Essential Elements of a Data Safety and Monitoring Plan for Clinical Trials Funded by the NCI
Background
Essential Elements
Special Circumstances
Appendix
Essential Elements of a Data Safety and Monitoring Plan for Clinical Trials Funded by the NCI
This document outlines the essential elements of an adequate plan for data and safety monitoring (DSM) of clinical trials. It is intended to assist investigators and institutions in the formulation of DSM plans for all phases of cancer clinical trials, in accordance with National Institutes of Health (NIH) requirements. We suggest that institutions sponsoring a significant number of clinical trials formulate institutional DSM plans that can be broadly applied to the individual trials in their portfolio. Investigators from institutions or organizations without institutional DSM policies may also find this document useful as a guide in fashioning suitable DSM plans for their individual trials.
To get an idea of what a final DSM plan might consist of, see Data and Safety Monitoring Example Plans.
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Background
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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Essential Elements
1. Monitoring the progress of trials and the safety of
participants.Description of these monitoring processes should include a
number of elements. Who actually monitors the trials? How often are the data
examined in the course of trial conduct? What do the monitors look for? What
procedures are in place to insure adequate feedback of information to
researchers and medical decision-makers, so that trials involving excessive
risk in relation to anticipated benefits are terminated appropriately? What is
the oversight or supervisory role of institutional committees, if appropriate?
What procedures does the institution have for coordinating multi-center
trials, if applicable?
In relation to who actually has responsibility for monitoring a trial, DSM
plans should explain how the institution averts or manages any conflict of
interest implicit in having a principal investigator (or a direct report of
the PI) as the only monitor of trials that pose significant risk to study
subjects.
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2. Plans for assuring compliance with requirements
regarding the reporting of adverse events (AEs). The plan should describe
the processes and oversight that the institution has in place for assuring
that AE reporting requirements are actually met. For multi-center trials
coordinated by the institution, the plan should outline procedures by which
the institution establishes a central reporting entity that collects and
reports AEs to all necessary destinations, including co-investigators at
participating institutions.
The requirements for proper reporting of AEs on clinical trials are complex
(summarized in the Appendix). Possible destinations for AE reports include the
institutional IRB, the sponsor (if an IND is involved), the FDA (for AEs from
commercially available agents), and, if gene transfer is involved, the NIH
Office of Biotechnology Activities (OBA). Note that current federal
regulations almost always require reporting of AEs in all categories of
clinical trials to the institutional IRB, in addition to what is specified in
the Appendix.
Note also that there is no requirement that individual AEs be reported
in real time to the NCI, unless NCI is also the IND sponsor of the study (see
the Appendix). Where appropriate, investigators should summarize toxicities or
adverse consequences of interventions as part of the progress reports in their
non-competitive (Type 5) or competitive (Type 2) renewal applications.
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3. Plans for assuring that any action resulting in a
temporary or permanent suspension of an NCI-funded clinical trial is reported
to the NCI grant program director responsible for the grant.These actions
include, for example, any FDA actions that affect NCI-funded trials (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-053.html).
It also includes actions by an IRB or by a commercial sponsor, or by the
investigator him/herself, if an NCI-funded trial is involved.
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4. Plans for assuring data accuracy and protocol
compliance. Institutions should describe what quality-control procedures
are in place for assuring data accuracy and completeness in studies funded by
NCI.
If an IND is in place, quality-control procedures are generally stipulated by
the IND sponsor and may be simply referenced or summarized in the DSM plan.
For studies not done under an IND, the institution should describe whatever
procedures are in place to assure data integrity and protocol adherence.
Appropriate procedures may range, for example, from regular data verification
and protocol compliance checks performed by a data manager and a principal
investigator, to a formal external data-audit process by an agent external to
the institution.
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Special Circumstances
For behavioral and nutritional Phase I-III trials, the NCI requires that a DSM
plan be in place appropriate to the anticipated level of risk involved in the
particular study. A DSMB can be constituted at the investigators
discretion and seems particularly appropriate when investigators anticipate the
possibility of early stopping based on emerging differences in either risk or
benefit.
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Certain types of NCI career and training awards may support clinical trials,
directly or indirectly. NCI's DSM policy covers those career and training
awards in which the trainee has direct responsibility for conduct of the
clinical trial or in which award funds directly support the trial.
Responsibility for compliance with NCI's DSM policies rests with the grant
recipient; this may be either the trainee or the training program director,
depending on the award (individual versus institutional). Trainees in a
mentored career program should consult with their mentors about adapting or
designing suitable DSM plans for their clinical trials. In most cases the
trainees will be in a mentored stage of their career and will lack the
experience needed to provide appropriate oversight of the trial. The DSM plan
must therefore clearly identify the senior individual responsible for
monitoring the trial and the function of the trainee in this process.
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For institutional career development programs (e.g., K12, R25T) in which clinical trials are an integral part, applicants should provide with their application a "Special Institutional Statement Regarding Human Subjects Research under K12 or R25T Support". This statement must be provided to NCI Program staff for evaluation and approved before the initial grant award can be issued, and submitted for evaluation and approval with each "Application for a Continuation Grant."
More information about these awards is available on the NCI's Cancer Training Branch (CTB) Web site. Specifically,
-
For individual career development awards in which the grantee has direct responsibility for trial conduct or in which award funds directly support the trial, the DSM plan covering the trial may NOT be an institutional plan. The DSM plan must be tailored specifically to the clinical trial. Guidance on the content and organization of an NCI DSM plan may be found under the Essential Elements section of the Data and Safety Monitoring Guidelines.
