Feature Article

Planning for Data and Safety Monitoring in Clinical Research Studies: Developing Your Study-Specific DSMP
November, 2006 Issue

Mary-Tara Roth, RN, MSN, MPH
GCRC Research Subject Advocate (RSA)

Author has nothing to disclose with regards to commercial support.

Educational Objectives:

At the end of this activity, participants should be able to:

• Recognize that the level of monitoring that should be put in place for a study depends on the nature, size and complexity of the study.
• Develop a DSMP for a study with which you are familiar.
• Recognize that a DSMP must be created before a study begins.
• Recommend the appropriate level of monitoring for a particular study.

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• Introduction
• Background on Regulations and Guidance related to Data and Safety Monitoring in Clinical Trials
• Assigning the Level of Monitoring
• Who conducts on-going monitoring, what is monitored, and how frequently?
• What is the reporting mechanism? How are adverse events (Aes) graded, attributed, and reported?
• Conclusion
• Quiz

Introduction

All researchers want to be prepared for adverse events, but what goes into assembling a data and safety monitoring plan (DSMP)? Is it possible to prepare for known and unknown events? How can the Principal Investigator (PI) best protect the safety of subjects and the validity of the data? This article will guide investigators through the regulations and offer suggestions for building a DSMP.

Background on Regulations and Guidance related to Data and Safety Monitoring in Clinical Trials

Under Federal Regulations, the IRB must make a determination that, “where appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects” (45 CFR 46.111(a)(6) and 21 CFR 56.111(a)(6)). To assist the IRB in making this determination, the PI is asked to include a detailed description of the DSMP in Section H of INSPIR. The DSMP is considered an essential component of the IRB protocol because the IRB believes this up-front planning makes the study safer for research participants. Several guidance documents have been issued by NIH to define data safety monitoring in clinical research studies. These are presented in Table 1, along with bulleted summaries.

All clinical studies require monitoring, but monitoring plans are individualized based on the risk and complexity of the study. Per regulations, the PI assumes responsibility for the overall conduct of the study (21 CFR 312.60). As such, the PI is responsible for the monitoring of the study, although he/she may assign study staff and others certain monitoring responsibilities that are within their scope of practice and training. Minimal risk studies may require only limited monitoring by the PI at regular intervals, while higher-risk studies require more frequent monitoring, including outside monitoring. Outside monitors might include an independent safety officer, a sponsor monitoring committee or board, or an outside independent group of experts, often (but not always) referred to as a Data Safety Monitoring Board (DSMB). These are formal committees that have the function of conducting interim monitoring, analysis and oversight (see Ellenberg, S., Fleming, T., DeMets, D. for more information).

A DSMP is a plan and process, individualized to the study, which prospectively defines the methods to be used by the Sponsor, PI and study team to oversee safety of study participants by evaluation of study data. The DSMP helps ensure the safety of the participants and the integrity and validity of the data by prospectively planning for regular, on-going monitoring. The minimal content of a DSMP is:

- Assignment of the level or intensity of monitoring based on the risk assessment.

- The identification of those responsible for on-going monitoring of the study specifying what each individual or group will monitor and the frequency of monitoring. (This includes monitoring of interim analysis results and stopping points for the entire study.)

- AE definitions, grading and the AE/SAE (serious adverse event) reporting mechanism.

Assigning the Level of Monitoring

In assigning the level of monitoring for a particular study, several factors warrant consideration, the most important being risk. Risk in research is defined as “the probability of harm or injury (physical, psychological, social, or economic) occurring as a result of participation in a research study.” (OHRP IRB Guidebook). The risk is determined based on many factors such as known vs. unknown side effects of the interventions and procedures, complexity of the study design (single vs. multi-site, low vs. high number of participants, blinded vs. un-blinded, long follow-up vs. short follow-up timeframe), the risk-to-benefit ratio, the potential for invasion of privacy or breach of confidentiality, the potential for physiological impact, the study population, and potential for conflicts of interest.

