Introduction

These requirements and guidelines created by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) detail the safety reporting processes that investigators are required to follow when conducting NIAMS-supported clinical research studies. The goals of these guidelines are to outline the NIAMS requirements for reportable events, and to ensure the proper reporting procedures are followed by study personnel to monitor the safety of research participants. The NIAMS expects all clinical research grantees to adhere to these requirements and guidelines; however, the process may slightly vary depending on the level of risk involved in the study and whether the study utilizes a monitoring body for the data and safety oversight.

This document outlines the NIAMS reporting requirements for Adverse Events (AEs), Serious Adverse Events (SAEs), Unanticipated Problems (UPs), Protocol Deviations, Serious or Continuing Noncompliance, and Suspension or Termination of Institutional Review Board (IRB) Approval. Should investigators foresee a deviation from the NIAMS requirements, they are required to promptly discuss it with the NIAMS Program Officer and Clinical Management Team.

Additionally, please note that the National Institutes of Health (NIH) under 45 CFR 46.108(4) and 45 CFR 46.113 requires reporting of certain incidents (i.e., serious or continuing noncompliance, unanticipated problems, suspension or termination of IRB approval, and adverse events) under the NIH Grants Policy Statement Section 4.1.15. Each Institution/Principal Investigator (PI) is required to have and follow written procedures to ensure that the aforementioned events are promptly reported to the Office of Human Research Protections (OHRP).

Safety Monitoring Oversight and Responsibilities

The NIAMS assesses the risk for all clinical studies, determines the appropriate level of data and safety oversight, and may assign a monitoring body type, including but not limited to a NIAMS-appointed Data and Safety Monitoring Board (DSMB), NIAMS-appointed Observational Study Monitoring Board (OSMB), NIAMS-appointed Safety Officer(s) (SOs), or internally-appointed DSMB or SO. These groups are hereafter referred to as “monitoring body”.

While safety monitoring oversight is a responsibility of the NIAMS and assigned monitoring body, other entities may also have overlapping or additional oversight responsibilities related to safety reporting that must be considered in the safety reporting development process. These other entities include, but not limited to, other funding NIH Institutes and Centers (if applicable), IRB, Food and Drug Administration (FDA), Office of Human Research Protections (OHRP), study Medical Monitor (MM), study Principal Investigator (PI), and clinical site investigators. Given that the NIAMS, IRB, and FDA reporting timelines can vary, investigators should adhere to all applicable reporting requirements and outline a process that will be followed for the study. Please note that studies not using a monitoring body mentioned above (e.g., NIAMS-appointed DSMB or OSMB, NIAMS-appointed SO, internally-appointed DSMB or SO) are still required to report events under the NIH Grants Policy Statement Section 4.1.15. These events include AEs, UPs, serious or continuing noncompliance, and suspension or termination of IRB approval. Investigators should follow the reporting timelines of these events per their IRB policies and OHRP reporting guidance.

Adverse Event Reporting

The NIAMS requires reporting of all adverse events to the NIAMS and monitoring body. All AEs regardless of their expectedness or relatedness are reported in aggregate as part of the routine Data and Safety Monitoring (DSM) Report to the NIAMS and monitoring body; typically, twice per year. See the Safety Reporting Assessment Flowchart. For studies not using a monitoring body, AEs are expected to be reported to the NIAMS in the Research Performance Progress Report (RPPR) on an annual basis.

Serious Adverse Event Reporting

The investigator or designee from the study team is responsible for conducting and providing an assessment of the serious adverse event. All SAEs (regardless of expectedness or relatedness) must be reported in an expedited manner to the NIAMS and the monitoring body within 48 hours of the investigator becoming aware of the event. For studies not using a monitoring body, it is still required that SAEs be reported to the NIAMS within 48 hours of the investigator becoming aware of the event.

The expedited initial SAE report should be submitted to the NIAMS and monitoring body with any available information; it is acceptable if the report is not complete. Follow-up reports should be provided as additional information becomes available. All SAEs must be followed to resolution and a final report should be submitted detailing the outcome.

For additional details describing the review and adjudication process for SAEs, please refer to the “Serious Adverse Events Review Process and Adjudication” section below.

Unanticipated Problem Reporting

All unanticipated problems are reported to the NIAMS and the monitoring body within 48 hours of the investigator becoming aware of the event. Similar to SAE reports, the initial UP report is acceptable even if the report is not complete. Follow-up reports should be provided as additional information becomes available. For studies not using a monitoring body, it is still required that UPs be reported to the NIAMS within 48 hours of the investigator becoming aware of the event.

