Presentation regarding history, purpose, role, functions, meeting, member responsibilities, report of a Data and Safety Monitoring Board (DSMB)

1. Data and Safety Monitoring Board
(DSMB) – an Overview
Dr Sukanta Sen
MBBS, DNB, MD, MNAMS
Kolkata, India

2. Overview
DSMB?
History of DSMB?
Why a DSMB?
Purpose, role and functions of DSMB
DSMB composition
 DSMB meetings

3. The Name Game
•Data & Safety Monitoring Boards (DSMB)
•Independent Data Monitoring Committee (IDMC)
•Data Monitoring Committee (DMC)
•Data Review Board (DRB)
The terms DSMB and DMC are synonymous and can be
used interchangeably.

4. What is a Data Safety Monitoring Board or Data
Monitoring Committee?
In a 2006 guidance document, the FDA defines a Data Safety
Monitoring Board (DSMB) or Data Monitoring Committee
(DMC) is a group of individuals with pertinent scientific
expertise that
• reviews, on a regular basis, the accumulated research data
from an ongoing clinical trial;
• advises the sponsor and/or researcher regarding the
continuing safety of trial subjects and those yet to be recruited
into the research trial; and
• advises as to the continuing validity and scientific merit of
the trial.
Ref: http://www.fda.gov/OHRMS/DOCKETS/98fr/01d-0489-gdl0003.pdf

5. Why a DSMB?
ICH E9 on Statistical Principles: “The independence of
the IDMC is intended :
to control data sharing of important comparative
information; and to protect the integrity of the
clinical trial from adverse impact resulting from
access to trial information.”

6. History of DSMBs
•Historically, the National Institutes of Health (NIH) began
sponsoring multicenter trials in the 1960s.
• A task force under Dr. Bernard Greenberg of the University of
North Carolina was asked by the former National Heart Institute
to develop an advisory document concerning the organization and
conduct of large, multi-center trials of new treatment interventions.
The report, known as the Greenberg Report, was issued in 1967
and formally published in 1988.
•The Greenberg Report recommended having an independent
group of experts, i.e., individuals not directly involved in the trial
itself, advise the institute about the conduct of the trial.
•The Coronary Drug Project was among the first multi-center
clinical trials that used the Greenberg Report's operational model.

7. Dr. Bernard Greenberg
Source:
http://www.hsl.unc.edu/ specialcollections/exhibits/ gillings/history deans‐

9. 1994: It was recommended that every clinical trial, even
those that pose little likelihood of harm have an external
monitoring body
1998: Establishment of Data Safety Monitoring Board
(DSMB) is required for multi-site clinical trials involving
interventions that entail potential risk to the participants

10. (http://www.fda.gov/RegulatoryInformation/Guidances/ucm127069.htm)
2006 US Food and Drug Administration
Guidance Document

11. Data Safety Monitoring Boards in India
 India’s increasing participation in global clinical trials has seen a
steady expansion in relevant infrastructure and human resources.
 Upto 2006, very few studies have been initiated on product
development in India, the concept of having DSMBs for clinical
trials is still nascent.
 The Indian Good Clinical Practice (GCP) guidelines issued in
2001 suggest that ‘The sponsor may consider establishing an
Independent Data Monitoring Committee (IDMC) to assess the
progress of the study.’
 The revised ICMR Ethical Guidelines for Biomedical Research
on Human Participants(2006) specifically mandate the
constitution of a DSMB to review data emerging from research
on interventions in emergency situations.

12. For Monitoring of Clinical Trials (ICMR-DBT
Guidelines for Stem Cell Research – 2012)
Data Safety Monitoring Board (DSMB) shall
comprise independent members and shall be
constituted by the respective funding agency for all
clinical trials involving human subjects in case of
extramural funding or by the institutions/industry for
in-house supported clinical trials.
(Ref: http://icmr.nic.in/stem_cell_guidelines.pdf)

14. Types of Studies Requiring DSMB Oversight
All clinical studies require safety monitoring throughout the duration of the
research, but not all studies require monitoring by a DSMB.
A DSMB is often considered relevant in the following kinds of studies:
1. Controlled studies with mortality and/or severe morbidity as a primary
or secondary end-point.
2. Randomized controlled studies focused on evaluating clinical
efficacy and safety of a new intervention intended to reduce
severe morbidity or mortality.
3. Early studies of a high-risk intervention (risk of nonpreventable,
potentially life-threatening, complications; or risk of common, preventable
adverse events of interest [especially type A drug reactions]), whether or
not
randomized.
4. Studies in the early phases of a novel intervention with very limited
information on clinical safety or where prior information raises concern
regarding potential serious adverse outcomes.
(Ref: Ellenberg, S.S., Fleming, T.R., & DeMets, D.L. (2003). Data Monitoring Committees in clinical

15. 5. Studies where the design or expected data accrual is
complex, or where there may be ongoing questions with regard
to the impact of accrued data on the study design and
participants’ safety, particularly in studies with a long duration.
6. Studies where the data justify its early termination, such as
the case of an intervention intended to reduce severe
morbidity or mortality, which might turn out to have adverse
effects or lack of effect, resulting in increased morbidity or
mortality.
7. Studies carried out in emergency situations.
8. Studies which involve vulnerable populations.

