A. 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. These studies include clinical trials and other types of clinical research studies e.g., observational studies. The goal of these guidelines is 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. All NIAMS-funded clinical research grantees are expected 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 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 (PO) and Clinical Research Manager.

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). 

B. 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 establishment of safety monitoring oversight is a responsibility of the NIAMS as the funding agency, oversight duties are carried out in conjunction with the assigned monitoring body. Other entities that may include, but are not limited to, other funding NIH Institutes and Centers (if applicable), IRB, Food and Drug Administration (FDA), OHRP, study Medical Monitor (MM), study PI, and clinical site investigators may also have overlapping or additional oversight responsibilities related to safety reporting that must be considered in the safety reporting development process. Given that the NIAMS, IRB, and FDA reporting timelines can vary, investigators should outline a process that will be followed for the study so that all applicable reporting requirements are adhered to. Please note that studies not required by NIAMS to use a monitoring body mentioned above (e.g., NIAMS-appointed DSMB or OSMB, NIAMS-appointed SO, internally-appointed DSMB or SO) are still required to follow a process by which events are reported 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. 

The rest of this document only refers to processes for studies with a monitoring body.

C. Reporting Requirements and Timeline

Investigators for studies utilizing a monitoring body are expected to adhere to the following reporting requirements and timeline.

I. Adverse Event Reporting

All adverse events should be assessed by the investigator and/or qualified designee (e.g., medical sub-investigator) for severity, relatedness to the study/study intervention, expectedness, and seriousness (i.e., whether it meets any of the criteria for seriousness, such as resulted in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, etc.). The definitions for categorizing severity (e.g., mild, moderate, and severe), relatedness (e.g., not related, possibly/probably related, or definitely related to the study intervention), and expectedness (i.e., expected vs. unexpected) of AEs, as well as the criteria for seriousness, should be included in the applicable study materials (e.g., manual of operating procedures (MOP), data and safety monitoring plan (DSMP)) and should be consistent across study documents. Depending on the classification of an event, it may need to be reported to different oversight entities; see the NIAMS Safety Reporting Assessment Flowchart.

The NIAMS requires reporting of all adverse events regardless of their expectedness, relatedness, or severity to the NIAMS and monitoring body. These data must be reported in aggregate as part of the routine Data and Safety Monitoring (DSM) Report to the NIAMS and monitoring body. The following timelines must be followed for reporting AEs based on monitoring body type:

• For studies with a NIAMS-appointed monitoring body: The frequency for routine reporting to the NIAMS and monitoring body is typically semiannual; however, this timeline is determined during the introductory monitoring body meeting for each study. 
• For studies with an internally-appointed monitoring body: The frequency for routine reporting to the NIAMS and monitoring body is determined by the PI in consultation with the monitoring body.

The NIAMS AE Form and Open DSM Report templates are resources for data reporting that are available to investigators that can be utilized and tailored to an individual study as needed.

II. Serious Adverse Event Reporting

For any AEs that meet one of the pre-specified criteria for seriousness, the investigator or qualified designee from the study team is responsible for conducting and providing an assessment of the serious adverse event. The following timelines must be followed for reporting SAEs based on monitoring body type: 

• Studies with a NIAMS-appointed monitoring body: All SAEs (regardless of expectedness, relatedness, or severity) must be reported in an expedited manner to the NIAMS and monitoring body within 48 hours of the site PI becoming aware of the event.
• Studies with an internally-appointed monitoring body: All SAEs (regardless of expectedness, relatedness, or severity) must be reported in an expedited manner to the NIAMS within 48 hours of the site PI becoming aware of the event. However, the timeline for reporting SAEs to the monitoring body is determined by the PI in consultation with the monitoring body.

The expedited initial SAE report should be submitted to the NIAMS and to the NIAMS-appointed monitoring body (if applicable) with any available information by the 48-hour mark; 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.

The following information should be collected at a minimum for SAE reports to the NIAMS and to the NIAMS-appointed monitoring body (if applicable): participant ID; event term (i.e., SAE name/diagnosis); SAE onset date; SAE end date (or indication that event is ongoing); severity; relatedness; and expectedness. The NIAMS SAE Form template is a resource available for investigators that can be utilized and tailored to an individual study as needed.

