MOUNT SINAI SCHOOL OF MEDICINE
PROGRAM FOR THE PROTECTION OF HUMAN SUBJECTS
Guidance on Data Safety Monitoring Plans
PURPOSE
All human subjects research protocols conducted under the review of the Program for the Protection of Human Subjects at Mount Sinai School of Medicine must include a Data Safety Monitoring Plan to ensure the safety of participants and the validity and integrity of their data. The purpose of this document is to provide a systematic approach to fulfilling the requirements of Data Safety Monitoring Plans.
BACKGROUND
All human subjects research including that in which no interventions occur and which present only minimal risk require attention to standards for protection of data and of interaction with research participants. Protocols involving minimal risk to participants may be conducted using the minimum standardized Data and Safety Management Plan.
Clinical trials at MSSM will be monitored according to the following National Institutes of Health Policy for Data and Safety Monitoring (June 10, 1998.)
A clinical trial entails a relationship between participants and
investigators, both of whom must fulfill certain obligations for
the effort to succeed. Participants must be fully informed of
the study requirements throughout the conduct of the trial and
should comply with the rigors of the research protocol or be
allowed the opportunity to withdraw from participation. The
investigators must protect the health and safety of participants,
inform participants of information relevant to their continued
participation, and pursue the research objectives with
scientific diligence.
Although there are potential benefits to be derived from
participation in clinical research, the IRBs and the NIH must
ensure, to the extent possible, the safety of study participants
and that they do not incur undue risk and that the risks versus
benefits are continually reassessed throughout the study period.
SCOPE
This guidance applies to Protocol Directors conducting non-exempt human research under the auspices of MSSM PPHS review, and to all IRB members, and to PPHS staff members who review protocols involving human subjects research.
DEFINITIONS
Data Safety Monitoring Plan (DSMP): An organized, written plan to continuously evaluate the safety and well being of participants in research and the integrity of the data collected. The plan should be specific to each protocol. A DSMP should meet at least the minimum requirements, but may involve more extensive procedures as necessary or appropriate. Data and safety monitoring is distinguished from regulatory monitoring, in which the primary interest is compliance with Good Clinical Practice (GCP) (www.fda.gov/oc/gcp/) and the International Conference on Harmonisation (ICH) (www.ich.or) guidelines.
Data and Safety Monitoring Board or Committee (DSMB/DMC): In many cases the Protocol Director or Principal Investigator will be the only monitor of its safety and data. Other protocols will require an independent individual or committee. Fully independent external committees are usually referred to as Data and Safety Monitoring Boards, and tend to be used in research that involves high risk, multiple sites, or investigators with conflicts of interest.
Adverse Events/Serious Adverse Events/Unanticipated Problems: (See adverse event policy for details.) Data and safety monitoring is a critical tool in discovering adverse events and unanticipated problems that need to be managed and reported. An important aspect of adverse events in the context of data and safety monitoring is that expected or anticipated events must be defined in a DSMP and then tracked to determine if there is an increase in frequency or severity. These expected events are, in the absence of qualifying as serious adverse events due to their severe outcomes (e.g. hospitalization, etc), not routinely reportable to the PPHS as individual events. Once expected adverse events are defined in a DSMP, aggregated trends may reveal significant changes in the frequency or severity of these known events. Summaries of the specific adverse events tracked by the safety and monitoring plan should be reported as indicated in the DSMP andin accordance with the adverse event policy.
Regulatory/GCP Compliance Monitoring: GCP and ICH guidelines require that appropriate procedures are followed and documented. Regulatory monitoring visits focus on completion of CRFs and maintenance of proper regularly documentation. These monitoring processes may focus on the reporting of (as opposed to evaluating) serious adverse events. These regulatory monitoring processes should not be confused with data and safety monitoring.
Safety Monitoring: Safety monitoring involves systematic observation and recording of adverse events and a plan to routinely evaluate these events. For multi-centered studies, this process must be centralized, so that the incidence of events can be understood in relation to the total number of participants involved in the study.
