> Data and Safety Monitoring Subcommittee
All new cancer-related clinical trial applications proposing
to involve TMH subjects (treatment and non-treatment, regardless
of sponsorship) must be reviewed and approved by the Hospital
Scientific Review Committee and Hospital Ethics Committee.
These guidelines pertain to the scientific monitoring of clinical
trials approved by the Hospital Scientific Review Committee
and Hospital Ethics Committee.
This process is conducted under the Data and Safety Monitoring
Subcommittee of the HEC.
A clinical trial is defined 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 developing it.
With regard to diagnostic research (molecular or imaging diagnostics),
a study is considered 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. 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
policy, unless performing the diagnostic test itself imposes
some risk on study subjects.
Behavioral clinical trials test interventions aimed at eliminating
or reducing human activities associated with enhanced cancer
risk, such as tobacco use, poor nutrition, and sun exposure,
or eliminating or reducing morbidity associated with cancer
screening, diagnosis and treatment.
Institutional clinical trial:
An institutional (sometimes
referred to as investigator-initiated) clinical trial
is defined for the purposes of these guidelines as a
clinical research study authored by a member of the
TMC faculty or staff, not primarily sponsored nor subject
to monitoring by an outside agency (e.g. industry, cooperative
group, NIH, other institution). Although an investigator
may obtain investigational drugs and/or funding from
an outside agency or industry in support of the research,
if the clinical trial is not subject to monitoring by
that agency it will be categorized as an institutional
clinical trial and be internally monitored.
Monitoring is conducted on
all phase I and II therapeutic institutional clinical
trials, regardless of support, and its level is determined
by the degree of intervention and risk involved.
Sponsored/supported, large-scale, multi-site phase III
therapeutic intervention clinical trial:
These non institutional trials which involve significant
risk, are outside the scope of this system. Independent Data
and Safety Monitoring Boards (DSMBs) for such studies would
be established by the principal investigator and supported
through the funding agency.
Sponsored/supported phase III clinical trials which involve
only low risk (i.e. behavioral and nutritional research) would
be reviewed on a case-by-case basis, as their sample size
may be too large to be practically monitored by this system.
In some cases, these studies would require an independent
It is recognized that clinical trials sponsored by some groups
and industry are continually audited for compliance and monitored
Institutional clinical trials without outside sponsorship are
the focus of the monitoring system of this committee
a national cancer center, the TMC needs to ensure that research
data generated by the Center investigators are of high quality,
reliable and verifiable. To accomplish this objective, the
Data and Safety Monitoring Subcommittee is charged with the
mission of developing and enacting quality assurance procedures
to monitor the overall progress of institutional clinical
trials and for ensuring adherence to clinical trial and procedural
includes review of the overall progress of each study to insure
the safety of participants, validity of data, that the projected
accrual goals are met on a timely basis, that excess accrual
is avoided, that eligibility and evaluability rates do not
fall below minimum acceptable standards, that risks are not
excessive, and that adverse events are appropriately monitored
and reported to the appropriate agencies.
in this process is the goal of enhancing the quality of the
research by providing the investigator with constructive criticism.
The membership (Appendix I) of the Data and Safety
Monitoring Subcommittee is multidisciplinary and shall consist
minimally of three physician members and representatives from
the various Departments. Any member of the faculty may be
co-opted for cases requiring specific expertise.
The Director TMC shall appoint the Chair/Secretary
of the Data and Safety Monitoring Subcommittee.
Members of the Data and Safety Monitoring Subcommittee
shall be appointed by the Subcommittee Chair in consultation
with the Director TMC and Chairperson and Secretary
of the HSRC and HEC.
A monitoring team conducts on-site case reviews. The
monitoring team is comprised of a core group with additional
members selected as appropriate to the area under investigation,
size and complexity of the study and level of risk.
Nurses, and Clinical Research Associates/Fellows may
be selected and assigned as needed.
