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Highlights from ExL Pharma's 5th Data Monitoring Committees

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  • 1. Philadelphia, PA
    February 22-23, 2010
    Highlights from ExLPharma’s 5th Data Monitoring Committees/DSMB
  • 2. The Role of DMCs/DSMBs in Adaptive Trials:The Impact of DMCs/DSMBs on Decisions for Dosage Changes or Changes in Sample Size
    2
  • 3. DSMB/DMC
    3
    Data Safety Monitoring Board (DSMB) or Data Monitoring Committee (DMC) as defined in FDA Guidance “Establishment and Operation of Clinical Trial Data Monitoring Committees”:
    a group of individuals with pertinent expertise that reviews on a regular basis accumulating data from one or more ongoing clinical trials.
    DMC advises the sponsor regarding the continuing safety of trial subjects and those yet to be recruited to the trial, as well as the continuing validity and scientific merit of the trial.
  • 4. DSMB/DMC
    4
    DSMB periodically inspects “interim looks” at the data (prior to all planned patients being treated and followed) and makes recommendations about trial design/conduct based on these “interim looks” including:
    Continue trial as initially planned.
    Safety:
    Potentially stop the trial early if reasonable evidence of harm of new product (or dose) or control product
    Often based on incidence of AEs or serious AEs
    DMC safety recommendations not necessarily based on formal statistical rules
  • 5. DSMB/DMC
    5
    Example of DSMB Safety Recommendation
    Double-blinded trial (randomized): Placebo versus Experimental treatment in high risk population
    Patients scheduled to be treated over several months
    After the first 40 patients were enrolled (20 in each treatment group) and treated for 1 day to several weeks, DSMB inspected unblinded data:
    Experimental treatment had 4 life threatening serious adverse events (SAEs)
    Placebo group had none
    P-value=0.1060
    DSMB Recommendation was to terminate study despite “non-significant” safety p-value
  • 6. DSMB/DMC
    6
    Example of DSMB Safety Recommendation (cont’d)
    DMC Recommendation to stop trial was not easy
    Perhaps benefit of drug outweighed the risk? Tough to tell at this early stage, but it was thought perhaps it was best not to wait to find out.
    Sponsor does not necessarily need to follow DSMB recommendation
    E.g., Sponsor may decide:
    Continue trial as is
    Temporarily halt trial until further investigation
    Discuss with DSMB/DMC & regulatory agency reason for not following recommendation
  • 7. DSMB/DMC
    7
    Example of DSMB Safety Recommendation (cont’d)
    Sponsor does not necessarily need to follow DSMB recommendation (cont’d)
    Potential issue if trial continues:
    Sponsor was made aware of the 4 experimental group SAEs during DSMB deliberations
    Will this “awareness” affect subsequent study conduct (even unintentionally), causing bias in remaining safety data?
    Perception of bias?
    Suppose SAE prevalence “evened out” at end of study?
  • 8. DSMB/DMC
    8
    DSMB periodically inspects “interim looks” at the data (prior to all patients being treated and followed) and makes recommendations about trial conduct including:
    Efficacy (“Adapt the trial”) (cont’d):
    Change primary endpoint (not common -- in my experience)
    Remove non-efficacious dose(s) (for multi-dose trials);
    Requires formal statistical rules in order to:
    Not increase “Type I Error” rate or “significance level” (chance of a false positive trial)
    Minimize “Type II Error” rate (chance of false negative trial)
    DSMB/DMC unblinded or “partially” unblinded
  • 9. DSMB/DMC Committee Composition
    9
    Discussed in Section 4.1 of FDA Guidance
    Sponsor/Steering Committee appoints DMC
    CRO also sometimes asked by Sponsor to appoint DMC
    Members consist of
    At least 2 clinicians
    At least 1 statistician
    May also have other members; e.g.,
    Ethicist for high risk/vulnerable populations
    Non-scientist; e.g., consumer rep; patient (not in trial)
  • 10. DSMB/DMC Committee Composition
    10
    Ideally, DSMB/DMC members should have
    Experience in indication being studied
    Clinical trials experience
    DSMB/DMC experience
    Especially important for statistician on DSMB/DMC
    All members may not have all 3
    Opinion: Especially important for
    Statistician to have at least b and c;
    Clinician/physician to have at least a (and b);
  • 11. DSMB/DMC Committee Composition
    11
    Statistician should also have:
    Experience in statistical methods for clinical trials
    Experience in statistical rules for “adapting” design
    Members should be independent from Sponsor
    Not a sponsor employee
    Not an investigator
    No involvement in the study conduct or analysis planning
    No serious conflicts of interests
    All potential conflicts disclosed prior to each meeting
  • 12. DSMB/DMC Committee Composition
    12
    Each DSMB/DMC has a chair.
