Patient access to gene therapy medicinal products : a comprehensive review

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.Background Gene therapies have the potential to be a curative approach to a large number of genetic diseases. However, granting of a positive marketing authorisation does not equal patient access to therapy. Objectives The purpose of this paper is to identify a full set of hurdles potentially preventing patient access to gene therapies based on the available literature. Methods A review of the literature using systematic approach in two distinct databases was performed by identifying relevant, peer-reviewed publications, between 2012 and 2018. Results Seven major topics were identified as potential patient access hurdles, namely affordability, assessment of value, development of therapy, ethical/social factors, evidence generation, operational implementation and regulatory hurdles. From these, 25 additional subthemes were further identified. The most frequently mentioned obstacle in the literature is related to the affordability aspect especially focusing on high cost of therapy (84%) and therapy payment/reimbursement (51%). Importantly, the evidence generation focusing on limited trial outcomes (81%) seems as a strong obstacle in patient access to these therapies. Conclusions A growing number of gene therapies are expected to be developed and made available to patients and healthcare professionals. Improvement of patient access to gene therapies can only be achieved by understanding all hurdles, in a complete and integrated fashion, so that strategies are timely established to ensure gene therapies’ benefits are provided to patients and to the society.info:eu-repo/semantics/publishedVersio

A review of the continuous professional development system for pharmacists

Funding Information: The authors would like to acknowledge the work developed by the Council for Qualification & Admission: Ana Cabral, Carla Gomes, Francisco Batel Marques, Hugo Valente, Isabel Cunha, Laura Ribeiro, Luíza Granadeiro, Nuno Barros, Paula Campos, Paulo Cruz, Perpétua Gomes, Ricardo Lima, Rui Pinto, Liliana Ribeiro, Diana Costa, and the invaluable support of Fernanda Silva. The authors would like to acknowledge the support of the President of the Portuguese Pharmaceutical Society, Ana Paula Martins, and the National Board. Funding Information: This work was supported by the Portuguese Pharmaceutical Society. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Publisher Copyright: © 2021, The Author(s).Background: The Portuguese Pharmaceutical Society (PPS) implemented a system of Continuous Professional Development (CPD) for pharmacists in 2004. This system has evolved throughout the years, and currently all active pharmacists in Portugal are required to participate in the CPD program. Each CPD cycle takes 5 years. In each cycle, pharmacists must collect 15 CPD points, through participation in educational activities. The PPS accreditation process is managed via an online platform, where education/training providers, as well as pharmacists themselves, can submit educational activities for accreditation. Pharmacists may access their CPD status and assess their development at any point. The objective of this study was to analyze and review the educational activities submitted by providers over a 11-year period (2009–2019). Methods: Data from activities were retrieved from the PPS CPD online platform. All educational activities were labeled according to the area of pharmaceutical professional focus, type of promoter, and activity type. Results: During the study 3685 activities were analyzed. Over the last decade, submitted activities for accreditation increased in 52.6%. A significantly high proportion (98.9%) of these activities has been accredited. Promoters of activities were mostly pharmacies sectoral associations (29.6%), consultancy/training companies (19.6%), the PPS (18.5%), pharmaceutical industry (17.7%) and wholesalers’ consortia (9.0%). Academia represented only 2.3% of the total amount of educational activities. The most frequent topics were related to “pharmacology & pharmacotherapy” (9.9%), followed by “counselling” (9.8%) and “management & administration” (7.2%). The most accredited type of activities was face-to-face (68.9%) and e-learning trainings (13.1%). Conclusions: This study shows increasing interest in submitting CPD activities for accreditation between 2009 and 2019, but it also demonstrates that Academia could play a more interventive role in the lifelong learning education of Portuguese pharmacists.publishersversionpublishe

Development of TNBS-induced colitis: animal model to test new pharmacological approaches

