Continuous versus group sequential analysis for post-market drug and vaccine safety surveillance.
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ABSTRACT:
SUBMITTER: Silva IR
PROVIDER: S-EPMC4888780 | biostudies-literature | 2015 Sep
REPOSITORIES: biostudies-literature
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Project description:Statistical sequential hypothesis testing is meant to analyze cumulative data accruing in time. The methods can be divided in two types, group and continuous sequential approaches, and a question that arises is if one approach suppresses the other in some sense. For Poisson stochastic processes, we prove that continuous sequential analysis is uniformly better than group sequential under a comprehensive class of statistical performance measures. Hence, optimal solutions are in the class of continuous designs. This paper also offers a pioneer study that compares classical Type I error spending functions in terms of expected number of events to signal. This was done for a number of tuning parameters scenarios. The results indicate that a log-exp shape for the Type I error spending function is the best choice in most of the evaluated scenarios.
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Project description:Type I error probability spending functions are commonly used for designing sequential analysis of binomial data in clinical trials, but it is also quickly emerging for near-continuous sequential analysis of post-market drug and vaccine safety surveillance. It is well known that, for clinical trials, when the null hypothesis is not rejected, it is still important to minimize the sample size. Unlike in post-market drug and vaccine safety surveillance, that is not important. In post-market safety surveillance, specially when the surveillance involves identification of potential signals, the meaningful statistical performance measure to be minimized is the expected sample size when the null hypothesis is rejected. The present paper shows that, instead of the convex Type I error spending shape conventionally used in clinical trials, a concave shape is more indicated for post-market drug and vaccine safety surveillance. This is shown for both, continuous and group sequential analysis.
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Project description:Highlights • Active post-marketing safety surveillance on ROTASIIL, an oral rotavirus vaccine, was conducted in 9940 infants in India.• Three doses of ROTASIIL were administered at 6, 10 and 14 weeks of age, along with other EPI vaccines.• Most of the AEs were pyrexia and injection site reactions caused by the concomitant injectable vaccines.• No case of intussusception (IS) was reported.• ROTASIIL was safe and well tolerated. Background ROTASIIL, an oral live attenuated bovine-human reassortant pentavalent rotavirus vaccine, was approved in 2017. This post-marketing surveillance (PMS) was conducted to collect real-world data on the safety of ROTASIIL in India. Methods Observational, active PMS was conducted in approximately 10,000 infants aged ≥ 6 weeks. ROTASIIL was administered as a 3-dose regimen, at least 4 weeks apart, beginning at ≥ 6 weeks of age concomitantly with other Expanded Programme on Immunization (EPI) vaccines. Participants were followed for one month after the last dose. The adverse events (AEs) and serious adverse events (SAEs), including intussusception (IS) reported during the follow up period were collected. Findings A total of 9940 infants were enrolled and were considered for safety analysis. Around 9913 (99.7 %) infants received 2 doses, while 9893 (99.5 %) infants completed all three doses. Total 3693 AEs were reported in 2516 (25.3 %) participants. Most of these AEs were pyrexia (78.01 % of events) and injection-site reactions (19.14 % of events). Nearly all AEs were causally unrelated to orally administered ROTASIIL and could be caused by the concomitant injectable vaccines. Only 4 AEs (2 events of vomiting and 1 event each of discomfort and pyrexia) in 4 (<0.1 %) participants could be related to ROTASIIL. AEs were of mild or moderate severity and all resolved without any sequelae. A total of 2 SAEs (acute otitis media and skull fracture) were reported in 2 (<0.1 %) participants and were not related to ROTASIIL and recovered without sequelae. No case of IS was reported. Interpretation ROTASIIL was safe and well tolerated in this study. No safety concerns were reported. Funding The study was funded by SIIPL which is the manufacturer of the study product.
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Project description:A diligent, systematic, regular review of aggregate safety data is essential, particularly early after vaccine introduction, as this is when safety signals not identified during clinical development may emerge. In October 2017, the US Centers for Disease Control and Prevention Advisory Committee on Immunization Practices recommended the adjuvanted recombinant zoster vaccine (RZV; Shingrix, GSK) as the preferred vaccine for preventing herpes zoster (HZ) and related complications in immunocompetent adults aged ≥ 50 years. Subsequently, GSK experienced an unprecedented high demand for RZV. In this methodology paper, we summarize the enhanced measures undertaken to assess RZV safety during its early post-marketing experience in the USA, Canada and Germany. In addition to the routine signal-detection methods already in place for all vaccines, GSK established tailored and enhanced safety monitoring for RZV based on aggregate data of spontaneous reports and manufacturing data. Proactive, near real-time detection and evaluation of signals was a key objective. A dedicated in-house signal-detection tool customized for RZV was employed on a weekly (rather than the routine monthly) basis, allowing for a centralized, more frequent review of data on a single web-based platform. We also identified the background incidence rates of preselected medical events of interest in the first countries to introduce RZV (USA, Canada and Germany) to perform observed-to-expected analyses. This approach may offer a solution to the challenges associated with the assessment and monitoring of vaccine safety in an efficient and timely manner in the context of high vaccine uptake.