Protocol Deviation Reporting

It is the NIAMS policy that any protocol deviation that impacts participant safety must be reported to the NIAMS and the monitoring body within 48 hours of the investigator becoming aware of the event. All other protocol deviations that do not impact participant safety are reported in aggregate as part of the routine DSM Report to the NIAMS and monitoring body. For studies not using a monitoring body, investigators should follow their Institution’s policies for reporting to the IRB. No additional reporting is required to the NIAMS unless required by the IRB.

Serious or Continuing Noncompliance Reporting

Serious or continuing noncompliance must be reported to the NIAMS Program Officer and Grants Management Specialist within 3 business days of IRB determination. A copy of the IRB submission and determination must be submitted along with the report.

Suspension or Termination of IRB Approval Reporting

Any suspension or termination of IRB approval must include a statement of the reason(s) for the action and must be reported promptly to the NIAMS Program Officer and Grants Management Specialist within 3 business days of receipt by the investigator.

Serious Adverse Events Review Process and Adjudication

As mentioned above for studies with a monitoring body, the investigator is expected to provide an assessment of an SAE in an expedited manner to the NIAMS and the monitoring body. Please note that the process and reporting timeline for studies with an internally-appointed monitoring body differs from that for studies with a NIAMS-appointed monitoring body. These processes do not apply to studies not using a monitoring body.

For studies with an internally-appointed monitoring body, please refer to the NIAMS DSM Guidelines for Internal Safety Monitoring for further details regarding the reporting process.

For studies with a NIAMS-appointed monitoring body, the SAE is reviewed by the monitoring body SO and the NIAMS. The result of the NIAMS’ and SO’s independent assessment and review is shared with the investigator in a timely manner. The outcome of the review will either be that the NIAMS and SO agree or disagree with the investigator. Additional information may also be requested by the NIAMS and SO to aid in their review of the event. If the NIAMS and SO agree with the investigator assessment, the result is shared with the investigator, and no further action is required.

If the NIAMS and the SO disagree with the investigator’s assessment, the following will occur:

• The NIAMS’ and SO’s independent assessment and justification are sent to the investigator. The NIAMS and SO may or may not request additional information.
• The investigator has the opportunity to provide a rationale for their assessment and may or may not agree to amend the SAE report to match the NIAMS’ and SO’s assessment.
• If resolution cannot be achieved at this stage, the monitoring body Chair (if applicable) may be requested by the NIAMS to weigh in and provide their feedback on the conflicting SAE assessments by the investigator and the NIAMS/SO. If for any reason a mutually agreed upon assessment still cannot be reached, the NIAMS will further discuss the appropriate action that should be taken to resolve the difference in assessment between the parties. If a resolution cannot be accomplished over email, an ad-hoc meeting will be coordinated between the parties, including but not limited to the investigator, SO, monitoring body Chair (if applicable), and NIAMS.
  • Dependent upon the outcome of the ad-hoc meeting, one of the following may occur:
    • The investigator will update the SAE report to reflect the NIAMS’ and SO’s adjudication and resubmit it to the SO and the NIAMS for review.
      
      Note: If the updated adjudication changes the reporting requirements for the event (e.g., the SAE now meets the criteria for a UP), these new reporting requirements should be met.
    • The investigator will leave the report as is with their original adjudication and notify their IRB of the difference in the adjudication of the SAE, as well as provide a copy of the IRB communication to the NIAMS.
• As the monitoring body is advisory to the NIAMS, the NIAMS makes the final decision regarding the recommended adjudication of the SAE being shared with the investigator. Once the NIAMS makes a final decision about the adjudication of the SAE, further discussion with the monitoring body will not be needed.
• During this process of determining the adjudication of the SAE, the investigator should adhere to all applicable (IRB, FDA, etc.) reporting requirements and timelines for the SAE based on their original assessment of the event.

Please note, it is the investigator’s responsibility to ensure that reports of assessment of AEs are transmitted from the DSMB to the IRB. The NIH Guidance on Reporting Adverse Events to Institutional Review Boards for NIH-Supported Multicenter Clinical Trials can be accessed here: https://grants.nih.gov/grants/guide/notice-files/not99-107.html.

Additional Information

• Investigators and their study team should ensure that all internal processes and staff roles/responsibilities for the collection, assessment, and reporting of events to the appropriate groups are clearly described in the Manual of Operating Procedures (MOP) and the Data and Safety Monitoring Plan (DSMP).
• Multi-site trials with coordinating centers/data coordinating centers involved in the AE reporting process should ensure the NIAMS required timeline (i.e. within 48 hours of the investigator becoming aware of the event) is built into their internal process.    
• OHRP provides guidance for the appropriate timeframe for reporting AEs and UPs to the IRB and OHRP at the following link: https://www.hhs.gov/ohrp/regulations-and-policy/guidance/reviewing-unanticipated-problems#Q5.

The checklist below is intended to help investigators think through the elements that should be considered when drafting their safety reporting process.