Quality-by-Design for the safe development of medical devices containing nanomaterials. A study case in photodynamic therapy

Présentation PosterInternational audienceBackground. According to the new medical device regulation (MDR 2017/745), devices employing advanced materials containing nanomaterials will be classified as class III and will have to undergo (re-)assessment of risks. To that aim, the Quality-by-Design approach, as defined in ICH Q8-Q11 (QbD), is indisputably accepted and strongly recommended by the FDA and EMA for risk assessment during drug development. Some papers have emphasized the possible implementation of QbD in the medical device industry [1]. Nevertheless, to date no real and effective adaptation of this risk-based quality management approach has been adapted to biomedical devices manufacturing [2]. Objectives. Our goal is to develop both a new QbD paradigm and a web-based tool devoted to the safe development of class-III medical devices containing nanomaterials. This objective is pursued in the context of the European H2020 project TBMED (An Open Innovation test bed for the development of high-risk medical devices).Methods. A six-step QbD approach is proposed. The first four stages are devoted to the preclinical development while the next two steps concern the industrial implementation. Three categories of risk-assessment methods are used at different development steps: failure mode and effects analysis based on prior knowledge, statistical designs of experiments and Bayesian inference. To assess its applicability, we applied the integrated QbD approach to the development of a new medical device devoted to the realtime control of light during photodynamic therapy using nanoparticle-based photosensitizers. Results. The new SaaS platform, entitled “Nanologic”, is available at: (www.i-nano.eu). Four key documents for regulatory agencies are established during the preclinical study: the target product profile, the list of critical quality attributes (quality/safety descriptors), the list of critical material attributes and process parameters (risk factors associated with the design and production phases) and the design space: a key concept of risk assessment in QbD.Conclusion. We show how the QbD best practices can be adapted to the development of medical devices containing nanomaterials. Moreover, new questions still have to be investigated such as the solutions to be developed to better predict risks associated with the clinical proof of concept

Robust estimation of field potential duration in multi-electrode array signals

Présentation PosterInternational audienceElectrical signals measured by microelectrode arrays (MEAs) allow non-invasive long-term monitoring of cardiomyocyte cultures. However, variability of local responses between electrodes and noise makes difficult the accurate estimation of the field potential duration (FPD). False peaks are often detected and falsify the FDP estimated value, which finally requires for the user to perform some manual corrections for each well. This drawback not only slows down the analysis but also introduces arbitrary estimations and inter-individual errors. The main objective is to develop a new estimation method of FPD taking advantages of all the information contained in the signals measured by all the electrodes of the same well. The motivations are to automatically compute FPD and to improve the accuracy and robustness of the estimation compared to existing techniques already implemented in the available technologies

i-Cellulo: a SaaS platform for the automatic statistical analysis of cell impedance signals

Présentation PosterInternational audienceLabel-free methods such as cell impedance assays are in vitro tests increasingly used in drug development. An indirect difficulty with those technologies is the large amount of kinetic responses to be processed. Our objective is to automate the processing and analysis of those data with a web computational server available to all biologists and able to perform multivariate tests, response profile clustering and dynamic AC50 estimation. The proposed solution relies on a SaaS platform in which R-language algorithms have been implemented for the on-line processing of cell impedance signals. Three generic statistical problems are addressed: clustering of response profiles to screen compounds, multivariate testing to compare their activity and AC50 estimation to determine their concentration effects. ANOVA, Kruskall-Wallis and Tuckey’s range tests have been implemented for the multivariate testing. Hierarchical clustering based on Singular Spectrum Analysis were used for the non-supervised response profile classification. A Hill’s model structure and a maximum likelihood estimator were adopted for the AC50 calculation. Hundreds of tests were carried out on real in vitro signals to assess the practical relevance of i-Cellulo for the fast analysis and characterization of anti-cancer activities in early steps of drug development. Results clearly show the ability of this web-based solution to correctly discriminate, classify, compare and rank the anti-cancer responses of tested compounds compared to gold standards. With the advent of real-time cell measurement technologies in preclinical tests, new services for the analysis of high-content data are needed. i–Cellulo is a solution to that challenge and allows biologists to speed up their data analysis and facilitate interpretation of their results

Phonon Thermal Transport of URu2Si2: Broken Translational Symmetry and Strong-Coupling of the Hidden Order to the Lattice

