I N S T I T U T I O N AL R E V I E W B O AR D
Reporting of Unanticipated Problems Involving Risks to Subjects or Others
Federal regulations require that organizations have written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and relevant federal officials of unanticipated problems involving risks to subjects or others. Some unanticipated problems could also fall within the definition of an adverse event. 45 CFR §46.103(b)(5), 21 CFR §56.108(b)(1) and 21 CFR §312.66. In addition,
FDA regulations use the words "adverse effect" and "adverse experience" to describe occurrences that must be reported to the FDA.
Consistent with these regulations and the IRB SOP, this policy outlines the problems that
Investigators are required to report to the IRB to ensure prompt reporting of adverse events and unanticipated problems involving risks to human subjects or others.
It is suggested that the Internal (On-Site) and External (Off-Site) Flow Charts be used to facilitate review of this policy.
A. Definitions
Adverse Event: Any untoward physical or psychological occurrence or undesirable and unintended effect for a subject that may present itself during interventions and interactions used in the research or the collection of identifiable private information under the research, regardless of whether there may or may not be a relationship with the research intervention.
Anticipated Adverse Event: An adverse event that is not an unanticipated adverse event.
Unanticipated Adverse Event: Any adverse event, the specificity, frequency or severity 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 the protocol related-documents, such as the IRB-approved research protocol, any applicable investigator brochure, and the current IRB-approved informed consent document, and other relevant sources of information, such as product labeling and package inserts; or

the expected natural progression of any underlying disease or condition of the subject(s) experiencing the adverse event.
Unanticipated Adverse Device Effect : Any serious adverse effect on health or safety or any lifethreatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects.
Unexpected Adverse Drug Experience: Any adverse drug experience, the specificity, frequency or severity of which is not consistent with the current investigator brochure, or, if an investigator brochure is not required or available, the specificity, frequency or severity of which is not consistent with the risk information described in the general investigational plan.
Reporting Unanticipated Events/Problems, 02-09 Page 1 of 9

Related or possibly related to the research: An event is related to the research if, in the opinion of the CHRCO Principal Investigator, it could not have been produced by the subject's clinical condition or environment, follows a known pattern of response to intervention, disappears or decreases with reduction in dose or cessation of intervention and/or recurs with re-exposure and/or it was more likely than not to be the result of the collection/disclosure of identifiable private information in the research and/or the interventions used in the research,
Unrelated to the research: An adverse event is unrelated to the research if, in the opinion of the
CHRCO Principal Investigator, the adverse event is clearly due to extraneous causes (e.g., underlying disease or environment), does not follow a known pattern of response to intervention, and/or does not reappear or worsen with re-introduction of the intervention.
Serious Adverse Event: An event is considered serious if it results in death, is life-threatening, requires hospitalization or prolongation of hospitalization, causes persistent or significant disability or incapacity, is a birth defect or congenital malformation, represents, in the Principal Investigator's judgment, other significant hazards or potentially serious harm to research subjects or others, or any other event as described in the research protocol.
Serious Adverse Drug Experience: Any adverse drug experience occurring at any dose that results in any of the following outcomes: death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability or incapacity, or a congenital anomaly/birth defect. 21 CFR §312.32(a).
Internal (on-site) events: Adverse events experienced by subjects enrolled at the site(s) under the
IRB's jurisdiction for either multi-center or single-center research projects.
External (off-site) events: Adverse events experienced by subjects enrolled in multi-center clinical trials at sites other than the site(s) over which the IRB has jurisdiction.
FDA definition – Unanticipated problems:

A single occurrence of a serious, unexpected event that is uncommon and strongly associated with drug exposure.

A single occurrence, or more often a small number of occurrences, of a serious, unexpected event that is not commonly associated with drug exposure, but uncommon in the study population.

Multiple occurrences of an AE that, based on an aggregate analysis, is determined to be an unanticipated problem.

An AE that is described or addressed in the investigator's brochure, protocol or informed consent documents, but occurs at a specificity or severity that is inconsistent with prior observations.

A serious AE that is described or addressed in the investigator's brochure, protocol or informed consent documents, but for which the rate of occurrence in the study represents a clinically significant increase in the expected rate of occurrence.

