Hospitalization Endpoint in Clinical Trials of Outpatient Settings: using Anti-SARS-COV-2 Therapy as an Example.

Purpose: In response to the COVID-19 pandemic, the World Health Organization (WHO) developed a set of outcome measures for trials primarily aimed at hospitalised patients. However, a gap exists in defining outcome standards for non-hospitalised patients. Therefore, this study aims to discuss hospitalisation as a primary outcome in outpatient trials and its potential pitfalls, specifically focusing on trials related to anti-SARS-COV-2 therapy. Methods: In this narrative review, researchers thoroughly searched MEDLINE and ClinicalTrials.gov from January 2020 to December 2022, targeting Phase III randomized controlled trials involving outpatients with mild-to-moderate COVID-19. The trials were specifically related to anti-SARS-COV-2 monoclonal antibodies or antiviral agents. The study collected essential data, including the type of intervention, comparator, primary objective, primary endpoint, and the use of estimands in the trial. Results: The search identified 12 trials that evaluated the efficacy of anti-SARS COV-2 therapies in a predefined population. Three studies used hospitalisation and death as primary endpoints in high-risk patients receiving monoclonal antibodies. Nine studies assessed the efficacy of several antiviral agents: four trials used hospitalisation and death as the main endpoints, while others used different measures such as virologic measures using the Reverse Transcription-Polymerase Chain Reaction test (RT-PCR), the eight-point WHO ordinal scale, symptom alleviation by Day 7 and time to clinical response. Conclusion: Choosing hospitalization as an endpoint may provide meaningful data such as the cost-effectiveness ratio of a drug. However, different hospital utilisation patterns and investigator decisions could bias clinical outcomes if no specific criteria are considered. Therefore, investigators should have clear criteria for determining variables that influence this measure.

The bioequivalence study design recommendations for immediate-release solid oral dosage forms in the international pharmaceutical regulators programme participating regulators and organisations: differences and commonalities.

Bioequivalence (BE) studies are considered the standard for demonstrating that the performance of a generic drug product in the human body is sufficiently similar to that of its comparator product. The objective of this article is to describe the recommendations from participating Bioequivalence Working Group for Generics (BEWGG) members of the International Pharmaceutical Regulators Programme (IPRP) regarding the conduct and acceptance criteria for BE studies of immediate release solid oral dosage forms. A survey was conducted among BEWGG members regarding their BE recommendations and requirements related to study subjects, study design, sample size, single or multiple dose administration, study conditions (fasting or fed), analyte to be measured, selection of product strength, drug content, handling of endogenous substances, BE acceptance criteria, and additional design aspects. All members prefer conducting single dose cross-over designed studies in healthy subjects with a minimum of 12 subjects and utilizing the parent drug data to assess BE. However, differences emerged among the members when the drug's pharmacokinetics and pharmacodynamics become more complex, such that the study design (e.g., fasting versus fed conditions) and BE acceptance criteria (e.g., highly variable drugs, narrow therapeutic index drugs) may be affected. The survey results and discussions were shared with the ICH M13 Expert Working Group (EWG) and played an important role in identifying and analyzing gaps during the harmonization process. The draft ICH M13A guideline developed by the M13 EWG was endorsed by ICH on 20 December 2022, under Step 2.

Targeted next-generation sequencing of genes involved in Warfarin Pharmacodynamics and pharmacokinetics pathways using the Saudi Warfarin Pharmacogenetic study (SWAP).

BACKGROUND: Warfarin is an oral anticoagulant commonly used for treatment and prophylaxis against thromboembolic events. Warfarins's narrow therapeutic index window is one of the main challenges in clinical practice; thus, it requires frequent monitoring and dose adjustment to maintain patients' therapeutic range. Warfarin dose variation and response are attributed to several inter-and intra-individuals factors, including genetic variants in enzymes involved in warfarin pharmacokinetics (PK) and pharmacodynamics (PD) pathways. Thus, we aim to utilize the next-generation sequencing (NGS) approach to identify rare and common genetic variants that might be associated with warfarin responsiveness. METHOD AND RESULTS: A predesigned NGS panel that included 16 genes involved in Warfarin PK/PD pathways was used to sequence 786 patients from the Saudi Warfarin Pharmacogenetic Cohort (SWAP). Identified variants were annotated using several annotation tools to identify the pathogenicity and allele frequencies of these variants. We conducted variants-level association tests with warfarin dose. We identified 710 variants within the sequenced genes; 19% were novel variants, with the vast majority being scarce variants. The genetic association tests showed that VKORC1 (rs9923231, and rs61742245), CYP2C9 (rs98332238, rs9332172, rs1057910, rs9332230, rs1799853, rs1057911, and rs9332119), CYP2C19 (rs28399511, and rs3758581), and CYP2C8 (rs11572080 and rs10509681) were significantly associated with warfarin weekly dose. Our model included genetics, and non-genetic factors explained 40.1% of warfarin dose variation. CONCLUSION: The study identifies novel variants associated with warfarin dose in the Saudi population. These variants are more likely to be population-specific variants, suggesting that population-specific studies should be conducted before adopting a universal warfarin genotype-guided dosing algorithm.

