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<html lang="en-US">
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<HEAD>
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<TITLE>NIH Guide: NIH POLICY FOR DATA AND SAFETY MONITORING</TITLE>
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<META NAME="Title" CONTENT="NIH Guide: NIH POLICY FOR DATA AND SAFETY MONITORING">
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<META NAME="Filename" CONTENT="not98-084.html">
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<META NAME="Location" CONTENT="/grants/guide/notice-files/">
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<META NAME="Publication_Date" CONTENT="June 12, 1998">
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<META NAME="Keywords" CONTENT="NATIONAL INSTITUTES OF HEALTH">
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<BODY BGCOLOR="#FFFFFF" TEXT="#000000">
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<pre>
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NIH POLICY FOR DATA AND SAFETY MONITORING
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Release Date: June 10, 1998
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P.T.
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National Institutes of Health
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Policy
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It is the policy of the NIH that each Institute and Center (IC) should have a
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system for the appropriate oversight and monitoring of the conduct of clinical
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trials to ensure the safety of participants and the validity and integrity of the
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data for all NIH-supported or <20>conducted clinical trials. The establishment of
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the data safety monitoring boards (DSMBs) is required for multi-site clinical
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trials involving interventions that entail potential risk to the participants.
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The data and safety monitoring functions and oversight of such activities are
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distinct from the requirement for study review and approval by an Institutional
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Review Board (IRB).
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Background
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A clinical trial entails a relationship between participants and investigators,
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both of whom must fulfill certain obligations for the effort to succeed.
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Participants must be fully informed of the study requirements throughout the
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conduct of the trial and should comply with the rigors of the research protocol
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or be allowed the opportunity to withdraw from participation. The investigators
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must protect the health and safety of participants, inform participants of
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information relevant to their continued participation, and pursue the research
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objectives with scientific diligence.
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Although there are potential benefits to be derived from participation in
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clinical research, the IRBs and the NIH must ensure, to the extent possible, the
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safety of study participants and that they do not incur undue risk and that the
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risks versus benefits are continually reassessed throughout the study period.
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With this issuance, the NIH reaffirms the 1979 policy (NIH GUIDE, Volume 8, No,
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8, June 5, 1979) developed by the NIH Clinical Trials Committee. Among its
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recommendations was the concept that "every clinical trial should have provision
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for data and safety monitoring." The Committee further acknowledged that "a
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variety of types of monitoring may be anticipated depending on the nature, size,
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and complexity of the clinical trial. In many cases, the principal investigator
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would be expected to perform the monitoring function."
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In 1994, the Office of Extramural Research established the Committee on Clinical
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Trial Monitoring to review the oversight and management practices of the ICs for
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phase III clinical trials. One of the outcomes of this Committee's review was
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a strong recommendation that "all trials, even those that pose little likelihood
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of harm, should consider an external monitoring body." This policy affirms the
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Committee's recommendations concerning DSMBs.
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Principles of monitoring data and safety
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All clinical trials require monitoring -- Data and safety monitoring is required
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for all types of clinical trials, including physiologic, toxicity, and dose-
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finding studies (phase I); efficacy studies (phase II); efficacy, effectiveness
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and comparative trials (phase III); etc.
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Monitoring should be commensurate with risks -- The method and degree of
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monitoring needed is related to the degree of risk involved. A monitoring
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committee is usually required to determine safe and effective conduct and to
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recommend conclusion of the trial when significant benefits or risks have
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developed or the trial is unlikely to be concluded successfully. Risk associated
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with participation in research must be minimized to the extent practical.
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Monitoring should be commensurate with size and complexity <20> Monitoring may be
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conducted in various ways or by various individuals or groups, depending on the
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size and scope of the research effort. These exist on a continuum from monitoring
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by the principal investigator or NIH program staff in a small phase I study to
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the establishment of an independent data and safety monitoring board for a large
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phase III clinical trial.
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Practical and Implementation Issues:
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Oversight of Monitoring
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This policy provides each IC with the flexibility to implement the requirement
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for data and safety monitoring as appropriate for its clinical research
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activities. Thus, IC staff may either conduct or sponsor the monitoring of data
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and safety of ongoing studies or delegate such responsibilities to a grantee or
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contractor. Oversight of monitoring activities is distinct from the monitoring
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itself and should be the responsibility of the IC regardless of whether the
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monitoring is performed by NIH staff or is delegated. Oversight of monitoring
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must be done to ensure that data and safety monitoring plans are in place for all
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interventional trials, that the quality of these monitoring activities is
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appropriate to the trial(s), and that the IC has been informed of recommendations
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that emanate from monitoring activities.
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Institutes and Centers Responsibilities
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Though ICs may perform a variety of roles in data and safety monitoring and its
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oversight, the following are the minimum responsibilities of sponsoring ICs.
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Prepare or ensure the establishment of a plan for data and safety monitoring for
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all interventional trials.
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Conduct or delegate ongoing monitoring of interventional trials.
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Ensure that monitoring is timely and effective and that those responsible for
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monitoring have the appropriate expertise to accomplish its mission.