Any other AE or safety finding that would cause the sponsor to modify the investigator's brochure, study protocol, or informed consent documents, or would prompt other action by the IRB to ensure the protection of human subjects.
Reporting Unanticipated Events/Problems, 02-09 Page 2 of 9

OHRP definition – Unanticipated problems involving risks to subjects or others:

Unexpected (in terms of nature, severity or frequency) given the research procedures and the subject population being studied.

Related or possibly related to participation in the 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, including physical, psychological, economic or social harm, (i.e., are serious). Individual external adverse events rarely will meet these 3 criteria for an unanticipated problem.
B. Reporting Requirements
– types of adverse events or problems that Investigators must report to the IRB in writing:
1. FDA Drug/Biologic Studies.
(a) Any adverse event that occurs on a research study investigating a drug/biologic and is both (1) unanticipated and (2) a problem to the research as determined by the CHRCO
Principal Investigator. (Unanticipated problem is described above.)
(b) Adverse effects that may reasonably be regarded as caused by, or probably caused by, the drug. If the adverse effect is alarming, the Investigator shall report the adverse effect immediately. 21 CFR §312.64(b).
(c) The death of a subject is considered a fatal adverse event and thus should be reported as such only if one the following statements apply: (1) the death occurred within thirty days of last administration of the study drug/biologic or (2) the death is considered possibly related to the study drug/biologic.
2. Non-FDA Studies. Any adverse event or other problem must be reported to the IRB that meets the conditions of an unanticipated problem, i.e., it is:
(a) unanticipated;
(b) serious; and
(c) related or possibly related to participation in the research.
All 3 conditions must apply.
3. Device Studies.
(a) Any unanticipated adverse device effects that occur on a device trial (regardless of seriousness) must be reported to the sponsor and the IRB.
(b) Any fatal or life-threatening events must be reported to the IRB, in writing, regardless of whether or not the event was expected. Life threatening is defined as the patients being at substantial risk of dying at the time of the adverse event or it is suspected that the use or conti nued use of the product would result in the patient’s death. The IRB recognizes that the information pertaining to the event may not be complete at the time of the reporting. In such cases, this should be reflected in the Investigator's assessment and additional information provided when available.
Reporting Unanticipated Events/Problems, 02-09 Page 3 of 9

(c) The death of a subject who has an experimental device implanted at the time of death should be considered a fatal adverse event and thus reported accordingly, regardless of whether the subject was actively participating in the study at the time.
4. Deviations from the investigational plan.
(a) Investigators must promptly report to the IRB any changes in research activity (see 21
CFR §56.108(a)(3) and (4)). Investigators shall notify the sponsor and the IRB of any deviation from the investigational plan to protect the life or physical well-being of a subject in an emergency (see 21 CFR §812.150(a)(4)). Except in such an emergency, prior approval by the sponsor is required for changes in or deviations from a plan, and if these changes or deviations may affect the scientific soundness of the plan or the rights, safety, or welfare of human subjects, reporting to the FDA and IRB in accordance with 21 CFR §812.35(a) also is required.
(b) Protocol violations. Examples are study enrollment before informed consent is obtained, protocol changes implemented without IRB approval, administering incorrect dosage of study medication (regardless of injury), and the improper use of study equipment or devices (regardless of any injury).
(c) Accidental or unintentional deviations to the IRB-approved protocol that involved risks to the subject.
(d) All deviations and violations described above must be reported promptly to the IRB using the Deviation Report Form .
5. New information that indicates a change to the risks or potential benefits of the research, for example:
(a) An interim analysis or safety monitoring report indicates that frequency or magnitude of harms or benefits may be different than initially presented to the IRB.
(b) Change in FDA labeling and alerts, or withdrawal from marketing of a drug, device, or biologic used in a research protocol.
(c) A new trend in one type of adverse event within a protocol, serious or not.
(d) New information in the literature – a paper is published from another study that shows that the risks or potential benefits of the research may be different than initially presented to the IRB.
(e) Incarceration of a subject in a protocol not approved to enroll prisoners.
(f) Specific protocol-defined events that require prompt reporting to the sponsor.
(g) Sponsor imposed suspension for risk.
6. Complaints of subjects that indicate unanticipated risk or which cannot be resolved by the research staff.
7. Data and Safety Monitoring Report.
At the time of continuing review, if applicable, the
Investigator should submit the DSMB or DMC report, other monitoring report or the current annual report, as well as the Continuing Review (Internal Adverse Event) Tracking Log to provide the IRB with a summarization of all adverse events that have occurred on the study.
Reporting Unanticipated Events/Problems, 02-09 Page 4 of 9

