Saturday, November 3, 2007

Post-exposure prophylaxis for Hepatitis A: Temptation seizes even the most well-intentioned authors

Victor et al report in the October 25th NEJM ( the non-inferiority of Hepatitis A vaccine to Immune Globulin for post-exposure prophylaxis of hepatitis A. The results are convincing for the non-inferiority hypothesis: symptomatic hepatitis A occurred in 4.4% of subjects who received vaccine versos 3.3% of subjects who received immune globulin (RR 1.35%; 95% CI .70-2.67).

This is a very well-executed non-inferiority study. If one looks at the methods section, s/he sees that the authors described very well their non-inferiority hypothesis and how it was arrived at. Given the low baseline rate of symptomatic hepatitis A (~3%), a RR of 3.0 is reasonable for non-inferiority, as non-inferiority implies<2%> non-significant trend toward less symptomatic Hepatitis A in the immune globlin group, the authors suggest that this agent may be preferred.

Again, one cannot have his cake and eat it too. One either conducts a non-inferiority trial and accepts non-inferior results as meaning that one agent is non-inferior to the alternative agent, or one conducts a superiority trial to demonstrate that one agent is truly superior. If the point estimates in this trial are close to correct, and immune globulin is 1.1% superior to HAV vaccine, ~7300 patients would be required in EACH group to determine superiority at a power of 90% and an alpha of 0.05. So the current trial is no substitute for a superiority trial with~7300 patients in each group. Unless such a trial is performed, HAV vaccine and immune globulin are non-inferior to each other for post-exposure prophylaxis to HAV, period.

To sum up: one either believes that two agents are non-inferior (or more conservatively, equivalent) and he therefore conducts a non-inferiority trial and accepts the results based on the a priori margins (delta) that he himself specified - or he conducts a superiority trial to demonstrate unequivocally that his preferred agent is superior to the comparator agent.

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