1954 Salk polio vaccine trials

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1954 Salk polio vaccine trials

• Biggest public health experiment ever
• Polio epidemics hit U.S. in 20th century
• Struck hardest at children
• Responsible for 6 of deaths among 5-9 year olds

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Salk vaccine field trial

• Polio is rare but virus itself is common
• Most adults experienced polio infection without
  being aware of it.
• Children from higher-income families more
  vulnerable to polio!
• Children in less hygienic surroundings contract
  mild polio early in childhood while still
  protected from mothers antibodies. Develop
  immunity early.
• Children from more hygienic surroundings dont
  develop such antibodies.

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Salk vaccine field trial

• By 1954, Salk vaccine was promising
• Public Health Service and National Foundation for
  Infantile Paralysis (NFIP) ready to try the
  vaccine in population
• Vaccine could not be distributed without testing
• A yearly drop might mean the drug was effective,
  or that that year was not an epidemic year.
• Needed controls -- some children would get
  vaccine, some would not
• Raises question of medical ethics

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Salk vaccine trial

• Polio rate of occurrence is about 50 per 100,000
• Clinical trials needed on massive scale
• Suppose vaccine was 50 effective and 10,000
  subjects each in control and treatment groups
• Would expect 5 polio cases in control group and
  2-3 in treatment group
• Difference could be attributed to random
  variation
• Clinical trials needed on massive scale
• Ultimate experiment involved over 1 million

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How to design the experiment

• Treatment and control groups should be as similar
  as possible
• Taking volunteers would bias the experiment
• Fact volunteers tend to be better educated and
  more well-to-do than those who dont participate
• Relying on volunteers biases the results because
  subjects are not representative of the population
• Two proposals for clinical trials

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NFIP study Observed Control approach

• Offer vaccination to 2nd graders
• Use 1st and 3rd graders as control group
• Three grades drawn from same geographical
  location
• Advantage Not much variability between grades
• But there were objections

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NFIP Observed Control study

• In making diagnosis physicians would naturally
  ask whether child was vaccinated
• Many forms of polio hard to diagnose
• Borderline cases could be affected by knowledge
  of whether child was vaccinated
• Volunteers would result in more children from
  higher income families in treatment group
• Treatment group is more vulnerable to disease
  than control group
• Biases the experiment against the vaccine

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Randomized control approach

• Subjects randomly assigned to treatment and
  control groups
• Control group given placebo
• Placebo material prepared to
• look exactly like vaccine
• Each vial identified only by
• code number so no one involved
• in vaccination or diagnostic evaluation
• could know who got vaccine
• Experiment was double-blind, neither subjects nor
  those doing the evaluation knew which treatment
  any subject received

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Results of vaccine trials
The randomized, controlled experiment
Size Rate (per 100,000)
Treatment 200,000 28
Control 200,000 71
No consent 350,000 46
The NFIP/Observed Control study
Size Rate (per 100,000)
Grade 2 (vaccine) 225,000 25
Grade 1, 3 (control) 725,000 54
Grade 2 (no consent) 125,000 44
Source Thomas Francis, J r., An evaluation of
the 1954 Poliomyelitis vaccine trials---summary
report, American Journal of Public Health vol
45 (1955) pp. 1-63.
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Are the results significant?

• Results show NFIP study biased against vaccine
• Confounding between the effect of the vaccine and
  socio-economic status
• Chance enters the study in a haphazard way what
  families will volunteer, which children are in
  grade 2, etc.
• For randomized controlled experiment chance
  enters the study in a planned and simple way
  each child has 50-50 chance to be in treatment or
  control
• Allows for use of probability to determine if the
  results are significant

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Are the results significant?

• Two competing positions
• 1 The vaccine is effective.
• 2 The vaccine has no effect. The difference
  between the two groups is due to chance.
• Suppose vaccine has no effect. What are the
  chances of seeing such a large difference in the
  two groups?
• We wont do the calculations. But they are a
  billion to one against!
• The outcome is statistically significant because
  the effect is so large that it would rarely occur
  by chance