Regulatory Requirements and Guidelines for DSMB

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Regulatory Requirements and Guidelines for DSMBs
.Or who-advises-what in regard to DSMBs
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Regulatory Requirements and Guidelines for DSMBs
All sorts of trials academic, product
development, industry, governments. All
sorts of regulators . NIH, EMEA, MHRA, MRC All
sorts of research groups suggesting guidelines
TDR/WHO, Universities, Funding agencies,
NHS Aim of this session is to discuss an
overview of what is being requested and
recommended what the difference isthen
summarise how this relates for trials conducted
in Africa.
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Regulatory Requirements and Guidelines for DSMBs
Documents used in this overview WHO/TDR
Operational Guidelines for Establishment and
Functioning of Data Safety and Monitoring
Boards NHS RD Health Technology Assessment
Issue in Data Management and Interim Analysis of
Trials EMEA Committee for Medicinal Products
for Human Use, Guidelines on Data Monitoring
Committees. NIH further guidance on a data and
safety monitoring for phase i and phase ii trials
MRC Toolkit MRC/DH Joint project codify good
practice in publicly funded UK trials with
medicines AMANET Terms of Reference DSMBsfor
Vaccine Trials (RC)
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Regulatory Requirements and Guidelines for DSMBs

• WHO/TDR Operational Guidelines for
  Establishment and Function of Data Safety and
  Monitoring Boards.
• DSMBs are needed
• because trials should not continue if the design
  is no longer appropriate
• as a trial might reach its objective earlier
  than predicted, or the primary objective may
  never be achievable
• a positive trend to do harm within trials might
  become apparent
• trials may need modifying if accumulated data is
  not in-line with the original trial design
  assumptions
• Based on various national and
  international guidelines

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Regulatory Requirements and Guidelines for DSMBs

• WHO/TDR Operational Guidelines for
  Establishment and Function of Data Safety and
  Monitoring Boards.
• DSMBs might also need recommend protocol
  amendments such as
• Change in dosage of trial or concomitant
  medications
• Treatment duration of trial of concomitant
  medications
• Entry or exclusion criteria
• Sample size
• Recruitment rate

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Regulatory Requirements and Guidelines for DSMBs

• WHO/TDR Operational Guidelines for
  Establishment and Function of Data Safety and
  Monitoring Boards.
• DSMBs role
• Maintain the scientific integrity of the trial
• Protect the welfare of the subjects
• Maintain the credibility of the data
• Interim analysis conduct/review/recommend

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Regulatory Requirements and Guidelines for DSMBs

• WHO/TDR Operational Guidelines for
  Establishment and Function of Data Safety and
  Monitoring Boards.
• All trials need safety monitoring and many BUT
  NOT ALL need DSMBs. Definitely needed if
• Controlled CT with mortality or severe morbidity
  as primary or secondary endpoint.
• RCT evaluating clinical efficacy and safety of
  an investigational new product
• Early studies of a high risk new intervention
• CT design or data accrual is complex
• If there is uncertainty about whether the data
  will impact the trial design
• vulnerable populations
• Entry or exclusion criteria
• Sample size
• recruitment rate

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Regulatory Requirements and Guidelines for DSMBs

• WHO/TDR Operational Guidelines for
  Establishment and Function of Data Safety and
  Monitoring Boards.
• Role of DSMB. Review, Evaluate and then
  Recommend.
• Need to be Independent, Competent and Timely and
  properly constituted.
• Sponsor must select and appoint and write the
  charter.
• Membership should be multi-disciplinary, relevant
  and representative of participating countries

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Regulatory Requirements and Guidelines for DSMBs

• WHO/TDR Operational Guidelines for
  Establishment and Function of Data Safety and
  Monitoring Boards.
• All DSMBs need a charter.
• Description of board
• Objective
• Meetings
• Data management and security
• Documents
• Conditions of appointment
• Quorum
• reporting and communicating recommendations
• document management and archiving

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Regulatory Requirements and Guidelines for DSMBs

• NHS RD Health Technology Assessment Issue in
  Data Management and Interim Analysis of Trials
• RCT increasingly have DMCs. Important but not
  always.
• Criteria for NOT having a DMC
• Not possible for a DMC to make a contribution
• Where any observed differences would not prompt
  a protocol change (i.e.. stop the trial)
• Where there is no reason why a DMC decision
  would differ from internal monitoring

