A systematic review and meta-analysis of the morbidity of efficacy endpoints and bleeding events in elderly and young patients treated with the same dose rivaroxaban.

Rivaroxaban is a new direct oral anticoagulant, and the same dose is recommended for older and young patients. However, recent real-world studies show that older patients may need dose adjustment to prevent major bleeding. At present, the evidence for dose adjustment in older patients is extremely limited with only a few reports on older atrial fibrillation patients. The aim of this study was to review the morbidity data of adverse events and bleeding events across all indications for older and young patients treated with the same dose of rivaroxaban to provide some support for dosage adjustment in older patients. The PubMed, EMBASE, ClinicalTrials, Cochrane and Web of Science databases were searched for randomized controlled trials (RCTs) published between January 1, 2005, and October 10, 2023. The primary outcomes were the morbidity of bleeding events and efficacy-related adverse events. Summary estimates were calculated using a random effects model. Eighteen RCTs were included in the qualitative analysis. The overall morbidity of primary efficacy endpoints was higher in older patients compared to the young patients (3.37% vs. 2.60%, χ2 = 5.24, p = 0.022). Similarly, a higher morbidity of bleeding was observed in older patients compared to the young patients (4.42% vs. 6.03%, χ2 = 13.22, p < 0.001). Among all indications, deep vein thrombosis, pulmonary embolism and atrial fibrillation were associated with the highest incidence of bleeding in older patients, suggesting that these patients may be most need dose adjustment. Patients older than 75 years may require extra attention to prevent bleeding. The same dose of rivaroxaban resulted in higher bleeding morbidity and morbidity of efficacy-related adverse events in older patients compared to the young patients. An individualized dose adjustment may be preferred for older patients rather than a fixed dose that fits all.

High temperature shock threatens methane production via disturbing microbial interactions in anaerobic digestion.

Operational strategies shape microbial interactions determining anaerobic digesting process, but it is unclear whether and how the microbial network properties impact gas generation, especially in the transitional stage after operations. This research examined how the high temperature shock affected microbial diversity and network traits connected with the biogas production in a swine manure-fed anaerobic digester. Rising temperature (from 35 °C to 50 °C) significantly reduced biogas and methane production (p < 0.001) in the transitional stage due to the syntrophic loss of Methanomicrobiaceae and Firmicutes affiliated families. The high temperature shock reduced network modularity and thus caused the system functioning loss. Furthermore, the methanogenic stability was disrupted by high temperature shock (reduced the abundance of Methanosphaera but increased the abundance of Methanoculleus), which may result in the subsequent dysbiosis with other syntrophic communities. These findings suggest that the increased temperature-induced high network complexity and stability, but microbial communities need more time to restore the microenvironment via establishing the interactions of keystone species.

Innovative Design and Analysis for PK/PD Biosimilar Bridging Studies with Multiple References.

When there are multiple reference products, (e.g., EU-approved product and US-licensed product), a pharmacokinetic/pharmacodynamic (PK/PD) bridging study is often conducted in order to bridge the clinical data from the original region (e.g., Europe) to the new region (e.g., USA) in support of the biosimilar regulatory submission in the new region. The purpose is to avoid duplicated clinical trials for clinical similarity between a proposed biosimilar product and the reference product in the new region provided that there is no ethnic concern in the two regions. In this article, some innovative statistical designs for PK/PD biosimilar bridging studies are proposed. Statistical model and methods under the proposed statistical designs are studied. Power analysis for sample size requirement based on Schuirmann's two one-sided tests procedure is also derived and compared to pairwise testing using simulation.

Chitosan-based multifunctional flexible hemostatic bio-hydrogel.

