PREFACE
Investigators should consider using this template when developing the Data and Safety Monitoring Plan (DSMP) for clinical studies funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).
The goal of the DSMP is to provide a general description of a plan that you intend to implement for data and safety monitoring. The DSMP should specify the following:
- A brief description of the study design
- Primary and secondary outcome measures/endpoints
- Sample size and target population
- Inclusion and exclusion criteria
- A list of proposed participating sites and centers for multi-site trials
- Potential risks and benefits for participating in the study
- Procedures for data review and reportable events
- Roles and responsibilities of study staff and monitoring entity (referred to as “Monitoring Body”). These can include, but are not limited to, monitoring by a:
- Project Director (PD)/Principal Investigator (PI) (required)
- Institutional Review Board (IRB) (required)
- Designated medical monitor
- Internal Committee or Board
- Independent, NIAMS-appointed Monitoring Body (MB) which can include a Data and Safety Monitoring Board (DSMB), an Observational Study Monitoring Board (OSMB), a Safety Officer (SO) or Dual SOs
- Content and format of the safety report
- Data Management, Quality Control and Quality Assurance
Note that all sample text should be replaced with the study specific text. There is no need to include sections that are not relevant to the particular study. Please do not use the sample text verbatim.
TABLE OF CONTENTS
- 3.1 Definitions
- 3.2 Collection and Assessment of AEs, SAEs, UPs, and Protocol Deviations
- 3.3 Reporting of AEs, SAEs, UPs, Protocol Deviations, Serious or Continuing Noncompliance, and Suspension or Termination of IRB Approval
4.0 Interim Analysis & Stopping Rules
1.0 Study Overview
1.1 Study Description
This section outlines the overall goal of this project. It also describes the study design, primary and secondary outcome measures/endpoints, sample size/power calculation and target population, inclusion and exclusion criteria.
1.2 Study Management
This section includes the proposed participating sites and their responsibilities. In addition, this section should include the planned enrollment timetable (i.e. projected enrollment).
2.0 Participant Safety
2.1 Potential Risks and Benefits for Participants
This section outlines the potential risks and benefits of the research for the study participants and for society. It should include a description of all expected adverse events (AEs), the known side effects of the intervention, and all known risks or complications of the outcomes being assessed.
2.1.1 Potential Risks
Outline potential risks for study participants including a breach of confidentiality.
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2.1.2 Potential Benefits
Outline potential benefits for study participants or if there are no direct benefits to the participants.
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2.2 Protection Against Study Risks
This section provides information on how risks to participants will be managed. It should specify any events that would preclude a participant from continuing in the study. In general, the format and content of this section are similar to the Human Participants section of the grant application.
In addition, this section describes measures to protect participants against study specific risks including the data security to protect the confidentiality of the data.
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2.2.1 Informed Consent Process
This section explains the informed consent process. It should include, but not be limited to, who will be consenting the participant, how and under what conditions will a participant be consented, and that participation is voluntary. The informed consent process should meet the revised Common Rule requirements for consenting. For further details on this requirement, please visit: https://www.ecfr.gov/cgi-bin/text-idx?SID=921afb2e7909a2cf08c5f3ce160a0c96&mc=true&node=se45.1.46_1116.
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Study Information – Participants should be fully informed about the study by appropriately trained study staff and have adequate time to evaluate the pros and cons of participation.
Study Discussion – Participants should be encouraged to discuss the study with anyone they wish, particularly family and friends who might be affected (for example, persons who might be needed to provide transportation).
Study Data Security – Participant will be informed that study data will be de-identified to protect participant privacy and against possible identifiability.
Biospecimen Collection – Participants will be given the option to provide open-ended consent for most research uses of a variety of biospecimens collected. Each sample will be stripped of identifiers.
No Proxy Consent – To be eligible for participation in the study, participants must have the capacity to give their own informed consent.
Environment for Informed Consent – The setting in which consent is obtained should be as private as possible so participants can freely ask questions without embarrassment.
