Big data in drug development may not satisfactorily address the demands of precision medicine in a rare disease population, making the use of smaller clinical trials necessary. Consequently, the use ...of innovative design and analysis of these clinical trials using model-informed approaches have become indispensable. This requires informative exposure-outcome analysis, together with formal statistical analysis, which should include the strength of evidence for a study outcome. We demonstrate how knowledge can be gained, with supporting strength of evidence, from a small (data) clinical trial with a low dose of blarcamesine in the treatment of Rett syndrome (RTT). Based on a small data paradigm, pharmacometrics item response theory modeling and Bayes factor analysis were used to show that blarcamesine is efficacious in RTT.
In this study, the role of institutions as a determining factor in foreign direct investment (FDI) attraction into a developing country such as Nigeria is investigated. The study makes use of ...recently constructed measures of institutions' quality that cover three separate categories: civil and political liberties, freehold property rights and non-freehold (Customary) property rights, with particular attention given to the two property rights. The findings suggest that, in the case of Nigeria, in the short run, institutions do play a role in determining FDI attraction. In addition, the study highlights the need to unbundle institutions, given that specific aspects of freehold property rights have a positive and significant impact on FDI, even though freehold property rights as whole does not have a significant impact.
To fully assess the safety and efficacy of therapeutics before approval, the US Food and Drug Administration (FDA) has encouraged adequate representation and assessment of demographic subgroups in ...clinical trials through guidance documents and regulations. This study aimed to survey the demographics of participants in pivotal clinical trials, as well as the presence of analyses by sex on efficacy and safety for FDA-approved new drug applications (NDAs) and biologics license applications (BLAs) from 2010 to 2012. Medical and statistical reviews for new molecular entity drugs and biological products approved during this period were obtained from Drugs@FDA. All pivotal clinical trials referenced in the FDA reviews were evaluated for the participation of different demographic subgroups (such as sex, race/ethnicity, and age). Pivotal trials were defined as those phase 2 and/or phase 3 trials described in the labeling or the FDA medical reviews in support of the drug/biological approval. Eighty-three new molecular entities (66 NDAs and 17 BLAs) were approved by the FDA from 2010 to 2012. Overall, women constituted 45% of trial participants for NDAs and 65% for BLAs. Sex analysis related to safety and efficacy was reported in 92% of the surveyed FDA medical and statistical reviews. Most NDAs and BLAs (82%) had a study population that was representative of the sex distribution for the intended patient population; however, most study participants were whites (77%), and minority racial/ethnic groups had lower participation rates in the study population than would be representative of the US racial group populations.
The recommended zolpidem starting dose was lowered in females (5 mg vs. 10 mg) since side effects were more frequent and severe than those of males; the mechanism underlying sex differences in ...pharmacokinetics (PK) is unknown. We hypothesized that such differences were caused by known sex-related variability in alcohol dehydrogenase (ADH) expression.
Male, female, and castrated male rats were administered 2.6 mg/kg zolpidem, ± disulfiram (ADH/ALDH pathway inhibitor) to compare PK changes induced by sex and gonadal hormones. PK analyses were conducted in rat plasma and rat brain.
Sex differences in PK were evident: females had a higher C MAX (112.4 vs. 68.1 ug/L) and AUC (537.8 vs. 231.8 h(∗)ug/L) than uncastrated males. Castration induced an earlier T MAX (0.25 vs. 1 h), greater C MAX (109.1 vs. 68.1 ug/L), and a corresponding AUC increase (339.7 vs. 231.8 h(∗)ug/L). Administration of disulfiram caused more drastic C MAX and T MAX changes in male vs. female rats that mirrored the effects of castration on first-pass metabolism, suggesting that the observed PK differences may be caused by ADH/ALDH expression. Brain concentrations paralleled plasma concentrations.
These findings indicate that sex differences in zolpidem PK are influenced by variation in the expression of ADH/ALDH due to gonadal androgens.
The U.S. Food and Drug Administration (FDA) has made efforts to encourage adequate assessment of women, racial/ethnic minorities, and geriatric participants in clinical trials through regulations and ...guidance documents. This study surveyed the demographics of clinical trial participants and the presence of efficacy and safety analyses by sex for new drugs approved between 2013 and 2015 by the FDA Center for Drug Evaluation and Research.
New drug marketing applications submitted to FDA were surveyed for demographic data (sex, race, ethnicity, and age) and the presence of sex-based analyses for efficacy and safety. The Ratio of the Proportion of women in clinical trials for the indicated disease population relative to the estimated Proportion of women in the disease population (PPR) was calculated for new drug indications.
Of the 102 new drugs in this cohort (defined as new molecular entity drugs and original therapeutic biologics), sex was reported for >99.9% of trial participants, and women accounted for 40.4% of these participants. An estimated 77.2% of participants were White, 6.4% were Black/African American, and 29.1% were aged ≥65 years. Sex-based analyses for both efficacy and safety were conducted for 93.1% of applications. PPR was calculated for 82 new drugs for a total of 60 indications, of which 50 indications (83.3%) had a PPR ≥0.80.
Sex data are now collected for almost all study participants, and this study shows appropriate sex participation for most new drugs when estimated disease prevalence by sex (PPR) is considered. Therapeutic area and disease indication are important considerations when assessing the sex of participants because variation occurs depending on the disease under study. Some racial minorities, especially Blacks/African Americans, are still not well represented in most drug development programs and remain an area where improvement is needed.
