Data and Safety Monitoring Board (DSMB) – an Overview

Dr Sukanta SenMBBS, DNB, MD, MNAMS

Kolkata, India

OverviewDSMB?

History of DSMB?

Why a DSMB?

Purpose, role and functions of DSMB

DSMB composition

DSMB meetings

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.

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

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.”

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.

Dr. Bernard Greenberg

Source: http://www.hsl.unc.edu/ specialcollections/exhibits/ gillings/history‐deans

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

(http://www.fda.gov/RegulatoryInformation/Guidances/ucm127069.htm)

2006 US Food and Drug Administration Guidance Document

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. 

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)

Types of Studies Requiring DSMB OversightAll 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 clinicalefficacy and safety of a new intervention intended to reducesevere 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 notrandomized.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 trials. A practical perspective. pp. 12–13. )

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.

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.

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.

The functions of DSMBso 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.

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.

DSMB CharterThe 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

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 specialtiesAt least one biostatistician knowledgeable about analysis of trial dataWho might also be included in a DSMB?Medical ethicistOther 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

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).

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

Conditions of appointmentA 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 ofcandidacy, all potential or real conflicts of interest to thesponsor.A member to be willing to publicize his/her full name,profession, and affiliation(s).All reimbursement for work and expenses, if any, withinor related to a DSMB to be recorded and made availableto the public upon request.A member to sign a confidentiality agreement regardingmeeting 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.

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

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

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

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

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

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.

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

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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

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

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.

The Standard Operating Procedures (SOP) of DSMBProcedures 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.

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.