A dramatic increase in the total thermal conductivity (k) is observed in the Hidden Order (HO) state of single crystal URu2Si2. Through measurements of the thermal Hall conductivity, we explicitly show that the electronic contribution to k is extremely small, so that this large increase in k is dominated by phonon conduction. An itinerant BCS/mean-field model describes this behavior well: the increase in kappa is associated with the opening of a large energy gap at the Fermi Surface, thereby decreasing electron-phonon scattering. Our analysis implies that the Hidden Order parameter is strongly coupled to the lattice, suggestive of a broken symmetry involving charge degrees of freedom.Comment: 17 pages including figures, updated author institutions and acknowledgement

Characteristics associated with dietary patterns in Brazilian children under two years of age

OBJECTIVE: To analyze the dietary patterns of Brazilian children under two years of age and assess their association with sociodemographic characteristics and health service use. METHODS: This is a cross-sectional study with data from the 2013 National Health Survey (PNS). Patterns were found for two age groups by principal component analysis and their correlation with characteristics of interest was tested by linear regression models. RESULTS: We found two dietary patterns for our groups. The first consisted of the consumption of fresh or minimally processed foods and the second, of ultra-processed foods. The greater adherence of children between six and 11 months to the first pattern was associated with higher per capita family income and urban residences in the most developed regions of Brazil. At 12 months or more, adherence related to white race/color, higher per capita family incomes, residence in more developed regions, and visits to private childcare. Adherence to the second pattern among children under one year of age was inversely associated with Yellow or Indigenous race/color, residence in the Brazilian Northeast, and childcare in specialized public or private services. At 12 months or more, greater adherence was directly associated with Black or Brown children who resided in more developed regions, and inversely associated with those living in the Brazilian Northeast. CONCLUSION: We found two opposite dietary patterns in Brazilian children under two years of age and that several social determinants modify their chance of adhering to these patterns.OBJETIVO: Analisar padrões alimentares de crianças brasileiras menores de dois anos e verificar a sua associação com características sociodemográficas e de utilização de serviços de saúde. MÉTODOS: Estudo transversal com dados da Pesquisa Nacional de Saúde (PNS) de 2013. A identificação dos padrões foi realizada em dois grupos etários por meio da análise fatorial por componentes principais e a correlação às características de interesse, testada por meio de modelos de regressão linear. RESULTADOS: Em ambos os grupos foram identificados dois padrões alimentares: o primeiro foi caracterizado pelo consumo de alimentos in natura ou minimamente processado e o segundo marcado somente pelo consumo de alimentos ultraprocessados. A maior adesão das crianças entre seis e 11 meses ao primeiro padrão foi associada à maior renda familiar per capita, residência em área urbana e nas regiões mais desenvolvidas do país. Com 12 meses ou mais, a adesão foi relacionada com a raça/cor branca, maior renda familiar per capita, residência nas regiões mais desenvolvidas e realizar consultas de puericultura em serviços privados. No segundo padrão, a aderência entre os menores de um ano foi inversamente associada com raça/cor amarela ou indígena, residência na região Nordeste e realização de puericultura nos serviços públicos especializados ou nos privados. A partir dos 12 meses, a adesão foi diretamente associada com raça/cor preta ou parda e residência nas regiões mais desenvolvidas, e inversamente associada com residência na região Nordeste. CONCLUSÃO: O estudo identificou dois padrões alimentares opostos em crianças brasileiras menores de dois anos, sendo que diferentes determinantes sociais modificam a chance de adesão a esses padrões

Trends in all-cause mortality during the scale-up of an antiretroviral therapy programme: a cross-sectional study in Lusaka, Zambia.

OBJECTIVE: To follow the trends in all-cause mortality in Lusaka, Zambia, during the scale-up of a national programme of antiretroviral therapy (ART). METHODS: Between November 2004 and September 2011, we conducted 12 survey rounds as part of a cross-sectional study in Lusaka, with independent sampling in each round. In each survey, we asked the heads of 3600 households to state the number of deaths in their households in the previous 12 months and the number of orphans aged less than 16 years in their households and investigated the heads' knowledge, attitudes and practices related to human immunodeficiency virus (HIV). FINDINGS: The number of deaths we recorded - per 100 person-years - in each survey ranged from 0.92 (95% confidence interval, CI: 0.78-1.09) in September 2011, to 1.94 (95% CI: 1.60-2.35) in March 2007. We found that mortality decreased only modestly each year (mortality rate ratio: 0.98; 95% CI: 0.95-1.00; P = 0.093). The proportion of households with orphans under the age of 16 years decreased from 17% in 2004 to 7% in 2011. The proportions of respondents who had ever been tested for HIV, had a comprehensive knowledge of HIV, knew where to obtain free ART and reported that a non-pregnant household member was receiving ART gradually increased. CONCLUSION: The expansion of ART services in Lusaka was not associated with a reduction in all-cause mortality. Coverage, patient adherence and retention may all have to be increased if ART is to have a robust and lasting impact at population level in Lusaka