Only the term “minimal risk” is specifically defined by the federal regulations (45 CFR 46.102i). Any study where the risk exceeds the “minimal” risk threshold is considered “greater than minimal risk.” Although not specifically defined by the regulations, further grading of “greater than minimal risk” studies as “low,” “moderate,” or “high” risk serves to provide a framework for determining the level of monitoring needed. In general, as the level of risk rises, the frequency and intensity of the monitoring will also need to increase. Table 2 provides guidance monitoring at each risk level. (Note: these risk levels are not equivalent to the risk levels in Section E2 of INSPIR. Section E2 is used to determine the IRB review path rather than monitoring level.)

As an example, a study conducted at a single site with 20 healthy participants, using a known medication with modest side effects might be classified as greater than minimal risk (in Section E of INSPIR), but at the lower end of the continuum. Therefore the monitoring plan may be quite simple. A second study using the same medication in a large (e.g. >100 participants) multi-center trial may be considered as moderately higher on the continuum because more people are exposed to potential risk, and the added complexity in having multiple sites makes monitoring Aes more challenging. Such a trial will require a central safety monitor who reviews all Aes. If the study population were elderly patients with renal problems, the risk classification might be elevated to the highest level on the continuum, as there is a greater potential for SAEs in this vulnerable population. A high risk study would require a careful and more detailed DSMP as well as monitoring by an outside committee or Board.

Who conducts on-going monitoring, what is monitored, and how frequently?

The DSMP must include a description of ALL individuals involved in monitoring, the monitoring criteria, and the monitoring frequency . The DSMP will always include the study PI and, if so assigned, other members of the local study team and outside monitors. Often, industry and NIH-sponsored trials have a contract with an independent monitor who visits the site on a regular basis to conduct detailed reviews of Case Report Forms (CRFs) and assess adherence to the protocol. The Safety Officer and/or Medical Monitor, even at the sponsor level, are listed in the DSMP along with their monitoring responsibilities. If the study is monitored by an outside group (such as a DSMB), that group is listed along with the frequency and timing of its meetings. The study staff assigned by the PI to perform the monitoring must be adequately trained, and the type of monitoring to which they are assigned must fall within their scope of practice, licensure (if applicable) and training.

In writing the DSMP, the PI must try to forsee events which could affect the overall risk-to-benefit ratio for the study. An important component of the DSMP is a prospective statement of the stopping criteria for the entire study. In some cases, new information resulting from close monitoring will cause the study to be modified (i.e. new consent form). In other cases, it may be suspended (until more data can be analyzed) or even terminated. Such decisions frequently occur as a result of interim safety and efficacy review.

What is the reporting mechanism? How are adverse events (Aes) graded, attributed, and reported?

The local investigator is on the “front line” in assessing and reporting Aes. The study safety information depends on a consistent and reliable AE reporting mechanism set up at all study sites. The DSMP must address:

- The definition of Aes and SAEs in the context of the study.

- The grading scale used to determine “relatedness” of the AE to intervention.

- The grading scale used to determine the severity of an AE.

To ensure consistency among sites or even within a single site, the criteria and grading scales are specified in the DSMP. Formal criteria for grading symptoms or conditions, such as the World Health Organization Toxicity Criteria and the Cancer Therapy Evaluation Program Common Toxicity Criteria exist, but in some studies the PI or sponsor devise grading scales unique to that study.

Each DSMP must include the plan for reporting Aes and SAEs in conformity with the local IRB policies (see the algorithm in the February 2005 Clinical Research Times article ), federal regulations, and sponsor guidelines [HHS (45 CFR 46.103), FDA (drugs biologics: 21 CFR 312, 314.80; 600.80; devices: 21 CFR 812.150; unanticipated problems: 21 CFR 56.108), ICH GCP (3.38, 4.11, 5.17)]. Since reporting requirements often differ, the PI must consider when writing the DSMP that Aes and SAEs may need to be reported to the sponsor and the IRB within a different timeframe.

For more information on this topic, please see the Office of Clinical Research seminar series slides on this topic.

Conclusion

While designing a DSMP is complicated, this prospective planning will help protect participants' safety and safeguard the validity of the data and the success of the study. Investigators who conduct research in the General Clinical Research Center (GCRC) are required to use a GCRC DSMP template , while other investigators must devise an adequate DSMP on their own. All DSMP information must be included in your INSPIR application in Section H, with any supporting documents in Section S.

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