C. Time frame for reporting problems in writing:
Investigators must report problems to the IRB, in writing, in accordance with the following timelines.
1. Any unanticipated fatal or life-threatening events that are related or possibly related to the research must be reported within 24 hours after discovery by the Principal Investigator.
Life threatening is defined as the patients being at substantial risk of dying at the time of the adverse event or it is suspected that the use or continued use of the product would result in the patient’s death. The IRB recognizes that the information pertaining to the event may not be complete at the time of the reporting. In such cases, this should be reflected in the
Principal Investigator's assessment and additional information provided when available.
2. All other internal problems that require prompt reporting must be reported within 5 working days of the Principal Investigator becoming aware of the event or problem.
3. External problems that require prompt reporting (unanticipated and related or possibly related) are to be reported within 10 working days of their receipt by the Principal
Investigator.
4. Emergency protocol deviations taken without prior IRB review to eliminate apparent immediate hazard to research subjects must be reported to the IRB within 24 hours of the change in protocol and the circumstances that required its immediate implementation, using the Deviation Report Form .
5. Any unanticipated adverse device effects that occur on a device trial (regardless of seriousness) must be reported to the sponsor and the IRB as soon as possible, but in no event later than 10 working days after the Principal Investigator first learns of the effect. 21
CFR §812.150(a)(1)
6. All internal deaths, whether anticipated or unanticipated, that are not related to the research should only be reported to the IRB at the time of continuing review, using the Continuing
Review (Internal Adverse Event) Tracking Log .
7. Accidental or unintentional deviations to the IRB-approved protocol that did not involve risks, should only be reported to the IRB at the time of continuing review, using the Continuing
Review Deviation/Waiver Tracking Log.
8. Subject-specific waiver letters from the sponsor should be submitted to the IRB along with the Deviation Report Form (if required) and also listed on the Continuing Review
Deviation/Waiver Tracking Log .
D. Content of the required reports to the IRB:
The Principal Investigator must complete and submit with an original signature, the appropriate
IRB event reporting forms. The IRB relies on the expertise of our Investigators to assess the report. On the Event Report Form the Principal Investigator must assess the causality of the event, the seriousness of the event, and whether or not the event was anticipated. Also, the IRB needs the advice of the Investigators on whether a change in the protocol is necessary to minimize the risks to the subjects, whether the consent form should be revised to reflect this risk, and whether subjects on the study should be given additional information and/or sign a consent form addendum in light of this risk. Reports must include the following:
Reporting Unanticipated Events/Problems, 02-09 Page 5 of 9

