Hypertension Clinical Trial Informed Consent - PowerPoint

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					Placebo-Controls in Short-Term
Clinical Trials of Hypertension


        Sana Al-Khatib, MD, MHS
      Assistant Professor of Medicine
          Division of Cardiology
      Duke University Medical Center
“Is it ethical to use a placebo? The answer to
this question will depend, I suggest, upon
whether there is already available an orthodox
treatment of proved or accepted value. If there
is such an orthodox treatment the question will
hardly arise, for the doctor will wish to know
whether a new treatment is more, or less,
effective than the old, not that it is more
effective than nothing”.

            Sir A. Bradford Hill, BMJ 1963
                     Outline
Historical background
    1948 - Nuremberg Code
    1964 - Declaration of Helsinki
    1979 - The Belmont Report
Placebo controls in randomized clinical trials
    Randomization and blinding
    Types of control
    Importance of placebo controls
                   Outline
Placebo Controls in Short-Term Clinical Trials of
 Mild to Moderate Hypertension
    Background
    Methods
    Results
Conclusions
          Nuremberg Code
Issued in 1948 in response to the
 experiments of Nazi doctors
Main features:
  Voluntary consent of the human subject is
   absolutely essential
  Risks can not outweigh the benefits
  Animal experimentation should precede human
   experimentation
           Nuremberg Code
“ The experiment should be so conducted as
  to avoid all unnecessary physical and
  mental suffering and injury… Proper
  preparations should be made and adequate
  facilities provided to protect the
  experimental subject against even remote
  possibilities of injury, disability or death”.
      Declaration of Helsinki

International document issued in 1964
Main features:
  Medical care is different from medical research
  Study subjects should be assured of the best
    available treatment
      Declaration of Helsinki

“ In any medical study, every patient-
   including those of a control group, if any-
   should be assured of the best proven
   diagnostic and therapeutic method”.
       The Belmont Report
Issued in 1979 by the National Commission
 for the Protection of Human Subjects of
 Biomedical and Behavioral Research
Identifies three basic ethical principles
  Respect for persons
  Beneficence
  Justice
        The Belmont Report
“ Persons are treated in an ethical manner not
  only by respecting their decisions and
  protecting them from harm, but also by
  making efforts to secure their well-
  being…(1) do not harm and (2) maximize
  possible benefits and minimize possible
  harms”.
   Randomized Clinical Trial
The most powerful experiment for assessing
 the effectiveness of an intervention
A prospective study comparing the effect of
 an intervention against a control
           Randomization
Takes care of selection bias
Baseline characteristics known or not
 known to affect the outcome are evenly
 distributed between the randomized groups
                Blinding
Protects the study from confounding by
 variables that develop during follow-up
Prevents bias during data collection and
 assessment
          Types of Control
Placebo control
No treatment control
Positive control
Historical control
      Importance of Placebo
            Controls
Placebo controls offer a clear reference
 point
They increase the likelihood of attaining
 statistical significance with a smaller
 sample size. Trials may be done:
  More quickly
  Less cost
               Equipoise
Literally means equilibrium
It is not known which treatment is better
Placebo Controls in Short-Term
   Clinical Trials of Mild to
    Moderate Hypertension
              Background
Hypertension is a common disorder
It is a risk factor for stroke, myocardial
 infarction, CHF, and premature
 cardiovascular death
1990 review of 14 randomized clinical trials
 of antihypertensive therapy showed:
  42% risk reduction of stroke
  14% risk reduction of coronary artery disease
  21% risk reduction in vascular mortality
             Background
1991- SHEP and STOP-Hypertension found
 similar benefits in elderly patients
There is strong evidence that patients with
 hypertension should be treated
               Objective
To determine whether the use of placebo
controls in short-term clinical trials of Mild
to moderate hypertension is safe and
ethically appropriate
                     Methods
Literature review (1/97 through 12/98)
  MEDLINE database
Inclusion Criteria
   Randomized clinical trial
   Objective was to assess efficacy of an agent in the
    treatment of mild to moderate hypertension
   Use of placebo
   Non-pregnant adults
   Arbitrarily pre-specified a trial duration of 20 weeks or
    less
                 Methods
Data extraction
  Duration and location of the study
  Number and type of patients enrolled
  Type of anti-hypertensive medications used
  Whether IRB approval and informed consent
   were obtained
  Number of serious adverse events
                 Methods
Serious adverse events
  Stroke
  Myocardial infarction
  Congestive heart failure
  Death due to cardiac events or stroke
              Methods
Safety data were considered adequate if the
number and nature of adverse events were
given for both the placebo and active
treatment groups
         Statistical Analysis
We used the maximum likelihood method
 to combine the estimates of risk differences
This method assumes a fixed-effects model
 and requires numerical multiplication of the
 likelihood functions
Because the event rates in the combined
 studies were so small, we repeated the
 analysis using the Bayesian method
          Identification of Studies

                       267 citations



                       80 citations



35 studies: placebo   2 studies: placebo   43 studies: placebo in
in run-in period      in maintenance       run-in period +/-
                                           maintenance +/-
                                           withdrawal
                          Results
                                     N
Done in USA                          24
IRB approval                         64
Signed informed consent              69
Adequate safety data                 25
Placebo in run-in period             35
Placebo in maintenance                2
Placebo in run-in and maintenance    39
Placebo in run-in and withdrawal      1
Placebo in run-in, maintenance and
withdrawal                           3
                           Results
Serious adverse event        Active (4878)   Placebo (1604)

Death                        2                   2

Stroke                       2                   0

Myocardial infarction        2                   3

Congestive heart failure     0                   0

Total                        6                   5
Active
                Placebo safer
therapy safer
Active therapy safer   Placebo safer
              Conclusions
Short term exposure to placebo in clinical
 trials of mild to moderate hypertension does
 not seem to be associated with an increased
 risk of serious adverse events
Several possible explanations:
  Short duration
  Patients with mild to moderate hypertension
   with few co-morbidities
   Close monitoring during the study

				
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