Reporting of Unanticipated Problems Involving Risks to Subjects Or Others

INSTITUTIONAL REVIEW BOARD

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 life-threatening 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.

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.

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

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 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 Investigator's assessment and additional information provided when available.

(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).

(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.

(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.

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:

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.