Office of Human Research
Page Title

SOP No.: 604   ADVERSE EVENT RECOGNITION AND REPORTING

Author:    Office of Human Research

Effective Date:  October 1, 2007

Supercedes document dated:              N/A

Last Reviewed on:     N/A                                 

Results of Review:               N/A

This SOP pertains to:  the individuals and activities involved in collecting and handling specimens from participants enrolled in Food and Drug Administration (FDA)-regulated human subject research conducted within Thomas Jefferson University.

Responsibility for executing this SOP:  Investigator and Designated Research Personnel

Approved By:

 

J. Bruce Smith, MD

 

Associate Vice President for Research

 

(signature on file at OHR)

Approved By:

 

Steven E. McKenzie, MD, Ph.D.

 

Vice President for Research

 

(signature on file at OHR)

 

1. PURPOSE

This procedure describes the regulatory requirements for identifying, investigating and reporting adverse events that occur in individuals who are participating in any clinical study .

2. GENERAL INSTRUCTIONS

In conducting investigator-initiated trials, the Investigator is responsible for ensuring that all participating Investigators understand the requirements and procedures to report all serious adverse events or experiences (SAE) and adverse events (AE) according to applicable regulations and guidelines.

  1. The Investigator and all other participating Investigators are responsible for recognizing and reporting SAE, some of which may require immediate reporting by the Investigator to the FDA and other regulatory authorities
  2. The Investigator and all other participating Investigators are responsible for recognizing and reporting all other expected, unexpected and non-serious or routine AE as required by the clinical protocol.
  3. The Investigator and all other participating Investigators are responsible for the appropriate medical management and follow-up of participants who have experienced an AE while on study, irrespective of relationship to study treatment or investigational product.
  4. The Investigator and all other participating Investigators are responsible for communicating details of AE and any follow-up data to the IRB and any other relevant internal research review group.
  5. The Investigator, all other participating Investigators are responsible for documenting AE on the appropriate case report form (CRF) and other regulatory reporting forms (e.g., FDA MedWatch Form 3500A).
  6. The Investigator is required to prepare IND Safety Reports or other appropriate notification to all participating Investigators as a result of an SAE, including death, that are reported to the Investigator.
  7. The Investigator and participating Investigators or their designees are responsible for forwarding IND Safety Reports or other appropriate device-related notification to the IRB(s) of record and in accordance with the IRB(s) requirements.

3. SPECIFIC PROCEDURES

3.1 Identifying Adverse Events at the Clinical Site

3.1.1 Subject Assessment:

The Investigator and all other participating Investigators should assess each participant for the following throughout each participant's study participation and during the follow-up period specified in the protocol:

    1. Any adverse change from baseline (pretreatment) condition
    2. Any intercurrent illness that occurs during the course of a clinical study after treatment with the investigational product/treatment has started, whether considered related to the investigational product/ treatment or not
    3. Any effect that is unintended and unfavorable, such as a sign, a symptom, a laboratory abnormality, or a disease

3.1.2 Events for Investigation and Reporting

The Investigator should ensure that the following are appropriately investigated and reported by all participating Investigators:

    1. Spontaneous reports by participants
    2. Observations by key study personnel
    3. Reports to study staff by the participant's family or medical care providers
    4. Possible AE documented in medical records, progress notes, etc.
    5. Reports of a participant death within thirty (30) days after stopping treatment or during the protocol-defined follow-up period, whichever is longer, whether considered treatment-related or not

3.1.3 Adverse Event Monitoring:

The Investigator and all participating Investigators should consistently and routinely monitor for AE by taking proactive measures such as the following:

    1. Interview participants
    2. Review lab reports
    3. Review participants' medical records for additional information
    4. Review (if applicable) participants' diaries
    5. Communicate with participants' medical providers

3.1.4 Determination of Adverse Event Type:

The Investigator and all participating Investigators/designees should determine whether the AE is an SAE or not. The FDA definition for an SAE is:

Any adverse event occurring at any dose that results in any of the following outcomes:

    • Death
    • Life-threatening experience
    • Inpatient hospitalization or prolongation of hospitalization
    • Persistent or significant disability/incapacity
    • Congenital anomaly/birth defect

Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered an SAE when, based upon appropriate medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of outcomes noted above. Any event not qualifying as an SAE is considered an AE.

