NINDS Guidelines for Data and Safety Monitoring in Clinical Trials

• Introduction
• Policies on Data and Safety Monitoring
• Indedpendent Medical Monitor
• Safety Monitoring Committee
• Data and Safety Monitoring Board
  • Medical Safety Monitor

1. Introduction

This document describes the policies and procedures of the National Institute of Neurological Disorders and Stroke (NINDS) for monitoring interim data from ongoing clinical trials, including data summarizing study performance and the safety and efficacy of the treatment regimens. It explains the requirement for a monitoring plan to be included in the study protocol, the monitoring authority and procedures for different types of trials, and the responsibilities of the study investigators. This document describes the role of the NINDS in the data and safety monitoring process and defines interactions between the monitoring authority, the investigators, and the NINDS, including the flow of information to ensure prompt feedback to all parties. Finally, it discusses the role of the Medical Safety Monitor in ongoing monitoring of serious adverse events occurring in study participants.

These guidelines are intended to provide information for principal investigators who are conducting clinical trials, as well as prospective grantees and members of monitoring committees. The procedures outlined herein are in addition to (and not in lieu of) Institutional Review Board (IRB), Office for Human Research Protections (OHRP) and Food and Drug Administration (FDA) requirements, and any additional applicable National Institutes of Health (NIH) guidelines.

Top

2. Policies on Data and Safety Monitoring

a. NIH Policy

It is NIH policy that data and safety monitoring of a clinical trial is to be commensurate with the risks posed to study participants and with the size and complexity of the study. In addition, the NIH requires that an Institute supporting clinical research be responsible for oversight of data and safety monitoring, ensuring that monitoring systems are in place, that the quality of the monitoring activity is appropriate, and that the Institute is informed of recommendations emanating from monitoring activities. These policies are detailed in the documents NIH Policy for Data and Safety Monitoring (release date: June 10, 1998, http://grants.nih.gov/grants/guide/notice-files/not98-084.html) and Further Guidance on Data and Safety Monitoring for Phase I and Phase II Trials (release date: June 5, 2000, http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html).

b. NINDS Requirements for Monitoring

The NINDS requires that each clinical trial it supports, regardless of phase, have data and safety monitoring procedures in place to safeguard the well-being of study participants and to ensure scientific integrity. Monitoring must be performed on a regular basis throughout the subject accrual, treatment, and follow-up periods.

The specific approach to monitoring will depend on features of the clinical trial to be conducted. NINDS specifies several levels of monitoring: Data and Safety Monitoring Board (DSMB), Study Monitoring Committee (SMC) and Independent Medical Monitor (IMM).

Individuals or groups monitoring data and safety of trials will review the research protocol and ongoing study activities with emphasis on data integrity and study participant safety issues, including:

• Review of adverse events.
• Recommendations to the NINDS and Principal Investigator (PI) concerning continuation or conclusion of the trial(s).
• Protection of the confidentiality of the trial data and the results of monitoring.
• Review of data and study quality

Monitoring activities should be appropriate to the study, study phase, population, research environment, and degree of risk involved.

In small, single-site studies, safety monitoring is often performed by the independent medical monitor or a safety monitoring committee in conjunction with the study statistician. All Phase III studies and any high risk Phase I or II clinical trial will also require a DSMB. It may be desirable to utilize a DSMB for:

• Trials involving highly experimental therapies or specialized review procedures external to the NINDS (e.g., gene therapy or xenotransplantation);
• Trials involving substantial risk to study participants (e.g., studies with irreversible outcomes); or
• Trials involving particularly vulnerable study participants (e.g., children or persons with impaired ability to consent).

Note that in no instance should a trial have both a DSMB and an SMC; there must be only one monitoring authority.

Additionally, the NINDS requires that each DSMB-monitored and some SMC-monitored trials have an assigned Medical Safety Monitor (MSM), independent of the study investigators, who is responsible for review of individual serious adverse events (SAEs) as they occur, and regular reporting of SAEs to the DSMB/SMC and others, as appropriate. Information on the role and responsibilities of the MSM can be found in section 5.

