Implementation and Analysis of PROs in Clinical Trials

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					             Implementation and Analysis of
                 PROs in Clinical Trials

                        Jeff A. Sloan, Ph.D.

                   DIA Meeting, D.C., June 26, 2005

 Why is it difficult to deal with PROs?

• Relatively recent acceptance
       • 25 years ago physicians were the sole
             raters of patient pain

       • JCAHO 2000 guideline: every patient’s
             pain to be assessed upon intake on a 0-10

• Time and experience alleviates novelty and
       Checklist for designing, conducting and reporting
                  HRQL - PRO in clinical trials
      Patient Reported Outcomes (PRO) and Regulatory Issues : A European Guidance Document for the
   improved integration of health-related quality of life assessment in the drug regulatory process. Chassany
                            O et ERIQA Working Group. Drug Information Journal 2002.

         HRQL / PRO objectives                                   Statistical analysis plan
         • Added value of HRQL / PRO                             • Primary or secondary endpoint
         • Choice of the questionnaires                          • Superiority or equivalence trial
         • Hypotheses of HRQL / PRO changes                      • Sample size
                                                                 • ITT, type I error, missing data
         Study design
         • Basic principles of RCT fulfilled ?                   Reporting of results
         • Timing and frequency of assessment                    • Participation rate, data completeness
         • Mode and site of administration...                    • Distribution of HRQL / PRO scores
         HRQL / PRO measure                                      Interpreting the results
         • Description of the measure (items, domains…)          • Effect size,
         • Evidence of validity                                  • Minimal Clinically Important Difference
         • Evidence of cultural adaptation                       • Comparison with other criteria / scores
                                                                 • Number needed to treat…
                   Take home messages:
                    there is good news

      • There are problems with using PROs as
             indicators of efficacy in clinical trials.

      • There are scientifically sound solutions
             to these problems. The problems have
             been disseminated widely and
             consistently. The solutions have not.

        It takes a certain amount of bravery to work with PRO’s

     Primary goal: advance the state of the science
                  to help patients soar

             How do you analyze PRO data?

                 Science is a candle in the dark
                                          - Carl Sagan

  We will use the candle of science to improve the QOL of cancer patients
                … by answering
              scientific questions
• What is the value added of PROs to
     treatment trials?

• How do you deal with multiple endpoints?

• How do you handle missing data?

• What is the clinical significance of PRO
              What is the value added
              of additional questions?

                    Single-Item or Multiple-Item PRO?
      Situations where a single item may          Situations where a multi-item index
      suffice                                     may be needed
      Phase II study attempting to assess         A Phase III study where it is known that
      whether a treatment has any impact on       QOL is impacted and more delineation
      QOL                                         of which QOL components are affected
                                                  is needed
      A stratification factor for the presence    A screen to identify the presence or
      or absence of depressive issues             absence of clinical depression
      Need to assess fatigue/pain as a            Need to assess the impact of
      correlate of toxicity (brief fatigue/pain   fatigue/pain on the activities of daily
      inventory)                                  living (ADL items for pain/fatigue)
      Identifying patients who have need of       Detailing the QOL-related issues once
      further QOL assessment (e.g., score of      a cut off score on a single item has
      6 or less on a single item)                 been obtained
      A clinical setting wherein a basic idea     A clinical setting wherein precise
      of which domains of QOL (mental,            indications of the way in which the
      physical, social) may be affected by a      different domains of QOL may be
      particular treatment or situation           affected by a particular treatment or

                  Guidelines for endpoint determination

              • Several good references (Beitz, 1996;
                  Chassany, 2002; Fayers, 1999; Sloan, 2002)
              • Reliability and validity data available
              • Pilot/focus groups to establish R/V
              • What aspects of PROs are likely to
              •   Can one expect an overall change in
                  well-being, health status or QOL?

              Recipe for endpoint determination

• List PRO aspects likely to change.
• Operationalize each item from a tool.
• Survey clinicians/patients if unsure.
• Keep the total number of items under 25.
• Mock up tables with “perfect world” data,
     labels with “perfect” results.
•    Link sample size to a priori clinical
                  How do you deal
              with multiple endpoints?