Obligations – The participant should be given a copy of the informed consent forms after they are signed, dated and witnessed.
Copies of Informed Consent – Participants will be encouraged to keep the consent forms.
Witness Signature and Source Documentation – Anyone who signs a consent form will be asked to personally date it.
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3.0 Data and Safety Monitoring
3.1 Definitions
This section should describe how to identify AEs, SAEs and UPs. In the case where the intervention is a Food and Drug Administration (FDA) regulated drug, device or biologic, it should include the FDA definition, grading scale and “study relatedness” criteria of AEs.
3.1.1 Adverse Events (AEs)
The definition of adverse event here is drawn from the OHRP guidance (https://www.hhs.gov/ohrp/regulations-and-policy/guidance/reviewing-unanticipated-problems/index.html); for some studies, the ICH E6 definition may be more appropriate. Expected and unexpected AEs should be listed in this section.
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For the purposes of this study, AEs include any new events not present during the pre-intervention period or events that were present during the pre-intervention period which increased in severity. Examples of AEs include but are not limited to the following:
A clinically significant laboratory or clinical test result
An event that occurs as a result of a study procedure
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3.1.2 Serious Adverse Events (SAEs)
SAEs are a subset of all AEs.
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Results in death
Is life-threatening (places the subject at immediate risk of death from the event as it occurred)
Requires inpatient hospitalization or prolongation of existing hospitalization
Results in a persistent or significant disability/incapacity
Results in congenital anomaly/birth defect
Any other adverse events that, based upon appropriate medical judgment, may jeopardize the subject’s health and may require medical or surgical intervention to prevent one of the other outcomes listed in this definition (examples of such events include allergic bronchospasm requiring intensive treatment in the emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse)
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3.1.3 Unanticipated Problems (UPs)
The OHRP definition of UPs can be accessed using the link provided in Section 3.1.1 above.
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Unanticipated problems are defined as any incident, experience, or outcome that meets all of the following criteria:
Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the IRB-approved research protocol and informed consent document; and (b) the characteristics of the participant population being studied;
Related or possibly related to participation in the research. Possibly related means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and
Suggests that the research places participants or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.
SAEs that are unexpected and related or possibly related to participation in research are considered to be UPs because such events always suggest that the research places subjects or others at a greater risk of physical or psychological harm than was previously known or recognized.
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3.1.4 Protocol Deviations
This section should include the study definition of protocol deviations and define the events placing the participant at increased risk of harm or compromising the integrity of the safety data.
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Protocol deviations include, but are not limited to, the following:
Enrollment or randomization of an ineligible participant
Failure to obtain informed consent
Wrong intervention administered to participant
Unreported SAEs
Improper breaking of the blind
Use of prohibited medication
Mishandled samples
Multiple visits missed or outside study windows
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3.2 Collection and Assessment of AEs, SAEs, UPs, and Protocol Deviations
The section should include who is responsible for collecting these events, how the information will be captured, where the information will be collected from (e.g., medical records, self-reported), and what study form(s) will be used to collect the information (e.g., case report forms, direct data entry). This section should also include what type of information will be collected (e.g., event description, time of onset, assessment of seriousness, relationship to the study intervention, severity, etc.). Note that it is the NIAMS requirement to collect all AEs regardless of the expectedness or relatedness.
This section should also describe who is responsible for assessing these events. The individual(s) responsible should have the relevant clinical expertise to make such an assessment (e.g., physician, nurse practitioner, physician assistant, nurse). When assessing AEs and SAEs, the following information should be included:
- Relationship to study intervention
- Related
- Possibly/Probably (may be related to the intervention)
- Definitely (clearly related to the intervention)
- Not Related (clearly not related to the intervention)
- Related
- Expectedness
- Expected
- Unexpected
- Severity (Describe the method of grading an adverse event for severity. Please note that a severe AE and an SAE are distinct terms)
- Mild
- Moderate
- Severe
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AEs will be captured on the appropriate case report form. Information to be collected includes event description; time of onset; assessment of seriousness, severity, relationship to study procedures or interventions, and expectedness; medical care received; outcome of event; and time of resolution/stabilization of the event.