A comparison of methods for delineation of wave boundaries in 12 Lead ECG

Présentation posterInternational audienceObjective: In the diagnosis of cardiac diseases, the delineation of electrocardiogram is crucial in order to efficiently classify cardiac events. Delineation consists in detecting the different peaks and boundaries of the QRS-complex, P-wave and T-wave. Several techniques have been proposed to face this issue. The objective is to assess the detection performances of a recent approach (non-negative matrix factorization) that has never been applied to ECG delineation and to compare its results with three known methods: morphological approach, discrete wavelet transform and difference operation method

Analysis of in vivo responses by mixed-effect models reference

Présentation PosterInternational audienceObjectives. In in vivo experimentation, the large intra-group variability between animals is a major obstacle that prevents to detect significant therapeutic effects of treatment factors. Our objective is to assess a new statistical method able to better estimate and characterize the additive effects of the combination of an oncolytic virus (TG6002) and the prodrug flucytosine (5-FC) associated in an anti-cancer treatment. The experimental data are kinetics of tumor growth collected during in vivo assays carried out on mice. Methods. The experimental set up is decomposed into four main steps. Firstly, a full factorial design of experiments is proposed. TG6002 was tested at four concentrations in combination or not with 5-FC. Eight groups of 13 mice are randomly affected to each experimental condition. Secondly, we propose a mixed-effect model to describe the kinetic growth of the mean tumor diameter. In a third step, the model parameters are determined with a maximum likelihood estimator based on an expectation-maximization algorithm. Finally, effects of the two examined components are assessed with a Wald test.Results. With our model-based approach, we show a 3% reduction of the therapeutic response time due to 5-FC and a division by five of the growth delay with TG6002.Conclusion. Results confirm the practical relevance of mixed-effect kinetic models to increase the statistical power of statistical tests applied to in vivo studies and efficacy of the combination TG6002 with 5-FC

Quality-by-Design for the safe development of medical devices containing nanomaterials. A study case in photodynamic therapy

Présentation PosterInternational audienceBackground. According to the new medical device regulation (MDR 2017/745), devices employing advanced materials containing nanomaterials will be classified as class III and will have to undergo (re-)assessment of risks. To that aim, the Quality-by-Design approach, as defined in ICH Q8-Q11 (QbD), is indisputably accepted and strongly recommended by the FDA and EMA for risk assessment during drug development. Some papers have emphasized the possible implementation of QbD in the medical device industry [1]. Nevertheless, to date no real and effective adaptation of this risk-based quality management approach has been adapted to biomedical devices manufacturing [2]. Objectives. Our goal is to develop both a new QbD paradigm and a web-based tool devoted to the safe development of class-III medical devices containing nanomaterials. This objective is pursued in the context of the European H2020 project TBMED (An Open Innovation test bed for the development of high-risk medical devices).Methods. A six-step QbD approach is proposed. The first four stages are devoted to the preclinical development while the next two steps concern the industrial implementation. Three categories of risk-assessment methods are used at different development steps: failure mode and effects analysis based on prior knowledge, statistical designs of experiments and Bayesian inference. To assess its applicability, we applied the integrated QbD approach to the development of a new medical device devoted to the realtime control of light during photodynamic therapy using nanoparticle-based photosensitizers. Results. The new SaaS platform, entitled “Nanologic”, is available at: (www.i-nano.eu). Four key documents for regulatory agencies are established during the preclinical study: the target product profile, the list of critical quality attributes (quality/safety descriptors), the list of critical material attributes and process parameters (risk factors associated with the design and production phases) and the design space: a key concept of risk assessment in QbD.Conclusion. We show how the QbD best practices can be adapted to the development of medical devices containing nanomaterials. Moreover, new questions still have to be investigated such as the solutions to be developed to better predict risks associated with the clinical proof of concept