFR 46.113).

The phrase “unanticipated problems involving risks to subjects or others” is found but not defined in the HHS regulations at 45 CFR part 46.  OHRP considers unanticipated problems , in general, to include any incident, experience, or outcome that meets all of the following criteria:

• 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;
• 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
• 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.

OHRP recognizes that it may be difficult to determine whether a particular incident, experience, or outcome is unexpected and whether it is related or possibly related to participation in the research.  OHRP notes that an incident, experience, or outcome that meets the three criteria above generally will warrant consideration of substantive changes in the research protocol or informed consent process/document or other corrective actions in order to protect the safety, welfare, or rights of subjects or others.  Examples of corrective actions or substantive changes that might need to be considered in response to an unanticipated problem include: 

• changes to the research protocol initiated by the investigator prior to obtaining IRB approval to eliminate apparent immediate hazards to subjects;
• modification of inclusion or exclusion criteria to mitigate the newly identified risks;
• implementation of additional procedures for monitoring subjects;
• suspension of enrollment of new subjects;
• suspension of research procedures in currently enrolled subjects;
• modification of informed consent documents to include a description of newly recognized risks; and
• provision of additional information about newly recognized risks to previously enrolled subjects.

As discussed in the sections II and III below, only a small subset of adverse events occurring in human subjects participating in research will meet these three criteria for an unanticipated problem.

Furthermore, there are other types of incidents, experiences, and outcomes that occur during the conduct of human subjects research that represent unanticipated problems but are not considered adverse events.  For example, some unanticipated problems involve social or economic harm instead of the physical or psychological harm associated with adverse events.  In other cases, unanticipated problems place subjects or others at increased risk of harm, but no harm occurs.  Appendix B provides examples of unanticipated problems that do not involve adverse events but must be reported under the HHS regulations at 45 CFR 46.103(a) and 46.103(b)(5).

The HHS regulations at 45 CFR part 46 do not define or use the term adverse event , nor is there a common definition of this term across government and non-government entities.  In this guidance document, the term adverse event in general is used very broadly and includes any event meeting the following definition: 

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. 

In the context of multicenter clinical trials, adverse events can be characterized as either internal adverse events or external adverse events .  From the perspective of one particular institution engaged in a multicenter clinical trial, internal adverse events are those adverse events experienced by subjects enrolled by the investigator(s) at that institution, whereas external adverse events are those adverse events experienced by subjects enrolled by investigators at other institutions engaged in the clinical trial.  In the context of a single-center clinical trial, all adverse events would be considered internal adverse events.

In the case of an internal adverse event at a particular institution, an investigator at that institution typically becomes aware of the event directly from the subject, another collaborating investigator at the same institution, or the subject’s healthcare provider.  In the case of external adverse events , the investigators at all participating institutions learn of such events via reports that are distributed by the sponsor or coordinating center of the multicenter clinical trials.  At many institutions, reports of external adverse events represent the majority of adverse event reports currently being submitted by investigators to IRBs.

In OHRP’s experience, most IRB members, investigators, and institutional officials understand the scope and meaning of the term adverse event in the research context, but lack a clear understanding of OHRP’s expectations for what, when, and to whom adverse events need to be reported as unanticipated problems, given the requirements of the HHS regulations at 45 CFR part 46. 

The following Venn diagram summarizes the general relationship between adverse events and unanticipated problems: 

The diagram illustrates three key points:

• The vast majority of adverse events occurring in human subjects are not unanticipated problems (area A).
• A small proportion of adverse events are unanticipated problems (area B).
• Unanticipated problems include other incidents, experiences, and outcomes that are not adverse events (area C).

The key question regarding a particular adverse event is whether it meets the three criteria described in section I 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 and must be reported to appropriate entities under the HHS regulations at 45 CFR 46.103(a) and 46.103(b)(5).  The next three sub-sections discuss the assessment of these three questions.

A. Assessing whether an adverse event is unexpected

In this guidance document, OHRP defines unexpected adverse event as follows:

Any adverse event occurring in one or more subjects participating in a research protocol, the nature, severity, or frequency of which is not consistent with either:

• the known or foreseeable risk of adverse events associated with the procedures involved in the research that are described in (a) the protocol-related documents, such as the IRB-approved research protocol, any applicable investigator brochure, and the current IRB-approved informed consent document, and (b) other relevant sources of information, such as product labeling and package inserts; or
• the expected natural progression of any underlying disease, disorder, or condition of the subject(s) experiencing the adverse event and the subject’s predisposing risk factor profile for the adverse event.

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

Examples of unexpected adverse events under this definition include the following:

• liver failure due to diffuse hepatic necrosis occurring in a subject without any underlying liver disease would be an unexpected adverse event (by virtue of its unexpected nature) if the protocol-related documents and other relevant sources of information did not identify liver disease as a potential adverse event;
• Hodgkin’s disease (HD) occurring in a subject without predisposing risk factors for HD would be an unexpected adverse event (by virtue of its unexpected nature) if the protocol-related documents and other relevant sources of information only referred to acute myelogenous leukemia as a potential adverse event; and
• liver failure due to diffuse hepatic necrosis occurring in a subject without any underlying liver disease would be an unexpected adverse event (by virtue of its unexpected greater severity) if the protocol-related documents and other relevant sources of information only referred to elevated hepatic enzymes or hepatitis as potential adverse events related to the procedures involved in the research.

In comparison, prolonged severe neutropenia and opportunistic infections occurring in subjects administered an experimental chemotherapy regimen as part of an oncology clinical trial would be examples of expected adverse events if the protocol-related documents described prolonged severe neutropenia and opportunistic infections as common risks for all subjects. 

OHRP recognizes that it may be difficult to determine whether a particular adverse event is unexpected.  OHRP notes that for many studies, determining whether a particular adverse event is unexpected by virtue of an unexpectedly higher frequency can only be done through an analysis of appropriate data on all subjects enrolled in the research. 

In OHRP’s experience the vast majority of adverse events occurring in the context of research are expected in light of (1) the known toxicities and side effects of the research procedures; (2)  the expected natural progression of subjects’ underlying diseases, disorders, and conditions; and (3) subjects’ predisposing risk factor profiles for the adverse events.  Thus, most individual adverse events do not meet the first criterion for an unanticipated problem and do not need to be reported under the HHS regulations 45 CFR part 46.103(a) and 46.103(b)(5) (see examples (1)-(4) in Appendix C ).

B. Assessing whether an adverse event is related or possibly related to participation in research

Adverse events may be caused by one or more of the following:

• the procedures involved in the research;
• an underlying disease, disorder, or condition of the subject; or
• other circumstances unrelated to either the research or any underlying disease, disorder, or condition of the subject. 

In general, adverse events that are determined to be at least partially caused by (1) would be considered related to participation in the research, whereas adverse events determined to be solely caused by (2) or (3) would be considered unrelated to participation in the research. 

For example, for subjects with cancer participating in oncology clinical trials testing chemotherapy drugs, neutropenia and anemia are common adverse events related to participation in the research. Likewise, if a subject with cancer and diabetes mellitus participates in an oncology clinical trial testing an investigational chemotherapy agent and experiences a severe hypoglycemia reaction that is determined to be caused by an interaction between the subject’s diabetes medication and the investigational chemotherapy agent, such a hypoglycemic reaction would be another example of an adverse event related to participation in the research.

In contrast, for subjects with cancer enrolled in a non-interventional, observational research registry study designed to collect longitudinal morbidity and mortality outcome data on the subjects, the death of a subject from progression of the cancer would be an adverse event that is related to the subject’s underlying disease and is unrelated to participation in the research.  Finally, the death of a subject participating in the same cancer research registry study from being struck by a car while crossing the street would be an adverse event that is unrelated to both participation in the research and the subject’s underlying disease.    

Determinations about the relatedness of adverse events to participation in research commonly result in probability statements that fall along a continuum between definitely related to the research and definitely unrelated to participation in the research.  OHRP considers possibly related to participation in the research to be an important threshold for determining whether a particular adverse event represents an unanticipated problem.  In this guidance document, OHRP defines possibly related as follows:

There is a reasonable possibility that the adverse event may have been caused by the procedures involved in the research (modified from the definition of associated with use of the drug in FDA regulations at 21 CFR 312.32(a)).

OHRP recognizes that it may be difficult to determine whether a particular adverse event is related or possibly related to participation in the research.

Many individual adverse events occurring in the context of research are not related to participation in the research and, therefore, do not meet the second criterion for an unanticipated problem and do not need to be reported under the HHS regulations 45 CFR part 46.103(a) and 46.103(b)(5) (see examples (5) and (6) in Appendix C ).

C. Assessing whether an adverse event suggests that the research places subjects or others at a greater risk of harm than was previously known or recognized

The first step in assessing whether an adverse event meets the third criterion for an unanticipated problem is to determine whether the adverse event is serious .

In this guidance document, OHRP defines serious adverse event as any adverse event that:

• results in death;
• is life-threatening (places the subject at immediate risk of death from the event as it occurred);
• results in inpatient hospitalization or prolongation of existing hospitalization;
• results in a persistent or significant disability/incapacity;
• results in a congenital anomaly/birth defect; or
• 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).)

OHRP considers adverse events that are unexpected, related or possibly related to participation in research, and serious to be the most important subset of adverse events representing unanticipated problems because such events always suggest that the research places subjects or others at a greater risk of physical or psychological harm than was previously known or recognized and routinely warrant consideration of substantive changes in the research protocol or informed consent process/document or other corrective actions in order to protect the safety, welfare, or rights of subjects (see examples (1)-(4) in section Appendix D ). 

Furthermore, OHRP notes that IRBs have authority to suspend or terminate approval of research that, among other things, has been associated with unexpected serious harm to subjects (45 CFR 46.113).  In order for IRBs to exercise this important authority in a timely manner, they must be informed promptly of those adverse events that are unexpected, related or possibly related to participation in the research, and serious (45 CFR 46.103(b)(5)). 

However, other adverse events that are unexpected and related or possibly related to participation in the research, but not serious, would also be unanticipated problems if they suggest that the research places subjects or others at a greater risk of physical or psychological harm than was previously known or recognized.  Again, such events routinely warrant consideration of substantive changes in the research protocol or informed consent process/document or other corrective actions in order to protect the safety, welfare, or rights of subjects or others (see examples (5) and (6) in Appendix D ). 

The flow chart below provides an algorithm for determining whether an adverse event represents an unanticipated problem that needs to be reported under HHS regulations at 45 CFR part 46.

IV. What are other important considerations regarding the reviewing and reporting of  unanticipated problems and adverse events?

A. Reporting of internal adverse events by investigators to IRBs

For an internal adverse event , a local investigator typically becomes aware of the event directly from the subject, another collaborating local investigator, or the subject’s healthcare provider. 

Upon becoming aware of an internal adverse event, the investigator should assess whether the adverse event represents an unanticipated problem following the guidelines described in section III above .  If the investigator determines that the adverse event represents an unanticipated problem, the investigator must report it promptly to the IRB (45 CFR 46.103(b)(5)).

Regardless of whether the internal adverse event is determined to be an unanticipated problem, the investigator also must ensure that the adverse event is reported to a monitoring entity (e.g., the research sponsor, a coordinating or statistical center, an independent medical monitor, or a DSMB/DMC) if required under the monitoring provisions described in the IRB-approved protocol or by institutional policy . 

If the investigator determines that an adverse event is not an unanticipated problem, but the monitoring entity subsequently determines that the adverse event does in fact represent an unanticipated problem (for example, due to an unexpectedly higher frequency of the event), the monitoring entity should report this determination to the investigator, and such reports must be promptly submitted by the investigator to the IRB (45 CFR 46.103(b)(5)).

B. Reporting of external adverse events by investigators to IRBs

Investigators and IRBs at many institutions routinely receive a large volume of reports of external adverse events experienced by subjects enrolled in multicenter clinical trials.  These external adverse event reports frequently represent the majority of adverse event reports submitted by investigators to IRBs.  OHRP notes that reports of individual external adverse events often lack sufficient information to allow investigators or IRBs at each institution engaged in a multicenter clinical trial to make meaningful judgments about whether the adverse events are unexpected, are related or possibly related to participation in the research, or suggest that the research places subjects or others at a greater risk of physical or psychological harm than was previously known or recognized. 

OHRP advises that it is neither useful nor necessary under the HHS regulations at 45 CFR part 46 for reports of individual adverse events occurring in subjects enrolled in multicenter studies to be distributed routinely to investigators or IRBs at all institutions conducting the research.  Individual adverse events should only be reported to investigators and IRBs at all institutions when a determination has been made that the events meet the criteria for an unanticipated problem.  In general, the investigators and IRBs at all these institutions are not appropriately situated to assess the significance of individual external adverse events.  Ideally, adverse events occurring in subjects enrolled in a multicenter study should be submitted for review and analysis to a monitoring entity (e.g., the research sponsor, a coordinating or statistical center, or a DSMB/DMC) in accordance with a monitoring plan described in the IRB-approved protocol. 

Only when a particular adverse event or series of adverse events is determined to meet the criteria for an unanticipated problem should a report of the adverse event(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.  OHRP recommends that any distributed reports include:  (1) a clear explanation of why the adverse event or series of adverse events has been determined to be an unanticipated problem; and (2) a description of any proposed protocol changes or other corrective actions to be taken by the investigators in response to the unanticipated problem.     

When an investigator receives a report of an external adverse event, the investigator should review the report and assess whether it identifies the adverse event as being:

• unexpected;
• related or possibly related to participation in the research; and
• serious or otherwise one that suggests that the research places subjects or others at a greater risk of physical or psychological harm than was previously known or recognized. 

Only external adverse events that are identified in the report as meeting all three criteria must be reported promptly by the investigator to the IRB as unanticipated problems under HHS regulations at 45 CFR 46.103(b)(5).  OHRP expects that individual external adverse events rarely will meet these criteria for an unanticipated problem.   

C. Reporting of other unanticipated problems (not related to adverse events) by investigators to IRBs

Upon becoming aware of any other incident, experience, or outcome (not related to an adverse event; see Appendix B for examples) that may represent an unanticipated problem, the investigator should assess whether the incident, experience, or outcome represents an unanticipated problem by applying the criteria described in section I .  If the investigator determines that the incident, experience, or outcome represents an unanticipated problem, the investigator must report it promptly to the IRB (45 CFR 46.103(b)(5)). 

