scholarly journals Two-stage Bayesian hierarchical modeling for blinded and unblinded safety monitoring in randomized clinical trials

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Junhao Liu ◽  
Jo Wick ◽  
Renee’ H. Martin ◽  
Caitlyn Meinzer ◽  
Dooti Roy ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Drug Safety ◽  
Safety Data ◽  
Safety Monitoring ◽  
Safety Signal ◽  
Two Stage ◽  
Bayesian Hierarchical ◽  
Potential Safety ◽  
Stage 1

Abstract Background Monitoring and reporting of drug safety during a clinical trial is essential to its success. More recent attention to drug safety has encouraged statistical methods development for monitoring and detecting potential safety signals. This paper investigates the potential impact of the process of the blinded investigator identifying a potential safety signal, which should be further investigated by the Data and Safety Monitoring Board with an unblinded safety data analysis. Methods In this paper, two-stage Bayesian hierarchical models are proposed for safety signal detection following a pre-specified set of interim analyses that are applied to efficacy. At stage 1, a hierarchical blinded model uses blinded safety data to detect a potential safety signal and at stage 2, a hierarchical logistic model is applied to confirm the signal with unblinded safety data. Results Any interim safety monitoring analysis is usually scheduled via negotiation between the trial sponsor and the Data and Safety Monitoring Board. The proposed safety monitoring process starts once 53 subjects have been enrolled into an eight-arm phase II clinical trial for the first interim analysis. Operating characteristics describing the performance of this proposed workflow are investigated using simulations based on the different scenarios. Conclusions The two-stage Bayesian safety procedure in this paper provides a statistical view to monitor safety during the clinical trials. The proposed two-stage monitoring model has an excellent accuracy of detecting and flagging a potential safety signal at stage 1, and with the most important feature that further action at stage 2 could confirm the safety issue.

scholarly journals Correction to: Two-stage Bayesian hierarchical modeling for blinded and unblinded safety monitoring in randomized clinical trials

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Junhao Liu ◽  
Jo Wick ◽  
Renee’ H. Martin ◽  
Caitlyn Meinzer ◽  
Dooti Roy ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Hierarchical Modeling ◽  
Safety Monitoring ◽  
Bayesian Hierarchical Modeling ◽  
Two Stage ◽  
Bayesian Hierarchical

An amendment to this paper has been published and can be accessed via the original article.

scholarly journals Tuberculosis and viral hepatitis in patients treated with certolizumab pegol in Asia-Pacific countries and worldwide: real-world and clinical trial data

2020 ◽  
Author(s):  
Chak Sing Lau ◽  
Yi-Hsing Chen ◽  
Keith Lim ◽  
Marc de Longueville ◽  
Catherine Arendt ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Viral Hepatitis ◽  
Central Europe ◽  
Real World ◽  
Certolizumab Pegol ◽  
Safety Data ◽  
Asia Pacific ◽  
Hbv Reactivation ◽  
Post Marketing

Abstract Introduction/objectives To evaluate the incidence rate (IR) of tuberculosis (TB) and viral hepatitis B and C (HBV/HCV) during certolizumab pegol (CZP) treatment, worldwide and in Asia-Pacific countries, across clinical trials and post-marketing reports (non-interventional studies and real-world practice). Method CZP safety data were pooled across 49 clinical trials from 1998 to June 2017. Post-marketing reports were from initial commercialization until March 2015 (TB)/February 2017 (HBV/HCV). All suspected TB and HBV/HCV cases underwent centralized retrospective review by external experts. Incidence rates (IRs) were calculated per 100 patient-years (PY) of CZP exposure. Results Among 11,317 clinical trial patients (21,695 PY), 62 TB cases were confirmed (IR 0.29/100 PY) including 2 in Japan (0.10/100 PY) and 3 in other Asia-Pacific countries (0.58/100 PY). From > 238,000 PY estimated post-marketing CZP exposure, there were 31 confirmed TB cases (0.01/100 PY): 5 in Japan (0.05/100 PY), 1 in other Asia-Pacific countries (0.03/100 PY). Reported regional TB IRs were highest in eastern Europe (0.17/100 PY), central Europe (0.09/100 PY), and Mexico (0.16/100 PY). Across clinical trials, there was 1 confirmed HBV reactivation and no HCV cases. From > 420,000 PY estimated post-marketing CZP exposure, 5 HBV/HCV cases were confirmed (0.001/100 PY): 2 HCV reactivations; 1 new HCV; plus 2 HBV reactivations in Japan (0.008/100 PY). Conclusions CZP TB risk is aligned with nationwide TB rates, being slightly higher in Asia-Pacific countries excluding Japan. Overall, TB and HBV/HCV risk with CZP treatment is currently relatively low, as risk can be minimized with patient/physician education, screening, and vigilant treatment, according to international guidelines. Key Points:• TB rates were highest in eastern/central Europe, Mexico, and Asia-Pacific regions.• With the implementation of stricter TB screening and risk evaluations in 2007, especially in high TB incidence countries, there was a notable reduction TB occurrence.• Safety profile of biologics in real-world settings complements controlled studies.• TB and hepatitis (HBV/HCV) risk with certolizumab pegol (CZP) treatment is low.