Conflict of interest It is recognized that an
institutional monitoring system must utilize its own
faculty and research staff members to enable the system
to function. Inherent in this system is the potential
for a conflict of interest to exist. Even members of
the core monitoring team may have a relationship with
the study to be audited. Examples of indirect relationships
would include staff members who are involved in the
study’s HEC reports, drug dispensing, and research
laboratory procedures. Direct relationships would include
any physician who is a sub investigator on the study;
a radiologist responsible for determining tumor measurements
(even though blinded) on the subject patients; CRAs
or CRNs involved in study conduct, data management or
consenting of patients; a statistician involved in the
data analysis for the subject study; and any individual
who is supported by the grant supporting the subject
study. No one is allowed to serve on a monitoring team
with an indirect or direct relationship, as previously
defined, to the subject study.
Meetings. Data and Safety Monitoring Subcommittee
will meet on the first Friday of every month at 9.00
a.m. Incase the day is a public holiday, an alternate
date and time will be decided.
coordination. The Secretary to the Subcommittee
and is responsible for coordinating all meetings, monitoring
visits, monitoring reports, and communications with
the HEC. All records of the Subcommittee are maintained
in the CRS
Administrative Monitoring (all clinical trials)
All cancer-related clinical trials (treatment or non-treatment,
regardless of sponsorship) must have the approval of the HSRC
before the HEC will grant approval or approval to renew the
study (annually). All clinical trials as defined undergo compliance
monitoring through this system.
Institutional (Investigator-initiated) Clinical Trial Monitoring
Scientific progress and accrual:
All institutional clinical trials are monitored
yearly for scientific progress, accrual, and HEC
compliance. The Monitoring form (Appendix II)
is completed on each study being reviewed for
scientific progress. HEC compliance is reviewed
and summarized and accrual is reported. These
reports are then reviewed at the next meeting
of the Data and Safety Monitoring Subcommittee
for any necessary actions.
The Data and Safety Monitoring Subcommittee reviews
(each study on an individual basis) accrual rate
forecast relative to the characteristics of the
study participants and estimated duration of the
study. The general principles followed by the
Scientific Monitoring Subcommittee in its recommendations
regarding scientific progress and accruals are
At the end of the first year following activation,
the Scientific Monitoring Subcommittee reviews
accrual to the study. Based on the Principal Investigator’s
accrual forecast, if there is less than 25% of
the accrual projected, a letter to the investigator
would call attention to the original projection
and remind the investigator that the accrual is
being monitored. Accrual and scientific progress
are reviewed yearly thereafter and if accrual
continues to lag behind the predicted rate, the
study is placed on probation unless there are
extenuating circumstances and the investigator
is asked to justify continuing the study. These
responses are taken into consideration on an individual
basis. If no accrual has taken place after 2-3
years, termination of the study is recommended.
Letters to investigators are intended to alert
them to low accrual situations and offer constructive
suggestions as to how to improve accrual. These
might include altering the design or eligibility
criteria, seeking extramural funding, activating
the study at affiliate centers or through the
outreach network, etc.
The Data and Safety Monitoring Subcommittee regards
a situation of zero accrual as a potentially fatally
flawed study. In this situation, the above rules
may be adjusted and a recommendation for closure
made at year two.
At the time of annual review, any early stopping
rules for toxicity or response analysis described
in the statistical section of the clinical trial
are also reviewed to determine if a data review
point has been reached. The investigator is asked
to provide the Data and Safety Monitoring Subcommittee
with an update on the status if accrual has reached
that point. This is also scrutinized during on-site
Overaccrual within the range of 10-15% is not
a deficiency. However, beyond that, assessment
of reasons required.
Level of Monitoring
Determination of level of monitoring: At the time of
initial review of the institutional clinical trial by
the HSRC, a determination of the degree of monitoring
is made commensurate with the phase, endpoints, level
of intervention, degree of risk, size (single site vs.
multiple sites) and complexity of the trial.
At the time of initial review, the clinical trial is
reviewed to ensure that the following are adequately
Procedures to ensure the safety of subjects in accord
with the degree of risk.
Validity and integrity of the data (an adequate biostatistical
design must be present and procedures to ensure adequate
data capture and how the data will be evaluated).
Expected duration of the study based on a realistic
predicted enrollment rate based on the characteristics
of the participants.
Data management systems that will ensure subjects’
eligibility for the trial and data completeness and
for multiple-site studies, an operational plan (i.e.
eligibility checklist and data collections forms).
