Tuberculosis medicines for children in Europe: an unmet medical need.

The availability of first-line medicines for the treatment of drug-susceptible tuberculosis (TB) is inconsistent across European countries. This is particularly worrisome for child-friendly medicines. There are reported examples of physicians being forced to adapt and/or combine formulations intended for adults to treat children with TB. Reduced compliance, unknown effects on treatment outcomes and unpredictable toxicity are potential consequences of resorting to these suboptimal treatment options. Furthermore, the use of these alternatives may increase the risk of drug-resistant TB. This study analysed the availability and use of TB medicines in the European Union (EU)/European Economic Area, with a particular focus on child-friendly formulations. We sought to carry out a full review of the situation by means of a survey involving the EU regulatory network. Countries were asked to confirm marketing status of anti-drug-susceptible-TB medicines, ways used to overcome their absence in their territory and the general difficulties they face to treat children with TB. Results confirmed that rifampicin suspension is the only child-friendly formulation available in Europe, approved in just 10 member states. Overall, 24 countries out of 30 considered the lack of adequate drug-susceptible TB medicines an unmet medical need. To overcome this, countries confirmed that they resort to importation or use adapted formulations. The joint forces of European institutions and pharmaceutical industry are crucial for the development of paediatric formulations and contribute to better compliance and health outcomes.

Current and future developments in the pharmacology of asthma and COPD: ERS seminar, Naples 2022.

Pharmacological management of airway obstructive diseases is a fast-evolving field. Several advances in unravelling disease mechanisms as well as intracellular and molecular pathways of drug action have been accomplished. While the clinical translation and implementation of in vitro results to the bedside remains challenging, advances in comprehending the mechanisms of respiratory medication are expected to assist clinicians and scientists in identifying meaningful read-outs and designing clinical studies. This European Respiratory Society Research Seminar, held in Naples, Italy, 5-6 May 2022, focused on current and future developments of the drugs used to treat asthma and COPD; on mechanisms of drug action, steroid resistance, comorbidities and drug interactions; on prognostic and therapeutic biomarkers; on developing novel drug targets based on tissue remodelling and regeneration; and on pharmacogenomics and emerging biosimilars. Related European Medicines Agency regulations are also discussed, as well as the seminar's position on the above aspects.

Hospital patient experiences of contact isolation for antimicrobial resistant organisms in relation to health care-associated infections: A systematic review and narrative synthesis of the evidence.

BACKGROUND: The alarming growth of antimicrobial resistance organisms (AMRs) and the threat caused by health care-associated infections require hospitalized individuals who are infected or colonized with AMRs to be cared for in isolation, predominantly in single rooms. None of the existing reviews focus on or specifically address the patient's experience of being cared for in contact isolation when affected by AMRs exploring this specific context. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance for the conduct of systematic reviews was applied. Five databases were searched from inception to April 2019, with keywords related to adult patient experiences, AMR, and contact isolation. The evidence was certified by 2 reviewers. Principles of thematic analysis were used to produce a narrative synthesis of the findings. RESULTS: Eighteen eligible studies were identified. Narrative synthesis resulted in 3 overarching categories reflecting the patient experience: privacy versus loneliness; emotional responses to isolation; quality of care, recovery, and safety in isolation. CONCLUSIONS: This review synthesizes existing evidence reflecting the patient experience of contact isolation. Study findings were often contradictory and may not reflect contemporary health care, such as shorter hospital stays, or societal preferences for greater privacy. Further research focusing on contemporary health care contexts is recommended.

Nonclinical data supporting orphan medicinal product designations in the area of rare infectious diseases.

This review provides an overview of nonclinical in vivo models that can be used to support orphan designation in selected rare infectious diseases in Europe, with the aim to inform and stimulate the planning of nonclinical development in this area of often neglected diseases.

A European regulatory perspective on cystic fibrosis: current treatments, trends in drug development and translational challenges for CFTR modulators.

In this article we analyse the current authorised treatments and trends in early drug development for cystic fibrosis (CF) in the European Union for the time period 2000-2016. The analysis indicates a significant improvement in the innovation and development of new potential medicines for CF, shifting from products that act on the symptoms of the disease towards new therapies targeting the cause of CF. However, within these new innovative medicines, results for CF transmembrane conductance regulator (CFTR) modulators indicate that one major challenge for turning a CF concept product into an actual medicine for the benefit of patients resides in the fact that, although pre-clinical models have shown good predictability for certain mutations, a good correlation to clinical end-points or biomarkers (e.g. forced expiratory volume in 1 s and sweat chloride) for all mutations has not yet been achieved. In this respect, the use of alternative end-points and innovative nonclinical models could be helpful for the understanding of those translational discrepancies. Collaborative endeavours to promote further research and development in these areas as well as early dialogue with the regulatory bodies available at the European competent authorities are recommended.