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

III. Unanticipated Problem (UP) Reporting

For any event that meets all three criteria for an unanticipated problem, the investigator or qualified designee from the study team is responsible for reporting this event to the relevant parties. 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. The following timelines must be followed for reporting unanticipated problems based on monitoring body type: 

• Studies with a NIAMS-appointed monitoring body: All unanticipated problems are reported to the NIAMS and monitoring body within 48 hours of the site PI becoming aware of the event. 
• Studies with an internally-appointed monitoring body: All unanticipated problems are reported to the NIAMS within 48 hours of the site PI becoming aware of the event. However, the timeline for reporting unanticipated problems to the monitoring body is determined by the PI in consultation with the monitoring body.

The NIAMS UP Form template is a resource available for investigators that can be utilized and tailored to an individual study as needed.

IV. Protocol Deviation Reporting

The timeline for reporting protocol deviations to the NIAMS differs depending on whether the deviation is related to participant safety. The following timelines must be followed for reporting protocol deviations based on monitoring body type: 

• Studies with a NIAMS-appointed monitoring body: Protocol deviations impacting participant safety are reported to the NIAMS and monitoring body within 48 hours of the site PI becoming aware of the event. All other protocol deviations that do not impact participant safety are reported to the NIAMS and monitoring body in aggregate as part of the routine DSM Report.
• Studies with an internally-appointed monitoring body: Protocol deviations impacting participant safety are reported to the NIAMS within 48 hours of the site PI becoming aware of the event; all other protocol deviations that do not impact participant safety are reported to the NIAMS in aggregate as part of the routine DSM Report. However, the timeline for reporting protocol deviations to the monitoring body is determined by the PI in consultation with the monitoring body.

V. Serious or Continuing Noncompliance Reporting

All studies regardless of monitoring type must report serious or continuing noncompliance to the NIAMS Program Officer and Grants Management Specialist within three business days of IRB determination. A copy of the IRB submission and determination must be submitted along with the report.

VI. 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 three business days of receipt by the investigator. This is required for all studies regardless of monitoring type.

D. Safety Reporting at a Glance

E. Serious Adverse Events Review Process and Adjudication for NIAMS-appointed Monitoring Body

For studies with a NIAMS-appointed monitoring body, the SAE is reviewed by the monitoring body SO and the NIAMS to determine whether they agree with the investigator’s assessment of relatedness and expectedness. 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’s assessment. 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’s 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 provides more details. 

F. Additional Information

• Investigators and their study team should ensure that all internal processes and staff roles/responsibilities for the identification, collection, assessment, and reporting of events to the appropriate groups are clearly described in the MOP and 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.

Checklist

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

• Have you included the appropriate regulatory definitions of an AE, SAE, UP, and protocol deviation for your study in the applicable study documents (i.e., protocol, MOP, and DSMP)?
• Who is responsible for identifying, collecting, assessing, and reporting AEs, SAEs, UPs and protocol deviations to the different oversight entities?
  • Is the NIAMS 48-hour expedited reporting window documented, if applicable?
  • What is your IRB’s reporting window for AEs, SAEs, UPs, and protocol deviations?
  • Have you included the reporting window for serious or continuing noncompliance and suspension or termination of IRB approval? Who is responsible for reporting these incidents?
  • How will this information be documented and transmitted? Via email or electronically entered into a database? Is there a form?  Other?
• Who is the responsible person for notifying the investigator? MM? IRB? NIAMS? FDA? OHRP? monitoring body?
• Who is responsible for providing the follow-up information to the NIAMS and monitoring body, and how will this information be transmitted?
• Do the applicable study documents including but not limited to the protocol, DSMP, and MOP clearly outline everyone’s role and reporting timelines in the safety reporting process?
• Do the applicable study documents include the definitions for categorizing severity, relatedness, and expectedness of AEs, and are these categories consistent across documents?
• Are the following required elements included in the SAE form for reporting SAEs to the NIAMS? 
  • Participant ID; event term (i.e., SAE name/diagnosis); SAE onset date; SAE end date (or indication that event is ongoing); severity; relatedness; and expectedness.