SOP #24 Unanticipated Problems and Adverse Events

Owner: Vice President of Academic Affairs
Author: CSS IRB
Contact: irb@css.edu
Policy Number: 24
Effective Date: 10/8/2021

 

Policy

Investigators are responsible for prompt reporting to the IRB of "any unanticipated problems involving risks to participants or others…" (21 CFR 56.108.(b)(1) and 45 CFR 46.108 (a)(4)(i)(ii)).  The IRB maintains responsibility for initial assessment of the risk/ benefit ratio in a research activity involving human participants. During the course of the project, investigators are required to promptly inform the IRB of any unanticipated negative effect or undesirable experience that is possibly, probably or definitely related to study procedure(s).

Purpose

The purpose of this standard operating procedure (SOP) is to ensure that adverse and serious adverse events are defined, recorded, reported, and evaluated as required by the CSS Institutional Review Board (IRB).  Principal Investigators are required to immediately submit to the IRB any unanticipated problems involving risk to human subjects or others. The notification to the IRB must occur no later than 2 weeks from the time of identification of the unanticipated problem.

Definitions

Adverse Events (AE’s)

OHRP defines an adverse event 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.  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. Attention must be paid to psychological harm (such as depression, thoughts of suicide, etc.), threats to privacy, or participant safety. An event is considered serious and must be reported when the participant experiences an unusually strong response, recurring problems, and/or death.

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.

Serious Adverse Event (SAE’s)

OHRP defines serious adverse event as any adverse event that:

  1. results in death;
  2. is life-threatening (places the subject at immediate risk of death from the event as it occurred);
  3. results in inpatient hospitalization or prolongation of existing hospitalization;
  4. results in a persistent or significant disability/incapacity;
  5. results in a congenital anomaly/birth defect; or
  6. 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 Problems Involving Risks to Subjects or Others (UPIRSO)

OHRP considers unanticipated problems, in general, to include any incident, experience, or outcome that meets all of the following criteria:

  1. Is the adverse event 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. Is the adverse event related or possibly related to participation in the research (in the OHRP 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. Does the adverse event suggest 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.

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).

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:

  1. 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
  2. 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.

Possibly Related

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.

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

  1. The procedures involved in the research;
  2. An underlying disease, disorder, or condition of the subject; or
  3. 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.

Prompt Reporting (See also, CSS IRB SOP # 03 IRB RECORDS)

  • The submission of at least a preliminary report of unanticipated problems to the CSS IRB within five calendar days of the Investigator determining that the event(s) possibly meets the definition of an unanticipated problem involving risks to subjects or others.
  • Promptly report (within 14 calendar days) unanticipated problems to appropriate institutional officials, applicable regulatory or oversight agencies, and, when appropriate, the sponsor or contract research organization and other sites involved in the research.

FDA - Unanticipated Adverse Device Effect (UADE)

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(s)).

Office for Human Research Protections OHRP

The Office for Human Research Protections (OHRP) provides leadership in the protection of the rights, welfare, and wellbeing of human subjects involved in research conducted or supported by the U.S. Department of Health and Human Services (HHS). OHRP is part of the Office of the Assistant Secretary for Health in the Office of the Secretary of HHS.

Example of Behavioral/Social Adverse Event

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 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. (See, CSS IRB SOP #26 Survey Research and Internet Research.)

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.

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 46.108 (a)(4)(i)(ii)).

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 IRB 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.

The flow chart 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.  See also, “What Incidents Should be Reported to OHRP”  Appendix A.

Reporting Requirements and Procedures

The Principal Investigator must promptly report any Unanticipated Problems to the IRB (See, Report Form Appendix B). The CSS IRB requires Investigators to report in accordance with the following guidelines in order to satisfy the prompt reporting requirement:

  1. Unanticipated Problems that are Serious Adverse Events must be reported to the IRB withinfive (5) business days of the Investigator becoming aware of the event. The IRB strongly recommends that a preliminary report be submitted by the researcher within 48 hours of learning of the Serious Adverse Event with a formal follow-up report submitted within the above timeline. Investigators should not include identifiable information in the report(s).
  2. Any other Unanticipated Problem should be reported to the IRB within two (2) weeks of theInvestigator becoming aware of the problem. The IRB strongly recommends that a preliminary report be submitted by the researcher within five (5) business days of learning of the Unanticipated Problem with a formal follow-up report submitted within the above timeline. Investigators should not include identifiable information in the report(s).
  3. The IRB Chair reports all Unanticipated Problems to the Institutional Official.  The InstitutionalOfficial notifies the supporting agency head (NIH or designee), and OHRP within one month of the IRB’s receipt of the report of the problem from the Investigator.
  4. In some cases, the requirements for prompt reporting may be met by submitting apreliminary report to the IRB, the IO, 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 (See, Appendix B). The primary consideration in making these judgments is the need to take timely action to prevent avoidable harms to other subjects.
  5. The CSS IRB will respond to participant complaints, CSS hotline reports, self-disclosures,reliable reports from another source, or requirements for clarification from an investigator in the same manner as an Unanticipated Problem Report.

