1. Data and Safety Monitoring
Boards (DSMB)
MADHURI.M. M’PHARM

2. What is a D(ata)S(afety)M(onitoring)B(oard)?
A committee charged with monitoring
 safety
 efficacy
 progress of a clinical trial
Aka
DMC, DSMC, IDMC, …

3. History
 Data and Safety Monitoring
 1979
 Every clinical trial should have provision for
data and safety monitoring
 The size of the monitoring committee
depends upon the nature, size, and complexity
of the clinical trial
 The Principal Investigator was expected to
perform the monitoring function but may have
had others to help

4.  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

5.  2006
 FDA guidance :
Establishment and Operation
of Clinical Trial Data Monitoring
Committees

6. Composition
Voting
•Physician(s) in specialty area (disease,
side effects)
•Epidemiologist/trial methodologist
•Statistician
•Clinical pharmacologist/safety specialist?
•Ethicist, patient representative, lawyer?
•Need effective chairman

7. Non-Voting
•Study or steering committee chair
•Sponsor representatives
•Reporting statistician

8. Voting members
3-10 experts in disease, study drug, clinical
trials
Multidisciplinary, independent
Disinterested – no conflict of interest
Experience on other DSMBs

Chair & statistician
 Some inexperienced to train them
Must take responsibilities seriously

9. Qualifications
1. Expertise in the field
2. Experience in conduct of CT & statistical
knowledge
3. Independence from direct management of
CT
4. No conflict of interest

10. Rationale for using DSMBs in
research
Ethical compact protecting trial participants
Sponsor: regulatory responsibilities
May alsoadvise about changes in protocol,
procedures
NIH often uses DSMB in an advisory capacity
– different from industry-sponsored trials

11. Trials that need a DSMB
Double-blind
Large (hundreds, thousands of subjects)
Multi-center/multi-national
Long duration
Endpoint: death or stroke or …

12. Participants have high intrinsic mortality risk
 HIV infection, cancer
 Sepsis, pulmonary disease, cardiac failure
Trial studying a new chemical entity
Recommended (strongly) by regulatory agency

13. Trials that DON’T need a DSMB
 Phase I studies, pilot studies (some)
 Studies of symptom relief
 Studies with other very close safety
monitoring

Timeline so short the DSMB can’t
operate

14. Requirements for DSMB’s
 NIH  FDA
 Typically require DSMB  Risk to trial participants
• Protocols that generate • Study endpoint
blinded/randomized data • Large trials of long-
• Multicenter protocols; duration
> minimal risk  Practicality
• Gene transfer protocols • Short trials
 May require DSMB  Assurance of scientific validity
• Protocols requiring • Inclusion of new scientific
special scrutiny knowledge without adding
 High public interest bias
 Vulnerable
populations

15. Purpose of DSMB
• Identify high rates of ineligibility determined after
randomization
• Identify protocol violations that suggest clarification
of changes to protocol are needed
• Identify unexpectedly high drop out rates that
threaten the trial’s ability to produce credible results
• Ensure validity of study results

16. Duties of DSMB
 Review the research protocol and plans for
data and safety monitoring
 Evaluate the progress of the trial with
periodic assessments of data quality and
timeliness, participant recruitment,
participant risks and benefits; Reports
from related studies

17.  Make recommendations to the IRB
and investigators concerning
continuation or conclusion of the trial
 Review the adverse event reports.

18. Timing of meetings
 Meets annually
 Periodically when
 Risk to subjects is high

Vulnerable subjects
 Large volume of data to review

19. Meetings
(Brief executive session)
Open session
Closed session
Executive session
Disseminate recommendations
Open session
Directly to sponsor representative

20. Initially an open session is conducted
• members of the clinical trial may be
present
• may focus on accrual, protocol
compliance, and general toxicity issues
• no outcome results discussed during
this session

21. Followed by a closed session
• DSMB members only
• outcome results discussed
• statistical reports (if necessary)
Finally an executive session
• DSMB members only
• discuss the general conduct of the trial
• all outcomes (including toxicities and AE)
• develop recommendations and vote if
necessary

22. Contents and intent of report
Purpose –allow DSMB to make informed decisions
1. Summary of protocol and outstanding issues
2. Recruitment and follow-up
3. Baseline data
4. Check of randomization
5. Timeliness of data & adjudication of endpoints
6. Adverse events with study-specific coding
7. Dosage of study medication
8. Vital signs and laboratory parameters
9. Outcome data

23. Recommendations from the DSMB
Shared with Sponsor, Steering Committee,
IRBs
Must prevent unblinding of study team
Be careful with communications!
During the trial, everyone reads tea leaves
DSMB must keep impeccable records

What did they know and when did they
know it?
 Did they change their behavior and rules in
response to data?

24. Are There Disadvantages to Having a
DSMB?
* YES!

Increases complexity of trial management
 Increases costs
 If the ethical imperatives discussed earlier
are not applicable, other (simpler)
monitoring approaches are usually
acceptable

25. Dechallange & Rechallange
 Dechallenge -The clinical decision to withdraw drug treatment
after a possible ADR occurred
 Considered to be -
+ve : if the reaction occurs at each dose & abates completely or
partially after withdrawal of drug
-ve : if the reaction does not abate after withdrawal of drug
Not applicable where :
* Drug is one dose treatment (vaccine )
* Reactions occurred after the drug was discontinued
* congenital anomaly (irreversible )

26.  Rechallenge- Reintroduction of the same drug which had
been withdrawn due to ADR following +ve dechallenge
 Considered to be
+ve : reoccurrance of similar signs & symptoms as that of
previous
-ve : failure of appearance of similar signs & symptoms as
that of previous one
Not applicable where
* same as that of rechallenge
for ethical reasons rechallenge is rarely performed but it
may eb carried out when the results are in the interest of
patient suffering the reaction, particularly when there
are no suitable alternative drugs

27. Thank you!
Merci!