Realizing the potential application of chitosan as an effective biomedical hemostatic agent has become an emerging research hotspot. However, fabricating a flexible chitosan-based hemostatic bio-hydrogel with self-adhesion feature in humid conditions and rapid hemostasis capability remains a challenge. Herein, we reported the development of chitosan-based hydrogels (DCS-PEGSH gels) with typical multilevel pore structures, which were cross-linked by 3-(3,4-dihydroxyphenyl) propionic acid-modified chitosan (DCS) and sebacic acid-terminated polyethylene glycol modified by p-hydroxybenzaldehyde (PEGSH). By precisely regulating the proportion of PEGSH, the fabricated bio-hydrogels displayed favorable cytocompatibility, suitable stretchability (∼780%), and blood absorbability (1300% ± 50%). Moreover, the strong adhesion (∼68.5 kPa) of the assembled bio-hydrogel ensured its firm adherence on pigskin and on bleeding wound in both static and dynamic humid environments without shedding, thus providing a long service life. The fabricated hydrogels exhibited shorter blood clotting time (50 s) and lower blood clotting index (BCI, 41) than the commercial chitosan sponge (288 s, BCI 65). Notably, the amount of blood loss from the liver in mice was reduced by almost 90% as compared to that for the control group. This study paves a solid way for developing a chitosan-based hydrogel with self-adhesive, self-healing, stretchability, biocompatibility, and antibacterial and antioxidant properties through molecular design and structural regulation, which will enable the biomedical application of chitosan in emergency hemostasis, particularly in joints and extremities. STATEMENT OF SIGNIFICANCE: The design and preparation of multifunctional integrated green adhesive bio-hydrogels while avoiding the use of organic solvents and toxic chemical reagents has been an emerging challenge. Herein, a flexible chitosan-based hemostatic bio-hydrogel that integrates multifunctional properties was successfully synthesized. The bio-hydrogel displayed suitable stretchability (780%) and blood absorbability (1300% ± 50%). Moreover, the strong adhesion (68.5 kPa) ensured firm adherence of the assembled hydrogel on pigskin and on the bleeding wound site in both static and dynamic humid environments without shedding, thus providing a long service life. In addition, the designed hydrogel showed good compatibility and antibacterial performance. The dynamic Schiff base endowed the bio-hydrogel with excellent self-healing performance without any external stimuli.

The use of real-world data/evidence in regulatory submissions.

The 21st Century Cures Act passed by the United States (US) Congress in December 2016 requires the US Food and Drug Administration (FDA) shall establish a program to evaluate the potential use of real-world evidence (RWE) which is generated from real-world data (RWD) to (i) support approval of new indication for a drug approved under section 505 (c) and (ii) satisfy post-approval study requirements. RWE offers the opportunities to develop robust evidence using high-quality data and sophisticated methods for producing causal-effect estimates regardless randomization is feasible. In this article, we have demonstrated that the assessment of treatment effect (RWE) based on RWD could be biased due to the potential selection and information biases of RWD. Although fit-for-purpose RWE may meet regulatory standards under certain assumptions, it is not the same as substantial evidence (current regulatory standard in support of approval of regulatory submission). In practice, it is then suggested that when there are gaps between fit-for-purpose RWE and substantial evidence, we should make efforts to fill these gaps based on a comprehensive evaluation of the treatment effect. We also review two RWE examples to show some potential use of RWE in clinical studies.

A mussel-inspired flexible chitosan-based bio-hydrogel as a tailored medical adhesive.

The significant progress in efforts to design hydrogel adhesive mimicking mussels' functions has been witnessed in recent years. However, it is still an arduous challenge to fabricate self-adhesive hydrogel adhesive that tradeoff of exalting features containing scalability, self-healing, degradability, biocompatibility, and antibacterial properties. Herein, we manufactured a multi-functional physical hydrogel adhesive by integrating catechol groups modified chitosan and polyvinyl alcohol (PVA). Intriguingly, the physical gels reinforce durable and repeatable adhesiveness due to the limited auto-oxidation of catechol groups of the 3-(3,4-dihydroxyphenyl) propionic acid modified chitosan (DCS), which can be adhered diametrically on human skin without shedding and residue. Additionally, the dynamic H-bonds between DCS and PVA endows the hydrogel to self-heal under a relatively mild stimulation. The assembly of silver nano armor remarkably enhances the mechanical strength and antibacterial of the hydrogel. Meanwhile, the metal coordination formed between the nano-silver and the hydroxyl groups of catechol and the electrostatic interaction between the silver ions and the hydroxyl groups also contribute to the hydrogel to achieve self-healing. This work provides a neoteric prospect in designing degradable hydrogels with stretchability, self-adhesion, self-healing, antibacterial and biocompatibility for potential applications in tissue adhesion and wound healing.

