COTTAGE HEALTH SYSTEM POLICY

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SUBJECT:

ADVERSE EVENT REPORTING

Adverse event reporting

 

DEPT: IRB POLICY #: 8012.02

 

GOAL:

  1. To establish a set protocol to be followed when a participant enrolled in a research study being conducted by an investigator, whose study is under the purview of the CHS IRB, experiences an adverse event.
  2. To establish a set protocol to be followed when an investigator, whose study is under the purview of the CHS IRB, receives external adverse event reports from the study sponsor.

POLICY:

All investigators engaged in human subjects research are required by Federal guidelines to report adverse events occurring in individuals participating in research to the IRB for review (whether they are the investigator's own participants or individuals enrolled at another site).

 

This policy currently reflects:

  • 21 CFR 312 - Investigational New Drug Application
  • 21 CFR 812 - Investigational Device Exemptions
  • 21 CFR PART 814 - Premarket Approval of Medical Devices (subpart h - Humanitarian Use Devices)
  • 45 CFR 46 - Protection of Human Subjects
  • 1996 International Conference on Harmonizaton E-6 Guidelines for Good Clinical Practice (ICH GCP Guidelines)
  • Guidance for Clinical Investigators, Sponsors, and IRBs:  Adverse Event Reporting - Improving Human Subject Protection (Food and Drug Administration (FDA) and Department of Health and Human Services (HHS) combined guidance dated April 2007);
  • Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events (Office of Human Research Protections (OHRP), HHS, dated January 15, 2007).

DEFINITIONS:

Adverse event (or experience):
Any untoward medical occurrence in a research participant receiving an investigational pharmaceutical product or investigational device; not necessarily having to have a causal relationship with the intervention.

 

The event may represent an unfavorable sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the investigational intervention.

  • Internal Adverse Event:  One occurring in a patient under the care of the local investigator whose study is under the purview of the CHS IRB (also referred to as "on-site" adverse events).
  • 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.  External Adverse events can be classified into two groups:

•    Off-site events are adverse events that have occurred in patients/participants at other sites who are enrolled in the same research study as that which local investigator is participating in.
•    Off-trial events are adverse events that have occurred in patients/participants at other sites, enrolled in different research studies than that which the local investigator is participating in, but who are receiving the same investigational intervention.

 

Unexpected adverse event:
Any adverse experience that is not identified in nature, severity or frequency in the current investigator brochure; or, if an investigator brochure is not required, is not identified in nature, severity or frequency in the risk information described in the general Investigational Plan, Study Protocol, consent document, or elsewhere in the current research application.

 

Rather than unexpected adverse event, the FDA uses the term unanticipated and describes it as a situation whereby the specificity or severity of the adverse event is not consistent with the current investigator's brochure or with other current risk information (based on 21 CFR 312.32(a)).  According to the FDA, this definition encompasses those events that may be enumerated in an Investigator's Brochure, but which occur -- in the investigator's judgment -- with an unexpected frequency and/or severity.

 

Unanticipated adverse device effect (UADE) is defined by the FDA as 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 (21 CFR 812.3).

 

Related Adverse Event:
Based on 21 CFR 312.32(a), related or possibly related adverse events are defined as:

  • Related adverse event:  There is a reasonable possibility that the adverse event may have been caused by the drug or intervention.
  • Possibly related adverse event:  It is possible that the adverse event may have been caused by the drug or intervention, but there is insufficient information to determine the likelihood of this possibility.

Serious adverse event:
The investigational intervention:

  • results in death
  • results in an event during which the subject was at risk of death; life threatening
  • results in hospitalization or prolongation of existent hospitalization
  • results in persistent or significant disability or incapacity
  • results in a congenital anomaly/birth defect/cancer
  • represents an overdose or a device failure

 

PROCEDURE:

General Information

1. The principal investigator must notify the IRB whenever there are unanticipated, intervention-related adverse events or problems originating from any site participating in the study.

 

2. The investigator must use the Offsite Adverse Event Report form (Word document) or the Onsite Adverse Event Report form (Word document).

 

3. The IRB Chair reviews all adverse events as expedited reviews.  If the IRB Chair determines that an adverse event indicates a risk or interventional problem of sufficient severity, it will be presented to the IRB at a convened meeting.  Otherwise, both on-site and off-site adverse events are reported to the IRB, but not reviewed by the Full Board.

 

4. Upon receipt of an adverse event report, the Chairperson may suspend enrollment of the study until the next meeting, permit the approval to stand until the next meeting, revise the continuing review timetable, or allow the study to continue with or without minor changes to the protocol or consent form.

 

5. The IRB may:

  • Require changes to the protocol or consent form;
  • Suspend or terminate approval of research if a given study is not being conducted in accordance with IRB and/or study guidelines;
  • Suspend or terminate approval of research if it judges the risks to participating subjects to exceed anticipated benefits.

6. If an internal unanticipated problem is reported by the local investigator, the IRB will assess the event and report it as needed to appropriate authorities.  If further reporting is necessary, the investigator will be apprised of these actions in writing.  Appropriate authorities may include:

  • CHS institutional officials
  • The Food and Drug Administration, if the study is a drug or device study (per regulations set forth at 21 CFR 56.108(b)(1))
  • The Office for Human Research Protection (OHRP) if the study is federally funded (per regulations set forth at 45 CFR 46.103(B)(5)(i))

7.  The investigator shall notify the Study Sponsor of all adverse events occurring in his/her patients according to the adverse event reporting guidelines outlined in the study protocol and or investigator's brochure.  The investigator shall simultaneously report all qualifying adverse events to the CHS IRB according to the reporting guidelines outlined in this policy.