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Regulatory Requirements and Guidelines for DSMBs

• NHS RD Health Technology Assessment Issue in
  Data Management and Interim Analysis of Trials
• - Advantages with both large and small DMCs
  dependant on protocol
• Consumer or ethicists on DMCs is controversial
• Costs should be covered but any further reward
  should be minimal
• Meetings should be face to face when possible.
  First meeting then teleconferences?
• Disadvantages of blinded data outweigh
  un-blinding
• DMCs should comment on draft and final reports

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Regulatory Requirements and Guidelines for DSMBs
EMEA title Role of DSMB is to strike the
important balance No Unavoidable risk vs.
Allow to continue for an adequate period and not
stopped too early to answer the question
DSMB needed in many trials but not all. . A
group of independent experts to assess progress,
safety data and efficacy end-points of a CT
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Regulatory Requirements and Guidelines for DSMBs

• EMEA title
• Assessing need
• Life-threatening, for example, almost always
  would need a DSMB.
• Weigh up the risk to the participant versus
  answering the question
• DSMB Not Useful When
• Not practical as CT is so short (so may apply
  even if life-threatening)
• Known drugs used within the licence
• Non-critical conditions (mild pain trials?)

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Regulatory Requirements and Guidelines for DSMBs

• EMEA title
• Methodological implications of DMC analysis on CT
  final analysis
• Inflation of type I error (false positive, i.e..
  treatment better than other when there was no
  difference).
• Possible bias on future conduct of a CT
• Important to keep these major methodological
  problems in connection with DMCs in mind. May
  influence decision on whether appropriate or not

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Regulatory Requirements and Guidelines for DSMBs

• NIH Regulatory requirements
• Need to submit a data safety and monitoring plan
  for all phase I III trials.
• This may or may/not include a DSMB. Usually
  require a DSMB if
• multi-centred
• Blinded
• High risk
• vulnerable population
• Need to provide justification if no DSMB
  required.
• Not necessarily appropriate if intervention is
  low risk. In this case close monitoring by
  investigator is adequate.

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Regulatory Requirements and Guidelines for DSMBs

• MRC Clinical Trial ToolKit Trial Monitoring
  Procedures
• www.ct-toolkit.ac.uk
• Explains ICH-GCP requirements
• Defines type of monitoring
• Trial Oversight committees
• Trial Management group
• Trial Steering committee
• Data monitoring committee
• Coordinating Centre good housekeeping
• Central Monitoring
• On-Site Monitoring
• . Helpful context of whole trial and not
  only form of monitoring!!!

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(GCP ICH 5.18.3)
... In general there is a need for on-site
monitoring, before, during
and after the trial however in exceptional
circumstances the
sponsor may determine... Statistically controlled
sampling may
be an acceptable method for selecting the data to
be verified."
Roles and Responsibilities
The Sponsor
Clinical Monitor responsibilities
GCP ICH 5.18.4 (q)
...Communicating deviations from the protocol,
SOPs, GCP and the
...Communicating deviations from the protocol,
SOPs, GCP and the
applicable regulatory requirements to the
investigator and taking
applicable regulatory requirements to the
investigator and takin
appropriate action designed to prevent recurrence
of the detected
appropriate action designed to prevent recurrence
of the detecte
deviations.
deviations.
GCP ICH 5.18.4 (e)
...Verifying that written informed consent was
obtained before each
subject's participation in the trial.
PharMed GCP, SOP' s and Audits
PharMed GCP, SOP' s and Audits
3/19/2007
M. Podoor, MD
Sponsor and Responsibilities
The Sponsor
Non Compliance
(GCP ICH 5.20.2)
If the monitoring and/or auditing identifies
serious and/or persistent
noncompliance on the part of an
investigator/institution, the sponsor
should terminate the investigator's/institution's
participation in the
trial. When an investigator's /institution's
participation is terminated
because of noncompliance, the sponsor should
notify promptly the
regulatory authorities
PharMed GCP, SOP' s and Audits
PharMed GCP, SOP' s and Audits
3/19/2007
M. Podoor, MD
Regulatory Requirements and Guidelines for DSMBs
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Regulatory Requirements and Guidelines for DSMBs

• Relevance to African Trials?
• - All aiming to work to ICH-GCP...right?
• Registration, funding and publishing
• Need to be ethical and gain ethics approval
• Product development trials
• Academic / locally led
• Practicalities . Back to assessing need.