16. Examples of DSMB Report useful in Drug Recall:
 The dramatic withdrawal of rofecoxib (Vioxx®) by Merck on 30
September 2004 was the result of a recommendation by a Data Safety
Monitoring Board (DSMB) to terminate a placebo-controlled study of this
drug in the prevention of colonic polyps because of a statistically
significant increase in adverse cardiovascular outcomes.
 Another drug trial terminated around that time (17 December 2004)
was by Pfizer, of celecoxib in the prevention of colonic polyps, because it
showed statistically significant evidence for increased cardiovascular event
rates.
 In 2002, a large, multicentre randomized controlled trial (RCT) testing
hormone replacement therapy in healthy, postmenopausal women was
terminated because it was felt that the evidence already generated from the
trial should be made available to the current and future trial participants to
help them make decisions about future use of hormone replacement
therapy.
 In all three cases, the decision to discontinue the trials was based on
the recommendation of a small group of people who constituted an
independent DSMB.

18. How DSMBs are Created
DSMBs should be created no later than prior to the
randomization of the first subject in the trial.
DSMBs are:
Often formed directly by the sponsor, often soon after
the investigators are selected
Formed according to documented procedures found in
the sponsor's standard operating procedures or policies.

19. The functions of DSMBs
o To review and approve the scientific methodology and safety of
a study prior to the research commencing.
o To provide written recommendation to the sponsor as to
whether a protocol should be amended prior to the study
proceeding.
o To provide independent, competent, efficient and timely
review of the data from an ongoing study by evaluating the
safety and clinical efficacy of data collected during the study and
by assessing reports on cumulated serious adverse events (SAEs).
o To conduct emergency reviews of data to assess safety and
futility related issues.
o To provide written recommendation to the sponsor as to
whether the study should proceed, be suspended or prematurely
terminated.
o To review and recommend appropriate amendments to the
DSMB charter and SOPs in order to ensure optimal DSMB
functioning.

20. CONSTITUTING A DSMB
When required by the nature of a study, a sponsor should
establish a DSMB to ensure the broadest possible coverage of
potential research participants, and the validity and
scientific integrity of the data.
The sponsor is responsible for establishing the DSMB’s
charter, which should be included (or referred to) in the
study protocol.
This may be undertaken with advice from investigators or
other parties involved in the study.

21. DSMB Charter
The charter is the principal organizational document for a
DSMB.
It provides information about general DSMB operations
and specific meetings.
Detailed information and guidelines concerning the following
areas should be included in the charter:
Membership composition
Member roles and responsibilities
Safety monitoring and analysis plan
Conflict of Interest (COI) assessment procedure
Efficacy data monitoring plan
Publications
Confidentiality and communication procedures

22. Who should be on the DSMB?
The PI or trial sponsor generally appoints the DSMB.
When appointing individuals to a DSMB, the following should be
considered: relevant expertise, experience in clinical trials,
experience as a member of other DSMBs, and a lack of conflict.
A DSMB may consist of as few as 3 members, but this number
should be large enough to include a representation of all needed skills
and experience.
Who is typically included in a DSMB?
Clinicians with expertise in relevant clinical specialties
At least one biostatistician knowledgeable about analysis of trial
data
Who might also be included in a DSMB?
Medical ethicist
Other types of scientists (i.e., clinical pharmacologist, toxicologist,
epidemiologist, laboratory scientist, etc.)
Best practice is to include an appropriate representation of gender
and ethnic groups

23.  Members should not be affiliated with the sponsor,
investigator(s), ethics committee(s), regulatory
authority(ies), site(s) or study staff.
 Members should also not have vested conflicts of
interest (e.g. a financial or other interest in an
intervention or product similar to the intervention being
studied).

24. Terms of appointment
A procedure should be established identifying the terms of
appointment for members of the DSMB, including
1.The duration of appointment
2.The policy for renewal of an appointment
3.The disqualification procedure
4.The resignation procedure
5.The replacement procedure

25. Conditions of appointment
A procedure stating the conditions of appointment should be
drawn up; it should include the requirements for:
A potential member to report in writing, at the time of
candidacy, all potential or real conflicts of interest to the
sponsor.
A member to be willing to publicize his/her full name,
profession, and affiliation(s).
All reimbursement for work and expenses, if any,
within
or related to a DSMB to be recorded and made available
to the public upon request.
A member to sign a confidentiality agreement regarding
meeting deliberations, applications, information on research
participants, and related matters; this agreement should cover
confidentiality requirements related to the intervention and
protocol-related information as well as study results.