1. An Event Report Form, which includes identifying information and a description of the event, why the event represents a "problem" for the study, why it is "unanticipated" and for non-
FDA studies, why the event is considered related or possibly related to the research.
2. A Reportable Adverse Event Tracking Log ; and
3. Any additional information necessary in evaluating the report (i.e.), any associated materials, if any, such as medical record notations, autopsy report, forms sent to a sponsor or the sponsor's safety report forms.
E. Adverse events or problems that do not require prompt reporting to the IRB:
1. For internal adverse events that are anticipated and related and are consistent with the frequency and severity listed in the informed consent document and any deaths that do not require prompt reporting, the Principal Investigator keeps a summary of the events that have occurred within the last approval period and submits the summary at the time of continuing review using the Continuing Review (Internal Adverse Event) Tracking Log . Except for deaths, unrelated internal events do not need to be included in this summary.
2. For reporting of external adverse events by investigators to IRBs, OHRP Guidance, January
15, 2007, advises ". . . that it is neither useful nor necessary under the DHHS regulations at
45 CFR 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. 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.
3. When an investigator receives a report of an external adverse event, the Principal
Investigator should determine whether the event was unanticipated and related or possibly related to the study drug/device/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. If the external event does not meet this reporting requirement it should not be reported to the IRB. If the sponsor insists that receipt of an event be acknowledged by the IRB, the Principal Investigator may submit a
Non-Reportable External Event Report Form to the IRB.
4. Occasionally, a sponsor will request that an external adverse event be reported for a study on which the event did not occur. For example, an adverse event of side effects from a certain drug may be reported on several studies involving that drug, even if the adverse event occurred in a subject enrolled on only one specific study. In this case the Investigator should not submit the adverse event or IND Safety Report unless there is an analysis/determination from the sponsor that an event is actually an unanticipated problem involving risks to subjects or others.
5. External adverse event reports that do not require prompt reporting to the IRB are reviewed, initialed and dated by the Principal Investigator and filed with the Investigator's research regulatory documents. They should not be submitted to the IRB, but are to be made available to the IRB upon request.
Reporting Unanticipated Events/Problems, 02-09 Page 6 of 9

6. Subject-specific waiver letters from the sponsor should be submitted to the IRB along with the Deviation Report Form (if required) and also listed on the Continuing Review
Deviation/Waiver Tracking Log .
F. IRB process for handling reported problems:
1. The IRB staff reviews the materials for an initial evaluation and to determine if the report includes the necessary information. If the report is incomplete, it is returned to the
Investigator with a request for the additional information. The Principal Investigator's assessment of external events must be provided or the report will be considered incomplete and will be returned to the Investigator.
2. If in the judgment of the reviewer, the report is definitely not an unanticipated problem involving risks to subjects or others, the following procedures are followed:
(a) If the report is for an external adverse event, the report is returned to the Investigator with an explanation for why it is being returned.
(b) If the report is for an internal event, the report is accepted, signed by the reviewer and filed in the IRB study file. A correction to the tracking log will be requested.
(c) If the report is for a publication, safety monitoring report, interim results; or other findings, the report is accepted, signed by the reviewer and filed in the IRB study file.
3. All other reports are referred to the full IRB for further action with the following exceptions.
(a) If, in the judgment of the reviewer, subjects may be at immediate risk of harm and there is insufficient time to wait for review by the convened IRB, the IRB Chair is consulted.
If the Chair determines that subjects are at immediate risk of harm, the Principal
Investigator will be required to suspend the study according to IRB policy for suspension or termination of research. (See the SOP on Suspension for Cause or
Termination.)
(b) For reports that are sent to the full IRB for review, the report is added to an IRB meeting agenda and is assigned to a primary reviewer by the IRB staff on the basis of the scientific expertise of the review. The primary reviewer and all other board members receive the following information:

A copy of the report;

A copy of all supplemental material attached to the report;

A copy of all tracking logs, if applicable;

A copy of the sponsor adverse event report form, if applicable;

A copy of the DSMB or safety report, if applicable; and

Any other relevant materials.
Reporting Unanticipated Events/Problems, 02-09 Page 7 of 9

