A Feasibility Study on Re-establishing the Bioavailability/Bioequivalence Unit of the Department of Pharmacology and Toxicology, College of Medicine-University of the Philippines Manila.

Objectives: The Bioavailability/Bioequivalence Unit (BA/BE Unit) of the Department of Pharmacology and Toxicology, College of Medicine, University of the Philippines Manila which has not been operational since 2012, is due for renewal of its accreditation. To date, there are only three Philippine Food and Drug Administration-accredited laboratories that perform bioequivalence studies in the Philippines. One of the prerequisites of registering specific generic medicines is the conduct of Bioequivalence (BE) studies which are performed to ensure that the generic drug is at par with the innovator drug. Thus, this study aimed to determine the feasibility of re-establishing the BA/BE Unit as a bioequivalence testing center. Methods: The feasibility study done is a qualitative descriptive analysis based on expansive literature review and performance of SWOT analysis within the BA/BE unit. Literatures were selected based on its assessed relevance to the study. The databases checked were PubMed and Google Scholar. The terms used were from the Medical Subject Heading (MeSH) including feasibility studies, therapeutic equivalency, and generic drugs. Literature review was performed on the factors affecting the four types of feasibility studies (market, technical, financial, and organizational). A SWOT analysis of the BA/BE Unit was done through the review of records and documents of previous BE studies and focus group discussion among the BA/BE Unit team members. Results: The BA/BE Unit conducted 24 bioequivalence studies from 2006-2009 and still receives inquiries from drug companies. It implements its QMS throughout the pre-analytical, analytical, and post-analytical stages of the workflow. Its organizational structure consists of qualified professionals with updated GCP and GLP certificates. Because of the adequately equipped facility, lower honoraria for government-employed personnel, and lower expenses for laboratories and in-patient admissions, the cost of conducting a bioequivalence study in the BA/BE Unit will be lower than in other BE centers. Conclusion: Based on the SWOT analysis and market, technical, financial, and organizational considerations, re-establishing the BA/BE Unit as a bioequivalence testing center is feasible.

Hegemonía en el pluralismo médico: articulaciones y relaciones en la atención, un estudio de caso / Hegemony in medical pluralism: articulations and relationships in care, a case study / Hegemonia no pluralismo médico: articulações e relações no atendimento, um estudo de caso

Este estudio tiene como objetivo describir y analizar el pluralismo médico y el tipo de relaciones de hegemonía-subalternidad entre diversas formas o saberes de atención, que se desarrollaron en el itinerario terapéutico de una padeciente de glaucoma, para mostrar el proceso articulatorio y transaccional entre distintos recursos terapéuticos, así como comprender qué elementos estructurales configuraron el itinerario y la elección terapéutica. La investigación es cualitativa, un estudio de caso en el cual se utilizó el enfoque narrativo. Para la reconstrucción de la narrativa se realizó una entrevista semiestructurada, dirigida por una guía temática previamente determinada por un conjunto de categorías apriorísticas, para posteriormente transcribir la entrevista y realizar un proceso de triangulación hermenéutica. Los resultados mostraron, en este caso, que la hegemonía en el pluralismo médico se constituyó mediante relaciones de equivalencia, así, la padeciente sustituyó el uso de medicamentos farmacológicos por terapias de medicina alternativa, no obstante, el proceso relacional de equivalencia se desarrolló en un contexto de significación biomédica, en el cual tratar o controlar la presión intraocular fue la premisa del remplazo. Asimismo, los procesos que desencadenaron la presencia de relaciones hegemónicas se constituyeron por diversos factores sociales, culturales y económicos como el desempleo, la seguridad social y el género, que desempeñaron un papel fundamental durante la búsqueda de la atención y del cuidado.

This study aims to describe and analyze the medical pluralism and the type of hegemony-subordination relation between forms of care or knowledge in the treatment of a patient with glaucoma to show the articulatory and transactional process between several therapeutic resources and understand which structural elements shaped the treatment itinerary and option. This is a qualitative research that used a narrative case study. To reconstruct the narrative, a semi-structured interview was conducted based on a thematic script previously established by a set of a priori categories to later transcribe the data and perform hermeneutic triangulation. Results showed that the hegemony in medical pluralism was based on equivalence relations, so that the patient replaced the use of pharmacological drugs with alternative medicine treatments. However, the relational process of equivalence developed itself in a context of biomedical significance, in which the treatment or control of intraocular pressure configured the substitution premise. Thus, the processes that triggered the hegemonic relations were constituted by various social, cultural, and economic factors such as unemployment, social security, and gender, which played a fundamental role during the search for care.