Sections 3, 4 and 5 of this document provide details about, respectively, the Independent Medical Monitor (IMM), Safety Monitoring Committee (SMC), and DSMB, including the role of a medical safety monitor.

c. Study Monitoring Plan

The NINDS requires that the protocol document include a section describing the proposed plan for interim data monitoring. This section will detail who is to be responsible for interim monitoring (i.e., a DSMB, an SMC, or the study investigator), what data will be monitored (i.e., performance and safety data only vs. efficacy data as well), the timing of the first data review (e.g., "the first interim look will occur when the initial 20 participants have completed the 6 month follow up visit"), and the frequency of interim reviews (which will depend on such factors as the study design, interventions and anticipated recruitment rate). The plan will specify "stopping guidelines" and other criteria for the monitors to follow in their review of the interim data.

A preliminary monitoring plan must be submitted as part of the Research Plan portion of the grant application for a clinical trial. The plan will be examined as part of the peer review process, and any comments and concerns will be included in an administrative note in the summary statement. NINDS staff will ensure that all concerns are resolved before the grant award is made.

Top

3. Independent Medical Monitor

An Independent Medial Monitor (IMM) may be appointed by the study Principal Investigator to oversee a clinical research project if there is more than minimal risk to the participants. The IMM will be independent of the study and have no real or apparent conflict of interest. The IMM is responsible for undertaking the monitoring responsibilities that are often the responsibility of a DSMB or SMC. The NINDS Program Director must approve of the IMM and specific monitoring procedures she/he will follow. In general, the IMM will operate in a manner similar to that of a SMC/DSMB. At each monitoring interval, the NINDS Program Director will receive notification by the IMM that she/he has reviewed the research protocol and ongoing study activities with emphasis on data integrity, protocol adherence and study participant safety issues. This will especially include the review of adverse events and reasons for losses to follow up, raising any concerns or issues with the NINDS and the Principal Investigator (PI), and recommending to the NINDS and PI the continuation, modification or conclusion of the trial, while protecting the confidentiality of the trial data and the results of monitoring.

4. Study Monitoring Committee

For trials not requiring a DSMB, a Study Monitoring Committee, appointed by the principal study investigator in consultation with the NINDS, may appropriately monitor other types of trials. A Study Monitoring Committee (SMC) will undertake monitoring responsibilities. Study investigators might participate in the SMC depending on the nature of the data being monitored and not affiliated with the institution in which the study is being conducted. Usually, however, the SMC will be composed of one or more scientists (generally physicians and a statistician) who are not involved in the study. The NINDS may appoint its own representative. The NINDS Program Director must approve the SMC membership and the specific monitoring procedures. In general, an SMC will operate in a manner similar to a DSMB.

Top

5. Data and Safety Monitoring Board

a. Responsibilities

NINDS-appointed Data Safety Monitoring Board (DSMB) is required for trials which may modify the current standards of treatment or public health policy, result in the licensing of a therapeutic agent or device, or extend approved indications to new groups of patients. This includes Phase III clinical trials and possibly some earlier phase trials.

The DSMB is responsible for assuring the NINDS that study participants are not exposed to unnecessary or unreasonable risks and that the study is being conducted according to high scientific and ethical standards. Specifically, the DSMB will:

• Assess the performance of the trial with respect to subject recruitment, retention and follow-up, protocol adherence, and data quality and completeness, in order to ensure the likelihood of successful and timely trial completion.
• Monitor interim data regarding the safety and efficacy of the study regimens, so that the trial will be concluded as soon as there is convincing evidence of the treatment effects. Note that for some protocols (e.g., for equivalency trials), the DSMB may primarily be charged with reviewing safety data rather than efficacy data. However, since lack of efficacy can be a safety and ethical concern, trends in adverse event data can best be evaluated when weighed against trends in efficacy. Thus the DSMB may, at its discretion, examine efficacy data as well as safety data for all studies.
• Review abstract and publications of main findings prior to submission to ensure the study is being reported appropriately.
• Review and consider any protocol modifications or ancillary studies proposed by the study investigators after the main trial begins to ensure that these do not negatively impact on the main trial. For example, addition of an ancillary study could burden the study participants so much that they are apt to discontinue participation in the trial. Protocol modifications will be considered in the context of their potential impact on scientific integrity and subject safety.
• Advise the NINDS and the study investigators as to whether a protocol should continue as scheduled or undergo a modification due to a finding from the monitoring process.

b. Membership

The DSMB is appointed by and advisory to the NINDS. The voting members may include physicians, laboratory scientists, statisticians, ethicists and patient advocates. Collectively, they will have appropriate expertise in the relevant scientific and safety monitoring areas. The precise number and areas of expertise of DSMB members will be dictated by the complexity of the study. Study investigators may suggest to the NINDS appropriate individuals to serve on the DSMB. NINDS representatives will participate on the DSMB as non-voting members.