Efficacy and Safety of Apremilast Monotherapy for Moderate to Severe Psoriasis: Retrospective Study

2018 ◽  
Vol 22 (3) ◽  
pp. 290-296 ◽  
Author(s):  
Arvin Ighani ◽  
Jorge R. Georgakopoulos ◽  
Linda L. Zhou ◽  
Scott Walsh ◽  
Neil Shear ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Real World ◽  
Plaque Psoriasis ◽  
Safety Data ◽  
Retrospective Chart Review ◽  
Oral Drug ◽  
Efficacy And Safety ◽  
Full Spectrum ◽  
Severe Plaque Psoriasis

Background: Apremilast is a new oral drug for the treatment of moderate to severe plaque psoriasis that reduces inflammation by inhibiting phosphodiesterase 4. Its efficacy and safety data are limited; hence, real-world outcomes are important for elucidating the full spectrum of its adverse events (AEs) and expanding generalizability of clinical trial findings. Objective: Assess the efficacy and safety of apremilast monotherapy in real-world practice. Methods: A retrospective chart review was conducted in 2 academic dermatology practices. Efficacy was measured as the proportion of patients achieving a ≥75% reduction from baseline Psoriasis Area and Severity Index score (PASI-75) or a Psoriasis Global Assessment (PGA) score of 0 (clear) or 1 (almost clear) at 16 weeks. Safety was measured as the proportion of patients reporting ≥1 AE at 16 weeks. Results: Thirty-four patients were included. Efficacy: 19 patients (55.9%) achieved PASI-75 or PGA 0/1. Safety: 23 patients (67.6%) experienced ≥1 AEs. Five patients (14.7%) withdrew treatment prior to week 16 due to AEs. One patient withdrew treatment due to mood lability and depression. Common AEs included headache (32.4%), nausea (20.6%), diarrhoea (14.7%), weight loss (8.8%), and loose stool (8.8%). Conclusion: Apremilast monotherapy had higher efficacy with similar safety outcomes in the real world compared to clinical trials. There were higher proportions of reported headaches compared to clinical trials. This study supports the apremilast monotherapy clinical trial findings, suggesting that it has an acceptable safety profile and significantly reduces the severity of moderate to severe plaque psoriasis. Limitations include the retrospective nature of the study.

Bayesian hierarchical model for safety signal detection in multiple clinical trials

2020 ◽  
Vol 99 ◽  
pp. 106183
Author(s):  
Yafei Zhang ◽  
Shuai Sammy Yuan ◽  
Barry A. Eagel ◽  
Hal Li ◽  
Li-An Lin ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Signal Detection ◽  
Hierarchical Model ◽  
Bayesian Hierarchical Model ◽  
Safety Signal ◽  
Bayesian Hierarchical

Interim results of a randomized phase II study of PEGPH20 added to nab-paclitaxel/gemcitabine in patients with stage IV previously untreated pancreatic cancer.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 439-439 ◽  
Author(s):  
Sunil R. Hingorani ◽  
William Proctor Harris ◽  
Tara Elisabeth Seery ◽  
Lei Zheng ◽  
Darren Sigal ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Trial ◽  
Phase Ii ◽  
Randomized Study ◽  
Safety Data ◽  
Stage Iv ◽  
Phase Iii ◽  
Clinical Hold ◽  
Stage 1 ◽  
Clinical Trial Information