Este estudo visa descrever e analisar o pluralismo médico e o tipo de relação de hegemonia-subalternidade entre diversas formas de atendimento ou conhecimentos, que ocorreram no tratamento de um paciente com glaucoma, com a finalidade de mostrar o processo articulatório e transacional entre diferentes recursos terapêuticos, bem como entender quais elementos estruturais moldaram o itinerário e a opção de tratamento. Trata-se de uma pesquisa qualitativa, que utilizou um estudo de caso com abordagem narrativa. Para a reconstrução da narrativa, foi realizada uma entrevista semiestruturada, com base em um roteiro temático previamente estabelecido por um conjunto de categorias a priori, para posteriormente transcrever os dados e realizar a triangulação hermenêutica. Os resultados mostraram que a hegemonia no pluralismo médico esteve baseada em relações de equivalência, de modo que o paciente substituiu o uso de medicamentos farmacológicos por tratamentos da medicina alternativa; no entanto, o processo relacional de equivalência desenvolveu-se em um contexto de significância biomédica, na qual o tratamento ou controle da pressão intraocular foi a premissa para a substituição. Desse modo, os processos que desencadearam a presença de relações hegemônicas foram constituídos por fatores sociais, culturais e econômicos diversos como desemprego, previdência social e gênero, os quais tiveram papel fundamental durante a busca por atendimento e cuidado.

Second International Consensus Study of Antipsychotic Dosing (ICSAD-2).

BACKGROUND: Expert consensus-based clinically equivalent dose estimates and dosing recommendations can provide valuable support for the use of drugs for psychosis in clinical practice and research. AIMS: This second International Consensus Study of Antipsychotic Dosing provides dosing equivalencies and recommendations for newer drugs for psychosis and previously reported drugs with low consensus. METHODS: We used a two-step Delphi survey process to establish and update consensus with a broad, international sample of clinical and research experts regarding 26 drug formulations to obtain dosing recommendations (start, target range, and maximum) and estimates of clinically equivalent doses for the treatment of schizophrenia. Reference agents for equivalent dose estimates were oral olanzapine 20 mg/day for 15 oral and 7 long-acting injectable (LAI) agents and intramuscular haloperidol 5 mg for 4 short-acting injectable (SAI) agents. We also provide a contemporary list of equivalency estimates and dosing recommendations for a total of 44 oral, 16 LAI, and 14 SAI drugs for psychosis. RESULTS: Survey participants (N = 72) from 24 countries provided equivalency estimates and dosing recommendations for oral, LAI, and SAI formulations. Consensus improved from survey stages I to II. The final consensus was highest for LAI formulations, intermediate for oral agents, and lowest for SAI formulations of drugs for psychosis. CONCLUSIONS: As randomized, controlled, fixed, multiple-dose trials to optimize the dosing of drugs for psychosis remain rare, expert consensus remains a useful alternative for estimating clinical dosing equivalents. The present findings can support clinical practice, guideline development, and research design and interpretation involving drugs for psychosis.

Revisiting the Mesenchymal "Stem vs. Stromal" Cell Dichotomy and Its Implications for Development of Improved Potency Metrics.

Mesenchymal stem/stromal cell (MSC)-based therapies have been evaluated in over 1500 human clinical trials for a diverse array of disease indication, but outcomes remain unpredictable due to knowledge gaps in the quality attributes that confer therapeutic potency onto cells and their mode of action in vivo. Based on accumulated evidence from pre-clinical models, MSCs exert therapeutic effects by repressing inflammatory and immune-mediated response via paracrine action following reprogramming by the host injury microenvironment, and by polarization of tissue resident macrophages following phagocytosis to an alternatively activated (M2) state. An important tenet of this existing paradigm is that well-established stem/progenitor functions of MSCs are independent of paracrine function and dispensable for their anti-inflammatory and immune suppressive functions. Herein, we review evidence that stem/progenitor and paracrine functions of MSCs are mechanistically linked and organized hierarchically and describe how this link may be exploited to develop metrics that predict MSC potency across a spectrum of activities and regenerative medicine applications.

An open-label, randomized, crossover study to evaluate the bioavailability of nanoemulsion versus conventional fat-soluble formulation of cholecalciferol in healthy participants.

