1954 Salk polio vaccine trials ► Biggest public health experiment ever ► Polio epidemics hit U.S. in 20 th century ► Struck hardest at children ► Responsible for 6% of deaths among 5-9 year olds

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 mother’s antibodies. Develop immunity early. ► Children from more hygienic surroundings don’t develop such antibodies.

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

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

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 don’t participate ► Relying on volunteers biases the results because subjects are not representative of the population ► Two proposals for clinical trials

NFIP study: “Observed Control” approach ► Offer vaccination to 2 nd graders ► Use 1 st and 3 rd graders as control group ► Three grades drawn from same geographical location ► Advantage: Not much variability between grades ► But there were objections

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

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

Results of vaccine trials The randomized, controlled experiment Size Rate (per 100,000) Treatment200,00028 Control200,00071 No consent 350,00046 The NFIP/Observed Control studySize Rate (per 100,000) Grade 2 (vaccine) 225,00025 Grade 1, 3 (control) 725,00054 Grade 2 (no consent) 125,00044 Source: Thomas Francis, J r., “An evaluation of the 1954 Poliomyelitis vaccine trials---summary report,” American Journal of Public Health vol 45 (1955) pp

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 chance to be in treatment or control ► Allows for use of probability to determine if the results are significant

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 won’t 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