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Design Issues in ABS Trials: Surrogates Endpoints & Non-Inferiority Trials October 29, 2003 PowerPoint PPT Presentation


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FDA Anti-Infective Drugs Advisory Committee. Design Issues in ABS Trials: Surrogates Endpoints & Non-Inferiority Trials October 29, 2003 Thomas R. Fleming, Ph.D. Professor and Chair of Biostatistics University of Washington. Design Issues in ABS Trials. Criteria for Study Endpoints

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Design Issues in ABS Trials: Surrogates Endpoints & Non-Inferiority Trials October 29, 2003

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Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

FDA Anti-Infective Drugs Advisory Committee

Design Issues in ABS Trials:

Surrogates Endpoints &

Non-Inferiority Trials

October 29, 2003

Thomas R. Fleming, Ph.D.

Professor and Chair of Biostatistics

University of Washington


Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

Design Issues in ABS Trials

  • Criteria for Study Endpoints

  • Use of Surrogate Endpoints

  • Non-Inferiority Design Issues

    • Choice of the NI Margin

    • Bio-creep with Repeated NI Trials

  • Active vs.Placebo controlled trials

  • Time to Event Analyses in ABS Trials


  • Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

    Design Issues in ABS Trials

    • Criteria for Study Endpoints

    • Use of Surrogate Endpoints

    • Non-Inferiority Design Issues

      • Choice of the NI Margin

      • Bio-creep with Repeated NI Trials

  • Active vs. Placebo controlled trials

  • Time to Event Analyses in ABS Trials


  • Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

    Criteria for Study Endpointsin ABS Clinical Trials

    • Measurable/Interpretable

    • Sensitive

    • Clinically relevant

    ~ Resolution/Improvement of ABS Symptoms

    ~ Reducing the time to Resolution


    Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

    Design Issues in ABS Trials

    • Criteria for Study Endpoints

    • Use of Surrogate Endpoints

    • Non-Inferiority Design Issues

      • Choice of the NI Margin

      • Bio-creep with Repeated NI Trials

  • Active vs. Placebo controlled trials

  • Time to Event Analyses in ABS Trials


  • Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

    Use of Surrogate Endpoints

    Treatment Effects on Surrogate Endpoints

    eg:~Radiological Resolution of Disease

    ~Microbiological Outcomes

    • Establishes Biological Activity

    • But Not Necessarily Clinical Efficacy


    Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

    Time

    Intervention

    Surrogate True Clinical

    Endpoint Outcome

    Disease


    Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

    Illustration:

    AIDS Patients with MAI Bacteremia

    Clarithromycin Dose (mg bid)

    500 1000 2000

    Bacterial Load 145 34 25

    12 wk Mortality 5.7% 25.5% 28.0%

    Chaisson et al, 1994


    Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

    Time

    Intervention

    Bacterial 12 week

    Load Mortality

    Disease


    Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

    Validation of Surrogate Endpoints

    Property of a Valid Surrogate

    ·Effect of the Intervention

    on the Clinical Endpoint

    is reliably predicted by the

    Effect of the Intervention

    on the Surrogate Endpoint


    Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

    Prentice’s Sufficient Conditions

    1.The surrogate endpoint

    must be correlated with

    the clinical outcome

    2.The surrogate endpoint

    must fully capture

    the net effect of treatment

    on the clinical outcome


    Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

    Validation of Surrogate Endpoints

    Statistical

    ·Meta-analyses of clinical trials data

    Clinical

    ·Comprehensive understanding of the

    ~Causal pathways of the disease process

    ~Intervention’s intended and unintended

    mechanisms of action


    Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

    Clinical Endpoints & Surrogates in ABS Clinical Trials

    •Clinical Endpoints:

    ~ Resolution/Improvement of ABS Symptoms

    • Surrogate Endpoints:

    ~Radiological Resolution of Disease

    ~Microbiological Outcomes

    Validation of Surrogate Endpoints requires

    more than correlation with Clinical Endpoints


    Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

    Design Issues in ABS Trials

    • Criteria for Study Endpoints

    • Use of Surrogate Endpoints

    • Non-Inferiority Design Issues

      • Choice of the NI Margin

      • Bio-creep with Repeated NI Trials

  • Active vs. Placebo controlled trials

  • Time to Event Analyses in ABS Trials


  • Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

    Dual Goals of Non-Inferiority Trials

    • To enable a direct evaluation

    of the clinical efficacy

    of EXP relative to Active Control

    • To contribute evidence to

    the evaluation of efficacy

    of EXP relative to Placebo


    Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

    •Active Control Effect

    ICH E9: “A suitable active comparator…

    could be a widely used therapy

    whose efficacy in the relevant indication

    has been clearly established& quantified

    in well-designed &

    well documented superiority trials

    & which can be reliably expected to have

    similar efficacy in the contemplated AC trial.”