Background: Nanoemulsion preparations of cholecalciferol available in the market claim to have better bioavailability than the conventional fat-soluble cholecalciferol. However, limited data are available in humans for such preparations. We, therefore, compared the relative bioavailability of two formulations of 60,000 IU cholecalciferol (nanoemulsion oral solution, water-miscible vitamin D3 [test] vs soft gelatin capsules [reference]) in healthy adult participants. Methods: In this randomized, open-label, two sequence, single-dose, two-way crossover study (CTRI/2018/05/013839), Indian participants aged 18-45 years received single dose of nanoemulsion and capsule formulations, under fasting conditions. Blood samples collected over 120 h were assessed to determine cholecalciferol concentrations. Pharmacokinetic parameters (area under the concentration-time curve up to 120 h [AUC0-120h], maximum observed drug concentration [Cmax], time to reach maximum drug concentration [Tmax], terminal half-life [T½el], and terminal elimination rate constant [Kel]) were estimated using baseline corrected data and analyzed using analysis of variance. Results: Among the 24 eligible participants, the relative bioavailability of nanoemulsion was significantly higher than the capsules by 36% (p = 0.0001) based on AUC0-120h. Similarly, Cmax of the nanoemulsion was significantly higher by 43% (p = 0.0001) than that of the capsules. The intra-participant variability for AUC0-120h and Cmax were 23.22% and 26.51%, respectively. The Tmax, T½el, and Kel were comparable for both the formulations. No adverse effects were noted with either of the two formulations. Conclusions: Nanoemulsion oral solution of cholecalciferol showed a greater bioavailability compared with soft gelatin capsules, under fasting conditions, in healthy human participants.

Is bad breath associated with dyspepsia? An association and an equivalence study

Abstract Halitosis affects all populations worldwide. The presence of chronic halitosis may be related to a health problem. Patients with bad breath usually seek a gastroenterologist and, in some cases, invasive and expensive exams, such as digestive endoscopy, are performed to investigate the etiology of halitosis. This study aimed to investigate whether the prevalence of bad breath in patients diagnosed with dyspepsia (any pain or discomfort in the upper abdomen) is higher than or equivalent to that in non-dyspeptic patients. This is a cross-sectional study that included 312 patients from university hospitals in the city of Rio de Janeiro (141 dyspeptic patients and 171 non-dyspeptic ones). The presence of halitosis was defined based on different cutoff points. Association analyses were performed using a log-binomial model and 95% confidence intervals were calculated for the coefficients, adjusting for sex and age. The equivalence test (Westlake) was used to test the hypothesis of equivalence between the proportions of patients with bad breath in the two groups (dyspeptic vs. non-dyspeptic), considering an equivalence band of ± 15%. The prevalence of bad breath ranged from 30% to 64% according to the definition of bad breath. Dyspepsia was not associated with bad breath in any of the three definitions of bad breath (two specific ones and a sensitive one). The proportion of patients with marked bad breath was equivalent in patients with and without dyspepsia.

Perioperative Efficiency of Sugammadex Following Laparoscopic Cholecystectomy in Clinical Practice.

Background: Studies have proposed that the routine use of the modified gamma-cyclodextrin, sugammadex, could provide perioperative time savings. However, these investigations have been limited to small group analyses. The purpose of this study was to test the effectiveness of sugammadex on perioperative times when compared to neostigmine under general clinical practice conditions following rocuronium-induced neuromuscular blockade for laparoscopic cholecystectomy. Methods: Following institutional review board approval, data from 1,611 consecutive surgical records for laparoscopic cholecystectomy were reviewed. Patient characteristics, type of primary neuromuscular blocking reversal agent, operating room (OR) discharge times, and postanesthesia care unit (PACU) recovery times were the measures of interest. Equivalence testing was used to determine the between-group differences of the reversal agents in the two perioperative time periods of interest. Results: OR discharge times averaged 10.9 (95% CI, 10-11.8) minutes for patients administered sugammadex and 8.9 (95% CI, 8.2-9.7) minutes for patients administered neostigmine. PACU recovery times averaged 77.6 (95% CI, 74.1-81.1) minutes for sugammadex and 68.6 (95% CI, 65.9-71.3) minutes for neostigmine. Equivalence testing demonstrated no improvement in the two perioperative times with sugammadex. Conclusion: These results suggest no perioperative time savings with sugammadex when compared to neostigmine following laparoscopic cholecystectomy under general clinical practice conditions.

Paediatric oral formulations: Why don't our kids have the medicines they need?

Medication use in children represents 15-20% of total drug sales. More than 50% of children receive at least one prescription medication a year. Despite this, few drugs have a paediatric formulation available. Furthermore, 80% of paediatric prescriptions are considered off-label. Off-label use is defined as the use of products that differ in dose, indication or route of administration from the one established in the summary of product characteristics. Off-label use is associated with an increased risk of adverse drug reactions, including therapeutic failure. The US Food and Drug Administration and the European Medicines Agency have made changes to regulations to incentivize the development of paediatric formulations. Novel paediatric formulations can ease drug administration, reducing medication errors, increasing dosing acceptability, medication adherence and improve safety. Two routes for paediatric drug approval are available, the traditional, requiring clinical trials and the formulation bridging path, where these formulations need to demonstrate equivalence with the existing adult formulations. New formulations seeking regulatory approval require bioequivalence studies, but the regulatory framework, which states that bioequivalence data are obtained from adults and then extrapolated to children, may be disregarding important physiological differences between these two populations of patients. It is important to ensure that drugs for children have been appropriately studied and are properly manufactured for them. Adequately designed studies will provide data that will improve our understanding of how drug disposition differs between adults and children and will pave the way for children to get the best possible treatment.