    Chosen by sponsor and other DSMB/DMC members
    FDA Guidance: chair capable of “facilitating discussion/integrating different points of view”.
    Chair provides DSMB/DMCs recommendation of future study conduct to sponsor or steering committee
    After inspection of interim data, DSMB/DMC members “vote” on a recommendation for future conduct of study
    Works best if “odd” number of DSMB/DMC voting members
  • 13. Statisticians in DSMBs
    Often 3 statisticians involved in the DSMB/DMC process
    DSMB/DMC Statistician
    Voting member of DSMB/DMC; helps interpret statistical aspect of results to other voting members, especially adaptive results and statistical repercussions of adapting the design.
    Analysis Statistician
    Generates interim results (often not a Sponsor employee)
    Unblinded to treatment group for each patient
    “Independent Statistician”
    Presents results to DSMB/DMC; answers DSMB/DMC statistical questions
    Non-voting
    “Go-between” between DSMB and Analysis Statistician
    All statisticians are not to be involved in analysis of final data or analysis planning
  • 14. “Fixed” Design
    “Fixed” clinical trial design (2 treatments)
    Compare “cure” rate across two anti-infectives:
    Specify an appropriate (superiority) null and alternative hypothesis:
    H0: πE = πC
    H1: πE ≠ πC
    where πE and πCare the true sensitivities of the experimental and control diagnostic, respectively.
    To calculate sample size, make assumption of the true πE, πC
    Determine sample size required to yield adequate power to reject H0 in favor of H1 at a given significance level
    14
  • 15. “Fixed” Design
    “Fixed” clinical trial design example (cont’d)
    For determining sample size, assume
    πE =0.80 and πC =0.70
    Two-sided 0.05 level of significance (false positive rate)
    Desire 80% Power
    1:1 Treatment Allocation
    Sample size per group (using two-sample z-test for proportions): 294 per group
    15
  • 16. Adaptive Trial Designs
    16
    Adaptive designs allow for re-designing the trial at some point during the trial, usually based on interim look(s) at aggregate efficacy data
    Stop trial for “futility” of experimental diagnostic
    Stop trial for overwhelming efficacy
    Increase sample size to ensure adequate (conditional) power by end of study
    Decrease sample size if (conditional) power >>original power
    Remove non-efficacious dose in dose-finding study
    Change primary endpoint
  • 17. Adaptive Trial Designs
    17
    The interim “look” at the data can be blinded or unblinded.
    Adapting the design of the study often has statistical repercussions, especially if re-design is based on an unblinded analysis
    Here, we will focus on adapting trial based on an unblinded interim analysis.
    Also may have operational repercussions
  • 18. Issues to Consider
    18
    Once DSMB gives recommendations arrive, could bias in final results occur?
    If DSMB says “increase the sample size by xx”:
    if Sponsor follows recommendation, study personnel may realize the product may be efficacious, and just needs a little more sample size to prove its efficacy with good confidence.
    Cause bias in future study conduct?
    If Sponsor does not follow recommendation, does Sponsor feel product then has small chance of being efficacious and bias remainder of study?
    E.g., may move resources off study, slowing study down or reducing quality?
  • 19. Issues to Consider
    19
    Once DSMB gives recommendations arrive, bias could result
    If DSMB/DMC recommends “continue the study as is”,
    Study personnel who may not understand the requirement for overwhelming efficacy, may think the product is not efficacious, otherwise study would have stopped for efficacy?
    Causes bias on remaining study personnel?
  • 20. Dosage Change
    20
    Most “pivotal” (Phase III) drug/biologic trials contain one dose of the experimental treatment and a control group
    Some Phase III may contain more than one dose of experimental however (especially those that may “skip” Phase II to get product to market faster in case of serious illness, e.g., ALS)
    Many Phase II’s have multiple doses of experimental to determine the dose of study in future pivotal Phase III
  • 21. Dosage Change
    21
    Suppose we have a trial with multiple doses of experimental treatment, and one control group
    Formal efficacy rules can be built in to “drop” inefficacious dose after interim analysis;
    E.g., drop dose(s) with CP<20% when compared to control
    Maybe use a more liberal (higher) threshold, especially in Phase II, if other doses showing more promise.
    Increase enrollment in doses with CP<80% but showing promise?
    In Phase II, control of false positive rate may not be as much of concern
    In Phase II, may not necessarily have to show treatment effect at 0.05 level of significance
    Perhaps calculate CP at 0.10 level of significance.