A robust regenerated cellulose-based dual stimuli-responsive hydrogel as an intelligent switch for controlled drug delivery.

Constructing robust hydrogels with biodegradability and dual stimuli-responsive by utilizing natural polymer as raw materials remains a sustaining challenge. Herein, we proposed an interpenetrating strategy in which N-isopropyl acrylamide (NIPAM) and acrylamide (AM) block copolymers were introduced as the second network into the carboxymethyl cellulose single network gel (CMC gel) to construct a dual-network robust hydrogel (CMC/PNIPAM-co-PAM). The dual-network design strategy effectively improves the mechanical strength of CMC gel. The hydrogel suggests intelligent dual stimuli-responsive behavior to pH and temperature. Furthermore, the copolymerization of NIPAM and AM regulated the low critical solution temperature (LCST) of the hybrid hydrogel, making it close to the physiological temperature of the human body. With the aim of evaluating its application in drug delivery, we loaded tetracycline into the dual-network hydrogel and simulated its release process under the pH microenvironment of the small intestine and the physiological temperature to infer its potential application in intestinal inflammation treatments. Moreover, it is proved that the strong hydrogel possesses good cytocompatibility in vitro biocompatibility testing. In addition, the embedding of tetracycline makes the hydrogel excellent antioxidant performance. This dual-stimulus response integrated hydrogel is expected to play a critical role in drug delivery and targeted therapy.

Composited Gels from Nature Growing Scaffold: Synthesis, Properties, and Application.

As a nature ultralight, well-aligned porous and anisotropy feedstock, cornstalk pith (CSP) has not been exploited for material design. Herein, we use CSP as substrate to prepare multifunctional elastic composite gels. First, CSP is pretreated by ferric chloride then immersed in an unsaturated monomer solution, following by a polymerization to form enhanced networks. The ferric ions act as junction sites for the combination between the polymer chains and the CSP matrix, therefore, dynamically reversible bonds are constructed. The bonds dissipate the compression force by breaking the dynamic bonds and reconstruct when the loading is removed. The reconstructed dynamic bonds endow an antifatigue performance of the prepared gels, in the cyclic compression test conducting 100 times with a 50% strain, and the gel holds a 94% elastic recovery. Furtherly, oil/water separation, cushioning system and biobased sensor are developed on the basis of what the matrix endows and what the reversible bonds exhibit. The preparation method in this study enriches a simply and high value-added method to utilize biobased material.

A reproducibility probability-based bias-adjustment approach on the specification of non-inferiority margin using historical data.

The effect of reference treatment over placebo, known as M1, is essential in the development of non-inferiority margin. We proposed a M1 adjustment approach to reduce the selection bias for collected data of historical trials. A quantitative illustration of selection bias of historical data is also defined. Simulation study shows that the proposed approaches would significantly reduce the bias when the proportion of positive studies in historical data is noticeably larger than the power of studies include in historical data. When historical data are constituted by only positive studies, the performance of the proposed method is also appreciable. However, when the proportion of positive studies is close to the power of studies included or the number of studies included is too small, the performance of the proposed approach may not be reliable. A real-data application is also presented. The proposed bias-adjustment approach is a reasonable method to reduce the over-estimate of effect size in the specification of non-inferiority margin. It could also be applied in most non-inferiority margin specification methods or be cooperate used with other bias-adjustment approaches.