IBD is a gastro-intestinal disorder marked with chronic inflammation of intestinal epithelium, dam- aging mucosal tissue and manifests into several intestinal and extra-intestinal symptoms. Currently used medical therapy is able to induce and maintain the patient in remission, however no modifies or reverses the underlying pathogenic mechanism. The research of other medical approaches is crucial to the treatment of IBD and, for this, it ́s important to use animal models to mimic the characteristics of disease in real life. The aim of the study is to develop an animal model of TNBS-induced colitis to test new pharmacological approaches. TNBS was instilled intracolonic single dose as described by Morris et al. It was administered 2,5% TNBS in 50% ethanol through a catheter carefully inserted into the colon. Mice were kept in a Tredelenburg position to avoid reflux. On day 4 and 7, the animals were sacrificed by cervical dislocation. The induction was confirmed based on clinical symptoms/signs, ALP determination and histopathological analysis. At day 4, TNBS group presented a decreased body weight and an alteration of intestinal motility characterized by diarrhea, severe edema of the anus and moderate morbidity, while in the two control groups weren’t identified any alteration on the clinical symptoms/signs with an increase of the body weight. TNBS group presented the highest concentrations of ALP comparing with control groups. The histopathology analysis revealed severe necrosis of the mucosa with widespread necrosis of the intestinal glands. Severe hemorrhagic and purulent exsudates were observed in the submucosa, muscular and serosa. TNBS group presented clinical symptoms/ signs and histopathological features compatible with a correct induction of UC. The peak of manifestations became maximal at day 4 after induction. This study allows concluding that it’s possible to develop a TNBS- induced colitis 4 days after instillation. DII é um distúrbio gastro-intestinal caracterizado por inflamação crónica do epitélio intestinal com dano associado da mucosa, manifestando-se a partir de sintomas intestinais e extra-intestinais. A terapia médica utilizada é capaz de induzir e manter o doente em remissão, mas não modifica ou inverte o mecanismo patogénico subjacente. A procura de outras abordagens terapêuticas é crucial para o tratamento de DII e, para tal, é importante o uso de modelos animais para mimetizar as características da doença. O objetivo do estudo é desenvolver um modelo animal de colite induzida por TNBS de modo a testar novas abordagens farmacológicas. O TNBS foi instilado por via intracolónica em dose única como descrito por Morris et al. Foi administrado 2,5% de TNBS em 50% de etanol através de um cateter inserido no cólon. Os animais foram mantidos em posição Tredelenburg para evitar o refluxo. Nos dias 4 e 7, os animais foram sacrificados por deslocamento cervical. A indução de colite foi caracterizada com base nos sintomas/sinais clínicos, determinação de ALP e análise histopatológica. No dia 4, o grupo TNBS apresentou uma diminuição do peso corporal e uma alteração da motilidade intestinal caracterizada por diarreia, edema severo do ânus e morbilidade moderada, enquanto nos dois grupos controlo não foram identificados quaisquer alterações nos sintomas/ sinais clínicos com um aumento do peso corporal. O grupo TNBS apresentou as maiores concentrações de ALP, comparando com os grupos controlo. A análise histopatológica demonstrou necrose grave da mucosa com necrose generalizada das glândulas intestinais. Foi observado exsudato hemorrágico e purulento ao nível da submucosa, muscular e serosa. O grupo TNBS apresentou sintomas / sinais clínicos e características histopatológicas compatíveis com uma correta indução de colite. O pico das manifestações tornou-se máximo ao 4º dia após a indução. Este estudo permite concluir que é possível desenvolver colite induzida por TNBS 4 dias após a instilação.

Trends in orphan medicinal products approvals in the European Union between 2010–2022

Background: Over the last twenty years of orphan drug regulation in Europe, the regulatory framework has increased its complexity, with different regulatory paths and tools engineered to facilitate the innovation and accelerate approvals. Recently, the proposal of the new Pharmaceutical Legislation for the European Union, which will replace at least three Regulations and one Directive, was released and its new framework is raising many questions. The aim of this study was to present a characterisation of the Orphan Medicinal Products (OMPs) authorised by the European Commission (EC), between 2010 and 2022, looking into eighteen variables, contributing to the ongoing discussion on the proposal and implementation of the new Pharmaceutical Legislation proposed. Methods: Data of the OMPs identified and approved between 2010 and 2022 were extracted from the European Public Assessment Reports (EPARs) produced by the European Medicines Agency. Information regarding legal basis of the application, applicant, protocol assistance received, type of authorization, registration status, type of molecule, ATC code, therapeutic area, target age, disease prevalence, number of pivotal clinical trials supporting the application, clinical trial designs, respective efficacy endpoints and number of patients enrolled in the pivotal clinical trials were extracted. A descriptive statistical analysis was applied. Results: We identified 192 OMPs approved in the period between 2010 and 2022. 89% of the OMPs have legal basis of “full application”. 86% of the sponsors received protocol assistance whereas 64% of the MAA benefited from the accelerated assessment. 53% of the active substances are small molecules; about 1 in 5 molecules are repurposed. 40% of the OMPs have oncological therapeutic indications and 56% of the OMPs are intended to treat only adults. 71% of the products were approved based on a single pivotal trial. Conclusions: This analysis of OMPs approved between 2010 and 2022 shows that a shift has occurred in the rare disease medicine development space. Through the period studied we observe an increase of non-small molecules approved, accelerated assessment received and non-standard MA’s granted

Attenuation of colonic injury and inflammation by administration of a phenolic extract of summer savory (Satureja hortensis l.) in experimental inflammatory bowel disease in mice