26. Conflicts of Interest
 Challenges with government funding over time have resulted
in increasing partnerships between industry and academia. As
a result of this increased collaboration, conflicts of interest
may arise.
 Conflicts of interest may be financial, intellectual, or
emotional in nature, as in situations where there is
competition for grants or scientific recognition

27. Qualifications for DSMB Members
It is important to have multiple disciplines represented, including:
 Trial-specific medical/clinical expertise (e.g., physicians)
 Biostatisticians
 Ad hoc experts (e.g., bioethicists, scientists, epidemiologists), as
needed
 Patient representatives, when appropriate

28. Ref: Herson, J. 2009. Data Safety Monitoring Committees in clinical trials. pp. 20–
21. Boca Raton, FL: CRC Press.

29. DSMB Member Responsibilities
DSMB responsibilities are typically described in the charter.
While the most critical responsibilities involve issues
concerned with safety and efficacy data monitoring, additional
responsibilities may include:
 Reviewing the draft study protocol and procedures to
identify and resolve any potential concerns members have
about monitoring the trial as indicated
 Identifying any potential scientific or ethical issues that
might arise during the conduct of the study
 Reviewing the basic soundness of the study design,
including, for example, the recruitment process, the informed
consent, appropriateness of primary endpoints and, if relevant,
making key recommendations to improve the overall design of
the study

31. Confidentiality
An important aspect of a clinical trial involves the
confidentiality of interim data results. This keeps the team
and sponsor from making unreliable judgments based on
limited data. Such hasty conclusions could negatively
impact subject accrual rates or adherence to trial regimen and
could introduce bias into outcome measurement and/or
collection. However, careful disclosure of certain data is
permitted:
 Communicating non-confidential information to clinical trial
stakeholders
 Preparing open reports that can be freely shared and
distributed to those attending open sessions
 Preparing closed reports that have distribution limited to only
those who attend closed session meetings

32. Quorum requirements
The DSMB charter should establish specific quorum
requirements for reviewing, and making recommendations on,
the study, which should include:
 The minimum number of members required to compose a
quorum (e.g. more than half the members).
 The professional qualifications required (e.g. physician,
biostatistician, paramedic, ethics).
 A quorum should include at least one physician with
experience in the medical field of concern, and one
biostatistician.

33. Meeting procedures
• Procedures for organization of the meetings should be
developed in accordance with the meeting requirements.
1. Organizational meeting:
• This initial meeting should be attended by the DSMB
members and representatives of the sponsor; members of
the study staff and the investigator(s) may also be invited.
• The DSMB members should review and discuss the DSMB
charter, including the role and responsibilities of the DSMB,
the protocol safety monitoring plan, and the statistical
methodology

34. 2. Early safety review meeting
• During the early stages of implementation of a study, a
meeting may be held to review early safety information and
factors relating to quality of conduct of the study.
3. Periodic review meetings
• The expected frequency of these meetings should be specified.
The DSMB charter should indicate whether the meetings are
to be held in person or by teleconference. The meetings should
review the efficacy and/or safety data generated during this
period, and should include a progress report from the
investigator, serious adverse events reports, and
cumulative safety data.
• The DSMB should take into account the quality of conduct of
the study and the accuracy of the data.

35. 4. Final study closeout meeting
• At the termination or conclusion of a study, the DSMB may
meet to consider the efficacy and/or safety data generated
from the study and provide any final recommendation to the
sponsor.
• A final assessment report can be considered.

36. Types of Meetings
 There are several types of DSMB meetings.
 The DSMB Charter should outline each type of
meeting to be utilized for a given trial and the
procedures to be followed.
• Typically DSMB meetings consist of orientation
and regular meetings.

37. Orientation Meetings - Purpose
• Orientation meetings should be held face-to-face if
possible, but can be done by telephone if face-to-face is not
feasible.
• The purpose of an orientation meeting is to review the data
safety monitoring board's charter, clarify any aspects of the
protocol as needed, and finalize a safety monitoring plan.

39. Regular Meetings
Regular meetings may include the following types of sessions:
 Open session
 Closed session
 Closed Executive Session
Open session
• The DSMB may request the attendance of the study team,
steering committee, investigator(s) and/or independent
consultant(s) to provide specific clarification or respond to
issues that have arisen.
• Open session discussion should focus on the conduct and
progress of the study, and pay special attention to the pooled
safety and efficacy data.