The effect of tranexamic acid on blood loss in orthognathic surgery: a randomized, placebo-controlled, equivalence study.

Orthognathic surgery can cause substantial bleeding. Recent meta-analyses concluded that there is a statistically significant reduction in perioperative blood loss with the preventive use of tranexamic acid (TA). However, the mean reported difference in bleeding was moderate, and the clinical relevance of this blood-sparing effect remains debated. We therefore conducted a prospective, double-blind, randomized, placebo-controlled equivalence study of the effect of TA in patients undergoing Lefort I or bimaxillary osteotomies. Our main outcome measure was total blood loss on postoperative day 1. The equivalence margin was ± 250 ml for the difference in blood loss and its 95% confidence interval. One hundred and forty-seven patients were randomized, of which 122 underwent bimaxillary osteotomies. Blood loss in the treatment group was 682 ± 323 vs. 875 ± 492 ml. The mean difference in bleeding was -132 [-243; -21] ml as per-protocol, but -193 [-329; -57] ml in intention-to-treat: the limits of this confidence interval exceeded the margin of equivalence. Similar results were obtained when analysing only patients undergoing bimaxillary osteotomy. Haemoglobin decreased by 1.8 ± 1.2 g/dl with TA, vs. 2.6 ± 1.1 g/dl with placebo (p<0.001). Our study did not demonstrate equivalence between TA and placebo on perioperative blood loss in orthognathic surgery. TA may reduce blood loss but without evidence of clinical consequences.

Calidad Biofarmacéutica e Intercambiabilidad de Medicamento / Biopharmaceutical Quality and Interchange of Drugs

Introducción: La industria farmacéutica que busca la aprobación para comercializar un medicamento genérico debe presentar datos que demuestren que la formulación genérica proporciona la misma calidad, eficacia y seguridad que el medicamento innovador. Por lo tanto, la mayoría de los medicamentos genéricos administrados por vía oral están aprobados en función de los resultados de uno o más estudios fisicoquímicos y biofarmacéuticos para demostrar bioequivalencia y posterior intercambiabilidad.Objetivo: Identificar en los artículos de investigación las posibles diferencias entre las pruebas fisicoquímicas y biofarmacéuticas de bioequivalencia de medicamentos genéricos con la de sus homólogos ya comercializados.Método: Se realizó la revisión de estudios de investigación originales, publicados desde enero del año 2003 hasta diciembre del 2019. Se consultaron 4 bases de datos Pubmed, ScienceDirect, Lilacs, Scielo. En inglés y español. Los descriptores utilizados fueron medicamento genérico, bioequivalencia, equivalencia terapéutica e intercambialidad, así mismo solo se seleccionaron aquellos artículos donde su forma farmacéutica de estudio fuese comprimidos.Resultados: Se seleccionaron en total 40 artículos para su evaluación, de los cuales 19 llegaron a la conclusión de bioequivalencia, otros 19 determinaron no bioequivalencia, para 1 no existía una conclusión definitiva, mientras que en 1 estudio que evaluaba a 3 medicamentos, la conclusión fue no bioequivalencia para 2 de ellos y para el tercero sí la había.Conclusión: La revisión revela que los estudios son insuficientes para indicar bioequivalencia entre los fármacos multifuentes (genéricos) y los innovadores, por lo que se necesita ampliar los estudios de bioequivalencia. (AU)

Introduction: The pharmaceutical industry seeking approval to market a generic drug must submit data demon-strating that the generic formulation provides the same quality, efficacy, and safety of the innovative drug. There-fore, most orally administered generic drugs are approved based on the results of one or more physicochemical and biopharmaceutical studies to demonstrate bioequivalence and subsequent interchangeability. Objective: Identify in research articles the possible differences between the physicochemical and biopharmaceuti-cal tests of bioequivalence of generic drugs with that of their corresponding innovative equivalents. Method: The original research studies, published from January 2003 to December 2019, were reviewed. 4 databases were consulted Pubmed, ScienceDirect, Lilacs, Scielo. In English and Spanish. The descriptors used were generic medicine, bioequivalence, therapeutic equivalence and interchangeability, likewise only those articles where their study pharmaceutical form was tablets were selected. Results: A total of 40 articles were selected for evaluation, of which 19 reached the conclusion of bioequivalence, another 19 determined non-bioequivalence, for 1 there was no definitive conclusion, while in a study that evaluated 3 drugs, the conclusion was no bioequivalence for 2 of them and bioequivalence for one. Conclusions: The review reveals that the studies are insufficient to indicate bioequivalence between multi-source (generic) and innovative drugs, so that bioequivalence studies need to be expanded. (AU)

Tackling the challenges of nanomedicines: are we ready?