Adverse event reporting (to the HSRC, HEC, funding
agency, sponsor and test agent)
If any of the above areas are not adequately addressed, they
required modifications are made with approval subject to their
For studies proposing enrollment at multiple sites,
the application will be required to state a plan
of organization (i.e. if dose escalation is involved,
how this will be managed operationally). Investigators
will be asked to describe a central reporting entity
that will be responsible for preparing timely summary
reports of adverse events for distribution among
sites and their IRB/HECs.
The frequency of the summary reports will depend
on the nature of the trials. If it is later observed
at the time of on-site monitoring reviews that a
trial has evolved from a single site to a multiple
site study, the investigator will be asked to provide
a description of the operational plan as a condition
of the audit.
In determining the level of monitoring, a study is
first categorized into one of the following classes:
Therapeutic Intervention studies:
These are institutional clinical trials proposing any form
of treatment of a cancer-patient population. This includes
all primary forms of anti-neoplastic therapy (chemical, biological,
internal and external radiation, surgery) and also includes
all forms of supportive treatments, prophylactic or otherwise
(hematologic growth factor support, anti-infectives, anti-fungals,
All treatment studies (phase I and II) undergo
on-site case monitoring after the first three patients
have been enrolled and treated.
In its initial review of the clinical trial, the
Data and Safety Monitoring Subcommittee determines
if the minimum level of monitoring is adequate.
If it determines that a more rigorous monitoring
plan is required, a plan specific to the clinical
trial will be determined and its details conveyed
to the principal investigator and HEC at the time
of initial review.
Pivotal to this determination is the phase of the
study. Since the level of risk is usually significantly
higher in Phase I and pilot studies, the level of
monitoring is commensurate with this. Reviews would
be triggered by accrual based on the anticipated
level of risk, but if in their monthly review of
adverse events for all institutional clinical trials
it became apparent to the subcommittee that toxicity
was higher than anticipated, intervening actions
would be taken.
If the study contains a primary response endpoint,
response evaluations by the investigator will be
reviewed on a selected case sample.
The minimum level of monitoring for institutional
treatment studies is the initial monitoring review
(described above) followed by repeat on-site monitoring
based on the findings for the initial review. If
the Data Mionitoring and Safety Subcommittee rate
the review “satisfactory”, the study
is subsequently reviewed annually for scientific
progress and accrual. On-site case reviews are not
routinely repeated. In reviewing these studies annually,
the progress report is reviewed and if the Scientific
Monitoring Subcommittee notes anything in the annual
report that would warrant an on-site review (such
as a concerning volume/severity of adverse events),
a monitoring visit will be scheduled and a case
sample selected at random for review. Subsequent
remonitoring would be based on those findings.
Studies are automatically scheduled for re-monitoring
if the initial review is rated anything less than
satisfactory (marginal, unsatisfactory). Each study
and its review findings are judged on a case-by-case
basis and follow-up actions are taken in accord
with the type and degree of the deviations or violations,
and the investigator’s response in terms of
corrective actions. The norm is to re-review the
study after 3-5 additional patients have been enrolled.
At that time, if a corrective plan of action has
been proposed its impact will be assessed.
Non-therapeutic intervention studies:
These clinical trials do not involve treatment of human
subjects, but involve a physical intervention. There may be
some degree of invasiveness, but the risk must be significantly
less than that imposed in therapeutic trials.
Because there is no therapeutic intent, these studies are
closely scrutinized since there may be no overt benefit to
human subjects from participation. Examples are diagnostic
clinical trials involving radiology, biopsy, endoscopy, phlebotomy,
tumor oxygenation studies, normal wound healing, biological
sample collection for laboratory correlates, and radiation
treatment planning. Because of their variability, these studies
are treated on a case-by-case basis in determining the degree
and frequency of monitoring. Essential to this determination
is the level of risk imposed weighed against potential benefits.
Non-therapeutic intervention studies are reviewed
initially by the Data and Safety Monitoring Subcommittee.
As for therapeutic studies, each new proposal will
be assigned a level of monitoring based on the degree
of risk, complexity, and nature of the trial at
the time it is initially reviewed.
Studies in this category may undergo the same minimal
level of monitoring as for therapeutic studies (initial
on-site monitoring after first 3 patients enrolled;
remonitoring based on findings).
