Clinical Trials Data Management by wulinqing

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									  Clinical Trials: Understanding
           Biostatistics
              Joseph Massaro
     Harvard Clinical Research Institute
Boston University Department of Biostatistics

                                            1
              March 21, 2008
                     Outline
•   Clinical trial definition and types of trials
•   Phases of pharmaceutical/biotech trials
•   Medical device trials
•   Major stat considerations for clinical trials




                                                    2
       Clinical Trial Definition

“…any form of planned experiment which involves
patients and is designed to elucidate the most
appropriate treatment of future patients with a given
medical condition.”
   – Pocock, from Clinical Trials: A Practical Approach
     (1984)



                                                          3
       Types of Clinical Trials
• Clinical Trials are performed in
   – Pharmaceutical Products (Synthetic “Drugs”)
   – Biotechnology Products (products made from
      human cells/tissues for example, such as
      vaccines, blood products)
   – Devices (e.g., cardiac stents, pacemakers)



                                                   4
Phases of Pharmaceutical/Biotechnology
            Clinical Trials
•   Pre-Clinical (in vivo, in vitro)
•   Investigational New Drug (IND) Application
•   Phase I - First time in humans
•   Phase II - Exploratory
     – Phase IIb
     – Phase II/III
• Phase III - Confirmatory
• New Drug Application (NDA)/Product License
  Application (PLA)
                                                 5
• Phase IV - Post Marketing
Phases of Pharmaceutical/Biotechnology
            Clinical Trials
•FDA Center for Drug
  Evaluation and Research Handbook at
  http://www.fda.gov/cder/handbook/index.htm;
        click on (a) “New Drug Development and Review” 
                     “IND Review Process”
        click on (b) “New Drug Development and Review” 
                     “New Drug Development Process”
• FDA Center for Drug Evaluation and Research
  general web site at http://www.fda.gov/cder
• FDA Center for Biologics Evaluation and Research
  general web site at http://www.fda.gov/cber

                                                       6
    Phase I Pharm/Biotech Trials
• First time in humans
• Objectives
   – Assess pharmacology/pharmacokinetics
        • How drug flows through body
        • How drug is excreted and how long (half-life)
   – Assess toxicology (safety)
        • Adverse events, Labs, EKGs, Vital Signs, Physical
          Exams
        • Determine maximum tolderated dose (MTD)
   – Performed usually in 15-20 subjects
   – No interest in efficacy
   – Descriptive Analysis
                                                              7
    Phase II Pharm/Biotech Trials
• Performed in usually 50-200 patients
  – Sample often based on time, cost considerations
• Concentrate on safety, but also look at
  efficacy
• Often exploratory in terms of efficacy
  – Find parameters on which product is efficacious?
  – Find magnitude of the product’s effect on these
    parameters?
• Contains control group (placebo/active)              8
    Phase II Pharm/Biotech Trials
• Multiple doses
• Find dose with best safety profile and best
  efficacy profile (not always the highest dose)
• Use results to design confirmatory Phase III
  trials
  – Not necessarily required to obtain statistical
    significance (“p<0.05”) in Phase II in order to
    move to Phase III
                                                      9
    Phase III Pharm/Biotech Trials
• Objective
  – Confirm efficacy of new drug seen in Phase II
  – Determine safety of new drug (especially for
    uncommon “adverse events”).
• Often called “Pivotal” trials




                                                    10
  Phase III Pharm/Biotech Trials
• Often performed in 2 treatment groups
  – Study drug vs. Control
     • Control may be Active or Placebo
     • Some suggest both Active and Placebo control
     • If Active-controlled, not necessary to show superiority,
       but “non-inferiority” or “equivalence”
     • FDA has no official rules about control group




                                                            11
   Phase III Pharm/Biotech Trials
• Sample size based heavily on statistics
  – If treatment works in population, we want a
    sample large enough to represent population
  – I.e., Want a high probability treatment works in
    sample
• FDA usually requires 2 phase III studies, with
  p<0.05 for efficacy (if superiority trial)
• For “large simple trials” (e.g., CV) only one
  large study may suffice (with, say, p<0.01 or
  p<0.001).                                     12
 Phase II/III Pharm/Biotech Trials
• Phase IIb, Phase II/III Trials