D. Content of reports of unanticipated problems submitted to IRBs

OHRP recommends that investigators include the following information when reporting an adverse event, or any other incident, experience, or outcome as an unanticipated problem to the IRB:

• appropriate identifying information for the research protocol, such as the title, investigator’s name, and the IRB project number;
• a detailed description of the adverse event, incident, experience, or outcome;
• an explanation of the basis for determining that the adverse event, incident, experience, or outcome represents an unanticipated problem; and

(4) a description of any changes to the protocol or other corrective actions that have been taken or are proposed in response to the unanticipated problem.

E. Changes to a multicenter research protocol that are proposed by an investigator at one institution in response to an unanticipated problem

For multicenter research protocols, if a local investigator at one institution engaged in the research independently proposes changes to the protocol or informed consent document in response to an unanticipated problem, the investigator should consult with the study sponsor or coordinating center regarding the proposed changes because changes at one site could have significant implications for the entire research study.

F. IRB review and further reporting of unanticipated problems

Once reported to the IRB, further review and reporting of any unanticipated problems must proceed in accordance with the institution’s written procedures for reporting unanticipated problems, as required by HHS regulations at 45 CRF 46.103(b)(5).  The HHS regulations at 45 CFR part 46 do not specify requirements for how such unanticipated problems are reviewed by the IRB.  Therefore, IRBs are free to implement a wide range of procedures for reviewing unanticipated problems, including review by the IRB chairperson or another IRB member, a subcommittee of the IRB, or the convened IRB, among others.  When reviewing a report of an unanticipated problem, the IRB should consider whether the affected research protocol still satisfies the requirements for IRB approval under HHS regulations at 45 CFR 46.111.  In particular, the IRB should consider whether risks to subjects are still minimized and reasonable in relation to the anticipated benefits, if any, to the subjects and the importance of the knowledge that may reasonably be expected to result.

When reviewing a particular incident, experience, or outcome reported as an unanticipated problem by the investigator, the IRB may determine that the incident, experience, or outcome does not meet all three criteria for an unanticipated problem.  In such cases, further reporting to appropriate institutional officials, the department or agency head (or designee), and OHRP would not be required under HHS regulations at 45 CFR 46.103(a) and 46.103(b)(5).

The IRB has authority, under HHS regulations at 45 CFR 46.109(a), to require, as a condition of continued approval by the IRB, submission of more detailed information by the investigator(s), the sponsor, the study coordinating center, or DSMB/DMC about any adverse event or unanticipated problem occurring in a research protocol.

Any proposed changes to a research study in response to an unanticipated problem must be reviewed and approved by the IRB before being implemented, except when necessary to eliminate apparent immediate hazards to subjects.  If the changes are more than minor, the changes must be reviewed and approved by the convened IRB (45 CFR 46.103(b)(4) and 46.110(a)).  OHRP recommends that for multicenter research protocols, if the IRB proposes changes to the protocol or informed consent documents/process in addition to those proposed by the study sponsor, coordinating center, or local investigator, the IRB should request in writing that the local investigator discuss the proposed modifications with the study sponsor or coordinating center and submit a response or necessary modifications for review by the IRB.

Institutions must have written procedures for reporting unanticipated problems to appropriate institutional officials (45 CFR 46.103(b)(5)).  The regulations do not specify who the appropriate institutional officials are.  Institutions may develop written procedures that specify different institutional officials as being appropriate for different types of unanticipated problems.  For example, an institution could develop written procedures designating the IRB chairperson and members as the only appropriate institutional officials to whom external adverse events that are unanticipated problems are to be reported, and designating the Vice President for Research as an additional appropriate institutional official to whom internal adverse events that are unanticipated problems are to be reported by the IRB chairperson. 

G. Reporting unanticipated problems to OHRP and supporting agency heads (or designees)

Unanticipated problems occurring in research covered by an OHRP-approved assurance also must be reported by the institution to the supporting HHS agency head (or designee) and OHRP (45 CFR 46.103(a)).  Typically, the IRB chairperson or administrator, or another appropriate institutional official identified under the institution’s written IRB procedures, is responsible for reporting unanticipated problems to the supporting HHS agency head (or designee) and OHRP.  For further information on reporting to OHRP, see the Guidance on Reporting Incidents to OHRP .

For multicenter research projects, only the institution at which the subject(s) experienced an adverse event determined to be an unanticipated problem (or the institution at which any other type of unanticipated problem occurred) must report the event to the supporting agency head (or designee) and OHRP (45 CFR 46.103(b)(5)).  Alternatively, the central monitoring entity may be designated to submit reports of unanticipated problems to the supporting agency head (or designee) and OHRP.

V. What is the appropriate time frame for reporting unanticipated problems to the IRB, appropriate institutional officials, the department or agency head (or designee), and OHRP?

The HHS regulations at 46.103(b)(5) require written procedures for ensuring prompt reporting of unanticipated problems to the IRB, appropriate institutional officials, any supporting department or agency head (or designee), and OHRP.  The purpose of prompt reporting is to ensure that appropriate steps are taken in a timely manner to protect other subjects from avoidable harm. 

The regulations do not define prompt .  The appropriate time frame for satisfying the requirement for prompt reporting will vary depending on the specific nature of the unanticipated problem, the nature of the research associated with the problem, and the entity to which reports are to be submitted.  For example, an unanticipated problem that resulted in a subject’s death or was potentially life-threatening generally should be reported to the IRB within a shorter time frame than other unanticipated problems that were not life-threatening.  Therefore, OHRP recommends the following guidelines in order to satisfy the requirement for prompt reporting:

• Unanticipated problems that are serious adverse events should be reported to the IRB within 1 week of the investigator becoming aware of the event.
• Any other unanticipated problem should be reported to the IRB within 2 weeks of the investigator becoming aware of the problem.
• All unanticipated problems should be reported to appropriate institutional officials (as required by an institution’s written reporting procedures), the supporting agency head (or designee), and OHRP within one month of the IRB’s receipt of the report of the problem from the investigator.

OHRP notes that, in some cases, the requirements for prompt reporting may be met by submitting a preliminary report to the IRB, appropriate institutional officials, the supporting HHS agency head (or designee), and OHRP, with a follow-up report submitted at a later date when more information is available.  Determining the appropriate time frame for reporting a particular unanticipated problem requires careful judgment by persons knowledgeable about human subject protections.  The primary consideration in making these judgments is the need to take timely action to prevent avoidable harms to other subjects.  

Before research is approved and the first subject enrolled, the investigator(s) and the IRB should give appropriate consideration to the spectrum of adverse events that might occur in subjects.  In particular, in order to make the determinations required for approval of research under HHS regulations at 45 CFR 46.111(a)(1), (2), and (6), the IRB needs to receive and review sufficient information regarding the risk profile of the proposed research study, including the type, probability, and expected level of severity of the adverse events that may be caused by the procedures involved in the research.  The investigator also should describe how the risks of the research will be minimized. 

In addition, depending upon the risks of the research and the likelihood that the research could involve risks to subjects that are unforeseeable, the IRB must ensure, if appropriate, that the research includes adequate provisions for monitoring the data collected to ensure the safety of subjects (45 CFR 46.111(a)(6)).  Such provisions typically would include monitoring, among other things, adverse events and unanticipated problems that may occur in subjects enrolled in the research.  The HHS regulations at 45 CFR part 46 do not require that the IRB conduct such monitoring, and OHRP believes that, in general, the IRB is not the appropriate entity to monitor research.

OHRP notes that adequate monitoring provisions for research, if deemed appropriate by the IRB, might include one or more of the following elements, among others:

• The type of data or events that are to be captured under the monitoring provisions.
• The entity responsible for monitoring the data collected, including data related to unanticipated problems and adverse events, and their respective roles (e.g., the investigators, the research sponsor, a coordinating or statistical center, an independent medical monitor, a DSMB/DMC, and/or some other entity).  (OHRP notes that the IRB has authority to observe or have a third party observe the research (45 CFR 46.109(e).)
• The time frames for reporting adverse events and unanticipated problems to the monitoring entity.
• The frequency of assessments of data or events captured by the monitoring provisions.
• Definition of specific triggers or stopping rules that will dictate when some action is required.
• As appropriate, procedures for communicating to the IRB(s), the study sponsor, the investigator(s), and other appropriate officials the outcome of the reviews by the monitoring entity.

The monitoring provisions should be tailored to the expected risks of the research; the type of subject population being studied; and the nature, size (in terms of projected subject enrollment and the number of institutions enrolling subjects), and complexity of the research protocol.

For example, for a multicenter clinical trial involving a high level of risk to subjects, frequent monitoring by a DSMB/DMC may be appropriate, whereas for research involving no more than minimal risk to subjects, it may be appropriate to not include any monitoring provisions.

For non-exempt research conducted or supported by HHS, the IRB must conduct continuing review of research at intervals appropriate to the degree of risk, but not less than once per year (45 CFR 46.109(e)).  At the time of continuing review, the IRB should ensure that the criteria for IRB approval under HHS regulations at 45 CFR 46.111 continue to be satisfied.  In particular, the IRB needs to determine whether any new information has emerged – either from the research itself or from other sources – that could alter the IRB’s previous determinations, particularly with respect to risk to subjects.  Information regarding any unanticipated problems that have occurred since the previous IRB review in most cases will be pertinent to the IRB’s determinations at the time of continuing review. 

It may also be appropriate for the IRB at the time of continuing review to confirm that any provisions under the previously approved protocol for monitoring study data to ensure safety of subjects have been implemented and are working as intended (e.g., the IRB could require that the investigator provide a report from the monitoring entity described in the IRB-approved protocol).   

OHRP recommends that, among other things, a summary of any unanticipated problems and available information regarding adverse events and any recent literature that may be relevant to the research be included in continuing review reports submitted to the IRB by investigators.  OHRP notes that the amount of detail provided in such a summary will vary depending on the type of research being conducted.  In many cases, such a summary could be a simple brief statement that there have been no unanticipated problems and that adverse events have occurred at the expected frequency and level of severity as documented in the research protocol, the informed consent document, and any investigator brochure.

OHRP recognizes that local investigators participating in multicenter clinical trials usually are unable to prepare a meaningful summary of adverse events for their IRBs because study-wide information regarding adverse events is not readily available to them.  In such circumstances, when the clinical trial is subject to oversight by a monitoring entity (e.g., the research sponsor, a coordinating or statistical center, or a DSMB/DMC), OHRP recommends that at the time of continuing review local investigators submit to their IRBs a current report from the monitoring entity.  OHRP further recommends that such reports include the following:

• a statement indicating what information (e.g., study-wide adverse events, interim findings, and any recent literature that may be relevant to the research) was reviewed by the monitoring entity;
• the date of the review; and
• the monitoring entity’s assessment of the information reviewed. 

For additional details about OHRP’s guidance on continuing review, see Guidance on Continuing Review - January 2007 .

Written IRB procedures should provide a step-by-step description with key operational details for complying with the reporting requirements described in HHS regulations at 45 CFR 46.103(b)(5).  Important operational details for the required reporting procedures should include:

• The type of information that is to be included in reports of unanticipated problems.
• A description of which office(s) or individual(s) is responsible for promptly reporting unanticipated problems to the IRB, appropriate institutional officials, any supporting department or agency heads (or designees), and OHRP.
• A description of the required time frame for accomplishing the reporting requirements for unanticipated problems.
• The range of the IRB’s possible actions in response to reports of unanticipated problems.

OHRP notes that many institutions have written IRB procedures for reporting adverse events, but do not address specifically the reporting requirements for unanticipated problems.  Such institutions should expand their written IRB procedures to include reporting requirements for unanticipated problems.

Glossary for Key Terms

Adverse event :  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).

External adverse event :  From the perspective of one particular institution engaged in a multicenter clinical trial, external adverse events are those adverse events experienced by subjects enrolled by investigators at other institutions engaged in the clinical trial. 

Internal adverse event :  From the perspective of one particular institution engaged in a multicenter clinical trial, internal adverse events are those adverse events experienced by subjects enrolled by the investigator(s) at that institution.  In the context of a single-center clinical trial, all adverse events would be considered internal adverse events.    

Possibly related to the research :  There is a reasonable possibility that the adverse event, incident, experience or outcome may have been caused by the procedures involved in the research (modified from the definition of associated with use of the drug in FDA regulations at 21 CFR 312.32(a)).

Serious adverse event :  Any adverse event temporally associated with the subject’s participation in research that meets any of the following criteria:

• requires inpatient hospitalization or prolongation of existing hospitalization;
• 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).

Unanticipated problem involving risks to subjects or others :  Any incident, experience, or outcome that meets all of the following criteria:

• related or possibly related to a subject’s participation in the research; and
• suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) related to the research than was previously known or recognized.

Unexpected adverse event :  Any adverse event occurring in one or more subjects in a research protocol, the nature, severity, or frequency of which is not consistent with either:

• the known or foreseeable risk of adverse events associated with the procedures involved in the research that are described in (a) the protocol–related documents, such as the IRB-approved research protocol, any applicable investigator brochure, and the current IRB-approved informed consent document, and (b) other relevant sources of information, such as product labeling and package inserts; or

Examples of Unanticipated Problems that Do Not Involve Adverse Events and Need to be Reported Under the HHS Regulations at 45 CFR Part 46

• An investigator conducting behavioral research collects individually identifiable sensitive information about illicit drug use and other illegal behaviors by surveying college students.  The data are stored on a laptop computer without encryption, and the laptop computer is stolen from the investigator’s car on the way home from work.  This is an unanticipated problem that must be reported because the incident was (a) unexpected (i.e., the investigators did not anticipate the theft); (b) related to participation in the research; and (c) placed the subjects at a greater risk of psychological and social harm from the breach in confidentiality of the study data than was previously known or recognized. 
• As a result of a processing error by a pharmacy technician, a subject enrolled in a multicenter clinical trial receives a dose of an experimental agent that is 10-times higher than the dose dictated by the IRB-approved protocol.  While the dosing error increased the risk of toxic manifestations of the experimental agent, the subject experienced no detectable harm or adverse effect after an appropriate period of careful observation.  Nevertheless, this constitutes an unanticipated problem for the institution where the dosing error occurred that must be reported to the IRB, appropriate institutional officials, and OHRP because the incident was (a) unexpected; (b) related to participation in the research; and (c) placed subject at a greater risk of physical harm than was previously known or recognized.
• Subjects with cancer are enrolled in a phase 2 clinical trial evaluating an investigational biologic product derived from human sera.  After several subjects are enrolled and receive the investigational product, a study audit reveals that the investigational product administered to subjects was obtained from donors who were not appropriately screened and tested for several potential viral contaminants, including the human immunodeficiency virus and the hepatitis B virus.  This constitutes an unanticipated problem that must be reported because the incident was (a) unexpected; (b) related to participation in the research; and (c) placed subjects and others at a greater risk of physical harm than was previously known or recognized.

