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Phase II_III Design_ Case Study

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					            Phase II/III Design: Case Study



Case study: Seamless Phase II/III Design for
Registration Program


Jeff Maca, Ph.D.
Senior Associate Director
Novartis Pharmaceuticals
Outline – Adaptive Seamless Case Study

 Motivation/definitions
 Adaptive seamless designs considerations
 Case study example
        •       Simulation details

 Conclusions




2 | Seamless Case Study / KOL Series | June 12, 2009
  Motivation

 Adaptive Designs: Using accumulating data to
 decide on how to modify aspects of the trial design,
 during the conduct of the trial and without violating
 the integrity of the trial

 An adaptive trial can plan at the design stage to
  correct for incorrect assumptions
 Adaptive trials can merge what might be
  considered two separate trials into one trial
 Improve efficiency in clinical development
 Careful planning is necessity
  3 | Seamless Case Study / KOL Series | June 12, 2009
Adaptive Seamless designs

Primary objective – combine “dose selection”
   and “confirmation” into one trial
 Although dose is most common phase IIb objective, other
        choices could be made, e.g. population

 After dose selection, change usually to new enrollments
        (patients could be re-randomized, and analyzed
        separately)

 Patients on terminated treatment groups can be followed
 All data from the chosen group and comparator is used in
        the final analysis. Appropriate statistical methods must
        be used
4 | Seamless Case Study / KOL Series | June 12, 2009
Adaptive Seamless designs
Statistical methodology for Adaptive Seamless Designs
   must account for potential biases and statistical
   issues

 Selection bias (multiplicity)
 Multiple looks at the data (interim analysis)
 Combination of data from independent stages
        •       Closed testing procedure (data from stages are
                separated) and Bonferroni type adjustment (data is
                pooled across stages) are two possible methods



5 | Seamless Case Study / KOL Series | June 12, 2009
Adaptive Seamless designs
With the added flexibility of seamless designs,
  comes added complexity.

 Careful consideration should be given to the feasibility for
        a seamless design for the project.

 Not all projects can use seamless development
 Even if two programs can use seamless development,
        one might be better suited than the other

 Many characteristics add or subtract to the feasibility

6 | Seamless Case Study / KOL Series | June 12, 2009
Adaptive Seamless designs
Enrollment vs. Endpoint

 The length of time needed to make a decision
        relative to the time of enrollment must be small
        •       Otherwise enrollment must be paused
 Endpoint must be well known and accepted
        •       If the goal of Phase II is to determine the endpoint for
                registration, seamless development would be difficult
 If surrogate marker will be used for dose
        selection, it must be accepted, validated and well
        understood
7 | Seamless Case Study / KOL Series | June 12, 2009
Adaptive Seamless designs
Clinical Development Time


 There will usually be two pivotal trials for
        registration

 Entire program must be completed in shorter
        timelines, not just the adaptive trial




8 | Seamless Case Study / KOL Series | June 12, 2009
Adaptive Seamless designs
Logistical considerations

 Helpful if final product is available for adaptive
        trial (otherwise bioequivalence study is needed)

 Decision process, and personnel must be
        carefully planned and pre-specified




9 | Seamless Case Study / KOL Series | June 12, 2009
 Phase II/III Adaptive Design – Case Study

Case Study Introduction
 Indication is a chronic disease
 Adaptive seamless design (ASD) to select final
    dose to support registration of new formulation

 Study will provide pivotal confirmation of efficacy,
    safety and tolerability of selected dose

 Two adaptive studies are running concurrently,
    one in mono-therapy, one in add-on therapy
 10 | Seamless Case Study / KOL Series | June 12, 2009
 Phase II/III Adaptive Design – Case Study

Case Study Introduction
 Bias towards selecting the lower dose, unless
    •       Low dose would not have high likelihood of success
    •       High dose had considerably better efficacy

 Selection probabilities and overall power derived
    via extensive simulation study

 Studies are planned to have interim analysis
    occurring at the same time
    •       Dose selection simultaneous for both studies
 11 | Seamless Case Study / KOL Series | June 12, 2009
  Phase II/III adaptive design : Study 1
                                                               Independent
                                                                  Dose
            STAGE 1 (phase IIb)                                  Selection         STAGE 2 (phase III)
                     High Dose

                                                                              Selected Dose

                    Low Dose




                    Placebo                                                  Active control

Screening               Dose Ranging                     Interim              Efficacy and Safety         Final
                          24 weeks                       Analysis                  52 weeks              Analysis


                                                Ongoing treatment
 12 | Seamless Case Study / KOL Series | June 12, 2009
  Phase II/III adaptive design : Study 2
                                                               Independent
                                                                  Dose
            STAGE 1 (phase IIb)                                  Selection         STAGE 2 (phase III)
                     High Dose
                                                                             Selected Dose
                     Low Dose


