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Background
Operational Definition of a Clinical Trial
Requirements for a DSMB
The Role of Institutional DSM Plans
Tailoring Institutional DSM Plans to Specific Studies
Review of DSM Plans by NCI Staff
NIH policy (http://grants.nih.gov/grants/guide/notice-files/not98-084.html
with additional description at
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html) requires
that grantees have in place procedures for DSM of clinical trials. This is to
insure the safety of participants, the validity of data, and the appropriate
termination of studies for which significant benefits or risks have been
uncovered or when it appears that the trial cannot be concluded successfully.
The NIH DSM policy covers clinical trials of all phases for which grant support
is sought. DSM plans must be in place before grants supporting such studies can
be funded. Applicants must submit a general description of the DSM plan for peer
review as part of the grant application and, subsequently, a more detailed plan
for review and approval by NCI staff prior to issuing a Notice of Grant Award.
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For purposes of this document, we define a clinical trial
operationally as a prospective study involving human subjects designed to answer
specific questions about the effects or impact of particular biomedical or
behavioral interventions; these may include drugs, treatments, devices, or
behavioral or nutritional strategies. Participants in these trials may be
patients with cancer or people without a diagnosis of cancer but at risk for it.
In the area of molecular or imaging diagnostics, we consider a
study to be a clinical trial if it uses the information from the diagnostic
test in a manner that somehow affects medical decision-making for the study
subject. In this way the information from the diagnostic may have an impact on
some aspect of outcome, and assessment of this impact may be a key goal of the
trial. By contrast, studies that do not use information from the diagnostic
test in any manner that can affect the outcome of study subjects, but whose
objective is only the gathering of data on the characteristics of a new
diagnostic approach, are not clinical trials and are not covered by this DSM
policy, unless performing the diagnostic test itself imposes some risk on
study subjects.
Behavioral clinical trials include interventions whose goals are to
increase behaviors (e.g. cancer screening, physical activity, fruits and
vegetable intake), eliminate or reduce behaviors (e.g., smoking, sun exposure)
and/or improve coping and quality of life (e.g., among cancer survivors) and
reduce the negative sequelae of treatment. Interventions may pertain to cancer
prevention, early detection, treatment, and suvivorship. Observational studies
and those that do not test interventions are not clinical trials.
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For some time now NCI policy has required that Data Safety Monitoring Boards
(DSMB) be in place for all Phase III randomized clinical trials (http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm).
The present document modifies this policy, in that there is no longer a blanket
requirement for DSMB in the cases of low-risk behavioral and nutritional trials.
As discussed further below, all such trials should include a DSM plan, but this
may or may not include a DSMB, depending chiefly on the anticipated level of
risk to participants.
Nor does NIH or NCI policy require that formal DSMB's be constituted for
clinical trials other than Phase III, though investigators or institutions may
wish to do so for certain non-Phase III trials involving particular risk,
complexity, likely decisions about early stopping, or the need to obviate
conflict of interest.
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Cancer clinical trials funded by the NCI are conducted in thousands of
institutions nationwide. Many of these institutions -- notably the comprehensive
and clinical cancer centers -- have particularly intensive clinical research
portfolios that include dozens or hundreds of trials. It makes sense for such
institutions to have in place institutional plans for an effective DSM
process. An effectively formulated and executed institutional plan should
improve both participant protection and trials conduct and should greatly reduce
the need to set up new policies ad hoc on a trial-by-trial basis. For
most investigator-initiated grant applications supporting clinical trials in an
institution with an already approved institutional plan, the investigator should
only have to supply the approved institutional plan in the human subjects
section of the grant application and describe how it applies to the specific
trials.
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The NCI clinical trials portfolio encompasses a vast array of investigation;
examples range across early feasibility studies in treatment, prevention, or
diagnosis; nutritional interventions to modulate risk of cancer; gene transfer;
and behavioral research relating to cessation of tobacco use. Accordingly, the
essential elements for DSM outlined below are described in general terms, and we
do not stipulate details of how this process should be carried out. We have used
general language to describe the essential content of such plans, leaving to
individual institutions and investigators wide discretion in how to carry out
these activities in an effective manner.
Clearly, a sensible DSM plan for a particular clinical trial must be based on
the medical or health-related context of the particular study and, in
particular, the degree of risk to which participants in the trial are exposed.
In applying an institutional plan to a particular trial, therefore, the
principal investigator will consider whether the institutional plan is
sufficiently specific or whether it needs some further tailoring to the
conditions of the particular trial. An institution might choose to have one
general plan, which investigators tailor to individual trials. Alternatively,
the institution might choose to have a plan that is essentially formulated in
modules, each of which describes in adequate detail how monitoring will be
accomplished for a major class of trials that the institution supports
(e.g., early-phase studies in treatment, behavioral studies, bone-marrow
transplantation, chemoprevention studies in healthy populations, etc.).
Investigators can then apply these plans to particular protocols with little or
no change in the description. For purposes of NCI review, as noted above,
investigators may append the institutional plan to the human subjects section of
their own grant applications and use these institutional documents in their
interactions with NCI staff reviewing their plan. Under most circumstances NCI
anticipates that a properly prepared institutional plan should suffice both for
peer review and for NCI staff review.
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NCI staff review of institutional or individual DSM plans prior to grant
award will focus on the adequacy with which the plan covers the essential
elements outlined below. It is not necessary that submitted plans (whether they
are institutional or individual) cover all possible aspects of each element down
to the last detail. Rather, the plan should describe processes for dealing with
these elements such that a reasonable reviewer would conclude that the
institution or investigator has a serious, robust process in place for assuring
the safety of research participants and the oversight of data integrity.
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