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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 ExLPharmas 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 (contd)
    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 (contd)
    Sponsor does not necessarily need to follow DSMB recommendation (contd)
    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) (contd):
    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: E = C
    H1: E C
    where E and Care the true sensitivities of the experimental and control diagnostic, respectively.
    To calculate sample size, make assumption of the true E, C
    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 (contd)
    For determining sample size, assume
    E =0.80 and C =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 IIs 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

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