Practical Issues in Clinical Inspection Process.

Regulatory inspection of clinical trial is necessary in order for (1) assessing compliance with statutory requirements and regulatory requirement governing the conduct of clinical trials and (2) verifying the accuracy and reliability of clinical trial data submitted to regulatory agencies such as the United States Food and Drug Administration (FDA) in support of research or marketing applications. This article provides an overview of clinical inspection process and issues that are commonly encountered during the conduct of clinical trials. In addition, a couple of sampling plans for clinical inspection of relatively large trials are proposed. The proposed statistical process for clinical inspection that will achieve a desired degree of inspection accuracy and reliability is useful when the resources of inspectors are limited. The proposed 2-stage sampling plan can be applied to clinical inspection for multicenter and/or multinational multicenter clinical trials.

On evaluation of consistency in multi-regional clinical trials.

In recent years, multi-regional clinical trials (MRCT) that conduct clinical trials simultaneously in Asian Pacific region, Europe, and the United States have become very popular for global pharmaceutical development. The main purpose of multi-regional clinical trials is to shorten the time for pharmaceutical development and regulatory submission, and approval around the world. In practice, however, clinical results observed from some regions (sub-population) may not be consistent with the results from other regions and/or all regions combined (entire population). The inconsistency observed may be due to ethnic differences in different regions, differences in medical practice, time points of assessment, or by random chance due to small sample size for the region. Some regional regulatory agencies require consistency evaluation between local country results and overall results. However, the challenge is there is no detailed guidance on the definition of 'consistency' and methodology to evaluate it. Therefore, the questions are: how to evaluate consistency and what statistical methods are appropriate to be used for consistency evaluation? In this article, several statistical tests for consistency (similarity) between clinical results observed from a specific sub-population and the entire population are proposed. These methods are compared through extensive simulation. As most published articles discussed consistency evaluation for superiority situations, we have discussed consistency evaluation for non-inferiority situation in this article through a simulated example concerning consistency in some countries. Recommendations of the statistical methods to be used for consistency evaluation are given. Other aspects that should be considered for consistency evaluation are also provided.

On hybrid parallel-crossover designs for assessing drug interchangeability of biosimilar products.

In recent years, a specific hybrid parallel-crossover design that consists of two sequences of treatments, namely R-R-R-R and R-T-R-T, where T and R is a proposed biosimilar product and an innovative biological product, respectively, have been proposed and received much attention for assessing drug interchangeability between T and R, where R could be either a US-licensed product or an EU-reference product. In practice, there are three types of hybrid parallel-crossover designs that are commonly employed in assessing drug interchangeability of biosimilar products. These three types of parallel-crossover hybrid designs include (1) a parallel + 2 × 2 crossover design, (2) a parallel + 2 × 3 crossover design, and (3) a parallel + 2 × 4 crossover design. This article provides a comprehensive review of these study designs including a complete N-of-1 randomized trial design. A specific hybrid parallel-crossover design, that is, (RRRR, RTRT) for addressing drug interchangeability in terms of switching and the relative risk between with/without alternation is discussed.

On the evaluation of reliability, repeatability, and reproducibility of instrumental evaluation methods and measurement systems.

Validation of instrumental evaluation methods or measurement systems plays an important role in both pharmaceutical and cosmetic research and development. In practice, it is suggested that validation should be performed according to performance characteristics as described in the United States Pharmacopedia and National Formulary (USP/NF, 2000) for analytical methods validation. A validated method or measurement system is expected to achieve a certain degree of accuracy and reliability. However, it is a concern whether the test results obtained are repeatable (with similar test samples) and/or reproducible (under similar but slightly different experimental conditions). In this article, reliability and repeatability/reproducibility of a measurement system estimated within a mixed-effects nested design are monitored by relevant variability acceptance limits. A method based on the concept of empirical power (reproducibility) is used to determine these acceptance limits and thus ensure that there is a high probability of repeatability/reproducibility of the tests results. Formulas or procedures for sample size requirements for comparing the variabilities between products are derived. An example is presented to illustrate the use of the proposed method.