Content of Unanticipated Problem Report

When making a report to the IRB, an Investigator should include the following information:

  1. appropriate identifying information for the research protocol, such as the title, Investigator’sname, and the IRB project number;
  2. a detailed description of the Adverse Event, incident, experience, or outcome; however, topreserve confidentiality, subject names and identifiable information should not be included in the report);
  3. an explanation of the basis for determining that the Adverse Event, incident, experience, oroutcome represents an unanticipated problem; and
  4. a description of any changes to the protocol or other corrective actions that have been takenor are proposed in response to the unanticipated problem.

The Investigator is responsible for assessing and documenting unanticipated problems and reporting to the IRB, as required by this policy, regardless of who observed or became aware of the event. (a) The Investigator should use his or her judgment when determining if an event is considered reportable. When in doubt, the investigator should contact the CSS IRB  for guidance.

  1. In the absence of the Investigator, a co-researcher can fulfill these requirements to meet thereporting timeline.
  2. In the absence of either the Investigator or a co-researcher, a student member of theresearch team or other research personnel must contact the IRB for direction.

Collaborative Research

Unanticipated Problems should be reported to the IRB of record.

  1. When the CSS IRB is the IRB of record, Unanticipated Problems must be reported in accordance with this SOP, regardless of where the Unanticipated Problem occurred. The CSS Investigator is responsible for coordinating the reporting.
  2. When a CSS Investigator is relying upon IRB review from another institution, Unanticipated Problems must be reported in accordance with the policies and procedures of that institution.

The Institutional Official or designee is responsible for reporting Unanticipated Problems to the supporting agency or designee, OHRP and the Food and Drug Administration (FDA), as required.

The Investigator must fulfill the reporting requirements of other organizations (e.g., Sponsor), which are not satisfied nor precluded by submitting an Unanticipated Problem report to the CSS IRB. Likewise, submitting Unanticipated Problem or Adverse Event reports to other organizations (e.g., Sponsor) does not satisfy the reporting requirement to the CSS IRB.

Food and Drug Administration

The FDA believes that only the following AEs should be considered as unanticipated problems that must be reported to the IRB.

  • A single occurrence of a serious, unexpected event that is uncommon and strongly associated with drug exposure (such as angiodema, agranulocytosis, hepatic injury, or Stevens-Johnson syndrome).
  • 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 (e.g., tendon rupture, progressive multifocal leukoencephalopathy).
  • Multiple occurrences of an AE that, based on an aggregate analysis, is determined to be an unanticipated problem. There should be a determination that the series of AEs represents a signal that the AEs were not just isolated occurrences and involve risk to human subjects (e.g., a comparison of rates across treatment groups reveals a higher rate in the drug treatment arm versus a control). We recommend that a summary and analyses supporting the determination accompany the report.
  • 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. For example, if transaminase elevation is listed in the investigator’s brochure and hepatic necrosis is observed in study subjects, hepatic necrosis would be considered an unanticipated problem involving risk to human subjects. We recommend that a discussion of the divergence from the expected specificity or severity accompany the report.
  • 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 (ordinarily, reporting would only be triggered if there were a credible baseline rate for comparison). We recommend that a discussion of the divergence from the expected rate accompany the report.
  • Any other AE or safety finding (e.g., based on animal or epidemiologic data) 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. We recommend that an explanation of the conclusion accompany the report.

Unanticipated Adverse Device Effects (UADE) must be reported by the clinical investigator to the sponsor and the reviewing IRB, as described below:

  • For device studies, investigators are required to submit a report of a UADE to the sponsor and the reviewing IRB as soon as possible, but in no event later than 10 working days after the investigator first learns of the event (21 CFR § 812.150(a)(1)).
  • Sponsors must immediately conduct an evaluation of a UADE and must report the results of the evaluation to FDA, all reviewing IRBs, and participating investigators within 10 working days after the sponsor first receives notice of the effect (§§ 812.46(b), 812.150(b)(1)). The IDE regulations, therefore, require sponsors to submit reports to IRBs in a manner consistent with the recommendations made above for the reporting of unanticipated problems under the IND regulations.  (See, CSS IRB SOP #40 Research Studies Involving Investigational Medical Devices.)

