NINDS Guidelines for Monitoring in Clinical Trials

NINDS and NIH has developed policies and guidelines for monitoring clinical trials. The following websites provide information that may be useful in the conduct of a clinical research project:

1. Purpose

This document describes the policies and procedures of the NINDS for monitoring interim data from ongoing clinical trials, including data summarizing study performance and the safety and efficacy of the treatment regimens.  The procedures outlined herein are in addition to –and not in lieu of– IRB, OHRP and FDA requirements, and any additional applicable NIH guidelines.

2. NINDS Requirements for Monitoring

The NINDS requires that each clinical trial it supports, regardless of phase, has 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 participant accrual, treatment, and follow-up periods.

Monitoring activities should be appropriate to the trial phase, participant population, research environment, and degree of risk involved.  Although the study PI will include a data and safety monitoring plan in his/her grant application, the level of monitoring required for each study is determined by NINDS staff and communicated to the study PI before the trial begins.  No study may begin enrolling participants until the monitoring authority has been put into place and approved the study protocol.

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 the summary statement.  NINDS staff will ensure that all concerns are resolved before the study begins enrollment.

In addition to the plans for safety monitoring, the NINDS requires that the protocol when applicable include a section describing the plan for interim analyses, the timing of the interim analyses relative to study events (e.g., "when 20 participants have completed 6 months of follow-up"), and the exact statistical analyses plans.  The NINDS requires that the interim analyses and their effect on alpha be pre-specified.  The NINDS also requires that any plans to adapt (e.g., sample size, randomization) be pre-specified and supported by relevant simulations when applicable.  Any decision rules (e.g., for stopping or pre-planned adaptation) must be clearly stated.  The interim analysis plans and statistical analysis plans are reviewed by the DSMB and may be modified by the DSMB. 

As mentioned earlier, the NINDS may require a higher level of monitoring than is specified in the PI’s preliminary Data and Safety Monitoring Plan.  In addition, the plan may be further modified in accordance with the IMM’s, the SMC’s or the DSMB’s requirements, both before the study starts enrollment and possibly mid-study.

NINDS will specify one of the several levels of monitoring:

  • Data and Safety Monitoring Board: typically for multi-center intervention trials or higher risk studies
  • Study Monitoring Committee: typically for single-center intervention trials or moderate risk studies
  • Independent Medical Monitor: typically for single-center intervention trials with lower risk
  • Monitoring by the study PI and local IRB

Each study must have only one monitoring authority.

2.1 Responsibilities of Data and Safety Monitoring Boards

Data and safety monitoring responsibilities for clinical trials consist of review of the research protocol and ongoing study activities, including review of data quality and completeness, review of fidelity to the study protocol, review of adequacy of participant recruitment and retention, review of adverse events, making recommendations to the NINDS and the study PI concerning trial continuation, modification, or conclusion.  More details about the role of a DSMB are presented in Section 3, below.

2.2 Responsibilities of the Study Monitoring Committee

Studies not monitored by a DSMB may be overseen by a Study Monitoring Committee.  SMC members (generally physicians and a statistician) will be appointed by the study PI in consultation with the NINDS and must be independent of the study, but can be from the same institution, unless the NINDS requires otherwise.  The NINDS Program Official must approve the SMC membership and the specific monitoring procedures, and may participate in SMC meetings.

2.3 Responsibilities of the Independent Medical Monitor

An Independent Medical Monitor should be appointed by the study PI to oversee a clinical research project if there is more than minimal risk to the participants, but the study is not sufficiently complex that a DSMB or SMC is necessary.  The IMM must be independent of the study and have no real or apparent conflict of interest.  The NINDS Program Official must approve of the IMM and specific monitoring procedures she/he will follow.  The IMM will operate in a manner similar to that of a SMC/DSMB.  At each monitoring interval, the NINDS Program Official will receive notification by the IMM that he/she has reviewed the research protocol and ongoing study activities with emphasis on data integrity, protocol adherence and study participant safety issues.  The IMM’s review will focus on AEs and reasons for losses to follow up, raising any concerns or issues with the NINDS and the 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.

The Independent Medical Monitor role is distinct from the role of a Medical Safety Monitor.  The MSM role is described below under section 2.5.