3.2 Clinical Management and Documentation of Adverse Events

3.2.1 Therapeutic Intervention:

The Investigator and all participating Investigators/designees should ensure that all appropriate resources are directed toward participant safety and well-being. They shall institute therapeutic intervention/support measures for participants experiencing an AE. If applicable:

    1. Discontinue therapy with the investigational product, comparator, or placebo
    2. Reduce dosage as per protocol
    3. Interrupt drug as per protocol
    4. Challenge as per protocol and if performed, under medical supervision

3.2.2 Adverse Event Follow-up

The Investigator and all participating Investigators should follow up and assess the AE until stabilized/resolved by:

    1. Directed or complete physical examination and clinical assessment
    2. Appropriate laboratory tests, diagnostic procedures and/or studies
    3. Medical/surgical consultants as needed

3.2.3 Breaking the Study Blind:

    1. If necessary for the immediate medical care of an AE in one of the participants, the investigational product blind may be broken. This breaking of the blind should be documented in the CRF and in the participant's file. The method of blinding and an example of a blinded label should be included in the clinical protocol.
    2. The Investigator and any participating Investigator should consult with the study pharmacist (if applicable) at the local institution or the sponsor/ CRO to assist in breaking the blind.
    3. The Investigator will ensure that unblinding events are reported to all IRBs of record

3.2.4 Adverse Event Documentation

The Investigator and all participating Investigators/designees should record AE(s) in appropriate source documents, noting the following:

    1. Nature of the event
    2. Severity of the event
    3. Probable relationship (causality) of AE to investigational product
    4. Date and time of AE onset
    5. Date and time of AE resolution, if available
    6. Possible test articles involved (investigational product, comparator, or placebo) with administration start/stop dates
    7. Dose, frequency, and route of administration, if applicable
    8. Concomitant medications and therapies: the Investigator and/or the reporter should separately list the concomitant medications that the participant was taking for the treatment of his/her underlying medical conditions and also the concomitant medications used for the treatment of the AE
    9. Clinical assessment of participant conducted at time of SAE/AE
    10. Results of any laboratory tests and/or diagnostic procedures
    11. Follow-up plan
    12. Record date/time of SAE/AE resolution and outcome, when available

3.3 Participating Investigator SAE(s) Reports to the Investigator

  1. The participating Investigator is expected to report any serious and unexpected adverse experiences, whether or not they are considered related to the investigational product, to the SI, sponsor/ CRO in the time frame as specified in the protocol, usually within 24 hours.
  2. The participating Investigator is expected to provide as much of the following information as is available to the SI, sponsor/ CRO:
    • Protocol name and number
    • Possible test articles involved (investigational product, comparator, or placebo) with administration start/stop date
    • Lot number and expiration date
    • Subject identifiers
    • Demographic data
    • Nature of the event
    • Severity of the event
    • Probable relationship (causality) of AE to investigational product
    • Date and time of AE onset
    • Date and time of AE resolution, if available
    • Dose, frequency, and route of administration, if applicable
    • Concomitant medications that the participant was taking for an underlying medical condition or disease and the therapeutic agents used for the treatment of the adverse event
    • Clinical assessment of participant conducted at time of SAE/AE
    • Results of any laboratory and/or diagnostic procedures, and treatment
    • Follow-up plan
    • Outcome
    • Autopsy findings (if appropriate)
  3. The participating Investigator will provide details about the AE to the Investigator, sponsor/ CRO as they become available. If additional information cannot be obtained for whatever reason, this will be documented.
  4. The participating Investigator should inform the Investigator, sponsor/ CRO when no other information is expected.
  5. The participating Investigator should provide the Investigator, sponsor/ CRO with a logical, complete, and accurate narrative description of the SAE based upon the above information.
  6. The participating Investigator should promptly determine an assessment of causality.
  7. The participating Investigator should communicate to the Investigator, sponsor/ CRO if the IRB requires revisions to the informed consent form or other measures.
  8. The Investigator will evaluate the AE(s) and determine; based on the severity of the adverse events or a change in incidence, whether the results require an evaluation by the Data Safety Monitoring Board if one has been constituted. The Data Safety Monitoring Board can institute measures such as stopping enrollment in the study, stopping one of the treatment arms, or modifying the dose of the study medications.
  9. The participating Investigator/designee should keep originals or photocopies of all relevant documentation, including facsimile confirmations, and file them in the participant's file.