439 Background: Poor outcome in pancreatic cancer (PDA) is associated partly with stromal hyaluronan (HA) accumulation, which compromises chemotherapy perfusion. PEGPH20, PEGylated recombinant human hyaluronidase, potentiates chemotherapy by depleting HA in tumors. Methods: In an ongoing, phase II, open-label, randomized study of PEGPH20+nab-paclitaxel (Nab)+Gemcitabine (Gem) (PAG) vs Nab+Gem (AG) in previously untreated stage IV PDA, pts receive PEGPH20 3 µg/kg twice weekly (C1), then weekly (C2+) with standard AG dosing. HA status was tested retrospectively. After a temporary clinical hold (Apr-Jul 2014) for an imbalance in thromboembolic (TE) events (29% PAG vs 15% AG), the protocol was amended to exclude high-TE-risk pts and add enoxaparin (LMWH) prophylaxis. Endpoints are PFS and TE events (primary); PFS and ORR by HA level and OS (secondary). Efficacy and safety data through Dec 2014 are for pts enrolled up to clinical hold (Stage 1); TE data are through Sep 2015 (Stage 2). Results: 135 pts were treated (74 PAG, 61 AG). PFS results are shown below (median follow-up 7 mo). In HA-high pts receiving PAG vs AG, ORR was 52% (1 CR) vs 24% (P=.038); ORR was 37% vs 38% in HA-low pts. OS was 12 mo vs 9 mo (HR=0.62) despite 12/23 PAG pts discontinuing PEGPH20 at clinical hold. Common ADRs (PAG vs AG) included peripheral edema (58% vs 31%), muscle spasms (55% vs 1.6%), and neutropenia (32% vs 18%). TE events were: Stage 1 42% vs 25% (no LMWH); Stage 2 (with LMWH; 40 mg/d or 40 mg/d increased to 1 mg/kg/d) 28% vs 29%; (1 mg/kg/d) 5% vs 6%; overall (40 mg/d or 1 mg/kg/d) 13% each arm (to be updated). Conclusions: Pts with HA-high tumors receiving PAG, vs AG, showed significant improvements in PFS and ORR and a trend toward improved OS. PAG was well tolerated, with TE events reduced with LMWH prophylaxis. A global phase III trial of PAG will initiate Q1 2016. Clinical Trial Information: NCT01839487. Clinical trial information: NCT01839487. [Table: see text]

scholarly journals Bayesian Augmented Clinical Trials in TB Therapeutic Vaccination

2021 ◽  
Vol 3 ◽  
Author(s):  
Dimitrios Kiagias ◽  
Giulia Russo ◽  
Giuseppe Sgroi ◽  
Francesco Pappalardo ◽  
Miguel A. Juárez
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Posterior Distribution ◽  
In Silico ◽  
Therapeutic Vaccination ◽  
Virtual Patients ◽  
Bayesian Hierarchical ◽  
Bayesian Hierarchical Method ◽  
Joint Posterior Distribution

We propose a Bayesian hierarchical method for combining in silico and in vivo data onto an augmented clinical trial with binary end points. The joint posterior distribution from the in silico experiment is treated as a prior, weighted by a measure of compatibility of the shared characteristics with the in vivo data. We also formalise the contribution and impact of in silico information in the augmented trial. We illustrate our approach to inference with in silico data from the UISS-TB simulator, a bespoke simulator of virtual patients with tuberculosis infection, and synthetic physical patients from a clinical trial.

Application of Metadata Repository and Master Data Management in Clinical Trial and Drug Safety

2015 ◽  
pp. 33-46
Author(s):  
Chandrakant Ekkirala
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Data Management ◽  
Drug Safety ◽  
Detailed Explanation ◽  
Master Data ◽  
Master Data Management ◽  
Metadata Repository ◽  
Definition Of

This chapter talks about metadata repository, and master data management in clinical trial and drug safety. The chapter begins with the definition of metadata repository and gives an explanation around the same, It talks about a well designed metadata repository and the characteristics associated with the same. A brief around why we need metadata and the reasons for the using the same has also been mentioned. The benefits of a well structured metadata repository was also mentioned in detail. The chapter then gives a detailed explanation on master data management and the usage of MDM in clinical trials. MDM solutions for clinical trials management is also explained in detail.

