an impractically long study commitment, likely much longer than 10 years. Compliance with this study protocol may prove difficult for parents over this length of time.

Clinical trials commonly mask participants and evaluators to the identity of the randomized treatments to prevent bias in the evaluation of treatment effects. In an RCT comparing the recommended schedule with an alternative schedule, masking of subjects would involve administration of placebo injections at the recommended vaccination times (for the alternative arm) and at the alternative times (for the recommended arm). Such a scheme would be cumbersome and difficult to implement, potentially causing errors in treatment administration and discouraging good compliance. It would also be unacceptable to parents, who would object to their children being repeatedly injected.

One key limitation of RCTs, which was discussed in Chapter 2 in the context of RCTs already performed to evaluate vaccine safety, is that they generally require large sample sizes to have adequate power. The power critically depends on the incidence rate of the adverse outcome in question. For example, a 90 percent power to detect a halving of the rate of an adverse event that occurs in 8 percent of children would require a relatively small sample size, likely no more than 2,000 participants. With disorders that are less common, for example, those that occur in only 1 percent of a population, one would need about 15,000 subjects to achieve a 90 percent power of detection. For events that occur very rarely, for example, in 0.25 percent of children, a trial would need upward of 50,000 participants to have the same level of power. Given the weak biological justification for the association of the immunization schedule with any adverse outcome, an RCT would have to include tens or hundreds of thousands of participants to be powered to look for a range of outcomes simultaneously, including those that are very rare (see Appendix D).

Only if observational studies suggest specific hypotheses to address could researchers use smaller sample sizes in follow-on RCTs. Given the large number of participants that would be required, the cost of such trials would also be prohibitive. Tens of millions of dollars would likely be required to adequately study the identified hypotheses. A federal investment in an RCT of the immunization schedule would therefore be infeasible, and unless further epidemiological evidence of safety problems from observational studies reveals a safety problem, such an investment could be considered wasteful.

Overall, the committee recognizes the value of the RCT in providing definitive data on the potential effects of the immunization schedule on adverse outcomes and asserts that the RCT should have a role in the overall research program on the safety of the schedule. Even though RCTs on individual and combination vaccines are part of the federal research



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