G. What the IRB considers when reviewing a report of a problem:
1. The primary reviewer summarizes the report at the convened IRB meeting and the full IRB will determine if the report meets the definition of an unanticipated problem involving risks to subjects or others by deciding if the event meets the following criteria:
(a) Unanticipated, i.e., not anticipated (in terms of nature, severity or frequency) given the research procedures and the subject population being studied; and
(b) Places subjects or others at a greater risk of harm or discomfort related to the research than was previously known or recognized (including physical, psychological, economic or social harm).
2. The IRB may decide to postpone a decision while awaiting additional information. If, in the judgment of the IRB, subjects may be at immediate risk of harm while waiting for this information, the Principal Investigator may be required to suspend the study according to
IRB policy for suspension or termination of research.
3. If the IRB determines that the event meets both criteria, then the event will be considered an unanticipated problem involving risk to subjects or others the IRB will consider the following actions and the event will be processed as follows:
(a) No action necessary;
(b) Modification to the protocol;
(c) Modification to the informed consent document(s) for future subjects
(d) Notification of current or past subjects by phone, letter or addendum to the informed consent document;
(e) Modification of the continuing review schedule;
(f) Monitoring of the research or consent process;
(g) Suspension or termination of the research according to IRB SOP on Suspension for
Cause or Termination;
(h) Referral to legal counsel, risk management or the institutional official; or
(i) Other appropriate action as determined by the IRB.
4. For a report of an accidental or unintentional deviation to the IRB-approved protocol that involved risks or has the potential to recur, the IRB will also consider if the event represents serious or continuing non-compliance according to SOP on Investigator Non-compliance.
5. For a report of an emergency protocol deviation taken without prior IRB review, the IRB will consider if the changes were consistent with the rights and welfare of subjects.
6. The IRB decision and required actions are documented and communicated to the Principal
Investigator.
7. The IRB submits a report of the unanticipated problem involving risk to subjects or others to appropriate institutional officials and entities according to IRB SOP on Reporting of
Unanticipated Problems, Terminations, Suspensions, and Non-compliance.
Reporting Unanticipated Events/Problems, 02-09 Page 8 of 9

8. If the IRB determines that the reported event or information does not meet the two criteria in paragraph G.1 above, then the event or information will be considered not to represent an unanticipated problem involving risk to subjects; therefore, no further action is required. The
IRB decision is documented and communicated to the Principal Investigator.
9. Investigators may appeal the IRB determinations regarding the report of an unanticipated problem involving risks to subjects or others. To appeal an IRB decision, the Investigator must submit a rationale or that of the sponsor and any supporting information.
H. IRB process for handling events that do not require prompt reporting to the IRB:
1. Internal events submitted on the Continuing Review (Internal Adverse Event) Tracking
Log at the time of continuing review are reviewed according to the IRB SOP on Continuing
Review.
2. Accidental or unintentional deviations to the IRB-approved protocol that do not involve risks are reviewed at the time of continuing review, using the Continuing Review
Deviation/Waiver Tracking Log .
3. External events submitted to the IRB using the Non-Reportable External Event Report
Form are reviewed by the IRB staff. The IRB staff stamps the form acknowledging receipt by the IRB office, the form is signed and dated by the reviewer, and a copy of the form is returned to the Investigator.
I. Additional reporting requirements for the Investigator:
1. A written notification of adverse experiences must be submitted to the study sponsor, and the FDA (for drugs, devices, and biologics). Details of the reporting requirements are as follows: Adverse events must be reported immediately to the sponsor (except for those events that the protocol or investigator's brochure identifies as not needing immediate reporting). The sponsor protocol should indicate when and how adverse events are to be reported. It is likely that the sponsor will require this immediate report be followed promptly by detailed written reports of the event. Investigators should contact the study sponsor for specific reporting requirements.
2. Safety Reports. Investigators should promptly report to the sponsor any adverse effects that may reasonably be regarded as caused by, or probably caused by, the drug. If the adverse effect is alarming, the Investigator shall report the adverse effect immediately. 21 CFR
§312.64(b).
3. Pursuant to 21 CFR §312.32 regarding IND Safety Reports, adverse events that are both serious and unexpected and Unexpected Adverse Drug Experiences must be reported to the FDA. In the case of industry-sponsored protocols, reporting to the FDA is usually accomplished through the normal reporting channel (i.e. Investigator to the sponsoring company to the FDA). In the case of Investigator-initiated research or research that does not involve funding from a sponsoring company, the Principal Investigator of the protocol assumes the responsibility to report adverse events to the FDA. In such instances,
Investigators should follow the reporting procedure of the FDA Medical Products Reporting
Program (MedWatch). Under the program, adverse events can be mailed, faxed, or reported online. The time requirement for MedWatch reporting varies according to the reporting method used (i.e., mailed, phone, faxed, or online). Additional information on FDA MedWatch reporting can be obtained from the FDA web site http://www.fda.gov/medwatch/index.html
.
Reporting Unanticipated Events/Problems, 02-09 Page 9 of 9