PURPOSE: This review provides an overview of the proceedings of the symposium "Tackling the Challenges of Nanomedicines: Are We Ready?" organized by the International Pharmaceutical Federation (FIP) Hospital Pharmacy Section and Non-Biological Complex Drugs (NBCDs) Working Group at the 2019 FIP World Congress of Pharmacy and Pharmaceutical Sciences. Debate centered on reasons underlying the current complex regulatory landscape for nanomedicines and their follow-on products (referred to as nanosimilars) and the pivotal role of hospital pharmacists in selecting, handling, and guiding usage of nanomedicines and nanosimilars. SUMMARY: The evaluation and use of nanomedicines are recognized among scientific, pharmaceutical, and regulatory bodies as complex. Interchangeability and substitutability of nanomedicines and nanosimilars are confounded by a lack of pharmaceutical and pharmacological equivalence, reflecting the inherent complex nature of these drug products and manufacturing processes. Consequences include implications for clinical safety and efficacy and, ultimately, comparability. Local regulatory approvals of some nanomedicines have occurred, but there is no standard to ensure streamlined evaluation and use of consistent measures of therapeutic equivalence of reference products and their nanosimilars. Hospital pharmacists are expected to be experts in the selection, handling, and substitution of nanomedicines and familiarize themselves with the limitations of current methods of assessing pharmaceutical and clinical equivalence of nanosimilars in order to ensure informed formulary decision-making and eventual patient benefit. CONCLUSION: Supportive guidance for pharmacists focusing on the substitutability and/or interchangeability of nanomedicines and their nanosimilars is needed. Current FIP guidance for pharmacists on therapeutic interchange and substitution should be extended to include nanomedicines and nanosimilars.

Intercambiabilidad de medicamentos en el Perú: panorama actual y perspectivas futuras

Los medicamentos genéricos desempeñan un papel importante en los sistemas de atención de salud, ya que representan una alternativa eficaz más asequible para la población. En el Perú, se estableció un reglamento que regula la intercambiabilidad de medicamentos genéricos (también llamados multifuentes), que define los procedimientos y requisitos a seguir para desarrollar estudios de equivalencia terapéutica in vivo e in vitro, siguiendo el enfoque de aplicación gradual y el criterio de riesgo sanitario. El cumplimiento de este reglamento permitirá un mayor acceso a medicamentos genéricos eficaces, seguros y de calidad. Mientras tanto, se siguen comercializando genéricos en ausencia de estudios de equivalencia terapéutica. Los estudios demuestran que algunos medicamentos fallaron en las comparaciones in vivo e in vitro con el medicamento de referencia. Esta implementación representa un gran desafío para los laboratorios fabricantes y los titulares de registros sanitarios a fin de demostrar la intercambiabilidad de sus productos farmacéuticos con el medicamento de referencia.

Generic drugs play an important role in healthcare systems as they represent an effective and more affordable alternative for the population. In Peru, a regulation of interchangeability of generic drugs (also called multisource drugs) was stablished to define the procedures and requirements for developing in vivo and in vitro therapeutic equivalence studies, following the gradual application approach and sanitary risk criteria. Compliance with the new regulation will allow greater access to effective, safe and quality generic drugs. Meanwhile, drugs continue to be marketed in the absence of therapeutic equivalence studies. Findings show that some drugs failed in in vivo and in vitro comparisons with the reference product. This regulation represents a great challenge for manufacturers and holders of sanitary registrations in order to demonstrate the interchangeability of their pharmaceutical products with the reference product.