All AEs occurring while on study are documented appropriately regardless of relationship. All AEs/SAEs will be followed until satisfactory resolution or the participant is stable.
All AEs will be assessed by the investigator for severity, expectedness, and relationship to the intervention using the protocol-specified definitions.
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3.3 Reporting of AEs, SAEs, UPs, Protocol Deviations, Serious or Continuing Noncompliance, and Suspension or Termination of IRB Approval
This section should describe who is responsible for reporting these events and the roles and responsibilities of each person on the clinical study team who is involved in the safety reporting to the IRB, FDA (if applicable), Monitoring Body, and NIAMS (through the NIAMS Executive Secretary). It should also include the Office for Human Research Protections (OHRP) and FDA reporting requirements. See NIAMS Reportable Events Requirements and Guidelines for more details.
3.3.1 AE Reporting Procedures
All non-serious AEs (regardless of expectedness or relatedness) are reported to the Monitoring Body and NIAMS (through the NIAMS Executive Secretary) semi-annually or as determined by the NIAMS.
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3.3.2 SAE Reporting Procedures
All SAEs (regardless of expectedness or relatedness ) must be reported in an expedited manner to the NIAMS and the Monitoring Body. There may be different timeline for reporting SAE to the IRBs, FDA (if applicable), Monitoring Body and the NIAMS. The timeline for reporting SAEs to the Monitoring Body and NIAMS (through the NIAMS Executive Secretary) is within 48 hours of the investigator becoming aware of the event so that a real time assessment can be conducted, and the outcome shared in a timely manner.
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The expedited initial SAE reports should be submitted with any available information and 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 submitted detailing the outcome.
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3.3.3 UP Reporting Procedures
All events that meet the criteria of a UP must be reported in an expedited manner to the NIAMS and the Monitoring Body. There may be different timeline for reporting UPs to the IRBs, OHRP/FDA (if applicable), Monitoring Body, and the NIAMS. The timeline for reporting UPs to the Monitoring Body and NIAMS (through the NIAMS Executive Secretary) is within 48 hours of the investigator becoming aware of the event so that a real time assessment can be conducted, and the outcome shared in a timely manner.
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All events that meet the requirements of a UP are reported to the IRB in accordance to their policy, within 10 days of participant disclosure to a clinical site.
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3.3.4 Protocol Deviation Reporting Procedures
Protocol deviations impacting participant safety are subject to expedited reporting to the Monitoring Body and NIAMS (through the NIAMS Executive Secretary) within 48 hours of the investigator becoming aware of the event so that a real time assessment can be conducted, and the outcome shared in a timely manner. All other events should be reported at the time of the routine DSMB meeting or submission of the safety report.
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Inclusion/exclusion criteria not met
Unreported SAEs
Use of prohibited medication
Incorrect lab tests drawn or missing lab tests
Intentional deviation from protocol, Good Clinical Practice, or regulations by study personnel
Protocol deviations that do not impact participant safety will be reported in aggregate as part of the routine data and safety monitoring report sent to the Monitoring Body and NIAMS.
Protocol deviations are reported to the IRB in accordance to their policy, within 10 days of identification of the event.
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3.3.5 Serious or Continuing Noncompliance
This section should include the process in place at your institution to capture and report serious or continuing noncompliance. It should include who is responsible for 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 to the NIAMS. The guidance on reporting incidents to OHRP should also be followed to provide the timeline of reporting to this regulatory body.
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3.3.6 Suspension or Termination of IRB Approval
This section should include the process for reporting study suspension or termination by the IRB. It should also include who is responsible for reporting to the NIAMS, OHRP, and the timeline for reporting of these events. 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 PI.