-
A DSM plan does not need to be provided for individual career development awards
in which:
-
The trial is a component of an NIH Cooperative Group trial;
-
The trial is a CTEP-supported protocol;
-
The trial is being partially or completely supported by an
investigator-initiated NIH R-grant, viz. R21, with an approved DSM Plan.
For individual career development awards in which a clinical trial will be
conducted that does not require the submission of a DSM plan, the grantee must
submit for evaluation a letter to NCI program staff describing their situation
and explaining why a DSM plan is not needed. This letter must be co-signed by
the institutional official authorized to evaluate issues pertaining to data
safety and monitoring; and, in the case of mentored awards, by the grantee's
mentor.
-
If the clinical trial is not to be started immediately upon award of an
individual career development award but will follow after a considerable lapse
of time (years), submission of a DSM plan to NCI for approval may be delayed
until the nature of the trial is clear and its initiation is in the near
future. This will insure that the DSM plan suits the needs of the trial.
-
For NCI career development awards for established investigators (K05, K24), a
DSM plan does not need to be provided. However, a Restriction term (Appendix C)
will be included in each Notice of Grant Award requiring that the grantee
remain in compliance with the NCI's policy on data and safety monitoring
throughout the project period.
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Appendix
TABLE A: Expedited Reporting for Phase I Studies (including hospitalization
* )
UNEXPECTED EVENT
|
EXPECTED EVENT
|
GRADES 2 - 3 Attribution of Possible, Probable or Definite
|
GRADES 4 - 5 Regardless of Attribution
|
GRADES 1 - 3
|
GRADES 4 - 5 Regardless of Attribution
|
Grade 2
- Expedited report within 10 working days
Grade 3
- Report by phone to IDB within 24 hrs. Expedited report to follow within 10
working days.
(Grade 1
- Adverse Event Expedited Reporting NOT required.) |
Report by phone to IDB within 24 hrs. Expedited report to follow within 10
working days.
This includes all deaths within 30 days of the last dose of treatment with an
investigational agent regardless of attribution.
Any late death attributed to the agent (possible, probable, or definite) should
be reported within 10 working days.
|
Adverse Event Expedited Reporting NOT required.
|
Report by phone to IDB within 24 hrs. Expedited report to follow within 10
working days.
This includes all deaths within 30 days of the last dose of treatment with an
investigational agent regardless of attribution.
Any late death attributed to the agent (possible, probable, or definite) should
be reported within 10 working days.
|
TABLE B: Expedited Reporting for Phase II and III Studies (including
hospitalization *
)
UNEXPECTED EVENT
|
EXPECTED EVENT
|
GRADES 2 - 3 Attribution of Possible, Probable or Definite
|
GRADES 4 - 5 Regardless of Attribution
|
GRADES 1 - 3
|
GRADES 4 - 5 Regardless of Attribution
|
Expedited report within 10 working days
Grade 1
- Adverse Event Expedited Reporting NOT required.)
|
Report by phone to IDB within 24 hrs. Expedited report to follow within 10
working days.
This includes all deaths within 30 days of the last dose of treatment with an
investigational agent regardless of attribution.
Any late death attributed to the agent (possible, probable, or definite) should
be reported within 10 working days.
|
Adverse Event Expedited Reporting NOT required.
|
Expedited report, including Grade 5 Aplasia in leukemia patients, within 10
working days.
This includes all deaths within 30 days of the last dose of treatment with an
investigational agent regardless of attribution.
Any late death attributed to the agent (possible, probable, or definite) should
be reported within 10 working days.
Grade 4 Myelosuppression or other Grade 4 events that do not require expedited
reporting will be specified in the protocol.
|
* For Hospitalization Only Any medical event equivalent to CTC Grade 3,
4, 5 which precipitated hospitalization (or prolongation of existing
hospitalization) must be reported regardless of requirements for Phase of
study, expected or unexpected and attribution.
Expedited reporting may not be appropriate for specific expected adverse events
for certain later Phase II and Phase III protocols. In those situations the
adverse events that will not have expedited reporting must be specified in the
text of the approved protocol. An expected Grade 3 event that is definitely
related to the investigational agent is only to be reported if the patient is
hospitalized using the generic reporting criteria, for instance. In a trial of
an investigational agent where Grade 3 diarrhea requiring hospitalization is
expected, only diarrhea requiring ICU care (Grade 4) might be designated for
expedited reporting.
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The controlling regulations are those of the Food and Drug Administration (21
CFR, Part 312.32: Expedited Safety Reporting Requirements for Human Drug and
Biological Products) and are available at
http://www.fda.gov/cder/aers/fr07oc97.htm
. They describe the responsibilities of the investigator and the IND holder.
Additional sponsor or institutional requirements may be appropriate for
specific agents and included in the pertinent protocol sections.
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Serious adverse events that occur with commercially available agents/devices are
reported through Food and Drug Administration Medwatch (http://www.fda.gov/medwatch/index.html).
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In addition to the reporting requirements for investigational agents (see A or
B above, as appropriate), investigators should adhere to NIH Guidelines for
Research Involving Recombinant DNA Molecules (Gene Transfer).
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-052.html)
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Serious adverse events must be reported according to applicable FDA regulations
(http://www.fda.gov/cber/vaers/vaers.htm).
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Since there are no standard grading scales for adverse events, defining
suitable grades for adverse events is the responsibility of individual
investigators for each protocol. Adverse events of a psychological nature can
occur with behavioral trials and should be specified for the particular
intervention in question.
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|