To avoid any appearance of conflict of interest, it is critical that DSMB members not be involved in the study, have no vested interest in its outcome, have no ties to the study investigators (e.g., not from the same institution and no history of extensive collaboration), and have no financial ties to any commercial concerns likely to be affected by the study's outcome. If at any time a DSMB member perceives that he/she or another member of the Board (including an NINDS representative) has a potential conflict of interest, he/she is obligated to bring the issue to the attention of the full DSMB for open discussion and resolution. The NINDS requires DSMB members to complete a conflict of interest disclosure form and a statement of confidentiality.

c. Initial Meeting

Before the study is opened to subject accrual, the DSMB will meet in conjunction with the principal study investigator and study statistician to review the study protocol, particularly the specific outcome definitions, the analysis plan, the procedures for recording and reporting SAEs, and the monitoring proposal. The informed consent document/process also will be inspected to ensure that all required elements have been included in language understandable to a typical study subject to be enrolled in the trial. The purpose of the DSMB review of the study design is to learn directly from the study investigators the goals of the study, its rationale, why a particular design was chosen, and how it differs from similar protocols being conducted by other investigators. The study investigators will present any specific issues they would like the DSMB to consider while monitoring. Although the proposed monitoring plan is included in the study protocol, it is useful for the DSMB to discuss it directly with the study investigators and to query them about specific issues. For example, the DSMB might propose a hypothetical scenario encountered while monitoring the study, and ask the study investigators how they would hope the DSMB would react to it and why. Once the study begins, the DSMB is less able to interact with the study investigators in this way without disclosing (or seeming to disclose) interim results.

It is possible that the DSMB will recommend modification or clarification of the protocol, especially relating to the monitoring plan. A carefully considered, final monitoring plan is important to establish at the outset, because any subsequent deviation from the pre-specified plan may diminish the scientific integrity and credibility of the study.

During the initial meeting of the DSMB, the Board will formulate its operating procedures. These procedures will include such issues as: the Board's meeting frequency; the types and formats of reports it will receive from the PI and study statistician; the policy on whether and how the members may be unblinded; what interim data (if any) may be released to the study investigators (e.g., overall event rate); and how minutes will be taken and distributed.

d. Meeting Format

The DSMB will meet regularly to monitor the cumulative safety data during the period when participants are receiving study intervention and during the participant follow-up period. Typically, the DSMB will meet on a semiannual basis; in no instance should more than 12 months elapse between DSMB reviews of cumulative safety data after the first subject has enrolled. DSMB meetings may occur by teleconference. The DSMB will monitor the study according to the guidelines specified in the study protocol and the operating procedures established at the initial meeting, unless the DSMB determines during the course of the trial that modification of the guidelines is in the best interest of the study and its participants. Such a decision may be based on new information that emerges during the course of the study (e.g., publication of the results of a similar trial), realization of inappropriate initial study assumptions, or the occurrence of an unanticipated scenario. The DSMB responsibilities for monitoring and oversight conclude when the study is done and data has been verified and ready for publication.

The DSMB Chair in conjunction with the NINDS representative who is responsible for the DSMB operations will set the meeting agenda, which will usually include Open and Closed Sessions. The DSMB members, the study statistician and the principal study investigator will attend the Open Session, at which data concerning study conduct and aggregate safety data are discussed. The DSMB members and the study statistician will attend the Closed Session. Any safety and efficacy data analyzed by treatment arm will be discussed only in the Closed Session. It is critical that information presented in the Closed Session not be revealed to the study investigators, except as explicitly authorized by the DSMB. The study investigators will remain blinded to the interim data because knowledge of emerging trends between treatment arms may influence subject enrollment, management and evaluation, thus compromising the study.

e. Interim Data Reports

The Format and reporting requirement of unblinded data should be discussed and agreed upon at the first DSMB meeting. In general, the study statistician will prepare study data reports and send these to the NINDS representative who is responsible for the oversight of the DSMB at least 14 days prior to the meeting. The NINDS representative will forward these meeting materials to the DSMB members. These reports will contain the most up-to-date data permitted by the timeframe necessary for the statistician to prepare and review the analyses. Interim data reports will usually consist of two parts, corresponding to the Open and Closed Sessions of the DSMB meeting. Only the DSMB members will receive copies of the Closed Session report, and at the conclusion of the meeting the statistician or the NINDS representative will collect all copies of the report.

