REST utilized a unique study design. Since it was necessary to both detect an elevated risk of intussusception at an early stage and to demonstrate that the safety profile of the vaccine was acceptable for licensure, a novel study design was necessary. Specifically, a continuous monitoring boundary was used in conjunction with a group-sequential design. The monitoring boundary was designed to detect an elevated risk in intussusception during biologically and clinically important timeframes while the group sequential design, with its large sample size and possibility of expanding enrollment to accrue more cases of intussusception, allowed for the demonstration of safety at the end of the study. Both the monitoring boundary and the group sequential design were critical to the demonstration of an acceptable product safety profile to support licensure and acceptance in the medical community.
Group-sequential designs had not been routinely used in clinical trials of new drugs or vaccines at the time REST was designed. This type of design has its pros and cons. The advantage of using this design is that it has the potential to draw a conclusion based on a more efficient sample size. The initial sample size for REST was 60
000 subjects, but an additional 10
000 subjects had to be enrolled because the criteria for stopping enrollment according to the primary endpoint was not met based on 60
000 subjects. Had this study been conducted using a classical fixed subject statistical design, the sample size would have been ~85
The disadvantage of the group sequential design is that the actual duration of the study and the study budget cannot be predetermined, resulting in the need to work within a range of study completion dates and a range of possible study costs. Uncertainty regarding the timing of study results, let alone the results themselves, can have a major impact on key decisions in moving a product forward, particularly with respect to investing in new manufacturing facilities and the need to develop backup compounds.
The detailed analysis of the association between intussusception and RRV-TV conducted prior to the start of this study necessitated the successful design of REST. Based on the previous experience with RRV-TV, we designed a study of PRV in which the age and timing at which intussusception occurred with RRV-TV was covered. Had the prelicensure studies of RRV-TV been conducted using a similar design, it is likely (≥85%) the studies of RRV-TV would have been stopped due to a safety concern, based on the safety boundaries, as was shown by the simulation results.
The success of this study was possible not only because of its large sample size but also because of the excruciating attention to detail employed in the study's execution. Extensive systems were utilized to track each subject in the trial. The success of these systems was shown by the remarkably low rate of subjects lost to follow-up (<0.1%). A low loss to follow-up rate is particularly important when trying to evaluate an uncommon serious adverse event such as intussusception. Furthermore, the reporting of potential cases of intussusception was handled in a conservative manner so that it was highly unlikely that a case could be missed. These methods, in conjunction with the routine involvement of the SEAC and DSMB in the evaluation of every possible case of intussusception, resulted in a very complete safety monitoring system.
A basic question in evaluating any new drug or vaccine is how much safety data are enough. REST was one of the largest prelicensure studies ever conducted for a vaccine. The prelicensure safety of most new vaccines is based on a sample size of ~5
000 subjects. The fact that this study was designed to address a specific concern over the relationship of PRV and intussusception and that no relationship was identified when comparing ~35
000 vaccine recipients to ~35
000 placebo recipients provides substantial reassurance to health care professionals, parents, and regulatory agencies of the safety of this vaccine. Nevertheless, postlicensure safety studies of PRV were still requested by regulatory agencies to gather additional information on the safety of the vaccine due to possible differences in the characteristics of infants who receive the vaccine in routine use compared with infants in clinical trials. Two controlled studies are now ongoing with this vaccine, one in a health maintenance organization conducted by the manufacturer involving approximately 44
000 subjects and one using the Vaccine Safety Datalink (VSD) cosponsored by FDA and CDC involving approximately 90
000 subjects. Both studies use a continuous monitoring of intussusception cases as they accrue with a pre-established safety boundary to alert investigators of any increased risk. In total, the safety data from pre- and postlicensure controlled studies will include over 169
000 recipients of PRV, a remarkably large number. The data obtained to date from the postlicensure studies confirm the excellent safety profile of the vaccine and lack of association with intussusception demonstrated in the prelicensure studies.