The events described in the above examples were unexpected in nature, related to participation in the research, and resulted in new circumstances that increased the risk of harm to subjects.  In all of these examples, the unanticipated problems warranted consideration of substantive changes in the research protocol or informed consent process/document or other corrective actions in order to protect the safety, welfare, or rights of subjects.  In addition, the third example may have presented unanticipated risks to others (e.g., the sexual partners of the subjects) in addition to the subjects.  In each of these examples, while these events may not have caused any detectable harm or adverse effect to subjects or others, they nevertheless represent unanticipated problems and should be promptly reported to the IRB, appropriate institutional officials, the supporting agency head and OHRP in accordance with HHS regulations at 45 CFR 46.103(a) and 46.103(b)(5).

Examples of Adverse Events that Do Not Represent Unanticipated Problems and Do Not Need to be Reported under the HHS Regulations at 45 CFR Part 46

• A subject participating in a phase 3, randomized, double-blind, controlled clinical trial comparing the relative safety and efficacy of a new chemotherapy agent combined with the current standard chemotherapy regimen, versus placebo combined with the current standard chemotherapy regimen, for the management of multiple myeloma develops neutropenia and sepsis.  The subject subsequently develops multi-organ failure and dies.  Prolonged bone marrow suppression resulting in neutropenia and risk of life-threatening infections is a known complication of the chemotherapy regimens being tested in this clinical trial and these risks are described in the IRB-approved protocol and informed consent document.  The investigators conclude that the subject’s infection and death are directly related to the research interventions.  A review of data on all subjects enrolled so far reveals that the incidence of severe neutropenia, infection, and death are within the expected frequency.  This example is not an unanticipated problem because the occurrence of severe infections and death – in terms of nature, severity, and frequency – was expected. 
• A subject enrolled in a phase 3, randomized, double-blind, placebo-controlled clinical trial evaluating the safety and efficacy of a new investigational anti-inflammatory agent for management of osteoarthritis develops severe abdominal pain and nausea one month after randomization.  Subsequent medical evaluation reveals gastric ulcers.  The IRB-approved protocol and informed consent document for the study indicated that the there was a 10% chance of developing mild to moderate gastritis and a 2% chance of developing gastric ulcers for subjects assigned to the active investigational agent.  The investigator concludes that the subject’s gastric ulcers resulted from the research intervention and withdraws the subject from the study.  A review of data on all subjects enrolled so far reveals that the incidence of gastritis and gastric ulcer are within the expected frequency.  This example is not an unanticipated problem because the occurrence of gastric ulcers – in terms of nature, severity, and frequency – was expected.  
• A subject is enrolled in a phase 3, randomized clinical trial evaluating the relative safety and efficacy of vascular stent placement versus carotid endarterectomy for the treatment of patients with severe carotid artery stenosis and recent transient ischemic attacks.  The patient is assigned to the stent placement study group and undergoes stent placement in the right carotid artery.  Immediately following the procedure, the patient suffers a severe ischemic stroke resulting in complete left-sided paralysis.  The IRB-approved protocol and informed consent document for the study indicated that there was a 5-10% chance of stroke for both study groups.  To date, 25 subjects have been enrolled in the clinical trial, and 2 have suffered a stroke shortly after undergoing the study intervention, including the current subject.  The DSMB responsible for monitoring the study concludes that the subject’s stroke resulted from the research intervention.  This example is not an unanticipated problem because the occurrence of stroke was expected and the frequency at which strokes were occurring in subjects enrolled so far was at the expected level. 
• An investigator is conducting a psychology study evaluating the factors that affect reaction times in response to auditory stimuli.  In order to perform the reaction time measurements, subjects are placed in a small, windowless soundproof booth and asked to wear headphones.  The IRB-approved protocol and informed consent document describe claustrophobic reactions as one of the risks of the research.  The twentieth subject enrolled in the research experiences significant claustrophobia, resulting in the subject withdrawing from the research.  This example is not an unanticipated problem because the occurrence of the claustrophobic reactions – in terms of nature, severity, and frequency – was expected.  
• A subject with advanced renal cell carcinoma is enrolled in a study evaluating the effects of hypnosis for the management of chronic pain in cancer patients.  During the subject’s initial hypnosis session in the pain clinic, the subject suddenly develops acute chest pain and shortness of breath, followed by loss of consciousness.  The subject suffers a cardiac arrest and dies.  An autopsy reveals that the patient died from a massive pulmonary embolus, presumed related to the underlying renal cell carcinoma.  The investigator concludes that the subject’s death is unrelated to participation in the research.  This example is not an unanticipated problem because the subject’s pulmonary embolus and death were attributed to causes other than the research interventions.
• An investigator performs prospective medical chart reviews to collect medical data on premature infants in a neonatal intensive care unit (NICU) for a research registry.  An infant, about whom the investigator is collecting medical data for the registry, dies as the result of an infection that commonly occurs in the NICU setting.  This example is not an unanticipated problem because the death of the subject is not related to participation in the research, but is most likely related to the infant’s underlying medical condition.

NOTE:  For purposes of illustration, the case examples provided above represent generally unambiguous examples of adverse events that are not unanticipated problems.  OHRP recognizes that it may be difficult to determine whether a particular adverse event is unexpected and whether it is related or possibly related to participation in the research.  In addition, the assessment of the relationship between the expected and actual frequency of a particular adverse event must take into account a number of factors including the uncertainty of the expected frequency estimates, the number and type of individuals enrolled in the study, and the number of subjects who have experienced the adverse event. 

Examples of Adverse Events that Represent Unanticipated Problems and Need to be Reported Under the HHS Regulations at 45 CFR Part 46

• A subject with chronic gastroesophageal reflux disease enrolls in a randomized, placebo- controlled, double-blind, phase 3 clinical trial evaluating a new investigational agent that blocks acid release in the stomach.  Two weeks after being randomized and started on the study intervention the subject develops acute kidney failure as evidenced by an increase in serum creatinine from 1.0 mg/dl pre-randomization to 5.0 mg/dl.  The known risk profile of the investigational agent does not include renal toxicity, and the IRB-approved protocol and informed consent document for the study does not identify kidney damage as a risk of the research.  Evaluation of the subject reveals no other obvious cause for acute renal failure.  The investigator concludes that the episode of acute renal failure probably was due to the investigational agent.  This is an example of an unanticipated problem that must be reported because the subject’s acute renal failure was (a) unexpected in nature, (b) related to participation in the research, and (c) serious.   
• A subject with seizures enrolls in a randomized, phase 3 clinical trial comparing a new investigational anti-seizure agent to a standard, FDA-approved anti-seizure medication.  The subject is randomized to the group receiving the investigational agent. One month after enrollment, the subject is hospitalized with severe fatigue and on further evaluation is noted to have severe anemia (hematocrit decreased from 45% pre-randomization to 20%).  Further hematologic evaluation suggests an immune-mediated hemolytic anemia.  The known risk profile of the investigational agent does not include anemia, and the IRB-approved protocol and informed consent document for the study do not identify anemia as a risk of the research.  The investigators determine that the hemolytic anemia is possibly due to the investigational agent.  This is an example of an unanticipated problem that must be reported because the hematologic toxicity was (a) unexpected in nature; (b) possibly related to participation in the research; and (c) serious. 
• The fifth subject enrolled in a phase 2, open-label, uncontrolled clinical study evaluating the safety and efficacy of a new oral agent administered daily for treatment of severe psoriasis unresponsive to FDA-approved treatments, develops severe hepatic failure complicated by encephalopathy one month after starting the oral agent.  The known risk profile of the new oral agent prior to this event included mild elevation of serum liver enzymes in 10% of subjects receiving the agent during previous clinical studies, but there was no other history of subjects developing clinically significant liver disease.  The IRB-approved protocol and informed consent document for the study identifies mild liver injury as a risk of the research.  The investigators identify no other etiology for the liver failure in this subject and attribute it to the study agent.  This is an example of an unanticipated problem that must be reported because although the risk of mild liver injury was foreseen, severe liver injury resulting in hepatic failure was (a) unexpected in severity; (b) possibly related to participation in the research; and (c) serious.     
• Subjects with coronary artery disease presenting with unstable angina are enrolled in a multicenter clinical trial evaluating the safety and efficacy of an investigational vascular stent.  Based on prior studies in animals and humans, the investigators anticipate that up to 5% of subjects receiving the investigational stent will require emergency coronary artery bypass graft (CABG) surgery because of acute blockage of the stent that is unresponsive to non-surgical interventions.  The risk of needing emergency CABG surgery is described in the IRB-approved protocol and informed consent document.  After the first 20 subjects are enrolled in the study, a DSMB conducts an interim analysis, as required by the IRB-approved protocol, and notes that 10 subjects have needed to undergo emergency CABG surgery soon after placement of the investigational stent.  The DSMB monitoring the clinical trial concludes that the rate at which subjects have needed to undergo CABG greatly exceeds the expected rate and communicates this information to the investigators.  This is an example of an unanticipated problem that must be reported because (a) the frequency at which subjects have needed to undergo emergency CABG surgery was significantly higher than the expected frequency; (b) these events were related to participation in the research; and (c) these events were serious.
• Subjects with essential hypertension are enrolled in a phase 2, non-randomized clinical trial testing a new investigational antihypertensive drug.  At the time the clinical trial is initiated, there is no documented evidence of gastroesophageal reflux disease (GERD) associated with the investigational drug, and the IRB-approved protocol and informed consent document do not describe GERD as a risk of the research.  Three of the first ten subjects are noted by the investigator to have severe GERD symptoms that began within one week of starting the investigational drug and resolved a few days after the drug was discontinued.  The investigator determines that the GERD symptoms were most likely caused by the investigational drug and warrant modification of the informed consent document to include a description of GERD as a risk of the research.  This is an example of an adverse event that, although not serious, represents an unanticipated problem that must be reported because it was (a) unexpected in nature; (b) possibly related to participation in the research; and (c) suggested that the research placed subjects at a greater risk of physical harm than was previously known or recognized.
• A behavioral researcher conducts a study in college students that involves completion of a detailed survey asking questions about early childhood experiences.  The research was judged to involve no more than minimal risk and was approved by the IRB chairperson under an expedited review procedure.  During the completion of the survey, one student subject has a transient psychological reaction manifested by intense sadness and depressed mood that resolved without intervention after a few hours.  The protocol and informed consent document for the research did not describe any risk of such negative psychological reactions.  Upon further evaluation, the investigator determines that the subject’s negative psychological reaction resulted from certain survey questions that triggered repressed memories of physical abuse as a child.  The investigator had not expected that such reactions would be triggered by the survey questions.  This is an example of an unanticipated problem that must be reported in the context of social and behavioral research because, although not serious, the adverse event was (a) unexpected; (b) related to participation in the research; and (c) suggested that the research places subjects at a greater risk of psychological harm than was previously known or recognized. 

In all of these examples, the adverse events warranted consideration of substantive changes in the research protocol or informed consent process/document or other corrective actions in order to protect the safety, welfare, or rights of subjects. 

NOTE:  For purposes of illustration, the case examples provided above represent generally unambiguous examples of adverse events that are unanticipated problems.  OHRP recognizes that it may be difficult to determine whether a particular adverse event is unexpected and whether it is related or possibly related to participation in the research.

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Unanticipated Problems

An Unanticipated problem is any event, experience, issue, instance, problem or outcome that meets all 3 of the following criteria:

• Is unexpected in terms of the nature, severity or frequency given the research procedures that are described in the protocol –related documents AND in the characteristics of the population under study.
• Is related or possibly related to participation in research.  This means that there is a reasonable possibility that the incident may have been caused by the procedures involved in the research study.
• The incident suggests that the research places the subject or others at greater risk of harm (physical, psychological, economic or social) than was previously known or recognized OR results in actual harm of the subject or others.  An unanticipated problem generally required a change in policy or procedure , warrants consideration of substantive changes to the protocol/consent or other immediate corrective actions in order to reduce the risk or eliminate immediate hazard.

Unanticipated Problems that meet the definition of an Serious Adverse Events

A small number of Adverse Events are considered Unanticipated Problems. If an Adverse Event meets ALL 3 the criteria listed above, then the event is considered an Adverse event AND an Unanticipated Problem: Those events that meet the definition of both adverse event and unanticipated problem are reported to the IRB-HSR through the Adverse Event reporting system as previously described using IRB Online .

For additional information on Serious Adverse Events: https://research.virginia.edu/irb-hsr/serious-adverse-events

Unanticipated Problems that meet the definition of Protocol Violation or Other Noncompliance Issue

A small number of Protocol Violations are considered Unanticipated Problems ONLY if they meet all 3 of the criteria listed above. Events that meet the definition of both protocol violation and unanticipated problem are reported to the IRB-HSR using the Protocol Violation/Noncompliance /Enrollment Exception Form.