REVIEW AND APPROVAL OF DATA AND SAFETY MONITORING PLANS
All non-exempt research involving human subjects at the Mount Sinai School of Medicine must have an approved Data and Safety Monitoring Plan. The requirements of DSMPs for all levels of human subjects research are described below. Compliance with DSMPs is a primary responsibility assumed by all protocol directors at MSSM. The MSSM PPHS reserves the right to alter the required level of monitoring as appropriate.
Generally the PPHS will accept DSMPs approved by the General Clinical Research Center’s, GCRC Advisory Committee (GAC) or the MSSM Cancer Center’s Protocol Review and Monitoring Committee (PR&MC). The Financial Conflict of Interest in Research (FCOIR) Committee may have specific requirements regarding data and safety management. The MSSM PPHS will not grant final approval of a project before the review process of either the GAC or FCOIR is completed. The PPHS will not decrease the level of oversight designated by the GAC, PR&MC or FCOIR approved DSMP without prior approval from the initiating committee. The MSSM PPHS reserves the right to increase the level of monitoring if deemed appropriate and to communicate these concerns to the initiating committee.
Industry sponsored protocols routinely engage professional regulatory monitors to assure quality of data collection and compliance with good clinical practice. Although there is an overlap between GCP monitoring and safety monitoring, the two should not be confused; Data and Safety Monitoring must include a plan to review the accumulating data.
REQUIREMENTS AND RECOMMENDATIONS FOR DATA AND SAFETY MONITORING For many NIH studies the monitoring plan must meet the requirements of the specific institute that is sponsoring the project. Links to the policies of the Institutes are included in Appendix A. Research with sponsors external to MSSM often requires appropriate data and safety monitoring plans.
Because DSMPs should be appropriate to the risk involved, the PPHS has provided a study risk assessment guide as part of the DSMP form in Appendix B. Low risk studies generally require the minimum plan. High risk studies will generally require a safety monitor other than the Protocol Director.
Minimum DSMP
The following minimum requirements apply to all projects, including retrospective reviews of medical records, use of tissue samples, and many minimal risk studies, such as observational and survey research. Because these minimum requirements apply to all studies, a specific written DSMP will not usually be required. The MSSM PPHS may alter the required level of monitoring if appropriate.
For all projects, the protocol director must have a plan to assure that data integrity will be maintained during its collection, storage and analysis. Projects should adhere to MSSM recommendations on the storage of research data. Loss of data containing identifiable information is considered to be an internal serious Unanticipated Problem and must be reported to the PPHS within 10 working/14 calendar days.
Any problems concerning the consent process and any patient complaints should be monitored by the investigator. Reports of such problems must be made at least annually. The discretion of the protocol director will guide the need to report these problems immediately or more frequently. Although unlikely, any unanticipated event that is related to the study and suggests that the research places subjects or others at a greater risk of harm than was previously known or recognized must be reported to the PPHS according to established policy.
The protocol director or principal investigator is the monitoring entity for the minimum DSMP. When a protocol director is not a faculty member, the supervising faculty member must be responsible for the data and safety monitoring aspect of the protocol.
A protocol director may request alterations to the minimum DSMP. Prospective studies that are minimal risk may request permission to be exempt from some of the reporting requirements for adverse events. For a prospective survey study, the protocol director might request permission to exempt death on protocol and serious adverse events reporting. All such requests will be reviewed by the PPHS.
Tailored Data and Safety Monitoring Plan
Research that is complex or involves more than minimal risk should have an appropriately tailored protocol-specific DSMP. This DSMP should describe how the protocol director or principal investigator will oversee the research participants' safety and well being, and how unanticipated problems presenting risks to participants or others, and adverse events will be characterized and reported. The plan should be tailored to the nature, size, and complexity of the research, the expected risks, the subject population being studied. Protocol directors and principal investigators may use the MSSM form or other documentation that provides the information requested on the form.