  • 22. Dosage Increase
    22
    Many Phase I trials are non-randomized, dose-escalating
    Enroll first k patients into lowest dose
    Follow for safety
    DSMB inspects safety results and gives the “OK” to move on to next dose
    Next set of k patients enrolled to next (higher) dose
    Continue through pre-planned doses
  • 23. Primary Endpoint Change
    23
    Medical device clinical trial example:
    Efficacy endpoint is survival at 30 days.
    DSMB/DMC performed formal pre-planned interim efficacy/futility analysis on endpoint
    Assessed if trial could be stopped early for overwhelming efficacy, futility, and sample size recalculation as necessary.
    DSMB/DMC also decided to inspect CP for “3-month survival” outcome at interim stage
    Not in DSMB/DMC charter
    Not Necessarily a problem, depending on what DSMB/DMC plans to do with this info
    Less patients available than at 30 days
  • 24. Primary Endpoint Change
    24
    Medical device clinical trial example (cont’d):
    Reason for request unclear:
    DSMB/DMC considering recommending change in primary endpoint?
    Data-driven decision?
    May increase chance of false positive study
    Sponsor requested to see interim 3 -month data
    Strongly recommend against that
    Data-driven decision and potential introduction of bias into trial
    Possible approach with no real repercussions:
    Use 3-month data to plan another study with 3-month outcome as primary endpoint.
  • 25. Conclusion
    25
    DSMBs/DMCs consist of experienced clinicians and at least one experienced statistician
    DSMBs/DMCs responsible for subject safety and scientific merit of study
    DSMBs/DMCs make recommendations on study design and conduct issues while the trial is ongoing
    Such recommendations may have repercussions and may introduce bias in remainder of study
    Important for DSMBs/DMCs to consider such issues
    Important to minimize such bias
  • 26. Acting on a DMC/DSMB Recommendation:How to prepare for and respond to DMC/DSMB recommendations
  • 27. 1. Identifying the need for DMCs/DSMBs - 1
    1998 - NIH Policy For Data and Safety Monitoring
    2001 - Draft FDA Guidance for Clinical Trial Sponsors: Establishment and operation of clinical trial data monitoring committees
    2003 - Draft CHMP Guideline on Data Monitoring Committees
    2004 - NEJM Data Safety and Monitoring Boards
    2004 – Small group processes relevant to data monitoring committees in controlled clinical trials: an overview of reviews
    2005 - Issues in data monitoring and interim analysis of trials - DAMOCLES Study Group
    2006 - Final CHMP Guideline on Data Monitoring Committees
    2006 - Final FDA Guidance for Clinical Trial Sponsors: Establishment and operation of clinical trial data monitoring committees
    2008 - JAMA commentary: When should data and safety monitoring committees share interim results in cardiovascular trials?
    Clear expectations
    Increased focus on the DMC
    Evolving role of the DMC
  • 28. 1. Identifying the need for DMCs/DSMBs - 2
    Changing Characteristics of Development Portfolios
    • Serious diseases
    • 29. Biologics
    • 30. Greater HA scrutiny
    Increasing Complexity of Development Programs
    • Earlier in development phase
    • 31. Large multi-site, multi-national clinical trials
    • 32. Multiple simultaneous indications
    Potential for Variation in DMC Interactions
    • Scope of DMC
    • 33. Interpretation of roles and responsibilities
    • 34. Alliance partnerships
    Greater need for DMCs
    Importance of clear DMC decisions
    Opportunity for improvement
  • 35. 1. Identifying the need for DMCs/DSMBs - 3
    2006 Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees
    2. Determining Need for a DMC
    All clinical trials require safety monitoring, but not all trials require monitoring by a formal committee that may be external to the trial organizers, sponsors and investigators.
    2.1 What is the Risk to Trial Participants?
    A fundamental reason to establish a DMC is to enhance the safety of trial participants in situations in which safety concerns may be unusually high, in order that regular interim analyses of the accumulating data are performed. We recommend that sponsors consider using a DMC when:
    • The study endpoint is such that a highly favorable or unfavorable result, or even a finding of futility, at an interim analysis might ethically require termination of the study before its planned completion;
    • 36. There are a priori reasons for a particular safety concern, as, for example, if the procedure for administering the treatment is particularly invasive;
    • 37. There is prior information suggesting the possibility of serious toxicity with the study treatment;
    • 38. The study is being performed in a potentially fragile population such as children, pregnant women or the very elderly, or other vulnerable populations, such as those who are terminally ill or of diminished mental capacity;
    • 39. The study is being performed in a population at elevated risk of death or other serious outcomes, even when the study objective addresses a lesser point;
    • 40. The study is large, of long duration, and multi-center.