National medicines policy development, Saudi Arabia.

Medicines are at the core of every health system. The World Health Organization recommends countries develop national medicines policies that guide production, procurement, prescription and provision of medicines so that people can access the medicines they need at prices they can afford, while avoiding irrational use. However, the development of such policies is rarely straightforward. We describe important components of the national medicines policy in Saudi Arabia, which was developed within a broader transformation of the health system and the economy. The new policy formalizes existing best practices, shapes emerging policies and sets a direction for future development in four main areas. First, the policy seeks to consolidate institutional roles to provide greater cohesion; second it aims to reshape procurement and prescribing habits, with a greater focus on cost containment; third, it lays out policies which focus on assuring a secure supply of good-quality medicines, including essential medicines with limited profit potential and new products. Finally, the policy supports the growth of the domestic pharmaceutical industry, including the development of human resources. Many sectors and institutions joined in the development of the medicines policy, which was underpinned by a review of the past and current pharmaceutical context in Saudi Arabia, and good practices globally. The resulting policy was built on evidence and endeavours to give clear direction to the pharmaceutical industry and implementing agencies on rules and requirements, professional norms and institutional roles. At the same time, it maintains flexibility to allow for adaptation in a rapidly evolving institutional landscape.

Les médicaments sont au cœur de tout système de santé. L'Organisation mondiale de la Santé recommande aux pays d'élaborer des politiques pharmaceutiques nationales qui déterminent la production, l'obtention, la prescription et la fourniture de médicaments, afin que la population puisse accéder aux traitements requis à un prix abordable sans toutefois tomber dans un usage irrationnel. Mais cette élaboration est rarement simple. Dans le présent document, nous abordons les principaux aspects de la politique pharmaceutique nationale en Arabie saoudite, développée dans le cadre d'une vaste transformation de l'économie et du système de santé. Cette nouvelle politique officialise les bonnes pratiques existantes, façonne les projets émergents et définit une orientation pour l'évolution future dans quatre domaines clés. Premièrement, elle cherche à renforcer le rôle des institutions pour améliorer la cohésion. Deuxièmement, elle vise à remanier les habitudes d'obtention et de prescription, en se focalisant sur la maîtrise des coûts. Troisièmement, elle établit des mesures destinées à assurer un approvisionnement sûr en médicaments de qualité, y compris en nouveaux produits et médicaments essentiels au potentiel de rentabilité limité. Et quatrièmement, elle soutient la croissance de l'industrie pharmaceutique dans le pays, notamment le développement des ressources humaines. De nombreux secteurs et institutions ont contribué à l'élaboration de cette politique, qui s'appuie sur une analyse du contexte pharmaceutique antérieur et actuel en Arabie saoudite ainsi que sur les bonnes pratiques mondiales. Le résultat repose sur des éléments et efforts tangibles. Il montre clairement à l'industrie pharmaceutique et aux organismes de mise en œuvre la marche à suivre en matière de règles et d'exigences, de normes professionnelles et de rôles institutionnels. Et dans le même temps, il prévoit suffisamment de flexibilité pour s'adapter à un paysage institutionnel en constante mutation.