For additional information on Protocol Violations and other Noncompliance Issues: https://research.virginia.edu/irb-hsr/managing-protocol-after-initial-approval  

Look under Protocol Violation/Noncompliance/Enrollment Exceptions section

Unanticipated Problems that meet the definition of Data Breach

A data breach may result from a violation of the Privacy Plan in the protocol (in which case it would be reported as a Protocol Violation.  However there may also be a data breach that does NOT result from a Protocol Violation and meets the criteria for an Unanticipated Problem.  If the Data Breach (not resulting from a Protocol Violation) meets all 3 of the following criteria below it would be reported using the Unanticipated Problem Reporting Form:

• The incident suggests that the research places the subject or others at greater risk of harm (physical, psychological, economic or social) than was previously known or recognized OR results in actual harm of the subject or others.  An unanticipated problem generally required a change in policy or procedure , warrants consideration of substantive changes to the protocol/consent or other immediate corrective actions in order to reduce the risk or eliminate immediate hazard.If the Data Breach meets the criteria of an Unanticipated Problem, the researcher must follow the IRB-HSR requirements for reporting an Unanticipated Problem

For more information on Data Breach:  https://research.virginia.edu/irb-hsr/data-breach

Reporting Timeline Requirement for Unanticipated Problems  

If an Unanticipated Problem should occur during the conduct of any study under the jurisdiction of the IRB-HSR, the PI should notify the IRB-HSR within 7 days from the time the PI/Study team receive knowledge of the event.

How to submit an Unanticipated Problem to the IRB

Events that meet the definitions of a Serious Adverse Event and unanticipated problem are reported to the IRB-HSR through the Adverse Event reporting system as previously described using IRB Online .

Events that meet the definition of both protocol violation/noncompliance and unanticipated problem are reported to the IRB-HSR using the Protocol Violation/Noncompliance/Enrollment Exception Form.

Look under Protocol Violation/Noncompliance/Enrollment Exceptions

Unanticipated problems that that are not the result of an adverse event or protocol violation must be submitted to the IRB-HSR within 7 calendar days from the time the study team receives knowledge of problem using the Unanticipated Problem Report.

Documentation of IRB’s Receipt of Unanticipated Problem

The IRB will provide a copy of the Unanticipated Problem Form OR the Protocol Violation/Noncompliance/Enrollment Form to document IRB receipt.  Documents should be placed in the regulatory files. 

If the Unanticipated Problem is an AE, then it will be reported using IRB Online and automatic emails will be returned to the study team to document receipt.  The emails should be placed in the regulatory files.

IRB Review of the Unanticipated Problem

All reports of Unanticipated Problems are reviewed by the full board.  Once the board’s review is complete the study team will receive an assurance form for the Full Board Determination: 

Any actions required by the board will be listed on the assurance form.  The study team must complete any actions required by the board and file the Assurance Form in the regulatory files.

Mandatory IRB reporting of Unanticipated Problems

Per federal regulations the IRB must report Unanticipated Problem to OHRP and the FDA (if applicable). If the Unanticipated Problem meets the definition of an Adverse Event, the sponsor is responsible for making the report to FDA.  Per IRB policy these reports are copied to institutional officials involved in research oversight.  The PI, study coordinator and IRB Coordinator will receive a copy of the letter

The study team is responsible for reporting Unanticipated Problems to their sponsor.

Version Date:  6-2-20

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GUIDANCE DOCUMENT

Adverse Event Reporting to IRBs — Improving Human Subject Protection Guidance for Clinical Investigators, Sponsors, and IRBs January 2009

This guidance is intended to assist the research community in interpreting requirements for submitting reports of unanticipated problems, including certain adverse events reports, to the institutional review board (IRB) under Title 21 of the Code of Federal Regulations (21 CFR) part 56 (Institutional Review Boards), part 312 (Investigational New Drug Application), and part 812 (Investigational Device Exemptions). Specifically, the guidance provides recommendations for sponsors and investigators conducting investigational new drug (IND) trials to help them differentiate between those adverse events that are unanticipated problems that must be reported to an IRB and those that are not. The guidance also makes suggestions about how to make communicating adverse events information to IRBs more efficient.

Submit Comments

You can submit online or written comments on any guidance at any time (see 21 CFR 10.115(g)(5))

If unable to submit comments online, please mail written comments to:

Dockets Management Food and Drug Administration 5630 Fishers Lane, Rm 1061 Rockville, MD 20852

All written comments should be identified with this document's docket number: FDA-2007-D-0202 .

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• National Institutes of Health

Guidance to NCCIH Investigators on Reporting Serious Adverse Events and/or Unanticipated Problems in NCCIH-Funded Clinical Studies

Revised november 8, 2023.

During the course of study conduct, serious adverse events* (SAEs) and/or unanticipated problems** (UPs) may occur and should be recorded and reported to NCCIH, the Institutional Review Board (IRB) of record, and the Independent Monitoring entity according to the timelines outlined in the NCCIH-approved Data and Safety Monitoring Plan (DSMP). 

NCCIH program directors will collect appropriate documentation and resolve outstanding queries when notified of an SAE and/or UP within an NCCIH-funded study. 

The following checklist outlines the submission of required information when notifying NCCIH.

CHECKLIST: (Required Submission to the NCCIH Program Director)

• SAE Report (formal report, not an email narrative) sent to IRB of record. If the study did not record the SAE on an institutional SAE Report Form, a sample SAE form can be found in the  NCCIH Clinical Research Toolbox . The submitted SAE form should contain a written narrative of the SAE, including a timeline of event occurrence and follow-up actions taken. 
• Confirmation that the SAE reporting occurred according to the timelines outlined in the NCCIH-approved DSMP. Provide the date when the IRB of record was notified of the event. If the reporting deviated from the NCCIH-approved DSMP, include a written explanation.
• Correspondence from the IRB regarding SAE next steps/actions (for Related or Possibly Related SAEs).
• Correspondence from either the Medical Monitor, the Independent Monitoring Committee, or the Data and Safety Monitoring Board (as described in the approved DSMP) regarding SAE next steps/actions (for Related or Possibly Related SAEs).
• If the SAE is also a UP, please include any correspondence between the institution/IRB and documentation from the local IRB reporting the UP to the  HHS Office of Human Research Protection (OHRP) .
• If formal changes to the NCCIH-approved study documents are also being requested, please submit a copy of the track-changed study documents. If it is a Routine Oversight Study, NCCIH may request the study protocol and the informed consent document. 

NCCIH will review the document submission and request additional information as warranted.  

*A serious adverse event (SAE) is one that meets one or more of the following criteria:

• Results in death
• Is life-threatening (places the subject at immediate risk of death from the event as it occurred)
• Results in inpatient hospitalization or prolongs existing hospitalization
• Results in a persistent or significant disability or incapacity
• Results in a congenital anomaly or birth defect

An important medical event that may not result in death, be life threatening, or require hospitalization may be considered an SAE when, based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

**An unanticipated problem is one that meets the following criteria: 

The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to subjects or others to include, in general, any incident, experience, or outcome that meets all of the following criteria:

• 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;
• Related or possibly related to participation in the research (“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
• 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.

Parameters for protecting the rights and welfare of participants in human subjects research studies.

Unanticipated Problems Involving Risks to Subjects or Others

For information about other types of required reporting, see the  Adverse Events (AEs), Other Reportable Information and Occurrences (ORIOs), and Other Required Reporting page.

Also see the University of Michigan Human Research Protection Program  Operations Manual, Part 12 .(PDF)

Please note that this guidance is for reporting to the IRB only and does not satisfy required reporting by an investigator to other internal or external oversight agencies or departments (e.g. the FDA , UMHS Compliance Office, DSMB , or Privacy Offices). 

It is a federal and university requirement that investigators of all human subjects research (whether FDA-regulated or not) report to the IRB any ‘unanticipated problems involving risks to the subjects or others' (hereafter referred to as ‘unanticipated problems'). The following guidance is intended to assist investigators in determining if an occurrence or other information constitutes an ‘unanticipated problem' in the regulatory sense. If you need further assistance evaluating whether or not an issue constitutes an unanticipated problem, please call or email the IRB Office.

The Three Criteria to Identify an Unanticipated Problem

OHRP considers unanticipated problems , in general, to include 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.

The Two Types of Unanticipated Problems

An unanticipated problem may be either one of two types:

• Type 1:  Potential harm
• Type 2  : Actual harm

A potential harm, a type 1 ‘unanticipated problem', is an issue that must be reported to the IRB whenever something comes to an investigator's attention regarding the research which indicates the  possibility  that previously unsuspected harm may occur (or may occur at a higher than expected rate) even though no one has yet experienced actual harm. It is an event, development, or information that potentially increases the likelihood of harm occurring in the future. For example, a concurrent study in animals might show that the new drug being used in a UM study causes cancer in a fashion that seems to be relevant to people. This indicates a previously unrecognized risk—that the research participants will have an increased cancer risk, even if none have actually developed cancer. This type of unanticipated problem is usually reported using the IRB form for  Other Reportable Information or Occurrences (ORIO). 

A type 2 ‘unanticipated problem‘ is a recognized harmful or unfavorable outcome that has actually occurred to a research subject, a set of subjects, another individual being treated in a similar fashion in a relevant non-research setting, or another person connected to the research study (e.g. one of the researchers or the spouse of a subject).

This type of unanticipated problem is an actual event(s), not a potential risk. These kinds of unanticipated problems are also  adverse events (AEs) . A series of AEs that signal the AEs were not just isolated occurrences and were significant to subjects' rights and welfare would be considered an unanticipated problem. An expected AE that occurs at a greater frequency or severity than expected would be an unanticipated problem. ‘Type 2' unanticipated problems should be reported to the IRB using the adverse event reporting form.

Because of their unanticipated and related nature, and because of the potential risks they suggest, these AEs require a special level of attention from investigators , IRBs , institutional officials, and others. ( Not all adverse events are ‘unanticipated problems' because most adverse events are ‘expected' as it is defined above. For details on how and when to report adverse events that are not unanticipated problems, refer to the IRB's adverse event reporting guidance. )

‘Seriousness' and Unanticipated Problems

An unanticipated problem -- because it is associated with potential risks -- is a problem that must be reported even if it is not felt to be serious. Adverse events that are unexpected and related, but  not  serious , would also be unanticipated problems if they suggest that the research places subjects or others at a greater risk of harm than had previously been known or recognized.

‘Others' and Unanticipated Problems

Although the primary mission of an IRB is to protect the rights and welfare of research subjects, federal regulations require investigators to report, and IRBs to evaluate, any unanticipated problem that may pose risks to people who are not the actual research subjects. The ‘others' are most often the researchers themselves or family members of the subjects, although they can be people not associated with the research in any way. If a research subject experienced an unexpected side effect like fainting, and fainted while driving a car, causing an accident in which a stranger was injured, this would be an unanticipated problem even if the subject was unharmed. If a laboratory reagent used in the research, but not actually administered to patients or research subjects, was found to be a potentially dangerous carcinogen, this would be an unanticipated problem posing a risk to others, namely the laboratory workers involved with the research or interacting with the research personnel in the same lab.

‘External' versus ‘UM' Unanticipated Problems

Investigators are required to report both internal and external unanticipated problems to the IRB .

A ‘UM' unanticipated problem is one that occurs on a study that is under the direct oversight of a UM investigator or a UM IRB. The participants are UM subjects. The terms ‘Internal' or ‘Local' are sometimes used in referring to a ‘UM' event. ‘UM' includes things that happen to UM subjects anywhere, even if not on University of Michigan property. For example, a problem with a subject enrolled by a UM student conducting a study in Uganda that was approved by a UM IRB is considered a ‘UM' event.

A problem that is not under the primary oversight of UM investigators or a UM IRB is referred to as an ‘External' unanticipated problem. These are events or information about which the UM investigator received a report or read a publication rather than an event the investigator handled. Other terms used include ‘Off-site' or ‘at other sites.'

When an investigator receives a report of an external unanticipated problem it should be submitted to the IRB.

External Adverse Event Reports and Unanticipated Problems

UM investigators participating in multi-site trials and those using sponsored agents routinely receive a large volume of reports of external adverse events . The HHS Office of Human Research Protections (OHRP) has released guidance urging sponsors that individual adverse events should only be reported to investigators at all institutions when a determination has been made by the sponsor that the events meet the criteria for an unanticipated problem .

OHRP recommends that any distributed reports include: (1) a clear explanation of why the adverse event or series of adverse events has been determined to be an unanticipated problem; and (2) a description of any proposed protocol changes or other corrective actions to be taken by the investigators in response to the unanticipated problem.

Nonetheless, investigators may continue to receive reports that have not been assessed by the sponsor. When a UM investigator receives a report of an adverse event that is unexpected and related to an agent or procedure used in the UM study, the UM investigator should review the report and assess whether it meets the criteria above for an unanticipated problem. If it does, then it should be reported to the IRB. Note that many reports labeled ‘unexpected' will not meet the criteria above. It is possible for an external adverse event report from a different study, or use of the agent or procedure in a different population or route of administration to constitute an unanticipated problem for a UM study. The UM investigator should assess whether or not the information in the report indicates a problem that affects the rights and welfare of UM subjects. If in the judgment of the UM investigator it does, then the report should be submitted.

If the report does not contain sufficient information for the UM investigator to make the needed assessment AND the source of the report (e.g. the sponsor) did not state the event is an “unanticipated problem” or an “unanticipated adverse device effect”, then a submission to the IRB is not required. Both FDA and the HHS Office of Human Research Protections have stated their expectation that an individual external adverse event will rarely meet these criteria for an unanticipated problem.

Additional Information for Investigational Device Studies

In addition to the general information above, studies involving FDA -regulated devices are required to follow the regulations at 21 CFR 812.

• The investigator must inform the sponsor of any  unanticipated adverse device effect  (UADE) during an study within 10 days.
• A ‘UADE' is defined as any serious adverse effect on the health or safety of subjects, or any life-threatening problem or death caused by, or associated with, a device, if that problem or death was not previously identified in nature, severity or degree of incidence in the investigational plan.
• A sponsor (the holder of the investigational device exemption (IDE) ) must immediately conduct an evaluation of a UADE and report to all investigators within 10 days.
• Investigators must send these reports to IRBs .

Examples of Unanticipated Problems

When and how to report unanticipated problems and unanticipated adverse device effects (uades) to the irb.

Serious unanticipated problems and UADEs must be reported within 7 calendar days of the problem (or within 7 calendar days of the study team becoming aware of the problem). Non-serious unanticipated problems must be reported within 14 calendar days of the problem (or within 14 calendar days of the study team becoming aware of the problem).