              An example of combined symptoms:
                    Gemzar (gemcitabine)
  • Indication: Advanced pancreatic cancer
  • Instrument or Method:
     • Negotiated PRO outcome, “clinical benefit
  •     PRO Domains Assessed:
         • Pain, analgesic consumption, performance
           status, weight
  •     Results:
         • Clinical benefit response was experienced by
           24% of patients receiving Gemzar versus 5% of
           patients receiving 5FU, p=0.002
                          Gemzar-specific clinical benefit response
               Analgesic                              Pain
              Consumption                           Intensity

                                    Pain                               Performance

       Improvement in both                             Stable                                Nonresponder
             parameters                           In both parameters                       Worsening in either
      Stable in one parameter,                                                                parameter
      improvement in another


                            Responder                                        Nonresponder
                    21% Increase in body weight                          Stable or decreased weight

              A patient was considered a clinical
              benefit responder to Gemzar if ….

   • The patient showed >=50% reduction in pain
         intensity or analgesic consumption, or a 20+
         point improvement in performance status (for at
         least 4 weeks with no worsening of other
          • Memorial Pain Assessment Card and
            Karnofsky Performance Scale
   •     The patient was stable on all of the parameters
         mentioned and showed a marked, sustained
         weight gain not due to fluid accumulation ( >7%
         increase maintained for 4 weeks)
               O’Brien Global Test
              for Multiple Outcomes
    • Example: Venlafaxine for Hot Flashes
       • Hot flash frequency per day
       • Hot flash average severity per day
          • none, mild, moderate, severe, very severe
          • scored 0, 1, 2, 3, 4
       • Hot flash score (severity times frequency)
       • Uniscale QOL
       • Hot flash affect on QOL
       • Toxicity incidence on 11 variables
                       O’Brien p-values
              Endpoints Included              p-value
    Hot Flash Frequency
    Hot Flash Average Severity     0.0071
    Hot Flash Score                         0.0050

    Uniscale QOL                                0.7528
    Hot Flash Affects QOL


               How do you handle the
              problem of missing data?

              Impact of hydrazine sulfate on colorectal cancer patient QOL

                  Impact of different imputation methods for missing data
              Effect of imputation method on treatment comparison

              The data are usually trying to tell you something….

                          …you just have to pay attention
              What is the clinical significance
                  of PRO assessments?

                  Two general methods
                 for clinical significance

          • Anchor-based methods requirements
              • independent interpretable
               measure (the anchor) which has
               appreciable correlation between
               anchor and target
          • Distribution-based methods
              • rely on expression of magnitude
               of effect in terms of measure of
               variability of results (effect size)
              The MID method in one slide

             The ERES Approach
• QOL tool range = 6 standard Deviations
• SD Estimate = 100 percent / 6
            = 16.7% of theoretical range

• Two-sample t-test effect sizes (Cohen):
    small, moderate, large effect (0.2, 0.5, 0.8 SD

• S,M,L effects = 3%, 8%, 12% of range
              Assessing Clinical Significance
• 1) Methods used to date
• 2) Group versus individual differences
• 3) Single item versus multi-item
• 4) Patient, clinician, population perspectives
• 5) Changes over time
• 6) Practical considerations for specific

                               • MCP, April, May, June 2002
  The solutions found for tumor response
       cutoffs may provide guidance

• We call a reduction of 50% a response.
• Have reductions of 49% all the time, but
     do not worry about misclassification.

• Moertel (1976) basis for 50% cutoff
• Find a cutoff and stick to it?

                          The Good News
• Statistical, Philosophical, Empirical, Clinical,
     Historical, Practical approaches to defining a
     clinically significant effect for symptom
     assessments are all in the same ballpark
• A 10 point difference on a 100-point scale (1/2 SD)
     is almost always going to be clinically significant
• Smaller differences may also be meaningful (data)
• Applies to groups or individuals (just different SD)
   Norman GR, Sloan JA, Wyrwich KW. Expert Review of Pharmacoeconomics and Outcomes
                                                     Research Sept 2004; 4(5): 515 – 519

                                     Sloan JA, Cella D, Hays R. J Clin Epidemiol (in press).
              What’s next?

            A Mayo/NCCTG meeting on
 FDA guidances on patient-reported outcomes (PRO)
   Discussion, Education, and Operationalization

• FDA to release guidances for assessing PRO’s in all
     clinical trials (3rd quarter 2005?)

• Meeting co-sponsored with FDA to:
       • provide a focused process to facilitate discussion among all
       • educate stakeholders on background, content, and concerns
       • provide an opportunity for input
       • delineate ways to best operationalize the guidance into clinical
• February 23-25, 2006, DC (Westfields Marriott, Chantilly,
  VA, 7 miles from Dulles)
• Seeking stakeholders involvement
New ideas have enabled us to make advances in PRO science

              With your help, there will be more to come
                   Thank you



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