Los medicamentos son el núcleo de todo el sistema sanitario. La Organización Mundial de la Salud recomienda a los países que desarrollen políticas nacionales de medicamentos que guíen la producción, la adquisición, la prescripción y el suministro de estos, de modo que las personas puedan acceder a los medicamentos que necesitan a precios que puedan pagar, evitando al mismo tiempo un uso irracional. Sin embargo, la elaboración de estas políticas no suele ser sencilla. En este documento se describen componentes importantes de la política nacional de medicamentos en Arabia Saudita, que se desarrolló en el marco de una transformación más amplia del sistema sanitario y la economía. La nueva política formaliza las mejores prácticas existentes, da forma a las políticas emergentes y establece una dirección para el desarrollo futuro en cuatro áreas principales. En primer lugar, la política busca consolidar las funciones institucionales para proporcionar una mayor cohesión; en segundo lugar, pretende remodelar los hábitos de adquisición y prescripción, centrándose más en la contención de los costes; en tercer lugar, establece políticas que se centran en asegurar el suministro de medicamentos de buena calidad, incluidos los productos nuevos y los medicamentos esenciales con un potencial de beneficio limitado. Por último, la política apoya el crecimiento de la industria farmacéutica nacional, incluido el desarrollo de los recursos humanos. Varios sectores e instituciones participaron en la elaboración de la política de medicamentos, que se sustentó en una revisión del contexto farmacéutico pasado y actual en Arabia Saudita, y de las buenas prácticas a nivel mundial. La política resultante se creó a partir de pruebas y se esfuerza por dar una orientación clara a la industria farmacéutica y a los organismos de ejecución sobre las reglas y requisitos, las normas profesionales y las funciones institucionales. Asimismo, mantiene la flexibilidad para permitir la adaptación en un panorama institucional que evoluciona muy rápido.

Blood pressure-lowering activity of statins: a systematic literature review and meta-analysis of placebo-randomized controlled trials.

PURPOSE: To investigate the blood pressure (BP)-lowering effects of statins by conducting a systematic review and meta-analysis of placebo-randomized controlled trials (RCTs). METHOD: We conducted a meta-analysis of placebo RCTs reporting antihypertensive effects of statins therapy. We only included RCTs that did not allow for concomitant antihypertensive therapy, or clearly stated that antihypertensive therapy was fixed throughout the study period. RESULTS: Our meta-analysis included 46 placebo RCTs, including 53 group comparisons and a total of 49,087 participants (24,589 participants in the statin groups and 24,498 participants in the placebo group). Subgroup analysis, based on use of concomitant antihypertensive, was performed. The meta-analysis showed that statin reduced systolic BP by - 1.6 mmHg (95% CI: - 2.50 to - 0.60), and diastolic BP by - 0.96 mmHg (95% CI: - 1.36 to - 0.56). Although the presence of concomitant antihypertensive therapy diluted the BP lowering effect of statins, it remained statistically significant and independent of the lipid-lowering activity. Furthermore, the BP -lowering effect of the statins was independent of the dose or type of statin (p > 0.05). CONCLUSION: Our results strengthen the evidence for pleiotropic effects of statins on BP that are independent of their lipid-lowering activity, supporting their beneficial role in hypertensive patients with dyslipidemia.

Top 10 most used drugs in the Kingdom of Saudi Arabia 2010-2015.

Medications usage has become a significant part of contemporary life. Many studies indicate that there is an excessive use and a considerable waste of medicines. This descriptive study aims at identifying the most used medicines in Saudi Arabia from 2010 to 2015 according to the statistics of specialized companies in the field. Comparison of the most commonly used drugs with those in the United States aims at clarifying similarities and differences. The results showed that the use of antibiotics and analgesics still accounted for the bulk, followed by proton pump inhibitors and anti-diabetics respectively, then anti-hyperlipidemic agents and erectile dysfunction treatments. The causes of this overuse vary according to the studies concerned between the self-medications and the over-prescription of the medication and the failure of the diagnostic and treatment procedures (malpractice). The recommendations are the strict application of prescribed and non-prescribed dispensing systems and the further establishment and application of national guides in the diagnosis and treatment of communicable diseases. The repetition of such studies is useful in reviewing health policies and regulations related to health practice in general and pharmacological policies in particular.

Saudi Vigilance Program: Challenges and lessons learned.

Pharmacovigilance is vital to public health. Adopting a robust spontaneous reporting system for adverse drug events can counteract most hazards that arise from utilizing medicinal products. Prior to the establishment of the Saudi Food and Drug Authority (SFDA), the number of pharmacovigilance-related activities in Saudi Arabia was limited. In 2009, the SFDA established the National Pharmacovigilance and Drug Safety Center (Saudi Vigilance). The pharmacovigilance system has remarkably improved during the past few years. Several initiatives have been taken to improve the program's performance. These initiatives include initiation of pharmacovigilance guidelines, enhancement of communication and reporting tools, training sessions for concerned staff and healthcare providers, and compliance from stakeholders. This review article provides an overview of what the Saudi Vigilance program is, focusing on the scope, mission and vision, hierarchy, operational themes, and overall work processes. Additionally, we will shed light on the challenges we encountered during the early phase and on our future plans.