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Project description:BackgroundAdverse drug reaction (ADR) is a major burden for patients and healthcare industry. Early and accurate detection of potential ADRs can help to improve drug safety and reduce financial costs. Post-market spontaneous reports of ADRs remain a cornerstone of pharmacovigilance and a series of drug safety signal detection methods play an important role in providing drug safety insights. However, existing methods require sufficient case reports to generate signals, limiting their usages for newly approved drugs with few (or even no) reports.MethodsIn this study, we propose a label propagation framework to enhance drug safety signals by combining drug chemical structures with FDA Adverse Event Reporting System (FAERS). First, we compute original drug safety signals via common signal detection algorithms. Then, we construct a drug similarity network based on chemical structures. Finally, we generate enhanced drug safety signals by propagating original signals on the drug similarity network. Our proposed framework enriches post-market safety reports with pre-clinical drug similarity network, effectively alleviating issues of insufficient cases for newly approved drugs.ResultsWe apply the label propagation framework to four popular signal detection algorithms (PRR, ROR, MGPS, BCPNN) and find that our proposed framework generates more accurate drug safety signals than the corresponding baselines. In addition, our framework identifies potential ADRs for newly approved drugs, thus paving the way for early detection of ADRs.ConclusionsThe proposed label propagation framework combines pre-clinical drug structures with post-market safety reports, generates enhanced drug safety signals, and can potentially help to accurately detect ADRs ahead of time.AvailabilityThe source code for this paper is available at: https://github.com/ruoqi-liu/LP-SDA.
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Project description:Information on rare adverse effects is often limited when a medication is initially approved for marketing. Medicines regulators use safety advisories to warn health professionals and consumers about emerging harms. This study aimed to identify characteristics and advice provided in cardiac safety advisories released by regulators in Australia, Canada, the United Kingdom, and the United States. This was a retrospective study of safety advisories about cardiac-related adverse events issued by these four international medicines regulators between 2010 and 2016. A descriptive overview was followed by a more detailed content analysis, focusing on recommended actions for health professionals, including monitoring advice. For the latter, we applied the systematic information for monitoring (SIM) scale to assess adequacy. Over this period, 164 safety advisories about cardiac harms were issued by the four regulators. There were 61 drugs with advisories of cardiac risk, only 9 (14.7%) of which had advisories from all regulators in countries where the drug was approved. The most common adverse events were cardiac arrhythmias (n = 97, 59.1%) and coronary artery disorders (n = 39, 23.8%). The most frequent advice to prescribers was to monitor patients (n = 74, 45.1%), although only 41.2% of these advisories provided detailed advice on how monitoring should occur. We found many differences in the decision to warn and the advice provided. Patient monitoring was most often recommended, but key information such as frequency or thresholds for action was often lacking. Healthcare professionals and consumers need consistent information about rare serious harms so that they can make informed decisions.
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Project description:Postoperative safety outcomes with laparoscopic intra-abdominal ultrasound-guided radiofrequency ablation, as performed by gynecologic surgeons new to the procedure, were evaluated and compared to the premarket, pivotal study. Post-procedure feedback from surgeons was reported. This was a post-market, prospective, single-arm analysis with 4 to 8 weeks follow-up among surgeons (n = 29) with varying levels of laparoscopic surgery experience participating in the ongoing, multinational Treatment Results of Uterine Sparing Technologies randomized clinical trial. Patients were premenopausal adult women (n = 110) desiring uterine-conserving treatment for symptomatic fibroids. During run-in, surgeons received proctored training. Following training, and after performing ≥ 2 procedures, surgeons provided self-assessment and feedback using a standardized form. Surgeons performed 105 procedures with 100 per-protocol patients. The average number of proctored cases per surgeon was 2.48. No acute (≤ 48 hours) serious adverse events occurred (0/101, 0.0%) compared with 2 acute serious adverse events in the premarket study (2/137, 1.46%). Both studies reported 1 near-term (∼30 days) serious adverse event (< 1% for both). In this study, the near-term complication was fever of unknown origin requiring hospitalization related to uterine entry/manipulation. This was categorized as probably device-related; the patient was treated with antibiotics and discharged. Twenty-six surgeons completed the evaluation form; none reported experiencing problems with the procedure. Minimally invasive gynecologic surgeons can learn laparoscopic intraabdominal ultrasound-guided radiofrequency ablation and perform it safely (in terms of acute and near-term serious adverse events) after ≥ 2 proctored cases. There were no significant differences in safety outcomes compared to the premarket, pivotal study.
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Project description:BACKGROUND AND OBJECTIVES:Although both licensed rotavirus vaccines are safe and effective, it is often not possible to complete the schedule by using the same vaccine formulation. The goal of this study was to investigate the noninferiority of the immune responses to the 2 licensed rotavirus vaccines when administered as a mixed schedule compared with administering a single vaccine formulation alone. METHODS:Randomized, multicenter, open-label study. Healthy infants (6-14 weeks of age) were randomized to receive rotavirus vaccines in 1 of 5 different schedules (2 using a single vaccine for all doses, and 3 using mixed schedules). The group receiving only the monovalent rotavirus vaccine received 2 doses of vaccine and the other 4 groups received 3 doses of vaccine. Serum for immunogenicity testing was obtained 1 month after the last vaccine dose and the proportion of seropositive children (rotavirus immunoglobulin A ?20 U/mL) were compared in all the vaccine groups. RESULTS:Between March 2011 and September 2013, 1393 children were enrolled and randomized. Immune responses to all the sequential mixed vaccine schedules were shown to be noninferior when compared with the 2 single vaccine reference groups. The proportion of children seropositive to at least 1 vaccine antigen at 1 month after vaccination ranged from 77% to 96%, and was not significantly different among all the study groups. All schedules were well tolerated. CONCLUSIONS:Mixed schedules are safe and induced comparable immune responses when compared with the licensed rotavirus vaccines given alone.
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