40. Closed session
• Only DSMB members should be present at the closed session.
• In this session, the DSMB should review the efficacy and safety
data, at times in unblinded format.
• The DSMB should consider the data in relation to the conduct
and progress of the study, and the study protocol.
• The DSMB should also decide, in closed session, on the written
recommendation it will present to the sponsor.

41. C. Closed Executive Session:
 This final session involves only DSMB voting members to
ensure complete objectivity as they discuss outcome results,
make decisions, and formulate recommendations regarding the
study.
 If treatment codes have been made accessible to the
DSMB, then the DSMB may unmask the data based on
procedures identified in advance.

43. Interactions with Other Groups
DSMBs interact with other groups, including:
The sponsor
The data analysis center (DAC) or biostatistician
The institutional review board (IRB)/ethics
committee (EC)
The FDA/DCGI or nondomestic regulatory body
Medical monitor

44. Interactions with the IRB
• DSMBs have responsibilities that complement with those of
an institutional review board (IRB), and the two work
separately. Adverse events (AE) are reported to both DSMBs
and IRBs, but at different intervals and in different formats.
• An IRB typically focuses on safety issues that pertain its own
given study site, while the DSMB reviews aggregated data
from all sites and according to study arm.
• PIs submit open DSMB reports or minutes to the IRB.

45. What is a Data and Safety Monitoring Plan?
A Data and Safety Monitoring Plan (DSMP) is a general
plan contained in the research protocol to ensure the safety of
the subjects and to ensure the validity of the data.
The essential elements of a data and safety monitoring plan
are:
1)monitoring the progress of trial and the safety of
participants;
2)a description of the mechanism for reporting unanticipated
problems involving risks to subjects as well as adverse events,
to the IRB, FDA/DCGI, sponsor and
3)plans for assuring data accuracy and protocol compliance.

46. What are the essential elements of the DSMP?
The plan should describe processes for dealing with the following:
1. Monitoring the Progress and Safety of the Trial
a. Assessment of potential risks for study participants. The screening
process and how it will be used to protect participants
b. Measures to protect participants against risk.
c. Plan to monitor the trials, including the type of information that will
be reviewed, the parameters for defining abnormal values, and
review periods.
d. Define the stopping rules for the study.
e. Any specific procedures are in place for activities such as monitoring
and reporting in multicenter trials, if applicable
• Plan to manage potential Conflicts of Interest

47. 2. Reporting of Unanticipated Problems (UPs)
a. Define what events will constitutes a UP (include a definition,
grading scale, and “study relatedness” criteria).
b. Define the process for assessing and timeline for reporting of
potential UPs.
3. Reporting of Suspensions or Terminations
a. Define the actions (FDA, Sponsor, IRB, etc.) that will be
reported and who will bear the responsibility for reporting.
4. Assuring Data Accuracy and Protocol Compliance
a. Define how data accuracy and protocol compliance will be
assured. (i.e., protocol compliance checks, external data-
audits, regular data verification,etc.).
b. Define reporting obligations for protocol deviations/violations
and noncompliance

48. Documents and Matters to be reviewed by the DSMB
Documents and matters to be reviewed by the DSMB include but are
not limited to:
o The research protocol in its entirety prior to the study commencing.
o Interim/cumulative data for evidence of study-related adverse
events.
o Interim/cumulative data for evidence of efficacy or futility
according to preestablished statistical guidelines.
o Data quality, completeness and timelines.
o Adequacy of compliance with goals for recruitment and retention,
including those related to the participation of vulnerable groups.
o Adherence to the protocol;
o Factors that might affect the study outcome or compromise the
confidentiality of the trial data.

49. The Standard Operating Procedures (SOP) of DSMB
Procedures should be established for:
selecting members, including the method of appointing a
member.
identifying conflicts of interest and criteria for determining
unacceptable conflicts of interests.
identifying the terms of appointment for members of the DSMB.
stating the conditions of appointment.
Defining the support of the DSMB.
Determining confidentiality of data, discussion and disclosure,
and processes to make disclosures where ethically indicated.

50. Reports from the DSMB
A. Verbal Report: At the conclusion of a DSMB meeting, the DSMB should
discuss its findings and recommendations with sponsor representatives and the
study investigators.
B. Summary Report: The DSMB will issue a written summary report that
identifies topics discussed by the DSMB and describes their individual findings,
overall safety assessment and recommendations. The rationale for
recommendations will be included when appropriate. This report will generally
not include confidential information. The DSMB Chair or designee is responsible
for drafting, circulating and obtaining approval from other DSMB members
within two (2) weeks of the meeting.
C. Closed Session Report: The DSMB may also prepare confidential minutes
that include details of closed session discussions.
D. Immediate Action Report: The DSMB Chair will notify the sponsor of any
findings of a serious and immediate nature or recommendations to discontinue all
or part of the trial.