2.4 Responsibilities of the PI and IRB

When a trial is of minimal risk or even if it is of more than minimal risk but involves only a single site, and if the trial involves only one intervention, the NINDS may determine that the study may be adequately monitored by the study PI and his/her IRB.  It is expected that the PI will be actively involved in reviewing the progress of each subject on study and will bring to the attention of the IRB adverse events and unexpected problems that may influence the IRB’s decision to allow the trial to continue, in accordance with the IRB’s policies.  In addition, the PI is expected to notify the NINDS Program Official.

2.5 Responsibilities of the Medical Safety Monitor

Each multi-center clinical trial supported by the NINDS will have an independent Medical Safety monitor (MSM), nominated by the study PI before participant enrollment begins and subsequently approved by the NINDS Program Official and by the NINDS DSMB, if applicable.  The MSM is a physician who is not involved in the study and who has no conflict of interest.  The MSM is responsible for ongoing monitoring of reports of SAEs submitted by the clinical centers in real time to ensure good clinical practice and to identify safety concerns quickly.  The MSM may suggest protocol modifications to prevent the occurrence of particular AEs, 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 MSM will usually evaluate SAEs blinded to treatment assignment, unless the DSMB/SMC approves partial or complete unblinding.  Specific procedures for MSM activities will necessarily vary from trial to trial.  For certain trials, the MSM 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 responsibilities of the MSM are worked out between the Steering Committee and DSMB/SMC in advance of starting the trial.

The MSM will prepare regular reports concerning SAEs (not segregated by treatment group) for submission to the PI, and subsequently to 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. In the event of unexpected SAEs or an unduly high rate of SAEs, the MSM will promptly contact the PI and the NINDS Program Official and, if applicable, the  NINDS DSMB Liaison, who will notify the DSMB Chair.  The DSMB/SMC may convene a meeting or teleconference 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 NINDS Program Official.

3. Data and Safety Monitoring Board

3.1 Overview

An NINDS-appointed 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. A DSMB is mandatory for all Phase 3 clinical trials, and it may be required for some earlier phase trials (e.g., trials that involve multiple sites, pose significant risk to participants, are conducted in vulnerable populations, use certain controversial interventions).

The DSMB will meet regularly in person or by teleconference, typically on a semi-annual basis, to monitor the cumulative safety data during participant follow-up. The in- person format is recommended for the initial meeting and then annually, when possible. In no instance should more than 12 months elapse between DSMB reviews of cumulative safety data after the first participant has enrolled. 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.

Except as explicitly authorized by the DSMB, it is critical that study investigators will remain masked to the interim data because knowledge of emerging trends between treatment arms may influence participant enrollment, management and evaluation, thus compromising the study by introducing bias. The DSMB decides in their first meeting if DSMB members will be unmasked. If the DSMB decides to remain masked, they should consider assigning one DSMB member, when possible a clinician, to be unmasked to treatment assignment. The unmasked DSMB member may decide to unmask other DSMB members as indicated, and for example based on concerns over SAE imbalances between study groups.

3.2 Responsibilities of the DSMB

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 participant recruitment, retention and follow-up, protocol adherence, and data quality and completeness, in order to ensure the likelihood of successful and timely trial completion.
  • Review the statistical analysis plan, including the interim analysis plan, stopping rules and randomization scheme
  • 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.
  • Review abstract and publications of main findings prior to submission to ensure the study is being reported appropriately.
  • Review and consider any protocol modifications proposed by the study investigators after the main trial begins to ensure that these do not negatively impact on the main trial. Protocol modifications will be considered in the context of their potential impact on scientific integrity and participant safety.
  • Monitor recruitment progress.
  • Monitor lost to follow-up.
  • Review data completeness and quality.
  • Monitor missing data.
  • Recommend planned adaptations based on pre-specified plans and decision rules.
  • Review and consider any ancillary studies proposed by the study investigators to ensure that they do not have a negative impact on the main trial.  
  • Review performance and participant safety data of active ancillary studies.

After each review, the DSMB will advise the NINDS and the study investigators as to whether a protocol should continue as scheduled or undergo a modification due to findings that emerged as a result of the monitoring process.

