FAQs: Adverse Events, Serious Adverse Events, and External Safety Reports

  1. Does SWOG have a policy regarding site review of external safety reports?

    SWOG has no policy on review of external safety reports. For trials under a local IRB, we defer to the policies and procedures of the local IRB. For trials under the CIRB, we defer to local institutional SOPs. If your site has a policy regarding this, SWOG recommends you follow that policy. If you do not already have a policy, we recommend that one be implemented.

    Best practice would be to download (no need to print unless it’s your site policy) all external safety reports and file them in the regulatory binder in case they need to be accessed in the future. Best practice would also include periodic review by the PI to fulfill their obligations to protect the rights, safety, and welfare of human subjects.

    Site review of external safety reports by sites can occur in many ways. One common method is to compile a list/spreadsheet of all safety reports that are considered related and unexpected to an IND. The PI can review the list periodically for any concerning events and review those individual reports if necessary. This is just an example; many other processes would be acceptable.

    Please feel free to contact ADR@swog.org with any additional questions.
  2. Patient 123456 had an adverse event on the last day of Cycle 1. Do I report the AE with Cycle 1 or Cycle 2?

    The adverse event should be reported within the same cycle it occurred. In this example, since the AE occurred on the last day of Cycle 1, it should be reported on the Cycle 1 Adverse Event Report.
  1. Patient 234567 experienced Grade 1 peripheral neuropathy starting on Day 8 of Cycle 3. Since the neuropathy is only Grade 1, does this need to be reported as an adverse event?

    Yes; unless otherwise specified in the protocol, all grades of adverse events (1-5), including abnormal laboratory findings, must be reported on the study’s Adverse Event Report form regardless of attribution to protocol treatment or clinical significance.

    Questions regarding adverse event reporting may be directed to ADR@swog.org.

    SourceORP Manual Chapter 15 Adverse Event Assessments (Login with CTEP credentials required to access link).
  1. It appears that the CTEP-AERS system requires the SAE to be attributed to the agent. Do I have to list the SAE as having a possible, probable, or definite attribution to the study treatment?

    If the SAE is unrelated to the study agents, it may be related to the cancer diagnosis, other concomitant medications, pre-existing conditions, or other causes. When applicable, an ‘other’ cause can be added in CTEP-AERS Section 7. If the cause is unknown, an ‘other’ cause named ‘Unknown’ may be added with a possible, probable, or definite attribution. This will allow submission of the report.
  1. Should I select the column/criteria “Required Intervention” on the "Adverse Events: Report" in RAVE?

    The column/criteria “Required Intervention” is only applicable to protocols that involve a device. In newer trials that do not involve devices, this column is being removed from the database. Where the column is still included, this column should be left blank if the trial does not involve a device.

    The six seriousness criteria for SWOG investigational drug trials are:
    1) Death
    2) Life-threatening
    3) Hospitalization 24 hours
    4) Persistent/significant disability
    5) Congenital/birth defect
    6) Other Important Medical Event (used when no options fit well such as an AESI)

    Source: National Cancer Institute. (2013). Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs [Section 2.1.22]. 
  1. After I submitted the Expedited Reporting Evaluation form, I received a query. Do I need to resubmit the Expedited Reporting Evaluation form again after resolving the query?

    Yes, you must re-submit the Expedited Reporting Evaluation form after each change to the Adverse Events: Report in Rave in order for the complete AE data to be evaluated using the CTEP-AERS rules engine.

    Sites must submit the Expedited Reporting Evaluation after correcting any missing information or changing any information on the Adverse Events: Report. A change in AE term, grade, attribution, seriousness criteria, or start/end dates may trigger a recommendation to create an SAE report or to amend an existing SAE report.

    Please feel free to contact ADR@swog.org to confirm whether an SAE report is necessary.

    Source: CTEP-AERS Help Resources. Reporting AEs for Rave Users. https://ctepcore.nci.nih.gov/ctepaers/help/webhelp/rave%20users/rave-overview.htm.
  1. S24XX study uses the RAVE/CTEP-AERS integration for AE reporting. However, the SAE reporting recommendations do not seem to be correct. How do I confirm if an SAE needs to be reported?

    For studies using the RAVE/CTEP-AERS integration, all RAVE recommendations for SAE reporting should be confirmed by consulting the protocol or contacting SWOG at ADR@swog.org.
  2. What does "Expedited Reporting" mean?