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4.0 Interim Analysis & Stopping Rules
This section provides information on planned interim analysis. Interim analysis may be conducted either due to pre-specified stopping rules as outlined in the protocol and at predetermined intervals, or as determined necessary by the Monitoring Body to assess safety concerns or study futility based upon accumulating data. An interim analysis may be performed for safety, efficacy and/or futility, and the reports are prepared by the unmasked study statistician or data coordinating center responsible for generating such reports. Rules for stopping the study, based on interim analysis, should be described.
If no interim analysis is planned, this should be noted within this section.
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5.0 Data and Safety Monitoring
This section identifies the name of the individual or entity responsible for data and safety monitoring, what information will be reviewed, and frequency of such reviews. A brief general introduction regarding data and safety monitoring oversight should be provided in section 5.0, and further details should be provided in the subsequent sections.
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5.1 Frequency of Data and Safety Monitoring
This section describes the frequency of data and safety monitoring reviews. As the reviews of reportable events (AEs, SAEs, UPs, and protocol deviations) are included in Section 3, this section should focus on the routine and ad hoc review of the full data and safety monitoring reports.
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Specific triggers for an ad-hoc review or initiation of the process of an ad hoc review will occur if there are unforeseen deaths or the threshold for SAE has been met.
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5.2 Content of Data and Safety Monitoring Report
This section describes the content of the data and safety monitoring reports. The specifics of the study and the requests of the Monitoring Body will guide requirements for additional tables and listings. Tables for multi-site studies will present aggregated data as well as data by site.
For studies with more than one intervention group, this section should indicate the plans for providing data stratified by masked intervention group (i.e., Group A vs. Group B) as part of the closed report to the Monitoring Body, while the open report should have data presented in aggregate without stratification by groups.
The complete data and safety monitoring report template should be included as an appendix.
Refer to the NIAMS Data and Safety Monitoring Board Report Templates (https://www.niams.nih.gov/grants-funding/conducting-clinical-research/trial-policies-guidelines-templates/data-safety-monitoring-guidelines-policies/clinical-study-templates-forms) for guidance.
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The data and safety monitoring reports include the following information:
CONSORT diagram and actual versus expected enrollment figures that illustrate recruitment and participation status.*
Data tables that summarize demographic and baseline clinical characteristics
Data quality tables that capture missing visits and missing case report forms
Safety assessments of aggregate tables of adverse events and serious adverse events
Listings of adverse events, serious adverse events, deaths, unanticipated problems and protocol deviations
Aggregate tables of clinical laboratory values
*Schulz KF, Altman DG, Moher D, for the CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomized trials. Ann Int Med 2010; 152.
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5.3 Monitoring Body Membership and Affiliation
This section includes a roster of the Monitoring Body’s name(s) and affiliation(s). For studies with a NIAMS-appointed Monitoring Body, the NIAMS Executive Secretary will provide the name(s) and affiliation(s) of the individual(s) serving once the Monitoring Body has been assembled. However, if this is an Internally-appointed Monitoring Body (i.e., PI-appointed), the study team should enter the information in this section once the NIAMS has confirmed that no conflicts of interest with the Monitoring Body member(s) are identified.
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Name
Title, Organization
Area of Expertise
Name
Title, Organization
Area of Expertise
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5.4 Conflict of Interest for Monitoring Bodies
This section describes the conflict of interest procedure for Monitoring Body members. For studies with a NIAMS-appointed Monitoring Body, the NIAMS Executive Secretary will conduct a conflict of interest check on each member prior to beginning their service and on an annual basis thereafter. For studies with an Internally-appointed Monitoring Body (i.e., PI-appointed), the study team should provide the name, affiliation, and curriculum vitae (if available) of the proposed Monitoring Body member(s) to the NIAMS Executive Secretary for a conflict of interest check to be conducted. Once the conflict of interest check is complete, this section should be updated to indicate that the NIAMS did not identify any conflicts of interest for the Monitoring Body member(s).