3.3 DSMB Membership

The NINDS-appointed DSMB has an advisory role to the institute. 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 of DSMB members and their areas of expertise will be dictated by the complexity of the study. Study PIs may suggest to the NINDS appropriate individuals to serve on the DSMB.

One member of the DSMB is designated as the DSMB Chair. The DSMB Chair is typically a physician.

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, and have no financial ties to any commercial concerns likely to be affected by the study's outcome. In general, DSMB members do not publish study related manuscripts with study team members, while a study is on-going, in order to prevent any possible or perceived conflicts of interest. If at any time a DSMB member perceives that he/she or another member of the Board 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(pdf, 40 KB) (pdf, 39 kb), on an annual basis.

The principal contact between NINDS and the DSMB is the DSMB liaison, who must maintain objectivity regarding trial outcomes to avoid influencing the DSMB, and confidentiality of DSMB discussions to avoid influencing trial conduct. The NINDS DSMB liaison, who  serves as the principal contact between NINDS and the DSMB,  is the federal government representative on the DSMB.

3.4 Role of the Independent Statistician

An independent statistician (as distinct from the study statistician) will be responsible for generating the unblinded interim analyses (i.e., closed session DSMB reports) and reporting to the DSMB; this statistician will have no other involvement in the trial.  The purpose for having an independent statistician is to help ensure that interim results from the trial will be kept confidential and that the Steering Committee will not be influenced by any knowledge of the study’s interim results.

Most trials supported by NINDS are funded through a grant awarded to a single organization, usually an academic institution.  The Principal Investigator is generally the director of the Clinical Coordinating Center for the trial and the chair of the Steering Committee.  A Statistical Analysis Center and a Data Management Center (or a combined Statistical and Data Management Center) are usually funded through subawards.  Both the study statistician and the independent statistician will typically be employees of the Statistical Analysis Center.  Despite these structural and financial arrangements, it will be necessary for a ‘firewall’ to be established to ensure that the independent statistician can operate autonomously from the Principal Investigator, study statistician and other members of the Steering Committee.

The Data and Safety Monitoring Plan in the grant application must describe the proposed firewall and how it will function to protect the quality and confidentiality of the interim data and related DSMB analyses.  Close adherence to the interim monitoring procedures outlined in the study-specific Statistical Analysis Plan (SAP) will help mitigate possible bias and preserve trial integrity.  Nevertheless, because DSMBs frequently need to modify these plans (e.g., to account for an unexpectedly low overall event rate), the Data and Safety Monitoring Pland and the SAP should clearly state that there must not be any restrictions on the data the independent statistician can access or the extent or timing of interim analyses he/she can perform, without alerting any member of the Steering Committee.

Despite the firewall, the independent statistician must be thoroughly familiar with the trial protocol, the SAP, the case report forms, and the processes for data collection and adjudication of safety and outcome events.  One way to achieve this may be to allow the independent statistician to work closely with the study statistician and data managers up until the point where the first interim analysis report is generated for the DSMB, at which time the firewall is implemented.

3.5 Initial Meeting

The first DSMB meeting takes place before the study is opened to participant accrual, with the goal of reviewing the study protocol, particularly the specific outcome definitions, the analysis plan, the procedures for recording and reporting SAEs, the monitoring proposal, pre-specified interim analysis plan and decision rules, and pre-specified plans for adaptation and decision rules. 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 participant to be enrolled in the trial. 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 this initial meeting, the DSMB liaison will explain the stewardship roles of NINDS staff who attend DSMB meeting as observers, and his/her responsibilities as the principal contact between the DSMB and NINDS, and the DSMB and PI. The DSMB will review the DSMB guidelines and formulate its operating procedures, including: the DSMB's meeting frequency; the types and formats of reports it will receive from the PI and independent statistician, 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. In addition, at the first meeting, the policy regarding masking of the DSMB members with respect to group data should be established.  DSMB data reports typically present closed session data by coded treatment group (e.g., “A/B”).  It is highly recommended that the DSMB have knowledge from the start of the study which treatment groups the codes represent.  If the DSMB initially elects to remain masked to these codes, the key must be available should the need for full unmasking arise.

