III.12

Unanticipated Problems Involvings Risks to Subjects or Others

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PURPOSE

1. The purpose of this policy and procedure is to describe submission and review of unanticipated problems involving risks to subjects or others.

SCOPE

2. This policy and procedure is applicable to all investigators, CPHS Members and ORSC Staff.

DEFINITIONS

3. Definitions:

3.1. Unanticipated problem involving risk to participants or others, is a problem that is unanticipated or unexpected, related to the research and places subjects or others at a greater risk of harm than was previously known or recognized.

3.2. Adverse Event - Any undesirable and unintended, although not necessarily unexpected, effect of the research occurring in human subjects as a result of (a) the interventions and interactions used in the research; or (b) the collection of identifiable private information under the research.

3.3. An adverse experience as defined by FDA regulations at 21 CFR 600.80(a) – Any adverse event associated with the use of a biological product in humans, whether or not considered product related, including the following: an adverse event occurring in the course of the use of a biological product in professional practice; an adverse event occurring from overdose of the product whether accidental or intentional; an adverse event occurring from abuse of the product; an adverse event occurring from withdrawal of the product; and any failure of expected pharmacological action.

3.4. A serious adverse drug experience as defined by FDA regulations at 21 CFR 310.305(b), 312.32(a), and 314.80(a) – 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/incapacity, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

3.5. An unanticipated adverse device effect as defined by FDA regulations at 21 CFR 812.3(s) – 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.

3.6. An unexpected adverse drug experience as defined by FDA regulations at 21 CFR 312.32(a) – Any adverse drug experience, the specificity or severity of which is not consistent with the current investigator brochure; or, if an investigator brochure is not required or available, the specificity or severity of which is not consistent with the risk information described in the general investigational plan or elsewhere in the current application, as amended.

POLICY

4. The Principal Investigator is responsible for the accurate documentation, investigation and follow up and timely reporting of the following problems:

1. Adverse event (any harm experienced by a participant regardless of whether the event was internal (on-site) or external (off-site) and regardless of whether the event meets the FDA definition of “serious adverse event”), which in the opinion of the principal investigator are both unexpected and related.
   1. An adverse event in which the nature and severity is not consistent with information in the relevant source documents is an unexpected adverse event.
   2. An adverse event is “related to the research procedures” when there are facts (evidence) or arguments to suggest a causal relationship.
2. Information that indicates a change to the risks or potential benefits of the research. For example:
   1. 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.
   2. 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.
3. A breach of confidentiality.
4. Change in FDA labeling or withdrawal from marketing of a drug, device, or biologic used in a research protocol.
5. Change to the protocol taken without prior IRB review to eliminate an apparent immediate hazard to a research participant.
6. Incarceration of a participant in a protocol not approved to enroll prisoners.
7. Event that requires prompt reporting to the sponsor.
8. Sponsor imposed suspension for risk.
9. Complaint of a participant when the complaint indicates unexpected risks or cannot be resolved by the research team.
10. Protocol violation (meaning an accidental or unintentional change to the IRB approved protocol) that harmed participants or others or that indicates participants or others may be at increased risk of harm.
11. Sponsor imposed suspension for risk.
12. Unanticipated adverse device effect

4.2. The above should be reported regardless of whether they occur during the study, after study completion, or after participant withdrawal or completion.

PROCEDURE

Assessment by Principal Investigator

5. The Principal Investigator must make a judgment about the expectedness of a problem. If the problem is an adverse event, the investigator must make a judgment about the causality of the adverse event. The Principal Investigator must also analyze the event and state whether protocol / consent form revisions are required.

5.1. Assessment of Expectedness - The Principal Investigator must state whether the problem is expected or unexpected. An unexpected problem is one, the nature and severity of which is not consistent with information in the relevant source document (s). For an investigational drug, the Investigator Brochure serves as the source document. Reports that add significant information on specificity or severity of a known, already documented serious adverse event constitute unexpected events. For example, a problem more specific or more severe than described in the Investigator’s Brochure would be considered unexpected.

