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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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Criteria for stopping enrollment (based on primary hypothesis)
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Figure 2: Criteria for stopping enrollment (based on primary hypothesis)

Mentions: The acceptable safety profile for stopping enrollment in accordance with the group sequential design was based on satisfying the upper bound of the 95% confidence interval estimate of relative risk being ≤10. The shaded region in Figure 2 shows case splits meeting this criterion. As previously discussed, the vaccine/placebo case splits that make up this region represent estimates of relative risk that also would be considered clinically acceptable for licensure. This region was also determined using exact binomial methods, with the impact of the interim stopping rules for negative results being considered. Because the study used interim stopping rules for negative results that were appropriately strict (and stricter than rules designed just to accept the primary hypothesis) and that covered two different day ranges (1–7 and 1–42), the group-sequential region of acceptance could not be determined using standard design techniques. Instead, the region was chosen according to that defined by the maximum number of vaccine cases v such that , corresponding to a relative risk of 10, and then evaluation of the design properties was done via simulation (described below) in order to account for the interim monitoring. The terminal P-value, point estimate, and confidence interval estimate of the relative risk were appropriately adjusted based on the group-sequential aspect of the design using the methodology described in Jennison and Turnbull [21].Figure 2


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)

Criteria for stopping enrollment (based on primary hypothesis)
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Criteria for stopping enrollment (based on primary hypothesis)
Mentions: The acceptable safety profile for stopping enrollment in accordance with the group sequential design was based on satisfying the upper bound of the 95% confidence interval estimate of relative risk being ≤10. The shaded region in Figure 2 shows case splits meeting this criterion. As previously discussed, the vaccine/placebo case splits that make up this region represent estimates of relative risk that also would be considered clinically acceptable for licensure. This region was also determined using exact binomial methods, with the impact of the interim stopping rules for negative results being considered. Because the study used interim stopping rules for negative results that were appropriately strict (and stricter than rules designed just to accept the primary hypothesis) and that covered two different day ranges (1–7 and 1–42), the group-sequential region of acceptance could not be determined using standard design techniques. Instead, the region was chosen according to that defined by the maximum number of vaccine cases v such that , corresponding to a relative risk of 10, and then evaluation of the design properties was done via simulation (described below) in order to account for the interim monitoring. The terminal P-value, point estimate, and confidence interval estimate of the relative risk were appropriately adjusted based on the group-sequential aspect of the design using the methodology described in Jennison and Turnbull [21].Figure 2

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