Biomarker qualification at the European Medicines Agency: a review of biomarker qualification procedures from 2008 to 2020

Regulatory qualification of biomarkers facilitates their harmonised use across drug developers, enabling more personalised medicine. This study reviews various aspects of the European Medicines Agency's (EMA) biomarker qualification procedure, including frequency and outcome, common challenges, and biomarker characteristics. Our findings provide insights into EMA's biomarker qualification process and will thereby support future applications. All biomarker-related "Qualification of Novel Methodologies for Medicine Development" procedures that started from 2008 to 2020 were included. Procedural data were extracted from relevant documents and analysed descriptively. In total, 86 biomarker qualification procedures were identified, of which 13 resulted in qualified biomarkers. Whereas initially many biomarker qualification procedures were linked to a single company and specific drug development program, a shift was observed to qualification efforts by consortia. Most biomarkers were proposed (n=45) and qualified (n=9) for use in patient selection, stratification, and enrichment, followed by efficacy biomarkers (37 proposed, 4 qualified). Overall, many issues were raised during qualification procedures, mostly related to biomarker properties and assay validation (in 79% and 77% of all procedures, respectively). Issues related to the proposed context of use and rationale were least common, yet, were still raised in 54% of all procedures. While few qualified biomarkers are currently available, procedures focus increasingly on biomarkers for general use instead of those linked to specific drug compounds. The issues raised during qualification procedures illustrate the thorough discussions taking place between applicants and regulators - highlighting aspects that need careful consideration and underlining the importance of an appropriate validation strategy

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Unmet Medical Need : An Introduction to Definitions and Stakeholder Perceptions

BACKGROUND: Despite increasing informal and formal use of unmet medical need (UMN) in drug development, regulation, and assessment, there is no insight into its definitions in use. This study aims to provide insight into the current definitions in use and to provide a starting point for a multi-stakeholder discussion on alignment. METHODS: A scoping and a gray literature review were performed to locate definitions of UMN in literature and on stakeholder websites. These definitions were categorized and then discussed among the multi-stakeholder author group via semistructured group discussions and open session workshops with a broader stakeholder audience. Issues with the formation of a common definition and mechanisms for use were discussed. RESULTS: The reviews yielded 16 definitions. Differences were evident, but all included 1 or more of the following elements: (adequacy of) available treatments (16 of 16: 100%), disease severity or burden (6 of 16: 38%), and patient population size (1 of 16: 6%). The stakeholder discussions led to a suggestion for a definition including the first 2 items and, depending on context, population size. The discussions also showed that quantification of UMN is highly dependent on the scope and the value framework in which it is used based on different stakeholder preferences and responsibilities. CONCLUSION: We encourage stakeholders that want to promote alignment on the concept of UMN to prospectively discuss the scope in which they want to apply the concept, what elements they find important for consideration in each case, and how they would measure UMN within the broader regulatory or value framework applicable

Unmet Medical Need : An Introduction to Definitions and Stakeholder Perceptions

BACKGROUND: Despite increasing informal and formal use of unmet medical need (UMN) in drug development, regulation, and assessment, there is no insight into its definitions in use. This study aims to provide insight into the current definitions in use and to provide a starting point for a multi-stakeholder discussion on alignment. METHODS: A scoping and a gray literature review were performed to locate definitions of UMN in literature and on stakeholder websites. These definitions were categorized and then discussed among the multi-stakeholder author group via semistructured group discussions and open session workshops with a broader stakeholder audience. Issues with the formation of a common definition and mechanisms for use were discussed. RESULTS: The reviews yielded 16 definitions. Differences were evident, but all included 1 or more of the following elements: (adequacy of) available treatments (16 of 16: 100%), disease severity or burden (6 of 16: 38%), and patient population size (1 of 16: 6%). The stakeholder discussions led to a suggestion for a definition including the first 2 items and, depending on context, population size. The discussions also showed that quantification of UMN is highly dependent on the scope and the value framework in which it is used based on different stakeholder preferences and responsibilities. CONCLUSION: We encourage stakeholders that want to promote alignment on the concept of UMN to prospectively discuss the scope in which they want to apply the concept, what elements they find important for consideration in each case, and how they would measure UMN within the broader regulatory or value framework applicable

Variació i canvi lingüístic en llengua catalana. La Lingüística de Corpus com a eina per a la investigació educativa en entorns multilingües

Hi ha un problema essencial en l’adquisició (aprenentatge) de llengua (la pròpia: L1) i de les alienes (L2) derivat de com és de difícil prendre consciencia de la varició i canvi lingüístic, és a dir, que les llengües canvies i tenen variació/ions (. estàndard/norma “vs.” dialecte), i que això respon a factors de l’evolució de la llengua, més enllà de la simple constatació que es produeixen diferències, sense traure’n l’entrellat

Lingüística de Corpus i Mediterrània Intercultural: investigació educativa per a l’aplicació de la Lingüística de Corpus en entorns multilingües diacrònics. Aplicacions del MetaCorpus CIMTAC

L'anàlisi del llenguatge literari dels clàssics de les lletres catalanes i de les traduccions de què han estat objecte al llarg dels segles i contemporànies ens poden fornir informacions molt interessants, lingüístiques i culturals. A més, ens poden ajudar a poder millorar el nostre coneixement sobre la història de la llengua, el canvi semàntic i la variació lingüística. Constituir corpus lingüístics (literaris i no literaris) amb perspectiva diacrònica i multilingüe ens pot ajudar a ampliar la perspectiva i, amb les eines informàtiques avinents, a poder datar els canvis semàntics (i el seu llindar). Es tracta de fer servir una metodologia interdisciplinar que té el valor afegit que s'hi apliquen, per als estudis diacrònics de la llengua catalana, mètodes i conceptes provinents d'altres àmbits de la lingüística

Lingüística de Corpus i Mediterrània Intercultural: investigació educativa per a l’aplicació de la Lingüística de Corpus en entorns multilingües diacrònics. Aplicacions del MetaCorpus CIMTAC

L'anàlisi del llenguatge literari dels clàssics de les lletres catalanes i de les traduccions de què han estat objecte al llarg dels segles i contemporànies ens poden fornir informacions molt interessants, lingüístiques i culturals. A més, ens poden ajudar a poder millorar el nostre coneixement sobre la història de la llengua, el canvi semàntic i la variació lingüística. Constituir corpus lingüístics (literaris i no literaris) amb perspectiva diacrònica i multilingüe ens pot ajudar a ampliar la perspectiva i, amb les eines informàtiques avinents, a poder datar els canvis semàntics (i el seu llindar). Es tracta de fer servir una metodologia interdisciplinar que té el valor afegit que s'hi apliquen, per als estudis diacrònics de la llengua catalana, mètodes i conceptes provinents d'altres àmbits de la lingüística