scholarly journals P11 Neonatal and paediatric protocol development and drug safety: points to consider for risk management and safety data collection

2019 ◽  
Vol 104 (6) ◽  
pp. e21.2-e22
Author(s):  
B Aurich ◽  
V Elie ◽  
E Jacqz-Aigrain
Keyword(s):  
Risk Management ◽  
Clinical Trials ◽  
Data Collection ◽  
Drug Safety ◽  
Safety Profile ◽  
Safety Data ◽  
Age Group ◽  
Baseline Trial ◽  
Paediatric Drug ◽  
Protocol Development

BackgroundProtocol development for neonatal or paediatric clinical trials needs to take into account the age group specifics of the study population (e.g. pharmacokinetics, reference values for laboratory data and vital signs). Drug safety and risk management for neonatal/paediatric trials require an understanding of how these change throughout childhood. We were interested in reviewing and summarising the literature to identify publications which provide researchers with practical information of how the neonatal/paediatric drug safety profile informs age group specific safety data collection and risk management in the protocol.MethodsPubmed, Embase and regulatory authority (RA) websites were searched for publications up to 31/12/2018 for children (0–18 years). In addition, the bibliography of included publications was reviewed to identify additional publications.ResultsRA websites provided general and disease specific guidance on neonatal/paediatric clinical trials with sections relating to drug safety. No publication was identified describing the practicalities of how the neonatal/paediatric drug safety profile can be included throughout the various sections of a clinical trial protocol. The existing literature was summarised providing an overview of how the neonatal/paediatric drug safety profile supports the development of the various protocol sections. For example laboratory values in the exclusion criteria and safety monitoring sections need to be adjusted for age. Vital sign and psychomotor assessment should be done at least at baseline, trial completion and follow-up. Monitoring of adverse events of interest requires consideration of how these may present in neonatal/paediatric patients.ConclusionsIn order to support the protocol development with regards to neonatal/paediatric drug safety a dual competence in both paediatrics and drug safety is required. This review provides an overview of the practical aspects related to neonatal/paediatric drug safety during protocol development.Disclosure(s)Nothing to disclose

scholarly journals The risk of malignancy is not increased in patients with multiple sclerosis treated with subcutaneous interferon beta-1a: analysis of data from clinical trial and post-marketing surveillance settings

2011 ◽  
Vol 17 (4) ◽  
pp. 431-440 ◽  
Author(s):  
Magnhild Sandberg-Wollheim ◽  
Gabrielle Kornmann ◽  
Dorina Bischof ◽  
Margaretha Stam Moraga ◽  
Brian Hennessy ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Safety Data ◽  
Data Set ◽  
Safety Database ◽  
Post Marketing Surveillance ◽  
Risk Of Malignancy ◽  
Post Marketing ◽  
Medical Dictionary

Background: Risks that are potentially associated with long-term therapies should be assessed. Objective: The present analyses were performed to determine the risk of malignancy in patients with multiple sclerosis (MS) receiving subcutaneous (sc) interferon (IFN) beta-1a, using pooled safety data from key clinical trials and data from the Merck Serono Global Drug Safety database. Methods: The standard Medical Dictionary for Regulatory Activities query “malignancies” was used to retrieve relevant cases from each data set. The incidence of malignancies per 1000 patient-years was calculated using the pooled safety data from clinical trials. The reporting rates of malignancy types were calculated for the post-marketing setting based on sales volume. Malignancies were grouped by organ localization and classified as medically confirmed or not medically confirmed according to the source of each report. The number of reported cases of each type was compared with the expected number in the general population. Results: Analysis of pooled safety data from 12 key clinical trials did not show an increased incidence of malignancy per 1000 patient-years with sc IFN beta-1a (4.0; 95% confidence interval (CI): 2.9–5.5) compared with placebo (6.4; 95% CI: 3.3–11.2). Analysis of the database shows that among the medically confirmed cases, reported to expected ratios ranged from 1 : 6 to 1 : 18 for solid tumours and from 1 : 2 to 1 : 9 for lymphohaematopoietic tumours. Conclusion: Safety data from both clinical trial and post-marketing settings suggest that treatment with sc IFN beta-1a does not increase the risk of malignancy in patients with MS.

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