  – Exploratory, but less so than Phase II
  – State a specific analysis; if successful, consider
    study as one of the Phase IIIs (“pivotal”)
  – If not successful, then consider as exploratory
    analysis for planning Phase III



                                                         13
    New Drug Application (NDA)
• “The data gathered during the animal studies and
  human clinical trials of an Investigational New Drug
  (IND) become part of the NDA.” (From FDA Center
  for Drug Evaluation and Research Handbook at
  http://www.fda.gov/cder/handbook/index.htm; click on
  “New Drug Development and Review”, “New Drug
  Application (NDA) Review Process”)

• Biologic equivalent is PLA (Product License
  Application)
                                                   14
 Clinical Trials in Medical Devices
• For further information, see FDA Center for
  Devices and Radiological Health (CDRH) web
  site at http://www.fda.gov/cdrh/index.html.




                                           15
      International Conference on
             Harmonisation
• The “International Conference on Harmonisation”
  (ICH), as quoted at at http://www.ich.org,
  – “is a unique project that brings together the regulatory
    authorities of Europe, Japan and the United States and
    experts from the pharmaceutical industry…”

  – “The purpose is to make recommendations on ways to
    achieve greater harmonisation in the interpretation and
    application of technical guidelines and requirements for
    product registration in order to reduce…”
                                                               16
 Statistical Issues in Clinical Trials
• Efficacy variables
  – Phase III (Confirmatory)
     • 1-2 Primary efficacy variable; e.g. Respiratory Distress
       Syndrome (RDS) in premature infants has 2 primary
       endpoints
        – RDS 24 hours after birth
        – 28-day survival
     • Show Rx effect in both endpoints (alpha=0.05 for each)
     • Show Rx effect in at least 1 endpoint (alpha=0.025 for
       each).

                                                              17
 Statistical Issues in Clinical Trials
• Efficacy variables

  – Phase III (Confirmatory)
     • Usually several secondary endpoints
        – In RDS trial: Fi02, Mean Airway Pressure, All-cause mortality,
          Incidence of Bronchopulmonary Dysplasia


     • How you “split the alpha” depends on objective of
       secondary endpoints (e.g. for label? just exploratory?)


                                                                    18
 Statistical Issues in Clinical Trials
• Blindness
  – Double-blind – neither investigator nor patient know
    treatment patient is receiving
     • Ideal situation
     • Removes potential bias
     • Still sometimes easy to ascertain the treatment patient is
       receiving (e.g., ALS study, lipid lowering study)




                                                               19
 Statistical Issues in Clinical Trials
• Blindness
  – Single-blind – investigator knows treatment patient
    is receiving
  – Open-label – patient and investigator know the
    treatment patient is receiving
     • Such trials occur in cases when comparing, say,
       chemotherapy with surgery
     • Have a blinded evaluation of patient outcome (someone
       not involved in treatment administration nor care of the
       patient).
                                                             20
 Statistical Issues in Clinical Trials
• Single-center or multi-center
  – Choice often depends on logistical issues
     • Can you obtain enough subjects in a single-center?
     • If so, can you obtain enough in an allotted amount of time
  – Is a single center representative of the population as
    a whole?




                                                             21
     Treatment-by-Center Interaction
• (Snapinn, 1998)
   – Why multiple centers?
      • Increase enrollment
      • Increase generalizability of results to population

   – Potential issue with multiple centers
      • Center demographics/center study conduct may affect
        treatment performance
      • Treatment-by-center (or treatment-by-clinic) interaction:
        A treatment difference that varies significantly across
        study centers
      • FDA would like assurance such an interaction does not
        exist so patients across centers can be pooled into one
        group for analysis
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    • Interpreting Interaction – The classical approach
      (Snapinn, 1998):
           Means by treatment group and center under various scenarios
                No interaction                                                  Quantitative Interaction
4
                                                                 4

3
                                                                 3

2
                                                                 2

1
                                                                 1

0
                                                                 0
     Clinic 1        Clinic 2        Clinic 3
                                                                          Clinic 1        Clinic 2         Clinic 3
                                                Qualitative Interaction

                          4

                          3
                                                                                        Treat 1
                          2
                                                                                        Treat 2
                          1

                          0
                                 Clinic 1          Clinic 2          Clinic 3
                                                        23

								
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