The Open Session report will focus on study participant accrual and demographics, data completeness, and other study performance measures, any new information (on the intervention or disease/disorder that may affect the outcome of the trial, and a list of publications or presentations. The Closed Session report will divide study participants according to cumulative data or coded treatment assignment (e.g., Treatments A vs. B), comparing subject demographics and baseline characteristics, rates of and reasons for treatment discontinuation and loss to follow-up, rates of SAEs and, if an interim efficacy analysis is scheduled, rates of efficacy outcomes (depending on the DSMB operating procedures).

Typically, the principal study investigator will have prepared a report addressing specific concerns he or she anticipates the DSMB will have regarding the conduct of the study. This report should be sent to the NINDS for distribution to the DSMB along with the Open Session report. Likewise, the study statistician's report for the Closed Session will usually contain his or her assessment of the progress of the trial, including recommendations on whether it should be terminated or modified. Interim data reports will generally include the following types of information, although only the Closed Session data reports will include comparisons by treatment group. If the randomization is stratified (e.g., by age), these tables and figures are presented by strata:

• A summary of monthly accrual and cumulative accrual, overall and by clinical center, compared to targets.
• A summary of baseline characteristics, overall and by treatment group.
• A summary of the completeness and quality of data collection forms.
• A summary of the status of enrolled participants, overall and by treatment group. (Study status includes whether the subject is on study or off study. For participants who are on study, there should be an indication as to whether they are on study treatment or off treatment. For participants who are off study, the reason should be indicated (i.e., completed study, died, refused further participation, lost-to-follow up, or other).
• Summaries of participants off treatment, including a listing by subject ID number of those who have permanently discontinued study treatment and summaries (overall and by treatment group) of the reasons for going off treatment, the proportion of participants off treatment prior to reaching the study outcome, and the proportion of participants going off treatment each study month.
• Assessments of whether the clinical centers have followed eligibility criteria and other protocol requirements.
• An assessment (e.g., based on pill counts or diaries) of subject adherence to the treatment regimen, overall and by treatment group.
• A summary of outcome rates by treatment group, if an interim efficacy analysis is scheduled.
• A listing of individual SAEs by subject ID number and a table of event-specific cumulative rates, overall and by treatment group.

View an outline for the DSMB Report.

f. Communication of DSMB Recommendations

At the conclusion of each DSMB meeting, the Board will provide a verbal report to the principal study investigator indicating areas of concern regarding performance and safety. The DSMB must not communicate any information that could lead to the unblinding of investigators or suggest interim treatment-specific results. Soon thereafter, the DSMB Chair in conjunction with the NINDS representative will provide the principal study investigator and the NINDS with a written summary of the Board's recommendations. In addition to the summary, the NINDS will include a memorandum to the principal study investigator documenting (a) the date of the review, (b) that all relevant interim safety and efficacy data were reviewed, (c) recommendations concerning the study execution or modifications to the study protocol, and (d) the anticipated date of the next review. The principal site investigator will promptly forward a copy of this memorandum to each participating study investigator for submission to their local IRBs, pursuant to the NIH's Guidance on Reporting Adverse Events to Institutional Review Boards for NIH-Supported Multicenter Clinical Trials (release date: June 11, 1999, http://grants.nih.gov/grants/guide/notice-files/not99-107.html).

If the DSMB recommends an amendment to the protocol, it must be approved by the NINDS representative, the IRBs and, for IND or IDE studies, the FDA. NINDS concurrence is required because some decisions may have significant programmatic implications. For example, a decision to extend the duration of a trial or increase the sample size has implications for the NINDS budget.

If as a result of interim data monitoring the DSMB determines that a trial (a) has answered the primary study question, (b) is futile or will not be able to reach a firm conclusion, (c) is not being conducted according to high scientific or ethical standards, or (d) poses an unreasonable or unnecessary risk to study participants, the DSMB will recommend to the NINDS representative that the study protocol be terminated, temporarily suspended or amended, as appropriate. If the NINDS representative concurs, this recommendation will be conveyed to and discussed with the principal study investigator before any action is taken. It will be important to ensure that the principal study investigator understands the DSMB's rationale. In addition, prior to a public announcement of a trial's early termination, a plan should be developed and implemented for notifying the study investigators, the IRBs and the study participants. When a study is conducted under an IND or IDE, the FDA and the involved biopharmaceutical companies or device manufacturers must also be notified. In addition, a decision to modify or terminate a trial may influence the conduct of another, similar clinical trial and as a courtesy, the NINDS may arrange to debrief that trial's study investigators or its DSMB in advance of the public announcement.