    Non-Inferiority Trials… Some Requirements


    Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

    Non-Inferiority Trials… Some Requirements

    STD should have clinical efficacy

    • that is of substantial magnitude

    • that is precisely estimated

    • with estimates that arerelevant to the setting

    in which the non-inferiority trial

    is being conducted


    Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

    Factors Influencing Choice of Margin

    • Active Control Effect

    ~magnitude of Active Control effect

    Eg:  = 45% – 80% = –35%

    ~precision of estimate

    Eg: 2 s.e. =  10% ( 175/arm )

    ~estimates relevant to setting of NI trial

    •Population •Supportive care •Endpoint assessment

    PLA – AC Cure Rate

    *

    (

    )

    –45% –35%–25% –12.5% 0%


    Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

    Factors Influencing the Choice of Margin

    and Interpretation of NI Trial Results

    • Clinical Relevance of Changes in:

    Benefits, Risks/Tolerance,

    Convenience, Resistance, etc.

    • Active Control Effect


    Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

    Factors Influencing Choice of Margin

    •Clinical Relevance of Changes in:

    Benefits, Risks/Tolerance,

    Convenience, Resistance, etc.

    Clinical importance of:

    - reduction in efficacy by 

    - altered safety/tolerance profile

    - altered convenience of administration

    - altered resistance or drug/drug interactions


    Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

    The Choice of the Margin in an NI Trial

    ICH E10: “The determination of the margin

    in a non-inferiority trial is based on

    both statistical reasoning & clinical judgment,

    and should reflect uncertainties

    in the evidence on which the choice is based,

    and should be suitably conservative.”


    Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

    “Bio-creep” with Repeated NI Trials

    Eg: Anti-viral Drugs Advisory Comm (10/4/01)

    Empiric Anti-fungal therapy

    of febrile neutropenic patients

    •Amphotericin B Deoxycholate

    •Ambisome vs Amphotericin B

    49.9% v 49.1% Mycosis Study Gp #32

    •Voriconazole vs Ambisome

    23.7% v 30.1% 95% CI: (– 12, – 0.1)


    Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

    Overview of Placebo-controlled ABS Trials

    • Fourteen Placebo-controlled Trials

    of Antimicrobials conducted in ’69 –’03

    (with nine conducted since ’96)

    • Outcome: Antimicrobial effect on

    Resolution or improvement of ABS symptoms, assessed at fixed time between 7-14 days


    Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

    70

    50

    30

    10

    -10

    -30

    -50

    -70

    1

    14

    2

    11

    3

    4

    10

    7

    5

    12

    6

    8

    9

    16

    13

    15

    Antimicrobial Efficacy ( 95% CI)

    Study


    Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

    NI Trials vs Placebo Controlled Superiority Trials

    •ICH E10: “The determination of the margin

    in a non-inferiority trial is based on

    both statistical reasoning & clinical judgment,

    should reflect uncertainties

    in the evidence on which the choice is based,

    and should be suitably conservative.”

    • When one cannot justify a non-trivial margin,

    placebo controlled trials provide

    an ethically and scientifically reliable approach

    to assessing the benefit-to-risk profile


    Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

    Design Issues in ABS Trials

    • Criteria for Study Endpoints

    • Use of Surrogate Endpoints

    • Non-Inferiority Design Issues

      • Choice of the NI Margin

      • Bio-creep with Repeated NI Trials

  • Active vs Placebo controlled trials

  • Time to Event Analyses in ABS Trials


  • Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

    Time to Event Analyses in ABS Trials

    • “In self-resolving diseases, it may be

    • more appropriate to measure time to

    • resolution or improvement of symptoms”

    • To have 90% power to detect a reduction

    • in time to resolution from 7 days to 5 days

    • (with the standard 2.5% false positive error rate)

    • one needs approximately 200 pts/arm.

    • (Stat Significance if one obtains about 1.3 days )


    Design issues in abs trials surrogates endpoints non inferiority trials october 29 2003

    Conclusions

    • Criteria for Study Endpoints

    • A Correlate does not a Surrogate Make

    • Non-Inferiority Design Issues

      • Choice of the NI Margin

      • Bio-creep with Repeated NI Trials

  • Placebo controlled trials

  • Time to Event Analyses in ABS Trials


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