If the unanticipated problem involved one or more persons experiencing actual harm , report the unanticipated problem as an adverse event. Refer to the  AE Reporting page and follow the instructions provided, using the external or internal form as appropriate.

If a person did not experience actual harm but an unanticipated problem entailed  potential harm, and/or risk of harm to subjects or others, refer to the  ORIO Reporting  page and follow the instructions provided.

If the IRB concurs that an event is an unanticipated problem the IRB will follow the policies and procedures outlined in the University of Michigan Human Research Protection Plan  Operations Manual, part 12 . (PDF)

• HHS Office of Human Research Protections (OHRP) —regulations require IRBs “have written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the department or agency head of (i) any unanticipated problems involving risks to subjects or others , or any serious or continuing non-compliance with this policy or the requirements or determinations of the IRB and (ii) any suspension or termination of IRB approval.” 45 CFR 46 .103(b)(5)
• HHS Food and Drug Administration—regulations require “written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the Food and Drug Administration of: (1) Any unanticipated problems involving risks to human subjects or others ; (2) any instance of serious or continuing non-compliance with these regulations or the requirements or de terminations of the IRB; or (3) any suspension or termination of IRB approval.” 21 CFR 56.108 (b)
• OHRP–  Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events
• FDA —  Draft Guidance for Clinical Investigators, Sponsors, and IRBs Adverse Event Reporting—Improving Human Subject Protection . (PDF)

Posted 9/28/2007, updated 4/16/2015

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Edited By: [email protected] Last Updated: May 30, 2018 at 1:00 PM

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Research integrity & assurance, research integrity & assurance office of research, innovation & economic development, unanticipated problems and adverse events.

What is an unanticipated problem?

Unanticipated problems involving risks to subjects or others (UAPs) refer to any incident, experience, outcome, or new information that:

• Is unexpected;  and
• Is at least possibly related to participation in the research;  and
• Indicates that subjects or others are at a greater risk of harm (including physical, psychological, economic, legal or social harm) than was previously known or recognized.

Any unanticipated problems must be reported to the HRPP according to the guidance in the When and how to I report? section of this page.

UAPs also encompass Unanticipated Adverse Device Effects, as defined below.

Definitions

Unanticipated Adverse Device Effect

What is an adverse event.

An adverse event (AE) is   any untoward or unfavorable 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. 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.

Some adverse events are also considered unanticipated problems and some are not. Adverse events that are also unanticipated problems must be reported to the HRPP.

For additional guidance on unanticipated problems, adverse events, and when to report them, visit this page from the Office of Human Research Protections or Contact us.

When and how do I report? 

Investigators must report the following events or issues to the HRPP as soon as possible but within  7 working days  after the investigator first learns of the event using the “Reportable New Information” form in iMedRIS. Failure to report the following events or issues within 7 working days will be considered noncompliance. If investigators are uncertain but believe that the event might represent an UAP, a report should be submitted.

Examples of UAPs include, but are not limited to:

• Actions taken without prior IRB review and approval to eliminate an apparent immediate hazard to a research subject(s);
• Sponsor or lead investigator/coordinating center-imposed suspension or termination of some or all research activities;
• An unanticipated event related to the research that exposes subjects to potential risk but that does not involve direct harm to subjects;
• A breach of confidentiality or loss of research data (e.g., a laptop or thumb drive is lost or stolen);
• Incarceration of a research subject;
• A subject complaint;
• An unanticipated event related to the research that results in actual harm or exposes individuals other than the research subjects (e.g., investigators, research assistants, students, the public, etc.) to potential risk;
• An interim analysis or safety monitoring report indicates that the frequency or magnitude of harms or benefits may be different than initially presented to the IRB;
• A report or publication that indicates the risks, benefits, or merit of the research are different from what was previously understood.

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Description

Investigators must report all potential unanticipated problems and events to the IRB.

Unanticipated problems (UPs) are defined as  any incident, experience or outcome that meets all of the following criteria :

• Unexpected  (unforeseen by the researcher or the research participant) in terms of nature, severity, or frequency, given the research procedures and the subject population being studied;
• Related or probably related to participation in the research , or if the event or problem probably or definitely affects the safety, rights and welfare of current participants;
• 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.

How to Report a Potential Unanticipated Problem

The Investigator must consider each problem, event, or new information and decide whether or not it represents an Unanticipated Problem using the criteria above.

If Unanticipated Problem Criteria Are Met:

Report the problem, event, or information using the Report Form application. The Report Form must be submitted promptly, within 10 working days from the time the investigator learns of the event. 

Steps to File a Report:

Complete a Report Form application.

Be sure to review the instructions carefully. Not all sections need to be completed based on the type of information you are submitting.

Submit the completed Report Form via email . Be sure to include any supporting documents with the application to explain the event.

If you will be making changes to the study based on the information you are reporting, an amendment will be needed. In the , be sure to state that you are submitting it based on a report form. In the report form application, be sure to state that you are submitting an amendment as part of your corrective and preventive action plan.  

If Unanticipated Problem Criteria Are Not Met:

• Document in the research record how the problem/event/information does not meet the UP Criteria.
• Summarize the problem/event/information in the next Continuing Review application.  

Examples of Potential Unanticipated Problems

• Adverse events
• A breach of confidentiality or privacy that involves real or potential risk (e.g. unauthorized use of disclosure of protected health information.)
• Adverse device effects
• Data and safety monitoring reports that indicate that frequency or magnitude of harms or benefits may be different than initially presented to the IRB
• A publication that shows that the risks or potential benefits or the research may be different than initially presented to the IRB
• Change in FDA labeling or withdrawal from marketing of a drug, device, or biologic used in a research protocol
• Incarceration of a participant in a protocol not approved to enroll prisoners
• Complaints from participants or others involved in the research that indicate unexpected risks or cannot be resolved by the research team
• Warning or determination letters issued by any funding agency or regulatory body including Office of Human Research Protections (OHRP), Department of Health and Human Services (DHHS), Food and Drug Administration (FDA)

Related Documents

• Report Form

Related FAQs

• Why do problems/events need to be reported?
• What are the consequences for submitting a possible Unanticipated Problem late?
• Once my project is determined exempt, do I need to do anything else with the application?

Related Research Topics

• Adverse Device Effects
• Adverse Events
• Breaches of Confidentiality
• Report Forms
• Complaints from Research Participants

Related Glossary Items

• Serious Adverse Event (SAE)
• Unanticipated Problem (UP)

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730. Unanticipated Problems Involving Risks to Participants or Others

Updated July 14, 2021

Per federal regulations, University and affiliate researchers must notify the IRB of unanticipated problems that involve risks to participants or others (henceforth referenced as Unanticipated Problems). Unanticipated Problems may encompass physical, psychological, social, legal, and economic harms; harm to dignity; and unexpected threats to privacy or safety.

To be considered an Unanticipated Problem, an event or situation must:

• be 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 population being studied;
• be related or possibly related to participation in the research (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
• suggest that the research places participants or others at a greater risk of harm than was previously known or recognized (i.e., involves new or increased risk).

Examples of Unanticipated Problems

The following incidents are likely to constitute Unanticipated Problems in the context of a research study:

• A laptop was stolen that contained identifiable participant data and the data were not encrypted.
• A processing error resulted in a participant receiving a dose of study medication much higher than the dose dictated by the IRB-approved research plan but that produced no detectable adverse effect.
• Participants received an investigational product that was obtained from donors who were not appropriately screened and tested for viral contaminants.
• Findings from a research project involving the same drug, indicated an adverse event that was described in the investigator’s brochure, was occurring at greater frequency than expected. A discussion of the divergence from the expected rate must accompany the report.
• A safety monitoring report indicated a change occurred in the nature, frequency, or severity of the expected risks of the research.
• Changes made to the research without prior IRB approval to eliminate apparent immediate harm.

Evaluation of Unexpectedness, Relatedness to Research, and Increased Risk

Evaluation of expectedness.

The following questions may be used to assess expectedness:

• Is the problem among the anticipated risks associated with the research procedures? (Anticipated events are those outcomes or effects that are listed as risks in the clinical protocol, IRB application, or consent documents.)
• If the problem was anticipated at the time of study design, does the problem now suggest that the research places participants at greater risk of harm than was previously known or recognized (i.e., the problem is more severe than expected)?
• If the problem was anticipated at the time of study design, is the problem occurring with greater frequency than expected?
• Did the problem result from the expected natural progression of any underlying disease, disorder, or condition of participants experiencing the problem or the participant’s predisposing risk factor profile for the problem?

Evaluation of Relatedness

Problems in research may be caused by:

• research procedures or interventions;
• an underlying disease or disorder of the participant; or
• something unrelated to the research and underlying diseases or conditions.

The investigator must consider these possibilities when determining if there is a reasonable chance that the problem may have been caused by the procedures involved in the research. Determinations about the relatedness of an event to participation in research generally fall along a continuum between “definitely related to the research” and “definitely unrelated to the research.” The IRB is concerned with events that are definitely or possibly related to the research.

For a single adverse event occurrence viewed as an isolated incident, relatedness to research may be difficult to evaluate. For many types of adverse events, determining the relevance and significance of the event to the research requires an analysis of all occurrences of the same (or similar) event. In multi-center trials, sponsors are in the best position to determine if an adverse event is or could be an Unanticipated Problem. Sponsors are responsible for assessing all events to identify those that are or could be Unanticipated Problems and for informing all investigators engaged in a multi-center trial of likely or possible Unanticipated Problems. Investigators are responsible for reporting events that are or could be Unanticipated Problems to the IRB.

Evaluation of Risk to Participants or Others

The third criterion for an Unanticipated Problem is evaluated by an assessment of whether the event or situation suggests that the research places participants or others at a greater risk of harm (e.g., physical, psychological) than was previously known or recognized.

Serious adverse events as well as adverse events that are not serious can be Unanticipated Problems if they meet the criteria of unexpectedness, relatedness to research, and increased risk. Serious adverse events (i.e., those that are life-threatening or involve death, significant or persistent incapacity; may require hospitalization; or jeopardize the participant’s health) always suggest that the research may be placing participants or others at greater risk of harm than was previously known or recognized. However, adverse events that are not serious may also suggest that the research poses greater risks than anticipated.

Adverse Events as Unanticipated Problems

The term “adverse event” is not defined in the Department of Health and Human Services (DHHS) regulations but is routinely used in clinical trials, and therefore warrants discussion in the context of Unanticipated Problems. Definitions for adverse events and serious adverse events are available on the IRB Policy Manual definitions page. Adverse events may be specific kinds of Unanticipated Problems, if they meet the criteria of unexpectedness, relatedness to research, and increased risk to participants or others.

IRB reporting requirements for adverse events depend on whether they represent Unanticipated Problems. Adverse events that meet all three criteria for an Unanticipated Problem (unexpectedness, relatedness to research, and increased risk) must be reported promptly to the IRB, as specified in this policy. Adverse events that do not meet the criteria for an Unanticipated Problem should be summarized at the time of continuing review, but do not require prompt reporting.

Regardless of whether they constitute Unanticipated Problems, investigators must report adverse events to the sponsor and safety monitoring board or committee as specified in the clinical protocol or contract.

For reporting purposes, it is also important to distinguish between local and external adverse events: Local events are those that occur at the University or affiliate investigator’s institution. External events are those that occur at a study site other than the University or affiliate investigator’s “home” institution.

Requirements for Reporting Local Adverse Events as Unanticipated Problems

Local events that require prompt reporting include:

• Local adverse events and local serious adverse events that meet the criteria for an Unanticipated Problem;
• Sponsor or monitoring entity notification, report, or assessment of a local adverse event (or series of same) as a possible Unanticipated Problem;
• Routine safety monitoring reports prepared by the Principal Investigator (PI) when the findings identify possible Unanticipated Problems or indicate changes are needed to protect participants.

Requirements for Reporting External Adverse Events as Unanticipated Problems

University and affiliate investigators participating in multi-center trials receive numerous external reports including reports of adverse events that occurred at other sites (i.e., external adverse events), routine safety monitoring reports, and assessments/notifications from the sponsor or safety monitoring board or committee. Reporting requirements vary according to the event, problem, or assessment.

External events that require prompt reporting include:

• Sponsor or safety monitor assessment/notification indicating one or more external adverse event or serious adverse event may be an Unanticipated Problem;
• Sponsor or safety monitor assessment/notification of external adverse events or serious adverse events that indicate immediate changes are needed to protect participants;
• Sponsor or safety monitor assessment/notification of external adverse events or serious adverse events that indicate changes are needed to reduce participant risk or inform participants of new or increased risk.

Reporting Timeframe

Non-exempt research.

For non-exempt research, events or situations that meet all three criteria for an Unanticipated Problem (unexpectedness, relatedness to research, and increased risk) must be reported promptly to the IRB, as specified below. Adverse events and adverse device effects that do not meet the criteria for an Unanticipated Problem should be summarized at the time of continuing review.

University/Affiliate investigators conducting investigational uses of humanitarian use devices (HUDs) must comply with the requirements for reporting adverse device effects as Unanticipated Problems.

The IRB requires reporting of Unanticipated Problems to occur within five business days of the problem becoming known, or within 48 hours if the situation or event involves a death or is life-threatening. Requirements for reporting local deaths in VA research are more stringent. See policy for reporting problems in VA research for specifics.

Exempt Research

For exempt research, investigators are advised to contact Research Integrity to discuss any Unanticipated Problems that may have occurred in their studies.

Reporting Unanticipated Problems to the IRB

For non-exempt and HUD studies, investigators must report Unanticipated Problems to the IRB by completing and electronically submitting the appropriate Reportable Event Form available in IRBNet. The information in the report should allow the IRB to evaluate each problem or situation. For example:

• Was the incident expected (i.e., identified in the application and consent form) or unexpected?
• Is the problem or situation related or possibly related to participation in the research?
• Does the problem or event suggest participants or others may be at greater risk of harm than was previously known or recognized?

