Laura Fregonese

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.

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.

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”.

The orphan framework as a new opportunity: an expert opinion

This is a review of the post-designation incentives framework that exists in Europe under its Orphan Medicinal Designation System. The aim of the article is to review and highlight specific regulatory mechanisms which are used or tailored to help in the development and licensing of products which receive an orphan designation. It is hoped that through this article there will be greater clarity of the post-designation incentives available to sponsors who obtain an Orphan Medicinal Designation.

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. Alternative nonclinical models for CFTR modulators are needed to increase prediction of clinical efficacy http://ow.ly/Tj8y30iQNiD

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 Societys 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. A highlights review of selected presentations from #ERSCongress 2017 by the @ERStalk Clinical Assembly http://ow.ly/p3fB30gSb24

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. Members of the @ERStalk Clinical Assembly give their highlights from #ERSLDN16 http://ow.ly/MkKb30a58J7

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.

A conceptual framework for reporting experience of physical activity in COPD

The importance of physical activity in chronic diseases is increasingly acknowledged. The amount of physical activity has been shown to predict mortality indirectly in patients suffering from multiple conditions [1], while physical inactivity is important predictor of the risk of hospital readmission, and associated with higher mortality in elderly [2] and in patients with chronic obstructive pulmonary disease (COPD) [3, 4]. However, even though physical activity represents one of the most intriguing extrapulmonary clinical aspects of patients suffering from COPD, there is little evidence that either pharmacological or nonpharmacological interventions ( e.g. counselling and rehabilitation) can enhance and durably maintain increased levels of physical activity in COPD or, conversely, that an increase in physical activity would result in favourable outcomes relevant to COPD patients [5]. Methods quantifying physical activity objectively, such as portable and wearable devices to monitor daily activities, are available and will allow further research on physical activity in COPD, and on its relation to the progression of the disease and the response to treatment [6–8]. COPD is traditionally measured by lung function, mainly forced expiratory volume in 1 s (FEV1) and the FEV1/forced vital capacity ratio. FEV1 correlates poorly with important symptoms such as breathlessness and with the impact of the disease on daily life in COPD [9]; it is therefore important to complement lung function assessment with measures directly related to the patients’ experience of the disease, such as patient-reported outcomes (PROs), for a comprehensive …