Analysis of clinical trials of dermatological drugs in China, 2020 / 中华皮肤科杂志

Objective:To deliver understanding of the latest research progress on clinical trials and approval of dermatological drugs in China in 2020.Methods:A registration and information disclosure platform for drug clinical studies and a query system for domestic and imported drugs in the National Medical Products Administration of China were searched for registered clinical trials and approved dermatological drugs, respectively. The number and stages of clinical trials, indications and classification of involved products, and listed dermatological drugs in 2020 were summarized and depicted.Results:There were 157 dermatological drug trials registered in China in 2020, accounting for 6.16% of all the 2 548 clinical drug trials, including 127 (80.9%) initiated by Chinese pharmaceutical enterprises and 25 (15.9%) international multicenter trials. Among the 127 drug trials initiated by Chinese pharmaceutical enterprises, bioequivalence trials were mostly common, accounting for 55.9% (71/127) . Compared with global pharmaceutical enterprises, domestic pharmaceutical companies initiated significantly decreased proportions of international multicenter trials (1.9% [3/157] vs. 14.0% [22/157], P < 0.001) , but significantly increased proportions of phaseⅠclinical trials and bioequivalence trials (24.4% [31/127] vs. 10.0% [3/30], 55.9% [71/127] vs. 0, respectively, both P < 0.001) . Totally, 90 kinds of dermatological drug were involved in all the trials, psoriasis, atopic dermatitis and melanoma were the most common indications, and innovative drugs accounted for 53.3% (48/90) ; the proportion of innovative drugs was significantly lower in domestic pharmaceutical companies than in global pharmaceutical companies (43.2% [32/74] vs. 16/16, P < 0.001) . In addition, 28 dermatological drugs developed by 22 pharmaceutical companies were approved in China in 2020, of which 21 drugs were developed by domestic pharmaceutical companies. Conclusion:Clinical drug trials carried out by domestic pharmaceutical companies mostly focus on generic drugs, and it is still necessary for domestic pharmaceutical companies to further improve the innovation ability.

Taxas de descontinuação do tratamento após a troca de um biológico originador por um biossimilar em pacientes com doenças inflamatórias intestinais: revisão sistemática e metanálise / Discontinuation rates following a switch from a reference to a biosimilar biologic in patients with inflammatory bowel disease: a systematic review and meta-analysis

ABSTRACT BACKGROUND: Biologics have revolutionized the treatment of inflammatory bowel disease (IBD). However, these drugs had a significant influence on treatment-related costs, which resulted in the development of biosimilars. OBJECTIVE: This systematic review and meta-analysis aimed to evaluate the drug discontinuation rate in the IBD population who switched from originator to biosimilars in real-world switching studies and address potential nocebo effects as reasons for drug discontinuation. METHODS: Medline (via PubMed), EMBASE, Cochrane Library, and abstract databases of selected congresses were screened for reports of monoclonal antibody (mAb) switching with a minimum post-switch follow-up of >6 months or three infusions. All available information on discontinuation rates was assessed. RESULTS: A total of 30 observational studies were included, involving 3,594 patients with IBD. Twenty-six studies reported a switch from infliximab to CT-P13, two studies involved a switch to SB2, and switching information was not available in two studies. The discontinuation rates were 8%, 14%, and 21% at 6, 12, and 24 months, respectively. The main reasons for drug discontinuation and their respective risks were: disease worsening (2%), remission (4%), loss of adherence (4%), adverse events (5%), and loss of response (7%). The quality of the evidence ranged from low to very low depending on the outcome analyzed. Subjective symptoms leading to drug discontinuation were infrequently reported, and the nocebo effect was clearly assessed in just one of the included papers. CONCLUSION: Discontinuation rates following a switch to a biosimilar in patients with IBD increase over time. However, it was not possible to confirm the nocebo effect as a reason for discontinuation. Therefore, long-term studies evaluating the use of biosimilars to monitor adverse events and potential nocebo effects in post-marketing surveillance are still needed.

RESUMO CONTEXTO: Os biológicos revolucionaram o tratamento da doença inflamatória intestinal (DII). Ademais, esses medicamentos influenciaram os custos relacionados ao tratamento. Tal aumento significativo nos gastos com o tratamento motivou desenvolvimento dos biossimilares. OBJETIVO: Esta revisão sistemática e metanálise objetivou avaliar a taxa de descontinuação de medicamentos na população com DII que foi submetida à troca do biológico originador para um biossimilar, em estudos observacionais que abordaram possíveis razões para a descontinuação do tratamento. MÉTODOS: Tendo como base de dados Medline (via PubMed), EMBASE, Cochrane Library e resumos de congressos médicos, foram rastreados artigos com relatos de troca de um biológico originador por um biossimilar, com acompanhamento pós-troca de no mínimo 6 meses ou três infusões. Todas as informações disponíveis sobre as taxas de descontinuação foram avaliadas. RESULTADOS: Foram incluídos no total 30 estudos observacionais, envolvendo 3.594 pacientes com DII. Vinte e seis estudos relataram uma mudança do infliximabe para CT-P13, dois estudos envolveram uma mudança para o SB2, e as informações sobre a troca não estavam disponíveis em dois estudos. As taxas de descontinuação foram de 8%, 14% e 21% aos 6, 12 e 24 meses, respectivamente. Os principais motivos para a descontinuação do medicamento e seus respectivos riscos foram: agravamento da doença (2%), remissão (4%), perda de adesão (4%), eventos adversos (5%) e perda de resposta (7%). A qualidade da evidência variou de baixa a muito baixa, dependendo do resultado analisado. Os sintomas subjetivos que levaram à descontinuação do medicamento foram relatados com pouca frequência, e o efeito nocebo foi claramente avaliado em apenas um dos artigos incluídos. CONCLUSÃO: As taxas de descontinuação após a mudança para um biossimilar em pacientes com DII aumentam com o tempo. No entanto, não foi possível confirmar o efeito nocebo como motivo da descontinuação. Portanto, ainda são necessários estudos em longo prazo avaliando o uso de biossimilares para monitorar eventos adversos e potenciais efeitos nocebo na vigilância pós-comercialização.