  • 2. What are the sponsor and DMC/DSMB responsibilitiespost-recommendation? - 1
    Health Authorities
    Development / brand teams
    Governance Committees
    Sponsor
    Steering
    Committee /
    Study PI
    Open session minutes
    Closed session minutes
    DMC
    IRBs
    Adjudication Committee
    Independent Statistician
    Ethics Committees
  • 41. 2. What are the sponsor and DMC/DSMB responsibilitiespost-recommendation? - 2
    Health Authorities
    Development / brand teams
    Governance Committees
    Sponsor
    Steering
    Committee /
    Study PI
    Open session minutes
    Closed session minutes
    DMC
    IRBs
    Adjudication Committee
    Independent Statistician
    Ethics Committees
  • 42. 2. What are the sponsor and DMC/DSMB responsibilitiespost-recommendation? - 3
    Health Authorities
    Development / brand teams
    Governance Committees
    Sponsor
    Steering
    Committee /
    Study PI
    Open session minutes
    Closed session minutes
    DMC
    IRBs
    Adjudication Committee
    Independent Statistician
    Ethics Committees
  • 43. 2. What are the sponsor and DMC/DSMB responsibilitiespost-recommendation? - 4
    Health Authorities
    Development / brand teams
    Governance Committees
    Sponsor
    Steering
    Committee /
    Study PI
    Open session minutes
    Closed session minutes
    DMC
    IRBs
    Adjudication Committee
    Independent Statistician
    Ethics Committees
  • 44. 3. Some guiding principles for continued successin handling future recommendations
    Make sure your company has SOPs for how to modify or terminate a study in an emergency
    Make sure that everyone knows their respective roles and responsibilities in anticipation of substantive DMC recommendations
    Make sure that everything is documented clearly and in a timely manner
    Make sure that the DMC (especially the chair) understands what is in scope and what is not
    Be prepared for increasing scrutiny from HA’s
  • 45. 4. Discussion supported by case study examples - 1
    Make sure that everyone knows their respective roles and responsibilities in anticipation of substantive DMC recommendations
    Mid-stage oncology product
    - Process of setting up a DMC
    - Clinical development TA lead asked for advice on who should be point of contact for the DMC
    - We advised that it should be the TA lead or equivalent, someone removed from the daily project responsibilities
    - Despite this the TA lead elected to nominate the medical monitor for that study to be the point of contact for the DMC
  • 46. 4. Discussion supported by case study examples - 2
    Make sure that everything is documented clearly and in a timely manner
    Late-stage cardiovascular product being developed for multiple indications with multiple DMCs in operation
    - A DMC chair raised a question as part of one of the recommendations following a routine, planned DMC meeting
    - The question itself was not related to a safety issue, but expressed dissatisfaction with the speed of adjudication and presentation of data
    - The project team worked hard to address operational issues that were preventing timely adjudication, however, the medical lead elected not to inform the DMC of their activities since it was “not a safety issue”
    - A follow up email from the DMC chair was received by the project team 4 weeks later, asking for an update regarding the adjudication process
    - The medical lead sent an email detailing the steps that were being taken to address this point
    - The adjudication rate improved, but the DMC chair persisted in drawing attention to this operational issue in the formal DMC recommendations for 6 months
  • 47. 4. Discussion supported by case study examples - 3
    Make sure that the DMC (especially the chair) understands what is in scope and what is not
    Late-stage cardiovascular product being developed for multiple indications with multiple DMCs in operation
    - A different DMC decided to conduct informal efficacy and safety analyses at every DMC meeting for one study, which was not included in the protocol or statistical analysis plan
    - As a result the DMC issued recommendations to suspend the study even ahead of the first planned interim analysis
    - The DMC also complained that the number of positively adjudicated endpoints were constantly changing
    - The frequency of the efficacy and safety endpoints were actually well within the expected rates, with an overall rate that was low
  • 48. 4. Discussion supported by case study examples - 4
    Be prepared for increasing scrutiny from HA’s
    Late-stage immunology product
    - Study in a new indication well underway
    - Project team receiving many safety-related requests from HA’s
    - The Swedish MPA requested a copy of the minutes from a recent DMC closed session
    - The DMC originally refused to provide the minutes directly to the HA
    - Ultimately, the DMC sent the closed sessions minutes to the sponsor, who then forwarded the package to the MPA
  • 49. Still have any questions? For additional information on ExLPharma’s Data Monitoring Committees/DSMB Conferences, please visit www.exlpharma.com

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