IRB Review and Response

Initial review of Unanticipated Problems will be conducted by the CSS IRB Chair (or designee). The IRB Vice Chair will serve as the primary designee for inquiry unless another IRB Member is specifically named by the IRB Chair or Institutional Official or a conflict of interest prevents this duty. The IRB Chair (or designee) is authorized to take the following actions in response to any incident report:

  1. Conduct an administrative review of the report, including assessing whether the incidentconstitutes an Unanticipated Problem and by whom it should be reviewed (e.g., the IRB Chair only, IRB Associate Chair only, an IRB subcommittee, or the convened IRB).
  2. If a convened IRB review is needed, the IRB Chair or designee assigns the incident report forreview at the next available regularly scheduled IRB meeting. Assignment to a convened meeting will occur by the processes found in CSS IRB SOP #27: Initial Review.
  3. Alternately, the IRB Chair may convene an emergency meeting of the IRB to review thereport.
  4. If the IRB Chair (or designee) finds that the rights, safety, and welfare of subjects arejeopardized by the research, the IRB Chair may suspend research until such time that the full IRB can convene to review the report.

When reviewing a report of an Unanticipated Problem, the IRB should consider whether the affected research protocol still satisfies the criteria for IRB approval under regulations at 45 CFR 46.111 (Criteria for IRB approval of research). See also, CSS IRB SOP 27: Initial Review. 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.

After reviewing the Unanticipated Problem report, the IRB may require the following actions, in order to protect the ongoing safety of research subjects:

  1. Modification of subject inclusion or exclusion criteria to mitigate the newly identified risks;
  2. Implementation of additional procedures for monitoring subjects;
  3. Modification of informed consent documents to include a description of newly recognized risks. This will be required whenever the information may relate to the participant’s willingness to continue participating;
  4. Provision of additional information about newly recognized risks to previously enrolled subjects;
  5. Observe the process of informed consent;
  6. Suspension of enrollment of new subjects;
  7. Suspension of research procedures in currently enrolled subjects;
  8. Suspension of the entire study; or
  9. Termination of approval for the entire study (See, CSS IRB SOP #31 Suspension or Termination of IRB Approval and Report Form).

If the response to an Unanticipated Problem requires an amendment of the research protocol and/or informed consent forms, an amendment request must be submitted to the IRB in accordance with SOP # 22: Modifications to Previously Approved or Exempt Research. If the changes are minor, they may be reviewed by expedited review procedures. If the changes are more than minor, they must be reviewed and approved by the convened IRB. Any such proposed changes in response to an Unanticipated Problem must be reviewed and approved by the IRB before being implemented, except when implementation is necessary to eliminate apparent immediate hazards to subjects.

Responsibility

The IRB Chair or his/her designee is responsible for reviewing all reports of unanticipated problems, ensuring the appropriateness of all IRB decisions and actions, and is responsible for reporting unanticipated problems to the OHRP or other outside institutions as needed and will notify the Institutional Official.

The Principal Investigator is reminded that any proposed changes to the 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 hazard to subjects.

The IRB Administrator is responsible for advising the IRB Chair on relevant institutional and regulatory requirements.

The Institutional Official or designee is responsible for reporting unanticipated problems to OHRP or other outside institutions as needed.

Investigational Medical Device Sponsors must immediately conduct an evaluation of a Unanticipated Adverse Device Event (UADE) and must report the results of the evaluation to FDA, all reviewing IRBs, and participating investigators within 10 working days after the sponsor first receives notice of the effect (§§ 812.46(b), 812.150(b)(1)). FDA encourages efforts by investigators and sponsors to ensure that IRBs receive meaningful UADE information.

Resources

OHRP Guidance  - Unanticipated Problems Involving Risks & Adverse Events Guidance (2007) https://www.hhs.gov/ohrp/regulations-and-policy/guidance/reviewing-unanticipated-problems/index.ht ml#Q1

FDA - Adverse Event Reporting to IRBs — Improving Human Subject Protection http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm Portions of this SOP relied on: “This information was obtained from Reportable Events:

Recommendations for Investigator-initiated Multisite Studies as part of SMART IRB, which is funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational

Science Awards Program, grant number 3UL1TR002541-01S1.”

21 CFR 812

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=812&showFR=1

FDA Adverse Event Reporting to IRBs — Improving Human Subject Protection https://www.fda.gov/media/72267/download

Purdue University - https://www.irb.purdue.edu/docs/new/sops-web.pdf

Children’s Hospital of Philadelphia (CHOP) - https://irb.research.chop.edu/policies

University of Southern Alabama -

https://www.southalabama.edu/departments/research/compliance/humansubjects/resources/601.adve rse.event.reporting.pdf

 

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