Multi-institutional and industry sponsored studies must have a DSMP established by the sponsor. A copy of the sponsor's DSMP, which includes the name of the contact person and all of the information requested in the MSSM DSMP form (See Appendix C), should be included with the MSSM DSMP. The sponsor's DSMP should identify the central reporting entity that will collect and report all adverse events to all investigators at participating institutions. After every review of the safety data, reports must be made available to local investigators. The reports must include all information necessary to assure that subject safety is not being compromised and that the results do not warrant early termination of the study. The protocol director or principal investigator will be required to provide summaries or copies of this documentation during PHHS review. Protocol directors may seek the assistance of the PPHS staff in determining appropriate documentation for a specific study.
There are three basic features of all Data and Safety Monitoring Plans:
1. A process to monitor the progress of the research and the safety of participants;
2. A process to assure compliance with requirements for the detection and
reporting of adverse events and unanticipated problems; and
3. A process to assure data accuracy and protocol compliance.
The DSMP will identify who will assess safety data for the study, and will clearly define responsibilities and roles of those gathering, monitoring, and evaluating the data. It will identify who will assess safety data for the study. The DSMP will include a schedule on which the data will be analyzed, and when any necessary action will be taken. Some DSMPs will define specific triggers or stopping rules, and will identify IRBs or other authorities, investigators or participants who will be notified of relevant information.
Monitor
The DSMP monitor is a person or group assigned to conduct interim monitoring of accumulated data from research activities to assure the continuing safety of research participants. DSMPs may also address ongoing evaluation of the relevance of the study question, the appropriateness of the study, and the integrity of the accumulating data.
The monitoring entity may be:
1. The protocol director;
2. A safety committee chaired by the protocol director;
3. A medical monitor other than the data monitoring committee,
internal to the sponsor or MSSM, or external;
4. A data and safety monitoring board or committee independent of the
investigator, either internal (primarily MSSM faculty), internal to a sponsor, or
external to MSSM and the sponsor; Considerations regarding DSMBs are contained in Appendix D
5. An NIH sponsored cooperative group, a coordinating or statistical center,
or a monitoring committee formed by a sponsor other than NIH.
If the study is blinded, and independent monitor may be needed to evaluate the data without breaking the blind for the investigators. The DSMP should clearly define the monitor, and the roles and responsibilities for gathering and processing data.
Identifying Data and Events
All clinical studies should have a mechanism in place to identify, record and report any unanticipated problem that is related to the study and suggests that the research places subjects or others at a greater risk of harm than was previously known, as well as those adverse events considered reportable according to established PPHS policy. (see Reporting and Processing of Adverse Events and Unanticipated Problems policy)
Clinical trials the primary endpoint of which is morbidity and/or mortality may specify these outcomes for ongoing evaluation during the study. For example, if a study is designed to test the efficacy of a new drug to prevent heart attacks, the interim analysis might be designed to compare the rate of heart attacks between the study drug and placebo. In this case, the data monitor should be able to review unblinded data.
The DSMP should address how expected adverse events will be monitored. These are the known or foreseeable adverse events associated with the procedures involved in the research. They are described in the PPHS approved research protocol, any investigator brochures, and the current PPHS-approved consent document, and in all other sources of information such as product labeling and package inserts. All DSMPs should provide means of tracking expected adverse events.
The definition of unexpected adverse events includes a change in the frequency or severity of expected adverse events. If the investigator becomes aware that an otherwise expected adverse event has increased in severity or frequency, this should be reported to the PPHS as an unexpected event.
For studies involving multiple established drugs the list of expected adverse events can be long and non-specific. The investigator must formulate a plan that realistically evaluate the safety of the study regimen. Some studies will have will have predetermined specific criteria for stopping the study; others may not have designated such decision points.
All DSMPs should assure that important and evident safety concerns are included in participant evaluations and recorded for review. For studies with complicated drug regimens with extensive side effect profiles, safety review may focus on one or a few specific side effects, and will not require that investigators routinely record the incidence of every side effect listed in the consent form.