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5.5 Protection of Confidentiality
This section describes how confidentiality of data presented to the Monitoring Body will be protected.
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5.6 Monitoring Body Responsibilities
A charter provides a detailed list of the Monitoring Body’s responsibilities. Listed in the sample text below are the responsibilities for a NIAMS-appointed Monitoring Body. Please ensure that all of the items are applicable for this study. For studies with an Internally-appointed Monitoring Body, the study team should ensure that a detailed list of the Monitoring Body’s responsibilities are provided in this section.
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Review the research protocol, Data and Safety Monitoring Plan (DSMP), and informed consent documents, including all proposed revisions. The Manual of Operating Procedures (MOP), which may contain the sections included above, is also reviewed.
Evaluate the progress of the study on an ongoing basis, as needed, including periodic assessments of data quality, participant recruitment, accrual and retention, participant risk versus benefit, performance of study site(s), and other factors that can affect the outcome.
Evaluate safety throughout the course of the study through the routine review of aggregated adverse event safety data, in addition to expedited review of unanticipated problems, serious adverse event reports, and protocol deviations impacting participant safety. The DSMB Safety Officer reviews the documentation provided by the study team and makes recommendations to the NIAMS regarding protection of the study participants.
Evaluate proposals of new sites (that differ from the approved application) and make a recommendation to the NIAMS as to whether the enrollment at the site(s) is expected to enhance overall enrollment. Activities include evaluating the patient population pool, catchment area description, recruitment plan, and target enrollment for any new clinical sites.
Consider the impact of factors external to the study when new information, such as scientific or therapeutic developments, becomes available and may affect safety of participants, their willingness to participate in the study or the ethics and conduct of the study.
Assist the NIAMS by commenting on any problems with study conduct or performance.
Ensure that the plan for maintaining the confidentiality of the study data and the results by the investigative team is appropriate.
Review and evaluate requests for protocol modifications.
Review data after completion of each cohort to approve does escalation, if applicable.
Review in advance of the study initiation the study specific stopping rules and plans for interim analyses as established by the PI and selected members of the study team. These plans outline the conditions under which a study may be stopped (e.g., difficulties in recruitment, retention, obtaining outcome measures, or other issues).
Review the interim analyses and/or accumulating data at the specified interval(s), and as appropriate and make a recommendation to continue, terminate, or modify the study based on observed benefit or harm in accordance with the planned stopping rules.
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6.0 Data Management, Quality Control, and Quality Assurance
This section describes how the site will collect, document, and review the data. Who will be responsible for data entry and ensure they are accurate and complete? Which database will be used? Does it have audit tracking capabilities? What is the data query process and frequencies? Are there any planned mitigation strategies in the event of non-compliance? What is the process for locking the final study datasets? Are there any procedures on data access and sharing as appropriate? Is there a description of security measures in place? (If you have a separate Clinical Monitoring and Data Management Plan, please reference it and utilize that information to help populate this section).
Each study should have standard operating procedures (SOPs) and/or a quality management plan that describe the following (if this is a multi-site study, each site should have SOPs and a plan):
- Staff training methods and how such training will be tracked
- How data will be evaluated for compliance with the protocol and for accuracy in relation to source documents
- The documents to be reviewed (e.g., case report forms, clinic notes, product accountability records, specimen tracking logs, questionnaires), who is responsible, and the frequency for reviews
- Who will be responsible for addressing quality assurance (QA) issues (correcting procedures that are not in compliance with protocol) and quality control issues (correcting data entry errors). It is anticipated that QA review and data verification will be performed by someone other than the individual originally collecting the data, or by double-data entry. The frequency of internal QA review and measures to be taken for corrective action (e.g., for trends in errors) should be included
- QA measures for participant recruitment, enrollment, enrollment targets, and for the validity and integrity of the data. E6 Good Clinical Practice (R1): 1.46 defines quality assurance as “All those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented (recorded), and reported in compliance with Good Clinical Practice (GCP) and the applicable regulatory requirement(s)”