Luces y sombras en la transmisión vertical de la enfermedad de Chagas / Challenges and opportunities in the vertical transmission of Chagas disease

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European Respiratory Society International Congress 2017: highlights from the Clinical Assembly.

This article contains highlights and a selection of the scientific advances from the European Respiratory Society's Clinical Assembly (Assembly 1 and its six respective groups) that were presented at the 2017 European Respiratory Society International Congress in Milan, Italy. The most relevant topics from each of the groups will be discussed, covering a wide range of areas including clinical problems, rehabilitation and chronic care, thoracic imaging, interventional pulmonology, diffuse and parenchymal lung diseases, and general practice and primary care. In this comprehensive review, the newest research and actual data as well as award-winning abstracts and highlight sessions will be discussed.

Demonstrating significant benefit of orphan medicines: analysis of 15 years of experience in Europe.

In the European Union demonstration of 'significant benefit' is mandatory if satisfactory methods exist for a disease targeted by a new orphan medicinal product. Significant benefit is required at the time of orphan designation, when it can be supported by preclinical studies, and at the time of marketing authorization, when clinical data are needed. For the first time, our work has identified, defined and organized the scientific grounds on which significant benefit is granted in the European Union, based on a review of the orphan medicinal products authorized in the years 2000-2015, and on the working experience of the Committee of Orphan Medicinal Products. The resulting conceptual framework is a tool for medicine developers to reflect on potential areas of advantage of their candidate products, and for a broad range of stakeholders to stimulate the discussion on the added value of orphan medicines across the whole development lifecycle.

Establishing rarity in the context of orphan medicinal product designation in the European Union.

In the European Union (EU) legislative framework for orphan medicinal product designation, establishing that a condition affects not more than five in 10,000 people is a prerequisite for applications based on rarity. Demonstrating this requirement to the Committee of Orphan Medicinal Products (COMP) can be a particularly challenging task for sponsors. Here, we identify and examine three common issues with the estimation of prevalence in orphan drug applications in the EU (the discernment between diagnosed and undiagnosed cases; the duration of the disease; and the need for an explicit contemporary conclusion) as critical factors for acceptable prevalence estimation. These concerns are discussed in detail based on recent examples of applications, which are reflected in published European Medicines Agency (EMA) documents.

Clinical highlights from the 2016 European Respiratory Society International Congress.

This article contains highlights and a selection of the scientific advances from the European Respiratory Society (ERS) Clinical Assembly (Assembly 1) and its six respective groups (Groups 1.1-1.6) that were presented at the 2016 ERS International Congress in London, UK. The most relevant topics for clinicians will be discussed, covering a wide range of areas including clinical problems, rehabilitation and chronic care, thoracic imaging, interventional pulmonology, diffuse and parenchymal lung diseases, and general practice and primary care. In this comprehensive review, the newest research and actual data will be discussed and put into perspective.

The future of the development of medicines in idiopathic pulmonary fibrosis.

The development of treatments for idiopathic pulmonary fibrosis (IPF) has been often disappointing. Building on authorized treatments that can benchmark the validity of treatment effect measures, the time has come to standardize endpoints and achieve consensus on their use for different clinical questions and specific IPF phenotypes. In order to facilitate the development of new medicines for IPF it is crucial that the knowledge of the disease and lessons learnt from past trials are taken forward to create international trial networks with involvement of patients, including biobanks and clinical data collection through a multinational registry. Interaction with regulators may be useful to align the initiatives of academia and pharmaceutical companies with the bodies ultimately responsible for licensing new products. Interaction can occur through the use of qualification programs for biomarkers and endpoints, and participation in innovative regulatory pathways and initiatives. Finally, the experience of IPF should be used to benefit even rarer interstitial lung diseases for which no treatment is available, including pediatric interstitial lung diseases. This commentary provides a perspective on the hurdles slowing the development and regulatory approval of medicines for IPF, and encourages close cooperation between investigators and drug regulators.

Steps forward in regulatory pathways for acute and chronic heart failure.

A workshop was organized by the Agenzia Italiana del Farmaco (AIFA) to discuss unmet needs and ways forward in the development of medicines in heart failure, their rationale, and cost-effective use. An integrated, multidisciplinary approach, including patients' needs and perspectives, was advocated by all the participants as the way to the most effective treatment regimens. More work is needed for reaching consensus on clinical and functional endpoints, for validating patient reported outcomes and measurements of well-being. Similarly, the integration into the clinical programmes of the health technology assessment/payers perspective, in particular, the evaluation of 'real-life' treatment effectiveness and of health as a value, would help in shifting the development and authorization of medicines from the molecule paradigm to their evaluation in the context of the whole health care regimen. Through this kind of workshop, AIFA is trying to build a template for meetings devoted to debate unmet needs with all stakeholders towards tentative road maps for the future.

