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Evaluating the safety of a rotavirus vaccine: the REST of the story.

Heyse JF, Kuter BJ, Dallas MJ, Heaton P, REST Study Te - Clin Trials (2008)

Bottom Line: The study demonstrated that the risk of intussusception was similar in vaccine and placebo recipients and that the vaccine prevented rotavirus gastroenteritis, ameliorated the severity of disease in those who had any disease, and substantially reduced rotavirus-associated hospitalizations and other health care contacts.We describe the rationale and methods used for sample size, continuous safety monitoring, group sequential design, and detailed study execution.The results of the study have been reported elsewhere.

View Article: PubMed Central - PubMed

Affiliation: Merck Research Laboratories, West Point, PA 19486, USA. joseph_heyse@merck.com

ABSTRACT
The Rotavirus Efficacy and Safety Trial (REST) was a blinded, placebo-controlled study of the live pentavalent human-bovine vaccine, RotaTeq (Merck & Co. Inc., West Point, PA). REST was noteworthy because its primary objective was to evaluate the safety of RotaTeq with regard to intussusception, a rare intestinal illness that occurs with a background incidence of approximately 50 cases per 100 000 infant years. The study involved approximately 70 000 infants at over 500 study sites in 11 countries. The study demonstrated that the risk of intussusception was similar in vaccine and placebo recipients and that the vaccine prevented rotavirus gastroenteritis, ameliorated the severity of disease in those who had any disease, and substantially reduced rotavirus-associated hospitalizations and other health care contacts. This report provides an in-depth review of the background, statistical and regulatory considerations, and execution of REST. We describe the rationale and methods used for sample size, continuous safety monitoring, group sequential design, and detailed study execution. The results of the study have been reported elsewhere. The design and conduct of this study may serve as a useful model for planning other future large-scale clinical trials, especially those evaluating uncommon adverse events.

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Statistical operating characteristics for REST study design
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Figure 3: Statistical operating characteristics for REST study design

Mentions: The REST study design had two simultaneous goals: (1) A high probability that if the vaccine was associated with an increased risk of intussusception this would be detected quickly and the study would be stopped early, and (2) A high probability that a safe vaccine would meet the end of study criteria. The statistical operating characteristics of REST were estimated using Monte Carlo simulation. Each simulation run generated 10 000 random sequences of vaccine and placebo cases. For each sequence, it was determined whether the sequence caused the study to (1) stop early according to the two safety monitoring boundaries, or (2) satisfy the primary safety criteria for stopping the study. Figure 3 shows the probability of each possible outcome for different levels of relative risk. For a vaccine with no increased risk of intussusception, there was a 0.06 probability that the study would stop early due to a safety concern, and a 0.94 probability of successfully reaching the end-of-study criterion. Figure 3 also shows the important role of the continuous safety monitoring in drawing a study conclusion. The probability of stopping the study early for safety concerns increased substantially for relative risks in the range of 2.5–6. For relative risks of 6 or greater, the study would have ended early almost with certainty. The simulation also allowed varying the relative risk profile over intervals of time through the follow-up period. This feature of the simulation was important in that it allowed modeling the risk profile reported for the RRV-TV in the CDC case-control and case series studies [7]. The same five intervals (1–2 days, 3–7 days, 8–14 days, 15–21 days, and 22–42 days) following each of the three doses were used. The probability of reaching one of the two unsafe boundaries was 0.85 for the CDC case-control profile and 0.91 for the CDC case-series profile.Figure 3


Evaluating the safety of a rotavirus vaccine: the REST of the story.

Heyse JF, Kuter BJ, Dallas MJ, Heaton P, REST Study Te - Clin Trials (2008)

Statistical operating characteristics for REST study design
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2602609&req=5

Figure 3: Statistical operating characteristics for REST study design
Mentions: The REST study design had two simultaneous goals: (1) A high probability that if the vaccine was associated with an increased risk of intussusception this would be detected quickly and the study would be stopped early, and (2) A high probability that a safe vaccine would meet the end of study criteria. The statistical operating characteristics of REST were estimated using Monte Carlo simulation. Each simulation run generated 10 000 random sequences of vaccine and placebo cases. For each sequence, it was determined whether the sequence caused the study to (1) stop early according to the two safety monitoring boundaries, or (2) satisfy the primary safety criteria for stopping the study. Figure 3 shows the probability of each possible outcome for different levels of relative risk. For a vaccine with no increased risk of intussusception, there was a 0.06 probability that the study would stop early due to a safety concern, and a 0.94 probability of successfully reaching the end-of-study criterion. Figure 3 also shows the important role of the continuous safety monitoring in drawing a study conclusion. The probability of stopping the study early for safety concerns increased substantially for relative risks in the range of 2.5–6. For relative risks of 6 or greater, the study would have ended early almost with certainty. The simulation also allowed varying the relative risk profile over intervals of time through the follow-up period. This feature of the simulation was important in that it allowed modeling the risk profile reported for the RRV-TV in the CDC case-control and case series studies [7]. The same five intervals (1–2 days, 3–7 days, 8–14 days, 15–21 days, and 22–42 days) following each of the three doses were used. The probability of reaching one of the two unsafe boundaries was 0.85 for the CDC case-control profile and 0.91 for the CDC case-series profile.Figure 3

Bottom Line: The study demonstrated that the risk of intussusception was similar in vaccine and placebo recipients and that the vaccine prevented rotavirus gastroenteritis, ameliorated the severity of disease in those who had any disease, and substantially reduced rotavirus-associated hospitalizations and other health care contacts.We describe the rationale and methods used for sample size, continuous safety monitoring, group sequential design, and detailed study execution.The results of the study have been reported elsewhere.

View Article: PubMed Central - PubMed

Affiliation: Merck Research Laboratories, West Point, PA 19486, USA. joseph_heyse@merck.com

ABSTRACT
The Rotavirus Efficacy and Safety Trial (REST) was a blinded, placebo-controlled study of the live pentavalent human-bovine vaccine, RotaTeq (Merck & Co. Inc., West Point, PA). REST was noteworthy because its primary objective was to evaluate the safety of RotaTeq with regard to intussusception, a rare intestinal illness that occurs with a background incidence of approximately 50 cases per 100 000 infant years. The study involved approximately 70 000 infants at over 500 study sites in 11 countries. The study demonstrated that the risk of intussusception was similar in vaccine and placebo recipients and that the vaccine prevented rotavirus gastroenteritis, ameliorated the severity of disease in those who had any disease, and substantially reduced rotavirus-associated hospitalizations and other health care contacts. This report provides an in-depth review of the background, statistical and regulatory considerations, and execution of REST. We describe the rationale and methods used for sample size, continuous safety monitoring, group sequential design, and detailed study execution. The results of the study have been reported elsewhere. The design and conduct of this study may serve as a useful model for planning other future large-scale clinical trials, especially those evaluating uncommon adverse events.

Show MeSH
Related in: MedlinePlus