Upon becoming aware of an Unanticipated Problem, investigators must determine if immediate corrective actions are necessary to protect the safety and welfare of research participants. Investigators must also consider what types of corrective measures should be taken to prevent future occurrences. The problem report must include a description and justification for all corrective actions taken without prior IRB approval.

Possible corrective actions investigators may take or propose (if the matter is not urgent) include but are not limited to the following:

• Change study procedures to minimize risks.
• Suspend the research, pending further review by the IRB or results from a monitoring entity or the sponsor.
• Amend the information shared with current and potential participants (as reflected in the consent form).
• Notify currently or previously enrolled participants of the problem, and related new or increased risks.

If the investigator believes that corrective actions are warranted to prevent future occurrences, these may be proposed at the time the report is submitted. If the Research Compliance Officer (RCO), Research Integrity Director, and IRB Chair concur that the proposed actions are sound, the PI may be instructed to submit a Project Amendment for IRB review.

IRB Review of Unanticipated Problem Reports

Within five business days of receiving a report of a possible Unanticipated Problem (or 48 hours if the problem is life-threatening or fatal), the RCO will consult with the Research Integrity Director and IRB Chair (or other qualified IRB member) to assess risk of harm to participants or others to determine if immediate corrective actions are needed to protect the participants or others and will make the necessary recommendations to mitigate such risks. Following this initial assessment, the problem will be evaluated for the three criteria for an Unanticipated Problem:

• The situation or event was unanticipated;
• The situation or event was related or possibly related to participation in the research;
• The situation or event suggests the research places participants or others at greater risk of harm than originally known.

Possible Unanticipated Problems will be reviewed at the next convened IRB meeting to confirm or reject a determination of Unanticipated Problem and make recommendations for the PI or others. If there are potential risks to participants which require action prior to a convened meeting, an emergency meeting may be convened (with the members attending either in person or via teleconference) or in exceptional safety circumstances, the Chair has the authority to suspend some or all the research activities. When this authority is exercised by the Chair, it will be reported at the next convened University IRB meeting. All sponsor assessments involving likely or possible Unanticipated Problems are reviewed by the IRB Chair or IRB subcommittee to determine if immediate action is necessary to reduce participant risks and will be reviewed at the next convened IRB meeting to confirm or reject a determination of Unanticipated Problem and make recommendations for the PI or others.

The materials for IRB review are available via access to the project in IRBNet (granted to Primary Reviewer and IRB members planning to attend the meeting), and include:

• Problem report or complaint form;
• Report of findings prepared by the RCO or designee, or IRB sub-committee; and
• Approved research plan and study documents (approved documents that are relevant to the review may be flagged as such).

To facilitate the review, the RCO sends the assigned reviewer the criteria for an Unanticipated Problem as defined by the DHHS Office for Human Research Protections (OHRP), and relevant excerpts from the IRB policy manual.

Possible IRB Recommendations Following Determination of Unanticipated Problem

The IRB takes whatever actions are deemed necessary to address the unanticipated problem(s). IRB votes as to whether the event represents an unanticipated problem involving risks to participants or others, serious noncompliance and/or continuing noncompliance. This vote will be recorded in the meeting minutes. If the University IRB votes to suspend or terminate the research study, the reasons for the suspension or termination will be documented.

Following determination of an Unanticipated Problem, the IRB may:

• request additional records or information about the event and its outcome;
• require training or education for research personnel;
• require monitoring of research activities by appropriate persons;
• require monitoring of the informed consent process by appropriate persons;
• request the IRB Chair (or Co-Chair) to meet with the involved investigator and/or research staff, and the appropriate department chair and/or dean to discuss the event/problem;
• require the PI to inform past and/or current research participants of the new or increased risk;
• require the PI to re-consent enrolled participants;
• require amendments to the research plan;
• require the PI to report to the IRB more frequently for this or all of her/his/their studies;
• reduce the approval period (i.e., require more frequent continuing reviews);
• require periodic audits by the RCO or other quality assurance or improvement auditors;
• restrict the PI’s research practice (e.g., limiting her/his/their research privileges to minimal risk or supervised projects);
• suspend IRB approval for one or more of the PI’s studies; or
• terminate IRB approval for one or more of the PI’s studies.

For multi-center studies, if the IRB or the local investigator proposes changes to the protocol or informed consent document/process, in addition to those proposed by the study sponsor or the coordinating center, the IRB should request in writing that the local investigator discuss the proposed modifications with the study sponsor or coordinating center and submit a response or necessary modifications for review by the IRB.

If the IRB determines that an Unanticipated Problem may violate other University policies, the appropriate authority will be notified of the IRB’s findings for possible further review and resolution by those bodies.

PI Notification of IRB Determination and Confirmation of Completion of IRB Required Actions

The PI will be notified in writing of the IRB’s determination and required actions.

Within 30 days of the IRB notification, the investigator must submit written confirmation that all actions have been implemented as required by the IRB.

The RCO will acknowledge receipt of the PI’s confirmation of implementation.

At a minimum, the following information should be included in the RCO report of IRB findings: 1. The nature of the event. 2. The findings of the University or IRB 3. Actions taken by the University or IRB 4. Reasons for the University’s or IRB’s actions. 5. Plans for continued investigation or action.

RCO Distribution of Unanticipated Problem Report

In addition to the IRB correspondence sent to the investigator, reports of any unanticipated problems involving risks to participants or others, any serious or continuing noncompliance, any suspension or termination of IRB approval will be sent to all applicable parties, which may include:

• The Office for Human Research Protections –for research funded by any agency that is a signatory to the “Common Rule” at 45 CFR 46;
• The Food and Drug Administration – for research that is subject to the FDA regulations at 21 CFR 50 and 56;
• The federal or non-federal external funding agency;
• The VA R&D Committee and the regional VA Office of Research Oversight;
• The Office of Sponsored Projects;
• Other University offices;
• The department chair;
• University legal counsel;
• University institutional officials.

Suspension or Termination of IRB Approval

If a study is suspended or terminated, new participants may not be enrolled and no study procedures may take place unless the IRB or IRB Chair determines that continuation of study procedures is in the best interest of currently enrolled participants (see policy for suspension and termination of IRB approval).

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Reporting Unanticipated Problems

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This website includes a page devoted to the discussion of reportable events . The information below relates to the PI's responsibility for reporting these events.

Unanticipated Problems

CHOP policy requires prompt reporting of any unanticipated problem involving risks to subjects or others to the IRB within 1 week of identification. Deaths and life-threatening events must be reported within 48 hours of discovery. Unanticipated problems include:

Adverse events that are serious, not anticipated and related to the research activity (SAEs). AEs that are not serious can be summarized at the time of continuing review.

Other unanticipated problems involving risks to subjects that are unexpected and related/possibly related to the research. Examples of reportable events include breaches of confidentiality and participant pregnancy or incarceration.

Protocol deviations should be considered unanticipated problems. When they represent unreasonable risks to participants they must be reported promptly even if the subject did not suffer an SAE (see below).

The IRB website contains additional information including, IRB SOP 408: Unanticipated Problems and the webpage on Reportable Events .

Protocol Deviations or Violations

Protocol deviations or violations are common during the execution of clinical research study. Some are not preventable - a subject fails to show up for a scheduled appointment or doesn't adhere to the drug treatment schedule - while others are due to one or more failures on the part of the study team. Most of the latter protocol deviations result from a failure to strictly follow the protocol.

There are occasions when a failure to comply with the protocol may be considered a failure to protect the rights, safety, and welfare of subjects because the non-compliance exposes subjects to unreasonable risks. For example, failure to adhere to inclusion/exclusion criteria that are specifically intended to exclude subjects for whom the study drug or device poses unreasonable risks may be considered failure to protect the rights, safety, and welfare of the enrolled subject. Similarly, failure to perform safety assessments intended to detect drug toxicity within protocol-specified time frames (e.g., CBC for an oncology therapy that causes neutropenia) may be considered failure to protect the rights, safety, and welfare of the enrolled subject. Investigators should seek to minimize such risks by adhering closely to the study protocol. From: Investigator Responsibilities — Protecting the Rights, Safety, and Welfare of Study Subjects .

These events must be reported to the IRB via the eIRB system through the Reportable Events pathway.

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NHLBI Adverse Event and Unanticipated Problem Reporting Policy

1.0 purpose - 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.

2.0 Scope - NHLBI Adverse Event and Unanticipated Problem Reporting Policy

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

3.0 Definitions - NHLBI Adverse Event and Unanticipated Problem Reporting Policy

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:

• Results in death;
• Is life-threatening (places the subject at immediate risk of death from the event as it occurred);
• Requires inpatient hospitalization or prolongation of existing hospitalization;
• Results in a persistent or significant disability/incapacity;
• Results in a congenital anomaly/birth defect; or
• 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:

• 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;
• 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
• 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.

4.0 Policy and Procedures - NHLBI Adverse Event and Unanticipated Problem Reporting 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

• 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

5.0 References - NHLBI Adverse Event and Unanticipated Problem Reporting Policy

• 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

Revision Record - NHLBI Adverse Event and Unanticipated Problem Reporting Policy

Contacts - nhlbi adverse event and unanticipated problem reporting policy.

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.

FAQs - NHLBI Adverse Event and Unanticipated Problem Reporting Policy

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.

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Office of the Vice Chancellor for Research

Unanticipated problems and other events requiring prompt reporting, unanticipated problems and other events requiring prompt reporting heading link copy link, date updated, printable version.

3.1 February 2, 2017 0279.pdf

Description

Approved by: Human Protections Administrator, Director of OPRS, and Executive IRB Chair AAHRPP REF#: 179 AAHRPP Elements: II.2.D.3., II.2.F.