Establishing medical plausibility in the context of orphan medicines designation in the European Union.

In the European Union, sponsors have the responsibility to demonstrate the "intention to diagnose, prevent or treat" a serious and rare condition before the Committee of Orphan Medicinal Products (COMP), for a medicinal product to meet the criteria for Orphan Designation. This requirement is commonly referred to as "medical plausibility" and the justification of this intention is assessed on the merits of each application by the COMP, which deliberates over the scientific evaluation of the evidence submitted. The scientific assessment of the applications for orphan designation by the Committee is based on the review of non-clinical (such as in vitro and in vivo) and/or clinical data submitted by the sponsor. Several challenges regarding the evidence provided emerge when the sponsor is applying for a designation at an early stage of development. Herein we discuss specific examples from the experience of the COMP, in order to elaborate on the type and level of evidence generally considered necessary for the purpose of justification of the intention to treat an orphan condition. Importantly, it is pointed out that bridging of data from other products, irrespectively of how comparable they may be, or from settings not directly associated with the condition as applied for designation, is by and large not a successful exercise and may only be exceptionally considered. It is further exemplified that, as reflected in the updated 'Guideline on the format and context of the applications for designation' and the guidance document 'Recommendation on elements required to support the medical plausibility and the assumption of significant benefit for an orphan designation' available on the EMA website, the sponsor should provide data with the specific product as applied for in specific models of the condition or in patients affected by the same condition subject of each application.

Use of biomarkers in the context of orphan medicines designation in the European Union.

The use of biomarkers within the procedures of the Committee of Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA) is discussed herein. The applications for Orphan Medicinal Product designation in the EU are evaluated at two stages. At the time of orphan designation application, the file undergoes an assessment to establish whether the proposed condition is a distinct and serious condition affecting not more than 5 in 10,000 people in the EU, and whether the product is plausible as a therapy for that condition. In cases where therapies already exist, the significant benefit of the candidate product over existing therapies is also evaluated. The orphan criteria are reassessed at the time of marketing authorisation, so that marketing exclusivity for the product in the orphan medical condition can be granted. Within this context, biomarkers have been used in submissions in order to define an orphan condition and to justify that the criteria for orphan designation are met. The current work discusses specific examples from the experience of the COMP, where biomarkers have played a decisive role. Importantly, it identifies the proposal of sub-sets of non-rare conditions based on biomarkers as a challenging issue in the evaluation of applications. In particular two specific requirements for the candidate orphan medicines in relation to the biomarker-based subsets are highlighted: the "plausible link to the condition" and the "exclusion of effects outside the subset".

Steps forward in regulatory pathways for acute and chronic heart failure.

A workshop was organized by the Agenzia Italiana del Farmaco (AIFA) to discuss unmet needs and ways forward in the development of medicines in heart failure, their rationale, and cost-effective use. An integrated, multidisciplinary approach, including patients' needs and perspectives, was advocated by all the participants as the way to the most effective treatment regimens. More work is needed for reaching consensus on clinical and functional endpoints, for validating patient reported outcomes and measurements of well-being. Similarly, the integration into the clinical programmes of the health technology assessment/payers perspective, in particular, the evaluation of 'real-life' treatment effectiveness and of health as a value, would help in shifting the development and authorization of medicines from the molecule paradigm to their evaluation in the context of the whole health care regimen. Through this kind of workshop, AIFA is trying to build a template for meetings devoted to debate unmet needs with all stakeholders towards tentative road maps for the future.

Profiling the proteome of exhaled breath condensate in healthy smokers and COPD patients by LC-MS/MS.

Three pools of exhaled breath condensate (EBC) from non-smokers plus healthy smokers (NS + HS, n = 45); chronic obstructive pulmonary disease (COPD) without emphysema (COPD, n = 15) and subjects with pulmonary emphysema associated with α(1)-antitrypsin deficiency (AATD, n = 23) were used for an exploratory proteomic study aimed at generating fingerprints of these groups that can be used in future pathophysiological and perhaps even clinical research. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was the platform applied for this hypothesis-free investigation. Analysis of pooled specimens resulted in the production of a "fingerprint" made of 44 proteins for NS/HS; 17 for COPD and 15 for the group of AATD subjects. Several inflammatory cytokines (IL-1α, IL-1ß, IL-2; IL-12, α and ß subunits, IL-15, interferon α and γ, tumor necrosis factor α); Type I and II cytokeratins; two SP-A isoforms; Calgranulin A and B and α1-antitrypsin were detected and validated through the use of surface enhanced laser-desorption ionization mass spectrometry (SELDI-MS) and/or by Western blot (WB) analysis. These results are the prelude of quantitative studies aimed at identifying which of these proteins hold promise as identifiers of differences that could distinguish healthy subjects from patients.