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Oversee monitoring activities.
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Respond to recommendations that emanate from monitoring activities.
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Performance of Data and Safety Monitoring
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The ICs will ensure the integrity of systems for monitoring trial data and
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participant safety, although they may delegate the actual performance to the
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grantee or contractor. Monitoring must be performed on a regular basis, and
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conclusions of the monitoring reported to the IC. Recommendations that emanate
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from monitoring activities should be reviewed by the responsible official in the
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IC and addressed. The ICs also have the responsibility of informing trial
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investigators concerning the data and safety monitoring policy and procedures.
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Considerations such as who shall perform the monitoring activities, the
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composition of the monitoring group (if a group is to be used), the frequency and
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character of monitoring meetings (e.g., open or closed, public or private), and
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the frequency and content of meeting reports should be a part of the monitoring
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plans. IRBs should be provided feedback on a regular basis, including findings
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from adverse-event reports, and recommendations derived from data and safety
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monitoring.
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Monitoring activities should be conducted by experts in all scientific
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disciplines needed to interpret the data and ensure patient safety. Clinical
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trial experts, biostatisticians, bioethicists, and clinicians knowledgeable about
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the disease and treatment under study should be part of the monitoring group or
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be available if warranted.
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Ideally, participants in monitoring outcomes of a trial are in no way associated
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with the trial. For trials that are conducted as part of a cooperative group,
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a majority of the individuals monitoring outcome data should be external to the
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group. ICs should require policies that evaluate whether the participants have
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conflicts of interests with or financial stakes in the research outcome; and when
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these conflicts exist, policies must exist to manage these in a reasonable
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manner.
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Generally, data and safety monitoring boards meet first in open session, attended
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by selected trial investigators as well as NIH program staff or project officers
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and perhaps industry representatives, and then in closed session where they
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review emerging trial data. When "masked" data are presented or discussed, no
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one with a proprietary interest in the outcome should be allowed. Participants
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in the review of "masked" or confidential data and discussions regarding
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continuance or stoppage of the study should have no conflict of interest with or
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financial stake in the research outcome. However, if there is an open session,
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they could be present.
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Confidentiality must be maintained during all phases of the trial including
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monitoring, preparation of interim results, review, and response to monitoring
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recommendations. Besides selected NIH program staff, other key NIH staff, and
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trial biostatisticians, usually only voting members of the DSMB should see
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interim analyses of outcome data. Exceptions may be made under circumstances
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where there are serious adverse events, or whenever the DSMB deems it
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appropriate.
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Individuals or groups monitoring data and safety of interventional trials will
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perform the following activities:
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Review the research protocol and plans for data and safety monitoring.
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Evaluate the progress of interventional trial(s), including periodic assessments
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of data quality and timeliness, participant recruitment, accrual and retention,
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participant risk versus benefit, performance of trial sites, and other factors
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that can affect study outcome. Monitoring should also consider factors external
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to the study when interpreting the data, such as scientific or therapeutic
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developments that may have an impact on the safety of the participants or the
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ethics of the study.
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Make recommendations to the IC, IRB, and investigators concerning continuation
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or conclusion of the trial(s).
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Protect the confidentiality of the trial data and the results of monitoring.
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Examples of Monitoring Operations
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The following provides examples of appropriate types of monitoring and oversight
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for different types of studies. These are illustrative only. The ICs must
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develop and implement monitoring activities and oversight of those activities
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appropriate to the study, population, research environment, and the degree of
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risk involved.
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Phase I: A typical phase I trial of a new drug or agent frequently involves
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relatively high risk to a small number of participants. The investigator and
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occasionally others may have the only relevant knowledge regarding the treatment
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because these are the first human uses. An IC may require the study investigator
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to perform continuous monitoring of participant safety with frequent reporting
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to IC staff with oversight responsibility.
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Phase II: A typical phase II trial follows phase I studies and there is more
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information regarding risks, benefits and monitoring procedures. However, more
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participants are involved and the toxicity and outcomes are confounded by disease
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process. An IC may require monitoring similar to that of a phase I trial or
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supplement that level of monitoring with individuals with expertise relevant to
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the study who might assist in interpreting the data to ensure patient safety.
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Phase III: A phase III trial frequently compares a new treatment to a standard
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treatment or to no treatment, and treatment allocation may be randomly assigned
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and the data masked. These studies usually involve a large number of
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participants followed for longer periods of treatment exposure. While short-term
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risk is usually slight, one must consider the long term effects of a study agent
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or achievement of significant safety or efficacy differences between the control
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and study groups for a masked study. An IC may require a DSMB to perform
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monitoring functions. This DSMB would be composed of experts relevant to the
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study and would regularly assess the trial and offer recommendations to the IC
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concerning its continuation.
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</pre>
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<P><HR><P>
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<A HREF="/grants/guide/WeeklyIndex.cfm?WeekEnding=06-12-98">Return to Volume Index</A>
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<A HREF="/grants/guide/index.html">Return to NIH Guide Main Index</A>
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