The DSMB and PI/study staff should not discuss the study or its progress outside the DSMB scheduled meetings and not without an NINDS representative. The NINDS representative will serve as a conduit for all correspondence between the DSMB and the PI or study staff.

g. Communications from Study Investigators

The principal study investigator will typically perform ongoing monitoring of study implementation parameters (e.g., recruitment, follow-up, compliance) in order to manage day-to-day study aspects and ensure quality control. These data reviews do not involve treatment group comparisons. If in the course of such monitoring, the investigator uncovers issues that may threaten the integrity of the study or subject safety (e.g., excessive dropout rate or unexpectedly high rate of adverse events), he or she should alert the NINDS representative to the DSMB, who will consult with the DSMB Chair as to whether a special meeting or conference call of the Board should be held.

In addition, for clinical trials funded in whole or in part by the NINDS and involving an IND or an IDE (regardless of who the official sponsor is), a participating study investigator is obligated to inform the NINDS of any significant communication from the FDA concerning the trial, including warning letters, investigator disqualification notices, clinical holds, etc., within 72 hours of first learning of this FDA communication. Formal notification should be made in writing, but initial notification may be done by telephone if a written notice would delay the notification. It should include a statement of the action taken or contemplated and the assistance needed to resolve the situation. This policy is detailed in the Notice to NIH Grantees/Contractors Regarding Letters or Notices from the Food and Drug Administration (FDA) (release date: September 22, 2000, http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-053.html). The NINDS will bring the matter to the attention of the DSMB.

Top

h. Medical Safety Monitor

The NINDS requires that each DSMB-monitored trial have an assigned Medical Safety Monitor (MSM), independent of the study investigators, who is responsible for review of individual serious adverse events (SAEs) as they occur, and regular reporting of SAEs to the DSMB and others, as appropriate. Some SMC's may also identify a MSM to review SAEs.

Each multi-center clinical trial supported by the NINDS will have an independent Medical Safety Monitor (MSM), nominated by the principal study investigator before subject enrollment begins and subsequently approved by the NINDS Program director (PD). The Medical Safety Monitor is a physician who is not involved in the study and who has no conflict of interest. The Medical Safety Monitor is responsible for ongoing monitoring of reports of SAEs submitted by the clinical centers in real time to ensure good clinical practice and to quickly identify safety concerns. The Medical Safety Monitor may suggest protocol modifications to prevent the occurrence of particular adverse events, e.g., modifying the protocol to require frequent measurement of laboratory values predictive of the event or to improve expeditious identification of SAEs. To minimize bias, the Medical Safety Monitor will usually evaluate SAEs blinded to treatment assignment, unless the DSMB/SMC approves partial or complete unblinding. Specific procedures for Medical Safety Monitor activities will necessarily vary from trial to trial in order to protect the safety of participants. For selected trials, the Medical Safety Monitor may serve as a resource to the clinical investigators for advice about management of SAEs but may not be involved in other aspects of the trial.

The Medical Safety Monitor will prepare regular reports concerning SAEs (not segregated by treatment group) for submission to the principal study investigator, the DSMB and, as appropriate, the FDA and collaborating biopharmaceutical companies or device manufacturers. Typically, such reports will be submitted on a regular basis, to be determined by the DSMB, for example real time, monthly or quarterly.

In the event of unexpected SAEs or an unduly high rate of SAEs, the Medical Safety Monitor will promptly contact the principal study investigator and the NINDS Program Director (PD) and if applicable, NINDS DSMB representative, who will notify the DSMB Chair. The DSMB may convene a meeting or teleconference of the Board to consider the concerns and plan appropriate action.

In the event that the MSM is unavailable for an extended period of time (i.e. extended vacation, sabbatical, illness, etc.) a back-up MSM will be nominated by the study PI and approved by the study PD. The responsibilities of the MSM are worked out between the Steering Committee and DSMB in advance of starting the trial.

6. Summary

The role and operating procedures of the IMM, SMC, DSMB, and MSM should be flexible to the needs of specific trials which they are responsible for. This flexibility should be emphasized and permitted, but standard operating procedures for study participant safety and data quality should be determined prior to the initiation of the trial and within the NINDS framework.