NIH POLICY FOR DATA AND SAFETY MONITORING

Release Date:  June 10, 1998

P.T.

National Institutes of Health

Policy

It is the policy of the NIH that each Institute and Center (IC) should have a
system for the appropriate oversight and monitoring of the conduct of clinical
trials to ensure the safety of participants and the validity and integrity of the
data for all NIH-supported or �conducted clinical trials.  The establishment of
the data safety monitoring boards (DSMBs) is required for multi-site clinical
trials involving interventions that entail potential risk to the participants.
The data and safety monitoring functions and oversight of such activities are
distinct from the requirement for study review and approval by an Institutional
Review Board (IRB).

Background

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.

With this issuance, the NIH reaffirms the 1979 policy (NIH GUIDE, Volume 8, No,
8, June 5, 1979) developed by the NIH Clinical Trials Committee.  Among its
recommendations was the concept that "every clinical trial should have provision
for data and safety monitoring."  The Committee further acknowledged that "a
variety of types of monitoring may be anticipated depending on the nature, size,
and complexity of the clinical trial.  In many cases, the principal investigator
would be expected to perform the monitoring function."

In 1994, the Office of Extramural Research established the Committee on Clinical
Trial Monitoring to review the oversight and management practices of the ICs for
phase III clinical trials.  One of the outcomes of this Committee's review was
a strong recommendation that "all trials, even those that pose little likelihood
of harm, should consider an external monitoring body."  This policy affirms the
Committee's recommendations concerning DSMBs.

Principles of monitoring data and safety

All clinical trials require monitoring -- Data and safety monitoring is required
for all types of clinical trials, including physiologic, toxicity, and dose-
finding studies (phase I); efficacy studies (phase II); efficacy, effectiveness
and comparative trials (phase III); etc.

Monitoring should be commensurate with risks -- The method and degree of
monitoring needed is related to the degree of risk involved.  A monitoring
committee is usually required to determine safe and effective conduct and to
recommend conclusion of the trial when significant benefits or risks have
developed or the trial is unlikely to be concluded successfully.  Risk associated
with participation in research must be minimized to the extent practical.

Monitoring should be commensurate with size and complexity � Monitoring may be
conducted in various ways or by various individuals or groups, depending on the 
size and scope of the research effort. These exist on a continuum from monitoring
by the principal investigator or NIH program staff in a small phase I study to
the establishment of an independent data and safety monitoring board for a large
phase III clinical trial.

Practical and Implementation Issues:

Oversight of Monitoring

This policy provides each IC with the flexibility to implement the requirement
for data and safety monitoring as appropriate for its clinical research
activities.  Thus, IC staff may either conduct or sponsor the monitoring of data
and safety of ongoing studies or delegate such responsibilities to a grantee or
contractor.  Oversight of monitoring activities is distinct from the monitoring
itself and should be the responsibility of the IC regardless of whether the
monitoring is performed by NIH staff or is delegated.  Oversight of monitoring
must be done to ensure that data and safety monitoring plans are in place for all
interventional trials, that the quality of these monitoring activities is
appropriate to the trial(s), and that the IC has been informed of recommendations
that emanate from monitoring activities.

Institutes and Centers Responsibilities

Though ICs may perform a variety of roles in data and safety monitoring and its
oversight, the following are the minimum responsibilities of sponsoring ICs.

Prepare or ensure the establishment of a plan for data and safety monitoring for
all interventional trials.

Conduct or delegate ongoing monitoring of interventional trials.

Ensure that monitoring is timely and effective and that those responsible for
monitoring have the appropriate expertise to accomplish its mission.

Oversee monitoring activities.

Respond to recommendations that emanate from monitoring activities.