3.4 Reporting SAE(s) to the FDA by Investigator, sponsor/ CRO

  1. The Investigator, sponsor/ CRO is required to notify the FDA by IND Safety Reports of any serious adverse experiences that are both unexpected and associated with the use of the drug/biologic in the clinical studies conducted under an IND as soon as possible but no later than 15 calendar days after initial receipt of the information from any source.
  2. If the SAE is fatal or life threatening and associated with use of the drug/biologic, in clinical studies conducted under an IND, the Investigator, sponsor/ CRO is required to notify the appropriate FDA review division by telephone or fax within 7 calendar days of initial receipt of the information.
  3. If the Investigator, sponsor/ CRO identifies an SAE, or is notified of an SAE by another participating Investigator, the Investigator, sponsor/ CRO is required to prepare either an FDA MedWatch Form 3500A or a narrative describing the details of the SAE. The assessment of the SAE should include a review of similar SAE that were previously reported in the study, to determine trends or clinical significance.
  4. The Investigator, sponsor/ CRO should amend the Investigator Brochure according to the SAE findings, and distribute the revised Investigator Brochure as required.
  5. The Investigator, sponsor/ CRO is required to send a written report or notification of the IND Safety Report to all participating Investigators.
  6. The participating Investigator/designee should report IND safety reports to the IRB following the IRB procedures for reporting of Adverse Events.
  7. The participating Investigator should file a copy of all expedited safety reports in the site's study and participant files
  8. Regarding investigational medical devices, the Investigator should consult the Investigator, Sponsor/CRO and with the Office of Human Research, Division of Human Subjects Protection

3.5 Reporting SAE(s) and AE(s) to the IRB

For information on reporting SAE(s) and AE(s) to the IRB, please refer to Office of Human Research, Division of Human Subjects Protection Policy and Procedure GA-120

3.6 SAE Reporting for Gene Transfer Studies

For information on reporting SAE(s) for Gene Transfer Studies to the IRB, please refer to Office of Human Research, Division of Human Subjects Protection Policy and Procedure GA-120

4. APPLICABLE REGULATIONS AND GUIDELINES

21 CFR 312.32

IND safety reports

21 CFR 312.33

Annual reports
21 CFR 312.44 Termination
21 CFR 50.25 Elements of informed consent
21 CFR 56.108 IRB functions and operations
21 CFR 56.109 IRB review of research
21 CFR 56.115 IRB records
45 CFR 46.103 Assuring compliance with this policy-research conducted or supported by any Federal Department or Agency
45 CFR 46.109 IRB review of research
45 CFR 46.115 IRB records
45 CFR 46.116 General requirements for informed consent
FDA Information Sheets, October 1998 Continuing Review After Study Approval
May 1997 International Conference on Harmonisation; Good Clinical Practice:  Consolidated Guideline

5. REFERENCES TO OTHER APPLICABLE SOPs

GA-102

Responsibilities of the Research Team

PM-301

Site-Sponsor/CRO Communications

PM-302

Interactions with the Institutional Review Board

SM-403

Subject Management While on Study

DM-501

Data Management

6. ATTACHMENTS

A. Serious Event Report Form - ON-SITE or OFF-SITE
B. Adverse Event and Intercurrent Illness Log
C. Reporting IND Safety Reports to the IRB
D. SAE Reporting Requirements Summary (Drug & Device)
E.  FDA MedWatch Form 3500A

7. DEFINITIONS AND GLOSSARY

The following definitions from the Code of Federal Regulations and the International Conference on Harmonisation, Good Clinical Practice:  Consolidated Guideline apply to this SOP.

Adverse event: An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

Associated with the use of the drug:  There is a reasonable possibility that the experience may have been caused by the drug.

Disability:  A substantial disruption of a person’s ability to conduct normal life functions.

Life-threatening adverse drug experience:  Any adverse drug experience that places the patient, in the view of the investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that, had it occurred in a more severe form, might have caused death.

Serious adverse drug experience (ADE):  Any experience that results in death, in a life-threatening ADE, inpatient hospitalization or prolongation of hospitalization, a persistent or significant disability or incapacity, or congenital anomaly.

Unexpected adverse drug experience:  Any adverse experience the specificity or severity of which is not consistent with the current Investigator Brochure, or if an Investigator Brochure is not required, that is not consistent with the specificity or severity in the risk information described in the general investigational plan or elsewhere in the current application, as amended.

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