3.6 Meeting Format

The NINDS DSMB meeting format consists of open and closed sessions. The meeting format, including the number of open and closed sessions, and the participation in these sessions is at the discretion of the DSMB. The DSMB Chair, in conjunction with the NINDS DSMB liaison, is responsible for the DSMB operations and will set the meeting agenda. At each meeting, the DSMB liaison will update conflict of interest and remind DSMB members that NINDS staff attend as observers only.

Closed Sessions:  Only DSMB members and the NINDS DSMB liaison participate in closed sessions, to ensure complete objectivity as they discuss outcome results by treatment arm as needed, make decisions, and formulate recommendations regarding the study. The DSMB Chair may request additional participants during this session, e.g. medical safety monitor, independent statistician.

Open Sessions:  DSMB members, NINDS Project Scientist assigned to this study, NINDS Program Official assigned to this study, NINDS DCR director or designee, study PIs,  study statistician and independent statistician attend this session, at which data concerning study conduct and aggregate safety data are discussed.

If a DSMB member has concerns with NINDS staff attendance or participation at any of the above meetings, these should be addressed either to the DSMB liaison or to the NINDS DCR Director or designee.

3.7 Interim Data Reports

The format and reporting requirement of unmasked data should be discussed and agreed upon at the first DSMB meeting. At least 14 days prior to the meeting, the independent statistician will prepare study reports using the most recent data and send these to the NINDS DSMB liaison, who will provide the meeting materials to the DSMB members.

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 independent 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. All data in the Open Session report will be presented in the aggregate, i.e., not by treatment assignment. The Closed Session report will divide study participants according to cumulative data or coded treatment assignment (e.g., Treatments A vs. B), comparing participant demographics and baseline characteristics, rates of and reasons for treatment discontinuation and loss to follow-up, rates of adverse safety events 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 DSMB Liaison for distribution to the DSMB along with the Open Session report. Likewise, the independent 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 participant 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 participant 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 participant 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 serious adverse events (SAEs) by participant ID number and a table of event-specific cumulative rates, overall and by treatment group.
  • A listing of adverse events (AEs) by treatment group and body system.
  • A listing of protocol violations, if any.

View an outline for the DSMB Report(pdf, 312 KB) (pdf, 305 kb)

3.8 Communication of DSMB Recommendations

At the conclusion of each DSMB meeting, the DSMB 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 unmasking of investigators or suggest interim treatment-specific results. Soon thereafter, the DSMB Chair will provide meeting minutes, including the DSMB’s recommendations to the Director of the NINDS Division of Clinical Research, through the NINDS DSMB Liaison. The NINDS DCR Director will determine if the NINDS concurs with the DSMB’s recommendations. The NINDS DCR Director or designee will communicate concurrence or not with the study PI. The NINDS DSMB Liaison will provide the DSMB minutes and recommendations to the study PI, along with a memorandum 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 PI 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 (see NOT-99-107).

If the DSMB recommends an amendment to the protocol, it must be approved prior to implementation by the NINDS DCR Director, 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 i.e., crossing an efficacy or futility threshold (evidence of efficacy, evidence of lack of efficacy, or futility); (b) cannot recruit participants within a reasonable timeframe (as determined by the NINDS); (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 DSMB Liaison that the study protocol be amended, temporarily suspended, or terminated, as appropriate. If the NINDS DCR Director concurs, this recommendation will be conveyed to and discussed with the PI before any definitive action is taken. It will be important to ensure that the PI understands the DSMB's rationale. In addition, prior to a public announcement of a trial's early termination, a plan should be developed, reviewed by the DSMB and NINDS, and implemented for notifying the study investigators, the IRBs and the study participants. It is important that this communication emphasize that no urgent action is required to ensure the safety of the research subjects still under follow-up, if that is indeed the case.  When a study is conducted under an IND or IDE, the FDA and the involved biopharmaceutical companies or device manufacturers must also be notified.  Also, since a decision to modify or terminate a trial may influence the conduct of another, similar clinical trial, 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 the NINDS DSMB liaison. The NINDS DSMB liaison will serve as a conduit for all correspondence between the DSMB and the PI or study staff.

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

3.9 Communications from Study Investigators

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) (see NOT-OD-00-053).  The NINDS will bring the matter to the attention of the DSMB.

 

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