On safety margin for drug interchangeability.

As more and more generic (or biosimilar) drug products become available in the market place, it is a concern whether the approved generic (or biosimilar) drug products are safe and efficacious and hence can be used interchangeably. According to current regulation, most regulatory agencies such as the United States Food and Drug Administration (FDA) indicate an approved generic (or biosimilar) drug product can serve as a substitute for the innovative drug product. Bioequivalence (biosimilarity) assessment for regulatory approval among generic copies (or biosimilars) of the innovative drug product are not required. In practice, approved generic (or biosimilar) drugs are commonly used interchangeably without any mechanism of safety monitoring. In this article, current bioequivalence (or biosimilarity) limit is adjusted according to the observed geometric mean ratio and corresponding variability for development of safety margins for monitoring of drug interchangeability by minimizing the relative change in response with and without the switching.

Sample size requirement in analytical studies for similarity assessment.

For the assessment of biosimilar products, the FDA recommends a stepwise approach for obtaining the totality-of-the-evidence for assessing biosimilarity between a proposed biosimilar product and its corresponding innovative biologic product. The stepwise approach starts with analytical studies for assessing similarity in critical quality attributes (CQAs), which are relevant to clinical outcomes at various stages of the manufacturing process. For CQAs that are the most relevant to clinical outcomes, the FDA requires an equivalence test be performed for similarity assessment based on an equivalence acceptance criterion (EAC) that is obtained using a single test value of some selected reference lots. In practice, we often have extremely imbalanced numbers of reference and test lots available for the establishment of EAC. In this case, to assist the sponsors, the FDA proposed an idea for determining the number of reference lots and the number of test lots required in order not to have imbalanced sample sizes when establishing EAC for the equivalence test based on extensive simulation studies. Along this line, this article not only provides statistical justification of Dong, Tsong, and Weng's proposal, but also proposes an alternative method for sample size requirement for the Tier 1 equivalence test.

Analytical Similarity Assessment in Biosimilar Studies.

For assessment of biosimilarity, the US Food and Drug Administration (FDA) recommends a stepwise approach for obtaining the totality-of-the-evidence for demonstrating biosimilarity between a proposed biosimilar product and an innovative (reference) biological product. The stepwise approach starts with analytical studies for functional and structural characterization at various stages of manufacturing process of the proposed biosimilar product. Analytical similarity assessment involves identification of critical quality attributes (CQAs) that are relevant to clinical outcomes. FDA proposes first classifying the identified CQAs into three tiers according to their criticality or risking ranking relevant to clinical outcomes and then performing equivalence test (for CQAs in Tier 1), quality range approach (for CQAs in Tier 2), and raw data or graphical presentation (for CQAs in Tier 3) for obtaining totality-of-the-evidence for demonstrating biosimilarity between the proposed biosimilar product with the reference product. In practice, some debatable issues are evitably raised due to this complicated process of analytical similarity assessment. In this article, these debatable are described and discussed.

Some thoughts on drug interchangeability.

Current regulation for generic approval is based on the assessment of average bioequivalence. As indicated by the United States Food and Drug Administration (FDA), an approved generic drug can be used as a substitute for the innovative drug. FDA does not indicate that two generic copies of the same innovative drug can be used interchangeably even though they are bioequivalent to the same brand-name drug. In practice, bioequivalence between generic copies of an innovative drug is not required. However, as more generic drug products become available, it is a concern whether the approved generic drug products have the same quality and therapeutic effect as the brand-name drug product and whether they can be used safely and interchangeably. In this article, several criteria including a newly proposed criterion for assessing drug interchangeability are studied. In addition, comments on possible study designs and power calculation for sample size under a specific design are also discussed.