If a study involves only minimal risk (e.g. phlebotomy
only), no on-site case monitoring would necessarily
Non-therapeutic, non-physical intervention studies:
Studies in this category involve no physical intervention.
Research of this type includes cancer control investigations,
quality-of-life inventories, epidemiology research, smoking
cessation, cancer risk assessment, and use of excess discarded
Studies in this category are reviewed annually
for scientific progress and HEC compliance.
Because this type of research does not involve
any physical intervention, no on-site case monitoring
is done routinely.
If a study in this category imposes the potential
for untoward psychological reactions due to the
area under investigation or the type of disease
being investigated, or there are factors of a sensitive
nature that are felt to require surveillance, Data
and Safety Monitoring Subcommittee may decide to
perform some form of monitoring beyond the annual
On-site case monitoring is done in accord with
the monitoring plan determined upon initial review of the
clinical trial. If a study is monitored initially after the
enrollment of the first 3 subjects and the findings are less
than satisfactory, Data and Safety Monitoring Subcommittee
will determine when to remonitor the study based on the accrual
of additional subjects.
Once a clinical trial is identified for monitoring, the
Secretariat will forward the monitoring form to the monitoring
The principal investigator and study coordinators
of the study being monitored will be given written
notification that the clinical trial will be monitored.
The Monitoring Team contacts them to arrange a convenient
time for the visit by the Monitoring Team.
The investigator and the research staff are responsible
for gathering all materials germane to the review
- medical records, case reports forms, office and
If other centers are enrolling subjects, materials
needed for the review from the outside centers must
be provided to the Monitoring Team. The investigator
is advised that the assessment will be based on
the materials present at the time.
Monitoring Team visit.
Prior to the onsite visit, the monitoring team
will review the clinical trial to determine if the
study has met a data review point so that this can
be addressed at the time of the visit. The team
reviews the adverse event files to determine what
has already been filed on the study.
The monitoring team uses the primary medical record
as the central document. The primary source documents
are checked to ensure that subjects were not treated
on clinical trial prior to final HEC approval, informed
consent was properly obtained and executed, and
pre-therapy requirements, eligibility criteria,
treatment delivery, and adverse event reporting
are in accordance with the clinical trial.
The clinical trial staff is interviewed to ascertain
their data management systems and whether subjects
are being enrolled off-site. The required materials
are obtained from the sites and provided to the
Following the on-site visit, the Team completes
the Monitoring Form. These are presented to the
Data and Safety Monitoring Subcommittee. These forms
describe HEC compliance, consent, accrual, study
endpoints, data management systems, AE reporting,
and the findings regarding subject eligibility and
treatment delivery. Any areas where there does not
appear to be satisfactory compliance are note
findings of the monitoring team are reviewed and discussed
by the full Data and Safety Monitoring Subcommittee.
overall rating given to a study is a composite of scientific
progress, accrual, and the onsite-monitoring findings
of the conduct of the study.
a study were found to have no deficiencies in its conduct,
but was seriously lagging in accrual or violating its
stopping rules, the rating would reflect the latter,
and be unsatisfactory or marginal, depending on the
level of deficiency in the latter areas.
rating the conduct of the study, the Data and Safety
Monitoring Subcommittee categorizes deviations as "MAJOR"
or "MINOR". The Data and Safety Monitoring
Subcommittee exercises reasonable judgment in determining
if a deviation should be considered major or minor.
deviations would be those variances from clinical
trial specified criteria or procedures that make
the resulting data questionable. Examples of these
would be findings that render the subject ineligible,
failure to meet regulatory requirements (including
failure to document properly obtained informed consent
or not obtain properly executed informed consent
prior to the start of treatment), failure to comply
with HEC approval and/or re-approval guidelines,
treatment deviations (substantial alternation or
modifications of doses not in agreement with the
clinical trial specifications), and poor general
deviations would be those that do not affect the
outcome or interpretation of the study and are not
described above as major deviations. For example,
if a hematology value were within a small percentage
of variance from the requirement, this would be
categorized as a minor deviation. A significant
variance from a required measure of cardiac function,
such as a MUGA, would be considered major. An unacceptable
frequency of minor deviations will be treated as
a major deviation.
of adverse drug reaction (ADR) reporting:
new clinical trials are required to contain a description
of procedures for adverse event reporting at the time they
are reviewed by the HSRC. Depending on the type of intervention
proposed, the clinical trial must contain a grading system
for adverse events (i.e. Common Toxicity Criteria), reference
the reporting forms to be used (investigational vs. non-investigational
drug reporting), and describe oversight by the investigator
for grading and attribution to the study intervention.