Eficacia en el control de la anticoagulación de los diferentes fármacos antagonistas de la vitamina K disponibles en Chile

Background: Vitamin K antagonist medications (VKA) are essential for the prevention of thromboembolic events, but their effectiveness is influenced by multiple factors, such as the type of medication chosen. Aim: To evaluate the efficacy in anticoagulant control of the bioequivalent and non-bioequivalent drugs of acenocoumarol compared to the reference drug. To evaluate the efficacy of warfarin bioequivalents available in Chile. To contrast the overall anticoagulant control efficacy between acenocoumarol and warfarin. Material and Methods: The results of 69333 outpatient oral anticoagulation controls were analyzed. Patient were separated in groups according to the drug that they used. Subsequently, the proportions of controls outside the range for each of acenocoumarol and warfarin bioequivalent drugs were compared. Acenocoumarol non-bioequivalent drugs were also compared with the reference drug. Acenocoumarol was compared with warfarin. Results: Acenocoumarol bioequivalent drugs and the reference drug had a similar proportion of controls outside the range (Odds ratios (OR) 0.812; 0.969; 0.974 and 0.963). Non-bioequivalent drugs had a higher proportion than the reference drug (OR 1.561 and 2.037). Both warfarin brands have a similar proportion of controls outside of the range (OR 1.050). Acenocoumarol compared to warfarin had a significant higher proportion of controls outside the range (OR 1.191). Conclusions: The pharmacological presentation of vitamin K antagonists could influence anticoagulant control. Therefore, it is not prudent to switch these presentations frequently.

Expressividade do profissional da voz: processo de construção de um roteiro fonoaudiológico de observação / Expressiveness of voice professionals: construction process of a speech-language pathology assessment script

RESUMO Objetivo criar uma versão consenso de roteiro de observação fonoaudiológica da expressividade. Método o processo foi dividido em três etapas sendo a primeira levantamento e classificação das variáveis encontradas nos instrumentos apresentados na literatura; e nas etapas 2 e 3, na direção de trabalho coletivo, juízes especialistas (grupo focal I e II) criaram e adequaram, junto com a pesquisadora, a versão consenso do roteiro de avaliação da expressividade. Resultados a lista inicial apresentada aos juízes continha 48 variáveis presentes na literatura, sendo 11 relacionados a aspectos emocionais e de interpretação, 20 à expressividade oral, três a aspectos relacionados à expressividade verbal e, finalmente, 14 à expressividade não verbal. Na etapa 2, a versão inicial do roteiro do grupo focal I resultou num documento com 28 parâmetros distribuídos em três grupos temáticos de avaliação: aspectos gerais de comunicação, com três parâmetros; aspectos relacionados à expressividade oral, com 16; e aspectos relacionados à expressividade corporal, com nove parâmetros. Na etapa 3, a versão consenso, após a adequação do grupo focal II, também foi finalizada com 28 parâmetros, distribuídos em dois eixos temáticos. Conclusão a versão consenso do Roteiro Fonoaudiológico de Observação da Expressividade foi finalizada com 28 parâmetros, distribuídos em dois eixos temáticos sendo: de impacto inicial da comunicação, com seis parâmetros; e expressividade, com 22.

ABSTRACT Purpose To create a consensus version of a speech-language pathology (SLP) script to assess the expressiveness of voice professionals. Methods The process was divided into three stages: stage 1 included a survey of the literature and classification of the variables found in the instruments used; in steps 2 and 3, through teamwork, expert judges (focus groups I and II) created and adapted, along with the researcher, a consensus version of the expressiveness assessment script. Results The initial list presented to the judges contained 48 variables found in the literature: 11 related to emotional and interpretation aspects, 20 associated with oral expressiveness, three related to issues of verbal expressiveness, and 14 related to nonverbal expressiveness. In stage 2, the initial version of the script of the focus group I resulted in a document with 28 parameters, distributed in three thematic assessment groups: general aspects of communication, with three parameters; aspects related to oral expressiveness, with 16 parameters; aspects associated with body expressiveness, with nine parameters. In stage 3, after adequacy by focus group II, the consensus version also resulted in 28 parameters, distributed in two thematic groups. Conclusion The consensus version of the SLP expressiveness assessment script for voice professionals was finalized with 28 parameters, distributed in two thematic axes: initial impact of communication, with six parameters; expressiveness, with 22 parameters.

