High development cost, low development success, cost-disciplined health-care policies, and intense competition demand an efficient drug development process. New compounds need to bring value to patients by being safe, efficacious, and cost-effective as compared with existing treatment options. Model-based meta-analysis (MBMA) facilitates integration and utilization of summary-level efficacy and safety data, providing a quantitative framework for comparative efficacy and safety assessment. This Commentary discusses the application and limitations of MBMA in drug development.
This analysis assessed whether seasonal change in 25-hydroxyvitamin D concentration was associated with bone resorption, as evidenced by serum parathyroid hormone and C-terminal telopeptide concentrations. The main finding was that increased seasonal fluctuation in 25-hydroxyvitamin D was associated with increased levels of parathyroid hormone and C-terminal telopeptide. Introduction: It is established that adequate 25-hydroxyvitamin D (25(OH)D, vitamin D) concentration is required for healthy bone mineralisation. It is unknown whether seasonal fluctuations in 25(OH)D also impact on bone health. If large seasonal fluctuations in 25(OH)D were associated with increased bone resorption, this would suggest a detriment to bone health. Therefore, this analysis assessed whether there is an association between seasonal variation in 25(OH)D and bone resorption. Methods: The participants were (n = 279) Caucasian and (n = 88) South Asian women (mean (±SD); age 48.2 years (14.4)) who participated in the longitudinal Diet, Food Intake, Nutrition and Exposure to the Sun in Southern England study (2006-2007). The main outcomes were serum 25(OH)D, serum parathyroid hormone (sPTH) and serum C-terminal telopeptide of collagen (sCTX), sampled once per season for each participant. Results: Non-linear mixed modelling showed the (amplitude/mesor) ratio for seasonal change in log 25(OH)D to be predictive of log sPTH (estimate = 0.057, 95 % CI (0.051, 0.063), p < 0.0001). Therefore, individuals with a higher seasonal change in log 25(OH)D, adjusted for overall log 25(OH)D concentration, showed increased levels of log sPTH. There was a corresponding significant ability to predict the range of seasonal change in log 25(OH)D through the level of sCTX. Here, the corresponding parameter statistics were estimate = 0.528, 95 % CI (0.418, 0.638) and p ≤ 0.0001. Conclusions: These findings suggest a possible detriment to bone health via increased levels of sPTH and sCTX in individuals with a larger seasonal change in 25(OH)D concentration. Further larger cohort studies are required to further investigate these preliminary findings. © 2013 International Osteoporosis Foundation and National Osteoporosis Foundation
Clinical trial simulation (CTS) and model-based meta-analysis (MBMA) can increase our understanding of small, first-in-patient (FIP) trial design performance to inform Phase 2 decision making. In this work, we compared dose-ranging designs vs. designs testing only placebo and the maximum dose for early decision making in psoriasis. Based on MBMA of monoclonal antibodies in the psoriasis space, a threshold of greater than a 50 percentage point improvement over placebo effect at the highest feasible drug dose was required for the advancement in psoriasis. Studies testing only placebo and the maximum dose made the correct advancement decision marginally more often than dose-ranging designs in the majority of the cases. However, dose-ranging studies in FIP trials offer important design advantages in the form of dose–response (D–R) information to inform Phase 2 dose selection. CTS can increase the efficiency and quality of drug development decision making by studying the limitations and benefits of study designs prospectively.
The purpose of this commentary is to place probability of trial success, or assurance, in the context of decision making in drug development, and to illustrate its properties in an intuitive manner for the readers of Clinical Pharmacology and Therapeutics. The hope is that this will stimulate a dialog on how assurance should be incorporated into a quantitative decision approach for clinical development and trial design that uses all available information.
It is unknown whether there is an association between vitamin D status and bone geometry parameters in older South Asian women, and whether this differs from same-age Caucasian women. This is the first study, to the authors' knowledge, to assess the relationship between vitamin D status and peripheral quantitative computed tomography (pQCT) indices of bone architecture in older South Asian women. To measure radius bone structure, pQCT scans (Stratec X2000L) at the distal (4%) and mid-shaft (66 %) sites were undertaken in n = 18 South Asian (mean age 63.5 y + / -3.6) and n = 50 Caucasian women (mean age 65.9 y + / -4.8 " SSIpol = polar strength strain index (predicted measure of ability to resist torsion forces); " " Fracture Load = predicted amount of Newtons required to fracture the bone. Unadjusted = unadjusted data; BMI = BMI (Body Mass Index) adjusted data.For BMI adjusted data, in Caucasians, there were significant correlations between vitamin D status and bone mass (r = 0.379 p = 0.013), strength strain index (r = 0.337 p = 0.029), area of the cortical layer (r = 0.343 p = 0.026) and predicted fracture load (r = 0.337 p = 0.029) at the mid-shaft (66 %) site. There were also positive correlations between vitamin D status and total area (r = 0.327 p = 0.035) at the distal (4 %) site. Therefore, in Caucasians, increased vitamin D was associated with increased bone mass, size and measures of bone strength at both distal and mid shaft sites. For Asians, the only significant correlations between vitamin D status and the bone parameters were for trabecular density (r = 0.547 p = 0.035) at the distal (4%) site, and there were no significant correlations at the mid shaft (66 %) site. This suggests, in Asians, increased vitamin D status was only associated with increased density in the trabecular layer, and only at the distal site (4%). Overall, vitamin D appears to be positively correlated with size, strength and mass parameters in Caucasians, and positively correlated with trabecular density in South Asians. Therefore, in both ethnic groups, vitamin D is associated with positive effects on radial bone parameters, and a stronger bone structure. However, the underlying mechanisms in the two ethnic groups may be different. Further research is required to investigate these differences.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.