POLICY Heading link Copy link

• UIC policy requires investigators to promptly report all unanticipated problems involving risks to subjects or others (referred to as unanticipated problems in this policy) to the UIC OPRS/IRB [45 CFR 46.103(b)(5), 21 CFR 56.108(b)(1)].
• Events determined by the IRB to represent unanticipated problems are reported to the institutional official and regulatory agencies as described in the UIC HSPP policy  Reporting of Unanticipated Problems, Suspensions, Terminations, and Non-compliance .
• Unanticipated problems involving risks to subjects or others:  refers to a problem or event that is unexpected, given the nature of the research procedures and the subject population being studied; related or possibly related to participation in research and suggests that the research places subjects or others at a greater risk of harm or discomfort related to the research than was previously known or recognized.
• UNANTICIPATED: means that the specificity, severity or frequency of the event is new and not expected based on (a) information contained in the protocol, investigator’s brochure, informed consent document, drug or device product information or other research materials; and (b) the characteristics of the subjects, including underlying diseases, behaviors, or traits.
• RELATED OR POSSIBLY RELATED means that the event or problem is more likely than not to have been caused by research because the event or problem may reasonably be regarded as caused by, or probably caused by, the research.
• GREATER RISK OF HARM means the research causes harm (including physical, psychological, economic, legal or social harm) to subjects or others (e.g., family members, co-workers, study staff) or places them at a greater risk of harm than was previously known or recognized.
• SERIOUS PROBLEM:  Problem that involves substantive harm ,or a genuine risk of substantive harm, to the safety, rights, or welfare of research subjects, research staff, or others; or substantively compromises the effectiveness of a facility’s human research protection or human research oversight programs.
• ADVERSE EVENT: An untoward physical or psychological occurrence in a human subject participating in research.  The event may be any unfavorable outcome, including abnormal laboratory result, symptom, disease or injury.  Adverse events may be expected or unexpected, may not necessarily be caused by the research, and may be serious or not.
• SERIOUS ADVERSE EVENT: A serious adverse event is an untoward occurrence in human research that results in death, life-threatening injury, inpatient hospitalization or prolongation of hospitalization, persistent or significant disability, or a congenital anomaly or birth defect.  Events not meeting the above criteria but requiring medical, surgical, behavioral, social, or other intervention to prevent one or more of these outcomes are also considered serious adverse events.
• Unanticipated Adverse Device Effect: Any serious adverse effect on health or safety or any life-threatening problem or death caused by or associated with a device used during human subjects research if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application, or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects.
• Internal/Local Events or Problems:  Events or problems occurring at UIC or other sites where the UIC IRB has oversight responsibility for the research and UIC IRB is the IRB of record.
• External Events or Problems: Events occurring at non-UIC sites, i.e., where UIC IRB has no oversight responsibilities.
• Protocol violation: Any deviations, whether accidental, unintentional or intentional, from the IRB-approved protocol that are implemented prior to IRB approval.
• Major protocol violations are those that cause harm to subjects or others, place them at increased risk of harm, impact the scientific integrity of the research, compromise the human subject protection program, have the potential to recur and/or represent possible serious or continuing non-compliance Major protocol violations may represent an unanticipated problem (particularly when unintentional) and/or potential serious noncompliance and require prompt reporting.
• Minor protocol violations are those not meeting at least one of the criteria in the preceding sentence.
• NON-COMPLIANCE: Conducting research involving human subjects in a manner that intentionally or unintentionally fails to comply with federal or state regulations, VA policies for VA research overseen by CHAIRb, UIC HSPP policies, or the requirements or determinations of the IRB. Examples include, but are not limited to, initiating research prior to IRB approval, implementing changes in the IRB-approved protocol without prior IRB approval, using inadequate procedures for informed consent, failing to meet education and training requirements and lapses in IRB approval.
• SERIOUS NON-COMPLIANCE: Non-compliance that results in either substantive harm (or genuine risk of substantive harm) to the safety, rights or welfare of human subjects, research staff or others, substantively compromises the effectiveness of the HSPP or substantively impacts the integrity of the research.
• CONTINUING NONCOMPLIANCE: Persistent failure to conduct research in compliance with federal or state regulations, VA policies for VA research overseen by CHAIRb, or requirements or determinations of the IRB.
• RISK:  A risk may reflect potential physical, psychological, social, or economic harm.
• ADMINISTRATIVE HOLD: An administrative hold is a voluntary action by an institutional official, investigator or sponsor to temporarily or permanently stop some or all research activities. For the full definition and additional information, please refer to the UIC HSPP policy Administrative Hold, Suspension, or Termination of IRB Approval .
• Local, serious adverse events which are unanticipated and related to the research
• Unanticipated adverse device effects
• Serious unanticipated problems which are related to the research
• Major protocol violations
• Apparent serious noncompliance
• Apparent continuing noncompliance
• Changes to the protocol made without IRB approval to eliminate apparent immediate harm to subjects
• Incarceration of a subject in a protocol not approved to enroll prisoners
• New information indicating an unexpected change to the risks or benefits of the research (i.e., an unanticipated problem).
• External adverse events that are i) unanticipated, ii) indicate research associated with a greater risk of harm to participants or others than previously known, and iii) more likely than not to have been caused by the procedures associated with or subject’s participation in the research. An analysis from sponsor, coordinating center or DSMB/DMC supporting that the event or problem meets the 3 criteria above must be included.
• Local adverse events or problems that are unanticipated and, while not meeting the criteria of serious, indicate research is associated with a greater risk of harm to participants or others than previously known.
• Administrative hold by investigator, sponsor, regulatory authorities, or other entities.
• Other events requiring prompt reporting by sponsor.
• Local adverse event or problem that is expected or is not associated with a greater risk of harm to participant or others than previously know
• External adverse event or problem lacking an analysis documenting that it is unanticipated, related or possibly related and associated with a greater risk of harm than previously known, such as Individual IND Safety or FDA MedWatch reports from external sites without an analysis
• The investigator is responsible for reporting adverse events and problems to the sponsor and any other agencies as specified in the protocol, data safety monitoring plan or other agreement.
• The investigator informs the IRB of an event requiring prompt reporting by submitting the UIC OPRS  Prompt Reporting to the IRB  form to OPRS within 5 working days of becoming aware of any events listed in IV.A. of the Policy section above  or within 15 days for those listed in IV.B. of the Policy section above.
• The prompt reporting criteria depend on the investigator to decide whether the event is anticipated or unanticipated; related to the research or not; and serious or not, or does or does not indicate the research is associated with a greater risk of harm than previously known.
• Examples of materials that should be submitted with the prompt reporting form include, when available, case report forms, DSMB/DMC reports, updated investigator brochures, amendment applications with revised protocol or consent form, or sponsor communications.
• Incomplete reports or those requiring revisions or additional information may be returned to investigators with an explanation for revision or, when time permits, the AD may gather the information directly from the investigator or research team.
• Reports of administrative hold by the investigator or sponsor are managed as described in the UIC HSPP policy Administrative Hold, Suspension or Termination of IRB Approval .
• Complaints and reports of observed or apparent noncompliance (including subject complaints, protocol violations, changes to the protocol made without IRB approval to eliminate apparent immediate harm to subjects, and allegations of non-compliance) are managed as described in the managed as described in the UIC HSPP policy  Handling Complaints and Allegations of Potential Non-Compliance with Human Subject Protection Regulations .
• Is unexpected in nature, severity or frequency given the research procedures and subject population;
• Related or possibly related to participation in the research, and
• serious; or
• Causes or places subjects or others at greater risk of harm or discomfort than was previously known or recognized. (Note: the answer is always ‘yes’ for serious adverse events)
• If the AD does not confirm the investigator assessment of unanticipated, related or possibly related, and serious or greater risk of harm than previously known, the submission of the prompt report is acknowledged with an explanation that the problem does not meet criteria for prompt reporting and whether other reporting requirements exist (i.e., continuing review, non-compliance).  The IRB is notified of the AD’s action at the next scheduled meeting via the agenda.
• If the event is determined to potentially meet the criteria of unanticipated, related or possibly related, and serious or greater risk of harm than previously known, the AD refers the problem/ event to the Chair or designee, or alternatively, the convened IRB if a meeting is scheduled within the 5 or 15 day timeline for review.
• For events referred to the Chair, designee or convened IRB, the AD consults with the Chair (or designee) to determine if immediate action is needed to protect the rights and welfare of human subjects.  Immediate action may include, but is not limited to, suspension of part (e.g., new subject recruitment) or all of the research (refer to UIC HSPP policy Administrative Hold, Suspension, or Termination of IRB Approval ).
• Additional Expertise. At any point during the review process, the IRB Assistant Director, IRB Chair (or designee) or convened IRB may request additional expertise (refer to UIC HSPP policy and procedure, Identification and Use of Ad Hoc Consultants ).
• within 5 business days for events listed in IV.A. of the Policy section,
• within 15 business days for events listed in IV.B. of the Policy section.
• If an IRB meeting is scheduled within the 5 or 15 day interval, respectively, the Chair may refer the matter to the convened IRB. (Refer to section IV below.)
• The Chair (or designee) is provided with the prompt reporting form, any supporting documentation and the protocol file, including the currently approved protocol, currently approved consent form, investigator brochure and previous reports of unanticipated problems/ events.
• Unanticipated AND
• Related to the research AND either
• risk is not greater than minimal
• risk is greater than minimal
• Additional information or revisions needed before a final  decision can be made.
• The problem or event does not meet the criteria of an unanticipated and related problem or adverse event.
• The problem or event may potentially represent a serious unanticipated and related problem or local serious unanticipated and related adverse event.
• The event may potentially represent an unanticipated and related problem or local unanticipated and related adverse event, and, while not serious, does indicate the research is associated with a greater risk of harm than previously known and the level of risk is greater than minimal.
• The event may potentially represent an unanticipated and related problem or local unanticipated and related adverse event, and, while not serious, does indicate the research is associated with a greater risk of harm than previously known and the level of risk is not greater than minimal.
• Potential serious unanticipated problem that is related to the research or local series unanticipated adverse event that is related to research: The Chair or designee decide the need for any actions necessary to prevent an immediate hazard to subject. This problem or event is referred to the convened IRB at the next meeting to make the final determination and to assess whether other actions are warranted.
• Potential unanticipated and related problem or local unanticipated and related adverse event that is not serious but indicates the research is associated with a greater risk of harm than previously known and the level of risk is greater than minimal: The Chair or designee decide the need for any immediate actions.  The problem or event is referred to the convened IRB at their next meeting to make the final determination and to assess whether other actions are warranted.
• Potential unanticipated and related problem or local unanticipated and related event that is not serious but indicates the research is associated with a greater risk of harm than previously known and the level of risk is not greater than minimal:  The Chair or designated reviewer decides the need for any corrective actions. This determination and corrective actions are communicated to the convened IRB at the next meeting via the agenda.
• Suspension of the research;
• Changes to the information disclosed during the consent process;
• Notification of current participants when such information may relate to the subject’s willingness to continue participation;
• Providing additional information to past subjects;
• Requiring current subjects to re-consent to participation;
• Alteration of the frequency of continuing review;
• Monitoring of the research or the consent process;
• Referral to other organizational entities (e.g., ORS, ethics officer, Associate Director for Compliance, Radiation Safety); and
• Revisions to the protocol.
• When the unanticipated problem determination is made by the convened IRB, the actions that may be taken by the IRB are described in IV. C. below.
• The Chair, or designee, documents the results of the review and any corrective actions on the appropriate review guide.  The results are added to the protocol file and communicated to the investigator.  Copies of the communication are provided to the academic Department Head, other relevant UIC oversight committees (e.g., investigational drug service, IBC, radiation safety, cancer center), UIC HPA, and, when review performed by Chair or designee, reported to the IRB via the agenda at the next meeting.
• The convened IRB may be asked to review a problem or event without prior review by the Chair or designee if the IRB meeting is scheduled within the 5 or 15 day interval.
• Prompt reporting form;
• Supplementary or follow-up information provided about the event;
• Protocol summary;
• Review guide for the event completed by the Chair or designee;
• Current approved research protocol (primary reviewers only);
• Current approved consent document; and
• All IRB members are provided access to the complete protocol file.
• Suspension or termination of the research;
• Whether or not previously enrolled subjects must be notified of the modification and, if so,
• When such notification must take place and how such notification must be documented.
• Copies of the communication are provided to academic Department Head, other relevant UIC oversight committees (e.g., investigational drug service, IBC, radiation safety, cancer center), and UIC HPA.
• Suspensions and terminations by someone other than the convened IRB must be reported to and reviewed by the convened IRB.
• The IRB also determines for subject complaints, protocol violations, changes to the protocol made without IRB approval to eliminate apparent immediate harm to subjects, and allegations of non-compliance whether they represent non-compliance and, if so, whether the finding of non-compliance is serious or continuing as described in the UIC HSPP policy  Handling Complaints and Allegations of Potential Non-Compliance with Human Subject Protection Regulations .  The IRB may also, at their discretion, make a determination of noncompliance for any other reports received.
• Unanticipated problems and other events requiring prompt reporting may originate at any of the participating institutions.
• Reportable events and problems requiring prompt reporting will be submitted to CHAIRb via the CHAIRb Portal by the lead site investigator for events which involve the entire research activity and by the participating local site investigators for reportable events and problems originating at the participating site.
• All reportable events and problems will be processed as per the above-stated policy and procedures unless specified below and with the exception that the CHAIRb Portal will be utilized.
• The participating site investigators and participating site liaisons will be copied on the correspondence to the lead investigator from the IRB.
• Research reviewed by CHAIRb are required to submit a table or list of minor protocol violations as part of the Continuing Review submission.
• The VA Local Site Investigator or VA research personnel from the VA participate site must orally notify the IRB Chair of any local research death that is both unanticipated and related to the research.
• The CHAIRb Chair or CHAIRb IRB administrative staff must alert ORO via email or telephone within 2 business days after receiving such notification and provide relevant information. The VA Facility’s Medical Center Director and ACOS/R&D must receive concurrent notification.
• Within 5 business days after receiving written notification of the death, the IRB Chair or designee must determine and document whether any actions are warranted to eliminate apparent immediate hazards to subjects.
• The death was both unanticipated and related to the research; or
• There is insufficient information to determine whether the death was both unanticipated and related to the research; or
• The death was not unanticipated and/or the death was not related to the research.
• Regardless of the determination, the convened IRB must also determine and document whether any protocol or informed consent revisions are warranted. If revisions are warranted, the convened IRB must determine and document whether or not investigators must notify or solicit renewed/revised consent from previously enrolled subjects; and if so, when such notification or consent must take place and how it must be documented.
• The IRB must notify the Medical Center Director and the ACOS/R&D of its determinations within 5 business days of the determinations.
• The participating VA local site investigator must submit a Prompt Report to the CHAIRb within 5 business days after becoming aware of any local, serious adverse event that is both unanticipated and related to the research .
• The participating VA local site investigator must submit a Prompt Report to the IRB within 5 business days after becoming aware of any serious problem that is both unanticipated and related to the research.
• Within 5 business days after receiving written notification of an SAE or serious problem, the IRB Chair or designee must determine and document whether any actions are warranted to eliminate apparent immediate hazards to subjects.
• The incident was serious and unanticipated and related to the research; or
• There is insufficient information to determine whether the incident was serious and unanticipated and related to the research; or
• The incident was not serious, and/or the incident was not unanticipated, and/or the incident was not related to the research.
• Actions were taken to eliminate apparent immediate hazards to subjects; or
• The IRB determined that the incident was serious and unanticipated and related to the research, or there was insufficient information to make the determination; or
• Protocol or informed consent revisions were warranted
• The UIC Human Protection Administrator (HPA) serve as the Chair’s designee for reporting on behalf of CHAIRb to the Medical Center Director and/or ACOS/R&D.
• Events determined by the IRB to be unanticipated problems, require suspension or  termination of approval or represent serious or continuing non-compliance are reported to institutional official and regulatory agencies as described in the UIC HSPP policy  Reporting of Unanticipated Problems, Suspensions, Terminations, and Non-compliance .

21 CFR 50.25(b)(5), 21 CFR 56.108(b)(1), 21 CFR 312.30(b)(2)(ii), 21 CFR 812.150(a)(1) 38 CFR 16.103 (b)(5)(i), 38 CFR 16.116(b)(5) 45 CFR 46.103(b)(5)(i), 45 CFR 46.116(b)(5) VHA Handbook 1058.1, VHA Handbook 1200.05 OHRP Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events, January 15, 2007 FDA Draft Guidance for Clinical Investigators, Sponsors, and IRBs: Adverse Event Reporting-Improving Human Subject Protection, April 2007

REVISION LOG:

Version (#, date) Replaces (#, date) Summary of changes

2.0, 10/01/08, 1.0, 8/10/07 Previously titled Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) and Other Adverse Events: Investigator Reporting Responsibilities and OPRS/IRB Processing and Reporting. Events reported through the prompt reporting process expanded, clarification of review procedures, description of corrective action and noncompliance determinations, reporting deadlines to IRB altered, and reporting requirements for research being performed at JBVAMC clarified.

2.1, 06/18/09 2.0, 10/01/08 Corrected small error to the number of VA Form 10-0420.

2.2, 12/17/09 2.1, 06/18/09 Revised all contents related to the JBVAMC to correspond with revisions in VHA Handbook 1058.01.

2.3, 01/25/11 2.2, 12/17/09 Updated to bring into compliance with VHA Handbook 1058.01, dated 5/21/10.

2.4, 04/27/12 2.3, 01/25/11 Updated to bring into compliance with VHA Handbook 1058.01, dated 11/15/11.  Addition of the addendum.

2.5, 03/01/16

2.4, 04/27/12

Removal of IRB #4 references.  Addition of CHAIRb.

3.0, 04/28/16

Addition of requirement for events to be related prior to submission.  Removal of requirement for Chair/designee to make determination prior to convened review.

3.1, 02/02/2017

Addition of hyperlinks; Editorial corrections.

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A. Introduction

These requirements and guidelines created by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) detail the safety reporting processes that investigators are required to follow when conducting NIAMS-supported clinical research studies. These studies include clinical trials and other types of clinical research studies e.g., observational studies. The goal of these guidelines is to outline the NIAMS requirements for reportable events, and to ensure the proper reporting procedures are followed by study personnel to monitor the safety of research participants. All NIAMS-funded clinical research grantees are expected to adhere to these requirements and guidelines; however, the process may slightly vary depending on the level of risk involved in the study and whether the study utilizes a monitoring body for data and safety oversight.