5.2. Assessment of Causality – For adverse events the Principal Investigator should evaluate the event and assess causality. The expression ‘reasonable causal relationship’ is meant to convey in general that there are facts (evidence) or arguments to suggest a causal relationship. For purposes of reporting, adverse event reports associated with marketed drugs usually imply causality. The following conditions might help to assess causality:

1. the event has a reasonable temporal relationship to the intervention,
2. the event could not have been produced by the underlying disease states,
3. the event could not have been due to other non-study interventions,
4. the event follows a known pattern of response to the intervention, or
5. the event disappears with cessation of intervention.

Reporting Timeframe

6. Investigators must report the reportable events described above to CPHS via iRIS within 7 days, unless the report involves the death of a participant, in which case the report needs to be provided to CPHS within 24 hours.

1. All problems involving local deaths, should be reported immediately – within 24 hours after first knowledge by the investigator.
2. All other problems must be reported as soon as possible but not later than 7 calendar days after first knowledge by the investigator.

CPHS Review Process

7. Upon receipt of reports, ORSC Staff will review them and determine if the report meets the following criteria: (1) unexpected, (2) related or possibly related to the research and (3) indicates that participants or others are at increased risk of harm.

a. If the report does NOT meet both criteria, the report is NOT an unanticipated problem involving risks to participants or others, and no further action is taken.
b. If the report meets both criteria, the report is an unanticipated problem involving risks to participants or others.

7.1. ORSC Staff will evaluate reports that meet the definition of unanticipated problems involving risks to subjects or others to determine if the problems involve more than minimal risk to subjects or others. The ORSC Staff will review the report and if applicable, the protocol and consent document to make this determination.

7.2. Unanticipated problems that involve no more than minimal risk to subjects or others may be reviewed by expedited procedure. ORSC Staff shall assign it for review by the Chairperson of the subcommittee that initially review the research proposal. If the Chairperson is not available, the ORSC Staff will assign it to one of the other subcommittee members or another CPHS member. The reviewer will review the report and if applicable, the protocol and consent document to make this determination.

7.3. ORSC Staff will include unanticipated problems involving greater than minimal risks to subjects or others in the agenda for the next full board meeting of the IRB that conducted the initial or previous continuing review of the research. Where possible, ORSC Staff shall assign it to the Chairperson of the subcommittee that initially reviewed the research. If the Chairperson is not available, ORSC Staff will assign it to one of the other subcommittee members or another CPHS member. The Reviewer and all CPHS members have access to all previous information regarding the research project in iRIS. The CPHS members will review the report and if applicable, the protocol and consent document. The IRB Chairperson may determine that immediate actions, such as the immediate suspension or termination or research, are needed to protect the rights and welfare of currently enrolled subjects. The Executive Chairperson and the Institutional Official can also perform this function.

8. Outcome of Review: The convened IRB Panel considers the following actions:

1. No action;
2. Modification of research protocol;
3. Modification of information disclosed during the consent process;
4. Additional information provided to past subjects;
5. Additional information provided to current subjects (required when such information may relate to subjects’ willingness to continue to take part in the research);
6. Request for the outcome of the most recent Data Safety Monitoring review;
7. Requirement that current subjects re-consent to participation;
8. Modification of the continuing review schedule;
9. Monitoring of the research;
10. Monitoring of the consent process;
11. Suspension of the research;
12. Termination of the research;
13. More information sought pending final decision;
14. Referral to appropriate institutional authorities such as legal counsel, Institutional Official
15. Any other actions.

8.1. If CPHS requires the Principal Investigator to make more than minor modifications in response to unanticipated problems involving risks to subjects or others, the Principal Investigator’s modifications will be reviewed at the subsequent full board meeting as per policy and procedure Change Requests and Protocol Amendment.

9. Reporting: After review by the convened IRB, the unanticipated problem involving risks to participants or others is reported to regulatory agencies and institutional officials following policy and procedure on Reporting.

RESPONSIBILITY

10. Investigator is responsible for timely reporting of unanticipated problems.

Applicable Regulations and Guidelines

1. 45 CFR 46.103(b)(5)(i)
2. 21 CFR 56.108(b)(1)
3. 21 CFR 312.53(c)(vii)
4. 21 CFR 312.66
5. 21 CFR 812(a)(1)
6. OHRP Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events
7. OHRP Guidance on Reporting Incidents to OHRP
8. FDA Information Sheets: Continuing Review After Study Approval

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Updated 2/2009, Report broken links