                     Placebo                                                 Selected Dose


                     Active control                                          Active control

Screening               Dose Ranging                     Interim              Efficacy and Safety         Final
                          24 weeks                       Analysis                  52 weeks              Analysis


                                                Ongoing treatment
 13 | Seamless Case Study / KOL Series | June 12, 2009
 Phase II/III Adaptive Design – Case Study

Studies are divided into three periods
 Period 1 (Dose selection)
 Intermediate period (during dose selection)
 Period 2 (long term safety and efficacy)




 14 | Seamless Case Study / KOL Series | June 12, 2009
 Phase II/III Adaptive Design – Case Study

Period 1
 Patients randomized equally to high dose, low
    dose and control (s)

 All patients complete 24 weeks of treatment
    which is the time to primary endpoint

 Roughly 100 and 150 patients in the two studies
    will be randomized

 Data from both studies will be used in selection
 15 | Seamless Case Study / KOL Series | June 12, 2009
 Phase II/III Adaptive Design – Case Study

Intermediate Period
 Patients randomized to non-placebo treatments
    will stay on treatment until dose selection is
    complete

 Patients on placebo will be switched to active
    treatment (if completed 24 weeks)

 Recruitment continues through this period


 16 | Seamless Case Study / KOL Series | June 12, 2009
 Phase II/III Adaptive Design – Case Study

Period 2
 Patients randomized to non selected dose(s) are
    switched to selected dose

 Placebo patients are switched to active treatment
 Patient randomized to selected dose or active
    control



 17 | Seamless Case Study / KOL Series | June 12, 2009
Phase II/III adaptive design: Case study
 Primary endpoint
     •       Continuous variable – measured after 24 weeks
     •       Dose selected on a 12 week measurement (early
             readout)
     •       Comparison with placebo for superiority
 Secondary endpoints
     •       Comparison of safety and efficacy over 24 weeks
     •       Long term safety measured over 52 weeks




18 | Seamless Case Study / KOL Series | June 12, 2009
    Phase II/III adaptive design: Case study

Objective of interim analysis
        To investigate two doses of new treatment versus placebo
         and active controls with respect to primary endpoint after
         12 weeks of treatment (early read-out)

        Independent external DMC will select dose to continue
         into period 2

        DMC would see analysis from both studies, and make
         same selection of dose for both studies

        Interim analyses must be timed to occur at the same time
         (harder to do in practice than on paper)

    19 | Seamless Case Study / KOL Series | June 12, 2009
Phase II/III adaptive design: Simulations

 Sample sizes for stage 1 and 2 based on
      extensive simulation work
      •       Stage 1 sample size chosen to ensure the “optimal”
              dose was chosen with high probability
      •       Various dose responses were investigated

 Stage 2 sample size sufficient to satisfy
      primary and secondary objectives of the
      study


 20 | Seamless Case Study / KOL Series | June 12, 2009
Phase II/III adaptive design: Simulations

 Decision rule has tendency towards picking
      lower dose
 In general, the low dose is selected unless
      high dose has “much” higher efficacy
      outcome, or low dose does not have
      “much” chance to succeed.
 Different thresholds were investigated to
      make this determination of “much”


 21 | Seamless Case Study / KOL Series | June 12, 2009
 Phase II/III adaptive design: Simulations

Output from simulation

 Selection probabilities for each of the two
      treatment doses
 Power conditional on the dose selected
 Overall power that the selected doses would
      be confirmed



 22 | Seamless Case Study / KOL Series | June 12, 2009
Phase II/III adaptive design: Simulations

Statistical methodology
 A multiplicity correction will be used for the
      final analysis to account for the two
      treatments
      •       Dunnett step-down methodology will be used
      •       Data not split by period with separate p-values
              (inverse normal/closed testing methodology),
              although would have similar power
 Procedure will control family-wise type I
      error rate for the primary endpoint

 23 | Seamless Case Study / KOL Series | June 12, 2009
Phase II/III adaptive design: Case study

DMC guidelines
 Numerical values given (not inferential)
 Thresholds are pre-defined (results from
      simulations ), for implementation by DMC
 Trials will not be stopped for efficacy at
      interim analysis
 Trials currently ongoing, with dose
      selection analysis upcoming shortly

 24 | Seamless Case Study / KOL Series | June 12, 2009
    Conclusions

 Adaptive seamless designs have an ability to improve the
        development process by reducing timelines for approval
 Extra planning is necessary to implement an adaptive
        seamless design protocol
       Simulations can be used to determine decision rules, and
        operating characteristics of such a design
 This case study successfully used simulations to plan and
        execute two simultaneous adaptive seamless designs
        which incorporate dose selection



    25 | Seamless Case Study / KOL Series | June 12, 2009

				
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