 

Reporting Requirements of Internal (Onsite Adverse Events)

If a subject under the care of an investigator whose study is under the purview of the CHS IRB suffers a fatal adverse event, the IRB must be notified within 24 hours of the investigator’s knowledge of the event.
    
All other onsite adverse events that meet ALL three of the following criteria are to be reported to the IRB within 10 working days of the investigator's knowledge of the event:

  • Moderate or severe in nature - AND
  • Events likely to be related to the investigational intervention - AND
  • Unexpected events (not outlined in the Investigator's Brochure or Study Protocol)

Minor, unrelated, and/or expected adverse events should not be submitted for review.  If such an adverse event is submitted to the IRB, it shall be stamped "received" and dated, and will be filed.  A copy of the stamped adverse event report will be returned to the investigator for filing.  Minor, unrelated, and/or expected adverse events may also be reported annually at the time of continuing review.  These adverse events may be submitted in tabular form.

 

Reporting of External Adverse Events

Investigators may receive adverse event reports from the sponsor involving subjects not under their care (External Reports).  Investigators are responsible for reviewing and evaluating ALL external adverse event reports (both offsite AND off-trial) coming from the sponsor.

 

It is the investigator's responsibility to be informed of the events occurring at other sites in order to determine how these risks may affect his/her patients.  Adverse event review is an integral part of the research, as a main goal of clinical research is to determine the risks associated with the interventional drug or device.  In addition, individually, most sites do not enroll a large number of participants; therefore an investigator would not be able to determine if serious adverse events were occurring in a significant number of people.

 

It is the investigator's duty to inform the IRB, because it is the IRB's role to determine whether or not the adverse events affect the risks to patients, or if changes to the consent form need to be made.  The IRB relies on the investigator's expertise to determine the significance of the adverse event and its relationship to the study.  It is not the responsibility of the IRB Chair or members of the IRB Committee to make this determination.

  • Offsite events are adverse events that have occurred in patients/participants at other sites who are enrolled in the same research study as that which local investigator is participating in.
  • Off-trial events are adverse events that have occurred in patients/participants at other sites, enrolled in different research studies as that which the local investigator is participating in, but who are receiving the same investigational intervention.

 

It is the investigator’s responsibility to be informed of the events occurring at other sites in order to determine how these risks may affect his/her patients. Adverse event review is an integral part of the research, as a main goal of clinical research is to determine the risks associated with the interventional drug or device. In addition, individually, most sites do not enroll a large number of participants; therefore an investigator would not be able to determine if serious adverse events were occurring in a significant number of people.

 

It is the investigator’s duty to inform the IRB, because it is the IRB’s role to determine whether or not the adverse events affect the risks to patients, or if changes to the consent form need to be made. The IRB relies on the investigator’s expertise to determine the significance of the adverse event and its relationship to the study. It is not the responsibility of the IRB Chair or members of the Committee to make this distinction.

 

Reporting Requirements of External (Offsite) Adverse Events
Offsite external adverse events must meet ALL three of the following criteria to be reported to the IRB:

  • Moderate, severe, or fatal in nature / all serious adverse events -  AND
  • Events likely to be related to the investigational intervention -  AND
  • Unexpected events (not outlined in the Investigator's Brochure or Study Protocol)

External offsite adverse events are to be submitted as soon as reasonably possible, using the External (Offsite) Adverse Event Report form. The external safety reports received from the sponsor should be attached.

External (offsite) adverse event reports are not to be submitted if all subjects at the local investigator site have completed study participation or if the adverse events do not require that previously enrolled subjects be notified.  As these events would be captured in a sponsor's Annual Report, they may be reported to the IRB by submitting the Annual Report for review.

Reporting Requirements of External (Off-Trial) Adverse Events

Because it may be very difficult for the local investigator to make interpretive decisions regarding adverse events experienced by patients at other sites participating in different research trials, he/she is not expected to complete the External (Offsite) Adverse Event Report form for off-trial adverse events.  It is not reasonable for the local PI to determine causality for these events, nor would he/she be familiar with another study's Investigator Brochure, protocol, or consent form to make recommendations regarding changes to these documents.  Therefore, external off-trial adverse events should not be submitted, unless the investigator recognizes a recurring incident which may pose as a risk to locally enrolled subjects.  In such situations, the investigator may submit the External (Offsite) Adverse Event Report form, with an explanation of why it is being submitted.

 

Unanticipated Adverse Device Effect Reporting
Device sponsors have an explicit requirement to conduct an evaluation of an unanticipated adverse device effect (UADE) and to present the results of this evaluation directly to the participating IRBs (21 CFR 812.150(b)(1)).

 

The IRB will review the UADE (in the same manner and following the same guidelines as previously outlined in this policy), make a determination, and respond in writing to the investigator.  The investigator will forward the IRB letter to the device manufacturer as recognition of the IRB's review of the UADE.

 

Protocol Deviations and Violations

If a protocol deviation or violation results in an adverse event to the participant, and the adverse event qualifies as a reportable adverse event, the investigator must follow the adverse event reporting guidelines.  It must be noted in the report to the IRB that a protocol deviation or violation was responsible for the adverse event and how it was related to the event.  Otherwise, the deviation/violation is to be reported as an obligation of "ongoing communication" as outlined in IRB policy #8012.05

 

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COTTAGE HEALTH SYSTEM POLICY

RECOMMENDED BY: Leilani Price DATE: 5/30/02

ORIGINAL POLICY EFFECTIVE DATE: 9/02

APPROVED BY: .. DATE: 5/30/02

DATE REVISED: 1/05; 12/10
DATE REVIEWED: 4/06; 1/08; 1/09