Pharmacokinetic (PK) data from 28 subjects who received 5-200-mg single ascending doses of ANAVEX3-71, formerly AF710B, were analyzed to characterize the PK of ANAVEX3-71 and its M8 metabolite. PK ...data from 12 subjects who received 160 mg ANAVEX3-71 under fed and fasted conditions were analyzed to characterize the effect of food on the PK of the drug and its M8 metabolite. PK was characterized using the standard 2-stage approach and the nonlinear mixed-effects modeling approach. Dose proportionality was determined using the power model. Two- and 3-compartment linear PK models were tested for the characterization of the PK of ANAVEX3-71 and its M8 metabolite. The PK of ANAVEX3-71 is linear, dose proportional, and time invariant. The drug is rapidly eliminated with a mean (standard deviation) apparent terminal elimination half-life of 3.56 (4.09) hours, while the M8 metabolite was eliminated with a mean (standard deviation) apparent terminal elimination half-life of 6.59 (1.64) hours. The population PK model was used to investigate the effects of covariates on the PK of ANAVEX3-71 and M8. Age, weight, and creatinine clearance were not explanatory of the variability in apparent clearance and apparent volume of the central compartment of ANAVEX3-71. Food had no effect on the PK of ANAVEX3-71 and its M8 metabolite.
Pollen grains have the potential to be effective plant-based biorenewable reinforcing fillers for polymers due to their high mechanical strength, chemical stability, and unique micro- and ...nano-structured surfaces. Pollen-polymer composites could form the basis for a new class of light-weight, high strength sustainable materials if compatible polymer-filler systems can be engineered. The exine shell of pollen, composed of sporopollenin, offers opportunities for surface functionalization to provide for compatibility between the pollen and the polymer matrix, but this idea has been previously unexplored. We present the first demonstration of surface functionalization of sporopollenin to enable incorporation of pollen as a reinforcing filler, using ragweed pollen in poly(vinyl acetate) (PVAc). Composites prepared with 'as received', untreated ragweed pollen displayed interfacial voids, degraded mechanical properties, and a decreased glass transition width with increased pollen loading, relative to neat PVAc. Composites prepared with pollen treated viaan acid-base surface preparation displayed improved interfacial morphology and increasing modulus with pollen loading (29% increase). Interfacial adhesion was optimal for pollen functionalized with vinyltrimethoxysilane (VTMS), followed by in situfree radical polymerization of PVAc. In situpolymerization of functionalized pollen resulted in simultaneous stiffening and strengthening of composites (80% increase in tensile strength). Films containing treated and functionalized pollen also displayed a wider glass transition regions in the presence of pollen filler relative to neat PVAc.
A simple solution processed layer-by-layer approach was used to immobilize metal nanoparticles (NPs) on the surface of ragweed pollen exine to obtain multifunctional particles with significant ...surface-enhanced Raman scattering (SERS), two-photon excited fluorescence, and enhanced adhesion properties. The rugged pollen exine was functionalized with an amine terminated silane and then treated with Ag or Ag@SiO2 NPs that were electrostatically attached to the exterior of the pollen by incubation in an NP solution of the appropriate pH. Nanoparticle agglomeration on the pollen gives rise to broadband near infrared (NIR) (785–1064 nm) plasmonic activity, and strong SERS signals from benzenedithiol deposited on NP–pollen composite particles were observed. In addition to SERS activity, the AgNP coating provides a twofold increase in the adhesive properties of the RW pollen exine on a silicon substrate, leading to a robust, adhesive, broadband NIR excitable SERS microparticle.
The application of population approaches to drug development is recommended in several US Food and Drug Administration (FDA) guidance documents. Population pharmacokinetic (and pharmacodynamic) ...techniques enable identification of the sources of inter- and intra-individual variability that impinge upon drug safety and efficacy. This article briefly discusses the 2-stage approach to the estimation of population pharmacokinetic parameters, which requires serial multiple measurements on each participant, and comprehensively reviews the nonlinear mixed-effects modelling approach, which can be applied in situations where extensive sampling is not done on all or any of the participants. Certain preliminary information, such as the compartment model used in describing the pharmacokinetics of the drug, is required for a population pharmacokinetic study. The practical design considerations of the location of sampling times, number of samples/participants and the need to sample an individual more than once should be borne in mind. Simulation may be useful for choosing the study design that will best meet study objectives. The objectives of the population pharmacokinetic study can be secondary to the objectives of the primary clinical study (in which case an add-on population pharmacokinetic protocol may be needed) or primary (when a stand-alone protocol is required). Having protocols for population pharmacokinetic studies is an integral part of 'good pharmacometric practice'. Real-time data assembly and analysis permit an ongoing evaluation of site compliance with the study protocol and provide the opportunity to correct violations of study procedures. Adequate policies and procedures should be in place for study blind maintenance. Real-time data assembly creates the opportunity for detecting and correcting errors in concentration-time data, drug administration history and covariate data. Population pharmacokinetic analyses may be undertaken in 3 interwoven steps: exploratory data analysis, model development and model validation (i.e. predictive performance). Documentation for regulatory purposes should include a complete inventory of key runs in the analyses undertaken (with flow diagrams if possible), accompanied by articulation of objectives, assumptions and hypotheses. Use of diagnostic analyses of goodness of fit as evidence of reliability of results is advised. Finally, the use of stability testing or model validation may be warranted to support label claims. The opinions expressed in this article were revised by incorporating comments from various sources and published by the FDA as 'Guidance for Industry: Population Pharmacokinetics' (see the FDA home page http:/(/)www.fda.gov for further information).
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