Switching medication products during the treatment of psychiatric illness.

BACKGROUND: The common practice of switching between branded (reference) medications and their corresponding generic products, between generic products, or even from a generic product to a branded medication during the treatment of central nervous system (CNS) disorders may compromise efficacy and/or tolerability. METHODS: We assessed the published literature from March 1, 2010 through June 30, 2017 via PubMed using the MeSH term 'generics, drugs' alone and in combination with class-specific terms (e.g., 'anticonvulsants', 'mood stabilisers'), for studies detailing outcomes following product switches. RESULTS: Although some studies comparing the initiation of reference versus generic drugs suggest equivalence between products, several studies detailing a switch between reference and generic products describe reductions in efficacy, reduced medication adherence and persistence, and increased overall health care resource utilization and costs associated with generic substitution. CONCLUSION: When product switches are considered, they should only proceed with the full knowledge of both patient and provider.

Relative Bioavailability of a Single 4-mg Dose of Somatropin Administered by Subcutaneous Injection or by Needle-free Device and Coadministered With the Growth Hormone Inhibitor Octreotide Acetate in Healthy Adult Subjects.

PURPOSE: Somatropin, used to treat growth hormone deficiency, has been traditionally administered by subcutaneous (SC) injection with needle and syringe. Needle-free devices offer ease of administration and may improve adherence and outcomes. This study evaluated the relative bioavailability of somatropin delivered with a needle-free device compared with traditional SC injection. METHODS: In this randomized, single-dose, crossover study, healthy adults aged 18 to 35 years received single 4-mg doses of somatropin via a needle-free device or SC injection, along with octreotide to suppress endogenous growth hormone production. Blood samples were analyzed for serum somatropin and insulin-like growth factor-1 (IGF-1) concentrations over 24 hours after somatropin dosing. Pharmacokinetic and pharmacodynamic parameters were evaluated by using noncompartmental methods, and bioequivalence was determined based on ln transformation of the AUC0-24, AUC0-∞, Cmax, area under the effect-time curve from time 0 to 24 hours (AUEC0-24), and maximum effect concentration (Emax). Bioequivalence was concluded if the 90% CIs of the needle-free device compared with the SC injection, constructed by using the two 1-sided hypotheses at the α = 0.05 level, for these pharmacokinetic/pharmacodynamic parameters fell within the 80.00% to125.00% regulatory acceptance range. FINDINGS: A total of 57 subjects completed both study periods and were included in the pharmacokinetic analyses. Point estimates (90% CIs) of the geometric mean ratio (needle-free device/SC injection) based on serum somatropin were 1.013 (0.987-1.040) for AUC0-24, 1.012 (0.986-1.038) for AUC0-∞, and 1.200 (1.137-1.267) for Cmax. For IGF-1, baseline-corrected point estimates (90% CIs) were 0.901 (0.818-0.993) for AUEC0-24 and 0.867 (0.795-0.946) for Emax. Non-baseline-corrected values were 0.978 (0.953-1.004) for AUEC0-24 and 0.953 (0.923-0.984) for Emax. Both treatments were well tolerated; blood glucose levels increased in nearly all subjects (98.3%). All adverse events were mild and resolved spontaneously within 24 hours. IMPLICATIONS: Bioequivalence was shown for a single 4-mg dose of somatropin delivered by using a needle-free device compared with SC injection based on ln-transformed AUC0-24 and AUC0-∞ but not ln-transformed Cmax.

Ensuring the Consistency of Biosimilars.

BACKGROUND: Biological products are subject to constant reappraisal by regulatory agencies and pharmaceutical companies once they have entered the market, since every improvement in their manufacturing process has the potential to alter the basic properties of these molecules. METHODS: Narrative review focusing on scientific literature as well as legal documents from regulatory agencies. RESULTS: Evaluating the impact of each manufacturing change of these drugs requires rigorous analyses in proportion to the anticipated risk of inducing more or less molecular micro-heterogenicity. There are currently more than 30 biosimilars of TNF-α blockers at different stages of testing, each with a specific manufacturing process. Although the initial demonstration of biosimilarity is now a well-established exercise, it does not guarantee that successive manufacturing changes will not result in a widening gap between drifted/evolved innovators and drifted/evolved biosimilars, as well as among the different biosimilars of a given original biologic. CONCLUSION: Given the structural complexity of TNF-α blockers-as well as of other biologic drugs included in the armamentarium of systemic inflammatory diseases-regulatory agencies should make available to the practitioner, in a simple and constantly updated way, all available data regarding quality standards of both original molecules and biosimilars. Furthermore, they should strive to guarantee that, once a compound has received approval, it maintains a level of consistency throughout its commercial life in order to maintain and increase confidence in these valuable drugs.