UIDB/04077/2020Summer Savory (Satureja hortensis L.) is a plant traditionally used as a food spice in the Mediterranean region. Surprisingly, not much is known about the health beneficial effects of its phenolic-rich extracts. The majority of publications have always focused on the properties of their essential oil. One of the main phenolic compounds of Summer Savory is rosmarinic acid, which has demonstrated anti-inflammatory outcomes in several animal models of inflammatory-mediated diseases. Inflammatory Bowel Disease (IBD) is a chronic inflammatory disease, in addition to Ulcerative Colitis and Crohn’s Disease, frequently related with increased morbidity and even mortality due to the complications associated, including colorectal cancer. Our work has shown, to our knowledge, for the first time, that administration of a phenolic extract of Summer Savory in a mouse model of Ulcerative Colitis led to the reduction of several markers for intestinal injury, including reduction of inducible nitric oxide synthase (iNOS) and Cyclooxygenase-2 (COX-2 or prostaglandin-endoperoxide synthase) expression, two well-known mediators of tissue inflammation and progression to cancer and led also to a reduction of the mortality. Given the chemical constitution found in the extract and the preclinical evidence of a beneficial effect of polyphenols in inflammatory processes, an opportunity arises for pharmacological modulation of pathways relevant for IBD and progression to cancer with phenolic-rich extracts.publishersversionpublishe

A proposed lectin-mediated mechanism to explain the in vivo antihyperglycemic activity of γ-conglutin from Lupinus albus seeds

Experiments conducted in vitro and in vivo, as well as clinical trials for hypoglycemic therapeutics, support the hypoglycemic properties of the lectin γ-conglutin, a Lupinus seed storage protein, by a mechanism not yet been clarified. Structural studies established that binding of γ-conglutin, in native and denatured form, to insulin occurs by a strong binding that resists rupture when 0.4 M NaCl and 0.4 M galactose are present, suggesting that strong electrostatic interactions are involved. Studies on binding of γ-conglutin in native and denatured form to HepG2 membrane glycosylated receptors were conducted, which reveal that only the native form of γ-conglutin with lectin activity is capable of binding to these receptors. Glycosylated insulin receptors were detected on purified HepG2 cell membranes and characterized by 1D and 2D analyses. Preclinical assays with male mice (CD-1) indicated that native and denatured γ-conglutins display antihyperglycemic effect, decreasing glucose in blood comparable after 120 min to that exhibited by the animal group treated with metformin, used to treat T2D and used as a positive control. Measurement of organ injury/functional biomarkers (hepatic, pancreatic, renal, and lipid profile) was comparable to that of metformin treatment or even better in terms of safety endpoints (pancreatic and hepatic biomarkers)info:eu-repo/semantics/publishedVersio

Pharmacotherapy of normobaric and hyperbaric oxygen

O oxigénio é considerado como um fármaco, que pode ser facilmente administrado em condições normobáricas, mas quando é utilizado em condições de pressão superiores à atmosférica requer compressão.Objectivo: Descrever estas duas modalidades terapêuticas – oxigenoterapia normobárica e oxigenoterapia hiperbárica.Fontes de dados: EBSCO, Pubmed, Elsevier, Science Direct, Springer link e Scielo. Métodos de Revisão: Artigos disponíveis desde 1980.Resultados: Foram incluídos artigos integrais de revisão e experimentais, que reportam a aplicação de oxigenoterapia normobárica e/ou hiperbárica em humanos e em modelo animal.Conclusões: As duas modalidades terapêuticas, oxigenoterapia normobárica e hiperbárica, têm normas específicas que devem ser minuciosamente seguidas de modo a ter um baixo risco de complicações.Oxygen is considered a drug that can be easily administered at normobaric conditions, but when is submitted to pressures higher than the atmospheric, it requires compression.Objective: To describe these two treatment modalities – normobaric oxygen therapy and hyperbaric oxygen therapy.Data base: EBSCO, Pubmed, Elsevier, Science Direct, Springer link and Scielo. Review Methods: Articles available since 1980.Results: were included review and experimental articles that explored the application of normobaric and hyperbaric oxygen therapy in human or in animals.Conclusions: The normobaric and hyperbaric oxygen therapy have specific rules that must be followed carefully in order to have a low risk of complications

Leveraging patient experience data to guide medicines development, regulation, access decisions and clinical care in the EU

Patient experience data (PED), provided by patients/their carers without interpretation by clinicians, directly capture what matters more to patients on their medical condition, treatment and impact of healthcare. PED can be collected through different methodologies and these need to be robust and validated for its intended use. Medicine regulators are increasingly encouraging stakeholders to generate, collect and submit PED to support both scientific advice in development programs and regulatory decisions on the approval and use of these medicines. This article reviews the existing definitions and types of PED and demonstrate the potential for use in different settings of medicines’ life cycle, focusing on Patient-Reported Outcomes (PRO) and Patient Preferences (PP). Furthermore, it addresses some challenges and opportunities, alluding to important regulatory guidance that has been published, methodological aspects and digitalization, highlighting the lack of guidance as a key hurdle to achieve more systematic inclusion of PED in regulatory submissions. In addition, the article discusses opportunities at European and global level that could be implemented to leverage PED use. New digital tools that allow patients to collect PED in real time could also contribute to these advances, but it is equally important not to overlook the challenges they entail. The numerous and relevant initiatives being developed by various stakeholders in this field, including regulators, show their confidence in PED’s value and create an ideal moment to address challenges and consolidate PED use across medicines’ life cycle