Performance of Data and Safety Monitoring

The ICs will ensure the integrity of systems for monitoring trial data and
participant safety, although they may delegate the actual performance to the
grantee or contractor.  Monitoring must be performed on a regular basis, and
conclusions of the monitoring reported to the IC.  Recommendations that emanate
from monitoring activities should be reviewed by the responsible official in the
IC and addressed.  The ICs also have the responsibility of informing trial
investigators concerning the data and safety monitoring policy and procedures.
Considerations such as who shall perform the monitoring activities, the
composition of the monitoring group (if a group is to be used), the frequency and
character of monitoring meetings (e.g., open or closed, public or private), and
the frequency and content of meeting reports should be a part of the monitoring
plans.  IRBs should be provided feedback on a regular basis, including findings
from adverse-event reports, and recommendations derived from data and safety
monitoring.

Monitoring activities should be conducted by experts in all scientific
disciplines needed to interpret the data and ensure patient safety. Clinical
trial experts, biostatisticians, bioethicists, and clinicians knowledgeable about
the disease and treatment under study should be part of the monitoring group or
be available if warranted.

Ideally, participants in monitoring outcomes of a trial are in no way associated
with the trial.  For trials that are conducted as part of a cooperative group,
a majority of the individuals monitoring outcome data should be external to the
group.  ICs should require policies that evaluate whether the participants have
conflicts of interests with or financial stakes in the research outcome; and when
these conflicts exist, policies must exist to manage these in a reasonable
manner.

Generally, data and safety monitoring boards meet first in open session, attended
by selected trial investigators as well as NIH program staff or project officers
and perhaps industry representatives, and then in closed session where they
review emerging trial data.  When "masked" data are presented or discussed, no
one with a proprietary interest in the outcome should be allowed.  Participants
in the review of "masked" or confidential data and discussions regarding
continuance or stoppage of the study should have no conflict of interest with or
financial stake in the research outcome.  However, if there is an open session,
they could be present.

Confidentiality must be maintained during all phases of the trial including
monitoring, preparation of interim results, review, and response to monitoring
recommendations.  Besides selected NIH program staff, other key NIH staff, and
trial biostatisticians, usually only voting members of the DSMB should see
interim analyses of outcome data.   Exceptions may be made under circumstances
where there are serious adverse events, or whenever the DSMB deems it
appropriate.

Individuals or groups monitoring data and safety of interventional trials will
perform the following activities:

Review the research protocol and plans for data and safety monitoring.

Evaluate the progress of interventional trial(s), including periodic assessments
of data quality and timeliness, participant recruitment, accrual and retention,
participant risk versus benefit, performance of trial sites, and other factors
that can affect study outcome.  Monitoring should also consider factors external
to the study when interpreting the data, such as scientific or therapeutic
developments that may have an impact on the safety of the participants or the
ethics of the study.

Make recommendations to the IC, IRB, and investigators concerning continuation
or conclusion of the trial(s).

Protect the confidentiality of the trial data and the results of monitoring.

Examples of Monitoring Operations

The following provides examples of appropriate types of monitoring and oversight
for different types of studies. These are illustrative only.  The ICs must
develop and implement monitoring activities and oversight of those activities
appropriate to the study, population, research environment, and the degree of 
risk involved.

Phase I: A typical phase I trial of a new drug or agent frequently involves
relatively high risk to a small number of participants.  The investigator and
occasionally others may have the only relevant knowledge regarding the treatment
because these are the first human uses.  An IC may require the study investigator
to perform continuous monitoring of participant safety with frequent reporting
to IC staff with oversight responsibility.

Phase II: A typical phase II trial follows phase I studies and there is more
information regarding risks, benefits and monitoring procedures.  However, more
participants are involved and the toxicity and outcomes are confounded by disease
process.  An IC may require monitoring similar to that of a phase I trial or
supplement that level of monitoring with individuals with expertise relevant to
the study who might assist in interpreting the data to ensure patient safety.

Phase III: A phase III trial frequently compares a new treatment to a standard
treatment or to no treatment, and treatment allocation may be randomly assigned
and the data masked.  These studies usually involve a large number of
participants followed for longer periods of treatment exposure. While short-term
risk is usually slight, one must consider the long term effects of a study agent
or achievement of significant safety or efficacy differences between the control
and study groups for a masked study.  An IC may require a DSMB to perform
monitoring functions.  This DSMB would be composed of experts relevant to the
study and would regularly assess the trial and offer recommendations to the IC
concerning its continuation.

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