This document outlines the NIAMS reporting requirements for Adverse Events (AEs), Serious Adverse Events (SAEs), Unanticipated Problems (UPs), Protocol Deviations, Serious or Continuing Noncompliance, and Suspension or Termination of Institutional Review Board (IRB) Approval. Should investigators foresee a deviation from the NIAMS requirements, they are required to promptly discuss it with the NIAMS Program Officer (PO) and Clinical Research Manager.

Additionally, please note that the National Institutes of Health (NIH) under 45 CFR 46.108(4) and 45 CFR 46.113 requires reporting of certain incidents (i.e., serious or continuing noncompliance , unanticipated problems, suspension or termination of IRB approval, and adverse events) under the NIH Grants Policy Statement Section 4.1.15 . Each Institution/Principal Investigator (PI) is required to have and follow written procedures to ensure that the aforementioned events are promptly reported to the Office of Human Research Protections (OHRP) . 

B. Safety Monitoring Oversight and Responsibilities

The NIAMS assesses the risk for all clinical studies, determines the appropriate level of data and safety oversight, and may assign a monitoring body type, including but not limited to a NIAMS-appointed Data and Safety Monitoring Board (DSMB), NIAMS-appointed Observational Study Monitoring Board (OSMB), NIAMS-appointed Safety Officer(s) (SOs), or internally-appointed DSMB or SO. These groups are hereafter referred to as “monitoring body.”

While establishment of safety monitoring oversight is a responsibility of the NIAMS as the funding agency, oversight duties are carried out in conjunction with the assigned monitoring body. Other entities that may include, but are not limited to, other funding NIH Institutes and Centers (if applicable), IRB, Food and Drug Administration (FDA), OHRP, study Medical Monitor (MM), study PI, and clinical site investigators may also have overlapping or additional oversight responsibilities related to safety reporting that must be considered in the safety reporting development process. Given that the NIAMS, IRB, and FDA reporting timelines can vary, investigators should outline a process that will be followed for the study so that all applicable reporting requirements are adhered to. Please note that studies not required by NIAMS to use a monitoring body mentioned above (e.g., NIAMS-appointed DSMB or OSMB, NIAMS-appointed SO, internally-appointed DSMB or SO) are still required to follow a process by which events are reported under the NIH Grants Policy Statement Section 4.1.15 . These events include AEs, UPs, serious or continuing noncompliance, and suspension or termination of IRB approval. Investigators should follow the reporting timelines of these events per their IRB policies and OHRP reporting guidance. 

The rest of this document only refers to processes for studies with a monitoring body.

C. Reporting Requirements and Timeline

Investigators for studies utilizing a monitoring body are expected to adhere to the following reporting requirements and timeline.

I. Adverse Event Reporting

All adverse events should be assessed by the investigator and/or qualified designee (e.g., medical sub-investigator) for severity, relatedness to the study/study intervention, expectedness, and seriousness (i.e., whether it meets any of the criteria for seriousness, such as resulted in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, etc.). The definitions for categorizing severity (e.g., mild, moderate, and severe), relatedness (e.g., not related, possibly/probably related, or definitely related to the study intervention), and expectedness (i.e., expected vs. unexpected) of AEs, as well as the criteria for seriousness, should be included in the applicable study materials (e.g., manual of operating procedures (MOP), data and safety monitoring plan (DSMP)) and should be consistent across study documents. Depending on the classification of an event, it may need to be reported to different oversight entities; see the NIAMS Safety Reporting Assessment Flowchart .

The NIAMS requires reporting of all adverse events regardless of their expectedness, relatedness, or severity to the NIAMS and monitoring body. These data must be reported in aggregate as part of the routine Data and Safety Monitoring (DSM) Report to the NIAMS and monitoring body. The following timelines must be followed for reporting AEs based on monitoring body type:

• For studies with a NIAMS-appointed monitoring body : The frequency for routine reporting to the NIAMS and monitoring body is typically semiannual; however, this timeline is determined during the introductory monitoring body meeting for each study. 
• For studies with an internally-appointed monitoring body: The frequency for routine reporting to the NIAMS and monitoring body is determined by the PI in consultation with the monitoring body.

The NIAMS AE Form and Open DSM Report templates are resources for data reporting that are available to investigators that can be utilized and tailored to an individual study as needed.

II. Serious Adverse Event Reporting

For any AEs that meet one of the pre-specified criteria for seriousness, the investigator or qualified designee from the study team is responsible for conducting and providing an assessment of the serious adverse event. The following timelines must be followed for reporting SAEs based on monitoring body type: 

• Studies with a NIAMS-appointed monitoring body : All SAEs (regardless of expectedness, relatedness, or severity) must be reported in an expedited manner to the NIAMS and monitoring body within 48 hours of the site PI becoming aware of the event.
• Studies with an internally-appointed monitoring body : All SAEs (regardless of expectedness, relatedness, or severity) must be reported in an expedited manner to the NIAMS within 48 hours of the site PI becoming aware of the event. However, the timeline for reporting SAEs to the monitoring body is determined by the PI in consultation with the monitoring body.

The expedited initial SAE report should be submitted to the NIAMS and to the NIAMS-appointed monitoring body (if applicable) with any available information by the 48-hour mark; it is acceptable if the report is not complete. Follow-up reports should be provided as additional information becomes available. All SAEs must be followed to resolution and a final report should be submitted detailing the outcome.

The following information should be collected at a minimum for SAE reports to the NIAMS and to the NIAMS-appointed monitoring body (if applicable): participant ID; event term (i.e., SAE name/diagnosis); SAE onset date; SAE end date (or indication that event is ongoing); severity; relatedness; and expectedness. The NIAMS SAE Form template is a resource available for investigators that can be utilized and tailored to an individual study as needed.

For additional details describing the review and adjudication process for SAEs, please refer to the “ Serious Adverse Events Review Process and Adjudication ” section below.

III. Unanticipated Problem (UP) Reporting

For any event that meets all three criteria for an unanticipated problem, the investigator or qualified designee from the study team is responsible for reporting this event to the relevant parties. Similar to SAE reports, the initial UP report is acceptable even if the report is not complete. Follow-up reports should be provided as additional information becomes available. The following timelines must be followed for reporting unanticipated problems based on monitoring body type: 

• Studies with a NIAMS-appointed monitoring body : All unanticipated problems are reported to the NIAMS and monitoring body within 48 hours of the site PI becoming aware of the event. 
• Studies with an internally-appointed monitoring body : All unanticipated problems are reported to the NIAMS within 48 hours of the site PI becoming aware of the event. However, the timeline for reporting unanticipated problems to the monitoring body is determined by the PI in consultation with the monitoring body.

The NIAMS UP Form template is a resource available for investigators that can be utilized and tailored to an individual study as needed.

IV. Protocol Deviation Reporting

The timeline for reporting protocol deviations to the NIAMS differs depending on whether the deviation is related to participant safety. The following timelines must be followed for reporting protocol deviations based on monitoring body type: 

• Studies with a NIAMS-appointed monitoring body : Protocol deviations impacting participant safety are reported to the NIAMS and monitoring body within 48 hours of the site PI becoming aware of the event. All other protocol deviations that do not impact participant safety are reported to the NIAMS and monitoring body in aggregate as part of the routine DSM Report.
• Studies with an internally-appointed monitoring body : Protocol deviations impacting participant safety are reported to the NIAMS within 48 hours of the site PI becoming aware of the event; all other protocol deviations that do not impact participant safety are reported to the NIAMS in aggregate as part of the routine DSM Report. However, the timeline for reporting protocol deviations to the monitoring body is determined by the PI in consultation with the monitoring body.

V. Serious or Continuing Noncompliance Reporting

All studies regardless of monitoring type must report serious or continuing noncompliance to the NIAMS Program Officer and Grants Management Specialist within three business days of IRB determination. A copy of the IRB submission and determination must be submitted along with the report.

VI. Suspension or Termination of IRB Approval Reporting

Any suspension or termination of IRB approval must include a statement of the reason(s) for the action and must be reported promptly to the NIAMS Program Officer and Grants Management Specialist within three business days of receipt by the investigator. This is required for all studies regardless of monitoring type.

D. Safety Reporting at a Glance

E. serious adverse events review process and adjudication for niams-appointed monitoring body.

For studies with a NIAMS-appointed monitoring body, the SAE is reviewed by the monitoring body SO and the NIAMS to determine whether they agree with the investigator’s assessment of relatedness and expectedness. The result of the NIAMS’ and SO’s independent assessment and review is shared with the investigator in a timely manner. The outcome of the review will either be that the NIAMS and SO agree or disagree with the investigator’s assessment. Additional information may also be requested by the NIAMS and SO to aid in their review of the event. If the NIAMS and SO agree with the investigator’s assessment, the result is shared with the investigator, and no further action is required.

If the NIAMS and the SO disagree with the investigator’s assessment, the following will occur:

• The NIAMS’ and SO’s independent assessment and justification are sent to the investigator. The NIAMS and SO may or may not request additional information. 
• The investigator has the opportunity to provide a rationale for their assessment and may or may not agree to amend the SAE report to match the NIAMS’ and SO’s assessment.
• The investigator will update the SAE report to reflect the NIAMS’ and SO’s adjudication and resubmit it to the SO and the NIAMS for review. Note: If the updated adjudication changes the reporting requirements for the event (e.g., the SAE now meets the criteria for a UP), these new reporting requirements should be met.  
• The investigator will leave the report as is with their original adjudication and notify their IRB of the difference in the adjudication of the SAE, as well as provide a copy of the IRB communication to the NIAMS.
• As the monitoring body is advisory to the NIAMS, the NIAMS makes the final decision regarding the recommended adjudication of the SAE being shared with the investigator. Once the NIAMS makes a final decision about the adjudication of the SAE, further discussion with the monitoring body will not be needed.
• During this process of determining the adjudication of the SAE, the investigator should adhere to all applicable (IRB, FDA, etc.) reporting requirements and timelines for the SAE based on their original assessment of the event.

Please note, it is the investigator’s responsibility to ensure that reports of assessment of AEs are transmitted from the DSMB to the IRB. The NIH Guidance on Reporting Adverse Events to Institutional Review Boards for NIH-Supported Multicenter Clinical Trials provides more details. 

F. Additional Information

• Investigators and their study team should ensure that all internal processes and staff roles/responsibilities for the identification, collection, assessment, and reporting of events to the appropriate groups are clearly described in the MOP and DSMP.
• Multi-site trials with coordinating centers/data coordinating centers involved in the AE reporting process should ensure the NIAMS required timeline (i.e. within 48 hours of the investigator becoming aware of the event) is built into their internal process. 
• OHRP provides guidance for the appropriate timeframe for reporting AEs and UPs to the IRB and OHRP .

The checklist below is intended to help investigators think through the elements that should be considered when drafting their safety reporting process.

• Have you included the appropriate regulatory definitions of an AE, SAE, UP, and protocol deviation for your study in the applicable study documents (i.e., protocol, MOP, and DSMP)?
• Is the NIAMS 48-hour expedited reporting window documented, if applicable?
• What is your IRB’s reporting window for AEs, SAEs, UPs, and protocol deviations?
• Have you included the reporting window for serious or continuing noncompliance and suspension or termination of IRB approval? Who is responsible for reporting these incidents?
• How will this information be documented and transmitted? Via email or electronically entered into a database? Is there a form?  Other?
• Who is the responsible person for notifying the investigator? MM? IRB? NIAMS? FDA? OHRP? monitoring body?
• Who is responsible for providing the follow-up information to the NIAMS and monitoring body, and how will this information be transmitted?
• Do the applicable study documents including but not limited to the protocol, DSMP, and MOP clearly outline everyone’s role and reporting timelines in the safety reporting process?
• Do the applicable study documents include the definitions for categorizing severity, relatedness, and expectedness of AEs, and are these categories consistent across documents?
• Participant ID; event term (i.e., SAE name/diagnosis); SAE onset date; SAE end date (or indication that event is ongoing); severity; relatedness; and expectedness.

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Lead - Clinical Research Coordinator - Cardiovascular Diseases

• Rochester, MN

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Don't miss this chance to join a world-class team and make a difference in the lives of millions of patients. Apply today and become part of the Mayo Clinic Experience. As a Lead - Clinical Research Coordinator, you will :

• Independently coordinate complex (i.e. interventional, therapeutic greater than minimal risk) clinical research protocols with minimal direction from the principal investigator and/or supervisor in compliance with regulatory laws and institutional guidelines. 
• Collaborate with the research team to assess feasibility and management of research protocols. 
• Ensure implementation of research protocols after IRB approval and provide information as appropriate for progress reports. 
• Screen, enroll, and recruit research participants. 
• Coordinate schedules and monitor research activities and subject participation. Identify, review, and report adverse events, protocol deviations, and other unanticipated problems appropriately. 
• Manage, monitor, and report research data to maintain quality and compliance. 
• Provide education/training for others within the department and serve as a first line resource for team members. 
• Perform administrative and regulatory duties related to the study as appropriate. 
• Perform administrative functions to support work unit. Some travel may be required. 
• Be involved with Protocol Development and Maintenance Activities Responsibilities that may include, but are not limited to: ongoing management of the protocol document and process through editing, amendments, proofing, coordination of study logistics (i.e. blood collection kits, data collection booklets, use of CRU, etc.), and verification of content to meet institutional and federal standards; communication with study sites and/or federal agencies regarding study status changes; Federal and Institutional Review Board (IRB) document preparation and submission; and provides consultative expertise regarding regulatory and policy requirements. 
• Accurately apply investigators' scientific data into a cohesive format for the protocol document and associated procedures that are consistent with internal and external policies and regulatory requirements. 
• Participate in other protocol development activities and execute other assignments as warranted and assigned. 

***Visa sponsorship is not available for this position.  This position is not eligible for F-1 OPT STEM extension.***

• HS Diploma with at least 6 years of clinical research coordination/related experience OR 
• Associate's degree/college Diploma/Certificate Program with at least 4 years of clinical research coordinator/related experience, Associate's in Clinical Research from an accredited academic institution without experience OR 
• Bachelor's with at least 2 years of experience in clinical research/related experience.

Additional Qualifications

• Graduate or diploma from a study coordinator training program is preferred. 
• One year of clinical research experience is preferred. 
• Medical terminology course is preferred. 

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