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

  1. Does SWOG require IRBs to review external safety reports and internal Serious Adverse Events?

    SWOG has no policy on review of safety reports. We defer to the policies and procedures of the local IRB although we encourage institutions to follow the guidance provided by the FDA and OHRP in regard to reporting of external adverse events. These guidance documents were issued in response to concerns raised by the IRB community that increasingly large volumes of individual adverse event reports submitted to IRBs — often lacking in context and detail — are inhibiting, rather than enhancing, the ability of IRBs to protect human subjects. The OHRP guidance clarifies that only a small subset of adverse events occurring in human subjects participating in research are unanticipated problems that must be reported.
  1. Patient 12345 had an Adverse event on the last day of Cycle 1. Do I report the AE with Cycle 1 or Cycle 2?

    Review Protocol Section 8 or Section 16.1 to determine how to proceed.  In addition, studies with CTEP-AERS integration can be identified by using the following online resources:

    On the CTSU protocol-specific page in the “Supported by” table, a green check mark will appear under the heading SAE Int
     On Medidata Rave – if the course/cycle folder has an EXPEDITED REPORTING EVALUATION form
    c. On your CTSU Dashboard, a green check mark will appear under the heading SAE Int

    Source: CTSU Website: Resources > CTSU Operations Information > Topic Specific Guidance & Education > Adverse Events: Identifying a CTEP-AERS Integrated Study (Login with CTEP IAM ID required to access link).
  1. Patient experienced Grade 1 neuropathy starting on Day 8 of Cycle 3. Since Grade 1, does this need to be reported?

    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 Events Form (AE Form) regardless of attribution to protocol treatment or clinical significance.

    Source: ORP Manual Chapter 15 Adverse Event Assessments (Login with CTEP IAM ID 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. Death NOS, Sudden death NOS, Fetal death, and Death neonatal do NOT require attribution of possible, probable, or definite.
  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 drug trials are:
    1) Death
    2) Life-threatening
    3) Hospitalization ⪰ 24 hours
    4) Persistent/significant disability
    5) Congenital/birth defect
    6) Other (used when no options fit well)

    Source: National Cancer Institute. (2013). Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs [Section 2.1.22]. 
  2. 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.

    Source: CTEP-AERS Help Resources. Reporting AEs for Rave Users. https://ctepcore.nci.nih.gov/ctepaers/help/webhelp/rave%20users/rave-overview.htm.
  1. SXXXX study uses 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 the Lead SAE Coordinator at adr@swog.org.
  2. What does "Expedited reporting" mean?

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

    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 the Lead SAE Coordinator at adr@swog.org or 210-614-8808 (Option 3, then Option 7).
  1. When a patient is on a treatment arm with both investigational and commercial agents, is the entire combination considered investigational?

    Yes; When a commercial agent is used on the same treatment arm as the investigational agent/intervention (also, investigational drug, biologic, cellular product, or other investigational therapy under an IND), the entire combination (arm) is then considered an investigational intervention for AE reporting.  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 submitted 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.)  The guideline is to use the system recommendations as a reminder to check the protocol to ensure that the event does not require 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.

          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?

    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 SAE that occurred 58 days after the last dose of investigational agent/intervention. The SAE does not appear to be listed in the SPEER table or other protocol exceptions. Does this need to be reported within 10 calendar days?

    SAEs occurring > 30 days after the last dose of investigational treatment or last date of intervention must have an attribution of possible, probable, or definite (as pertains to the investigational agent or 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. Patient 86420 had experienced persistent Grade 3 neuropathy, beginning on Cycle 1, Day 15. It did not get worse or resolve. Do I need to continue to report this AE during the Cycle 2 reporting period?

    No; For expedited reporting, a persistent adverse event (AE) must be reported only once unless the grade becomes more severe in the same or a subsequent course. A persistent AE is one that extends continuously, without resolution between treatment cycles/courses.  Much like Baseline Abnormalities, these are only reported once unless it worsens or completely resolves then returns, meeting reporting requirements.

    Source: NNational Cancer Institute. (2013). Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs.
  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 do you do when you find an adverse event in a patient chart, for example, when auditing several years after the patient was on study and that event constituted an SAE that should have been reported even if it was unrelated to the drug (e.g., hospitalization) but there is no documentation in the chart that it was reported?

    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).