- Sponsored multicentric Clinical Trials A two
member SAE monitoring team will review all the reports
received during the preceding month and compile data into
a central database. The team also reviews the AE reports
for appropriate reporting to the HEC (serious adverse
events and unexpected events). This review also enables
consistency of grading to occur.
- Institutional clinical trials A two member team
in rotation will review the SAEs reported from these trials
and will forward their recommendations to the HEC and
PI within 72 hours of receiving the report.
The investigator is responsible for submission of adverse
event reports to all agencies described in the clinical
trial (as appropriate to the test agent and trial).
These would include the pharmaceutical sponsor, and/or
FDA. Information on reporting requirements is periodically
distributed to all clinical investigators.
The SAE Monitoring Team compiles a monthly summary
report to the subcommittee depicting all adverse events
that have occurred during the preceding month for TMH
(and affiliate) patients enrolled on institutional clinical
trials. This report is reviewed by the Data and Safety
Monitoring Subcommittee and appropriate actions taken
if the volume or severity of adverse events for a particular
intervention or compound appears concerning.
During monitoring visits, if serious SAEs are found
which have not been appropriately reported, the Data
and Safety Monitoring Subcommittee will evaluate the
number and severity of the SAEs and this will be taken
into account in the overall rating.
following guidelines are used in determining an overall
Satisfactory. No major deviations.
Marginal. One major deviation.
Unsatisfactory. Two major deviations.
Actions Based on Rating
The Data and Safety Monitoring Subcommittee determines
the overall rating in accordance with the above
guidelines, which is conveyed to the investigator
If a study receives a satisfactory rating, it will
thereafter be reviewed for scientific progress and
accrual annually as long as it is active, but full
monitoring is not repeated.
Studies rated less than satisfactory are each judged
individually and follow-up actions are taken in
accordance with the type and degree of the deviations
Depending on the nature of the findings and the
investigator's response, early re-review will be
decided on a case-by-case basis at the discretion
of the Data and Safety Monitoring Subcommittee.
For example, if a corrective plan is proposed by
the investigator, this may warrant an early re-review
to determine its impact. If the only issue is underaccrual,
the recommendation will follow the guidelines described
above. If the case review reveals problems with
eligibility, a repeat on-site visit would be conducted
after a specified number of subjects have been enrolled
(usually 3). The Data and Safety Monitoring Subcommittee
may elect to recommend probation, suspension or
termination of the clinical trial if the level of
unacceptability warrants it.
The investigator also receives a copy of the summary
monitoring report. The cover letter, summary report,
and investigator's response are copied to the Chairman
of the HEC.
- Recommendation of Clinical Trial Suspension or Termination
Grounds for recommending suspension or termination
of a clinical trial to the HEC include, but are not
1. Zero accrual for 1-2 years or long-term low accrual.
2. Stopping rule violations.
3. Major violations in the conduct of the study (including
serious HEC violations) that result in an unacceptable
to recommend suspension or termination of a clinical
trial is carefully considered and takes into account
whether corrective actions had been requested at previous
reviews and were not implemented.
decision is made to recommend suspension or termination
of a clinical trial, the recommendation will be
made in a letter to the investigator. A letter
will be sent simultaneously recommending suspension
or termination of the clinical trial to the Chair
of the HEC.
HEC has the ultimate authority to effect termination
or suspension of a clinical trial.
Internal and External Reporting of Data and Safety
Monitoring Subcommittee Findings
Summary Monitoring Reports, all correspondence with principal
investigators, including the Data and Safety Monitoring
Subcommittee's final recommendations concerning re-review
or corrective plans needed, are sent to the Chairperson
of the HEC. Any correspondence and recommendations stemming
from administrative monitoring findings and accrual review
will also be sent to the HEC Chairperson.
Dr Rekha Batura, AMS
10 June 2003
Dr RF Chinoy,
30 July 2003
Dr KA Dinshaw,