    Expedited reporting is the term for reporting an adverse event that has become a Serious Adverse Event (SAE). These terms may be used interchangeably in SWOG protocols.

    Source: National Cancer Institute. (2013). Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs [Section 2.1.8].
  1. Who do I contact for questions pertaining to SAEs?

    For any SAE-related questions, please contact ADR@swog.org or 210-614-8808 (Option 6).
  1. When a patient is on a treatment arm with both investigational and commercial agents, which SAE Reporting Table should be used?

    When a commercial agent is used on the same treatment arm as the investigational agent/intervention, the entire combination (arm) is then considered an investigational intervention for AE reporting. The investigational SAE Reporting Table should be used. For any questions or clarification about SAE reporting in this situation, please email ADR@swog.org.

    Source: National Cancer Institute. (2013). Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs [Section 5.4].

  2. Adverse Events were reported in Rave. Then, the Expedited Reporting Evaluation was submitted. I thought that one of the AEs should be reported as an SAE per protocol, but the CTEP-AERS rules engine did not recommend this reporting. Is any further action required?

    The CTEP-AERS system is pre-loaded with basic rules for reporting.
    • These rules are used to help determine whether AEs require expedited reporting. It is possible that an AE won’t trigger the automated rules but still requires reporting as an SAE.
    • It is also possible that the rules may recommend an SAE report for all Grade 4 AEs; however, the specific Grade 4 AE is included in the SPEER table or protocol-specific exceptions for SAE reporting. If the event doesn’t meet protocol-specified reporting rules, it does not require expedited reporting. (For example, in many instances, AEs such as Grade 4 lymphocyte count decreased would not be considered serious.) Best practice is to use the system recommendations as a reminder to check the protocol to ensure that the event does not require expedited reporting; the automated RAVE recommendations for SAE reporting are not always correct.
    • If RAVE and/or CTEP-AERS do not recommend an expedited report, but one is needed, sites can override the recommendation by clicking Override in CTEP-AERS or change NONE → CREATE in RAVE.
    • If in doubt as to whether an SAE report is required per protocol-specified criteria, contact the SWOG SAE Coordinators for assistance at ADR@swog.org.

          Source: CTEP-AERS Help Resources. Reporting AEs for Rave Users

  1. I entered a Grade 3 urinary tract infection into RAVE. The patient was hospitalized for 48 hours. RAVE does not recommend an SAE report. What is the best course of action?

    On treatment arms with investigational agents, all AEs with hospitalization  24 hours require expedited reporting (unless otherwise indicated in the protocol exceptions/SPEER column). If RAVE does not recommend an SAE report when one is necessary, contact the SWOG SAE Coordinators at adr@swog.org for assistance.

    Source: National Cancer Institute. (2013). Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs [Section 2.1.10].

  2. The patient had a Grade 3 pleural effusion that occurred 58 days after the last dose of investigational agent/intervention. Pleural effusion does not appear to be listed in the SPEER table or other protocol exceptions. Does this need to be reported as an SAE?

    SAEs occurring > 30 days after the last dose of investigational treatment or last date of intervention must have an attribution of possibly, probably, or definitely related to the investigational treatment to require expedited reporting.

    Source: National Cancer Institute. (2013). Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs [Appendix 1].
  1. RAVE recommends an SAE report for a Grade 4 lymphocyte count decreased. This event did not meet any seriousness criteria. What is the best course of action?

    Consult the protocol to determine expedited reporting. On some studies, all Grade 4 cytopenias require expedited reporting. On many other studies, they only require expedited reporting if they are considered serious. The protocol will confirm whether this event requires expedited reporting. If there are any questions, please email adr@swog.org.

    Source: CTEP-AERS Help Resources. Reporting AEs for Rave Users
  1. What should be done when an SAE is discovered several years after the patient was on protocol treatment? If there is no documentation in the chart that it was reported to SWOG, how should we proceed?

    Since it is often several years after the close of a clinical study before a sponsor submits the results in support of a marketing application to FDA, SWOG should be contacted at adr@swog.org to determine if the potential SAE had, in fact, been reported. If not, it should be reported, complete with as much information as known at the time. Additionally, there have been times when seemingly unrelated SAEs have been revealed to be related to use of the drug when information across multiple sites is compiled, with larger numbers making rare events apparent.

    Source: “Good Clinical Practice: A Question & Answer Reference Guide,” Barnett International. The Guide is available at http://www.barnettinternational.com in electronic and paper form (https://www.magiworld.org/resources/journal/2719_Journal_1803.pdf#page=4).