Advanced therapies, hospital exemptions & marketing authorizations: the UK’s emerging regulatory framework for point-of-care manufacture

Hospital-centered manufacture, which consists in producing therapies close to the patient, within a hospital or in a nearby unit, is becoming increasingly viable and necessary. There are at least two modalities of this kind of manufacture: in what we name bedside manufacture, therapy production relies on hospital infrastructure and facilities, products can have all sorts of shelf life, and a small number of hospitals is involved; in the emerging modality called point-of-care manufacture, there is great reliance on portable manufacturing devices taken to the hospital, products have short or very short shelf life, and a large number of hospitals may be involved. The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) has proposed a new regulatory framework dedicated to point-of-care manufacture. A large range of products can be manufactured this way, including some Advanced Therapy Medicinal Products (ATMPs), which are medicines based on cells, genes or tissues. Bedside manufacture has been traditionally overseen via regulatory exemptions. In the European Union (EU), the manufacture of ATMPs in hospitals or for hospitals has been covered by the ‘Hospital Exemption’. In the UK, another exemption, known as the Specials scheme, has been used. Both exemptions are grounded on the specificities of hospitals and clinical needs. The MHRA’s current regulatory proposal introduces a new rationale in which point-of-care manufacture will be subject to a flexible and proportionate framework while following the regulatory pathway now valid for commercial products, including the conduct of clinical trials and the issuance of marketing authorizations. This brings about a market route that will coexist with the clinical route of exemptions.This article analyzes the implications and uncertainties of the UK’s possible move from regulatory exemptions (bedside manufacture) to marketing authorizations (point-of-care manufacture) for hospital-produced ATMPs. It also sheds light on strategic issues triggered by the MHRA’s proposal

Cognitive Foundations of Society: The Concept of Schemata in Cell, Gene, and Tissue Therapies

Interpreting how people accord meaning to life situations is an old challenge in sociology. Emphasis has been given to values shared within social groups; other sociologists have stressed the discursive or communicative dimensions of society. This paper seeks an alternative interpretation by combining sociological inquiry and insights from cognitive linguistics. It explores the concept of schema, which points to the unconscious identification of patterns in human experiences, enabling people to assimilate concepts such as FORCE, CONTAINMENT, and others. This paper focuses on discourses and views around advanced therapies: medicinal products based on genes, cells, or tissues. These therapies are frequently understood via two alternative schemata. The CURE schema foregrounds therapies’ long-term potential to revert disease and tends to underpin metaphoric reasoning; the IMPAIRMENT schema highlights specific limitations brought about by disease, being frequently associated with metonymic reasoning. Schemata underpin broader initiatives and decisions, including those adopted by regulatory and government agencies. As they constitute basic and socialized understandings, their study enables the identification of the cognitive and linguistic foundations of society

Point-of-care manufacture of advanced therapies: readiness measures for hospitals, companies, and regulatory agencies

Advanced Therapy Medicinal Products (ATMPs), such as cell and gene therapies, are promising for treating rare diseases, as well as some more prevalent conditions such as severe burns or diabetes. In some cases, it is necessary to adopt models where ATMPs are produced in clinical settings and immediately delivered to patients (point -of-care manufacture). This could enlarge the range of innovative therapies made available in the NHS, but also brings about considerable challenges

Institutional and infrastructure challenges for hospitals producing advanced therapies in the UK:the concept of ‘point-of-care manufacturing readiness'

Aim: To propose the concept of point-of-care manufacturing readiness for analyzing the capacity that a country, a health system or an institution has developed to manufacture therapies in clinical settings (point-of-care manufacture). The focus is on advanced therapies (cell, gene and tissue engineering therapies) in the UK. Materials & methods: Literature review, analysis of quantitative data, and qualitative interviews with professionals and practitioners developing and administering advanced therapies. Results: Three components of point-of-care manufacturing readiness are analyzed staff and institutional procedures, infrastructure, and relations between hospitals and service providers. Conclusion: The technical and regulatory experience that has been gained through manufacturing advanced therapies at small scale in hospitals qualifies the UK for more complex and larger-scale production of therapies in the future

Advanced therapies and the Brexit process:emerging geographies of legal responsibilities and market opportunities

This paper analyses how so-called Brexit, that is the United Kingdom’s departure from the European Union (EU), has modified the regional geography of Advanced Therapy Medicinal Products (ATMPs). The latter are therapies deriving from cell manipulation, gene editing, tissue engineering, or a combination of these techniques. Their development and delivery have been realised through research collaborations and commercial relations of international scope. In the EU, this has happened by means of a complex distribution of commercial activities and legal responsibilities. With Brexit, three main kinds of reconfigurations have occurred: the relocation of research and manufacturing activities; the reorganisation of quality control tests aimed to manage clinical risks; and the redistribution of legal responsibilities and representatives. This technical and legal reconfiguration is captured here by means of theoretical insights from the emerging domain of legal geography. Drawing on interviews conducted with both EU and UK professionals involved in ATMP development, this paper reveals the main challenges brought by Brexit to the current and future configuration of the ATMP landscape in the EU and the UK. Furthermore, it demonstrates how shifts in legal arrangements impact on science-intensive domains

PRODUÇÃO DE MEDICAMENTOS NO TERRITÓRIO BRASILEIRO: POLÍTICA FARMACÊUTICA E POLÍTICA TERRITORIAL

The present article derives from a Master research through which we explored the concept of “marginal upper circuit”, proposed by the geographer Milton Santos. In order to address this question, the production of medicines in the Brazilian territory was analysed. In this article, we focus on the spatial impacts of three main phenomena: firstly, the transposition of the global agreement on property rights (Trips agreement) into the Brazilian legislation. Secondly, the normative upheaval faced by the pharmaceutical activity in Brazil during the 1990s. Finally, the beginning of the production of generic medicines in 1999. We point out some technical and political challenges brought about in the current historical period, when the norms present themselves as the main factor within the spatial systems.O presente artigo deriva de uma pesquisa de Mestrado em que exploramos o conceito de “circuito superior marginal”, proposto pelo geógrafo Milton Santos. Para abordar essa questão, a produção de medicamentos no território brasileiro foi analisada. Neste artigo, enfocamos os impactos espaciais de três fenômenos principais: primeiro, a transposição do acordo global de propriedade intelectual (Trips agreement) na legislação brasileira. Segundo, a revolução normativa experimentada pela atividade farmacêutica no Brasil durante os anos 1990. Finalmente, o começo da produção de medicamentos genéricos em 1999. Sublinhamos alguns desafios técnicos e políticos que se impõem no atual período histórico, no qual as normas aparecem como a variável principal dos sistemas espaciais

Digital readiness in 3D bioprinting: software, governance and hospitals’ proto-clinical interfaces

Aim: To understand the process through which some hospitals have become ready to assimilate the digital technologies required for 3D bioprinting. By enhancing their digital readiness, hospitals will be able to develop the current proto-clinical potentialities of bioprinting. Materials & methods: We conducted interviews with bioprinting researchers, entrepreneurs and regulators in three countries (United Kingdom, Italy and Brazil). We analyzed bioprinting papers in which hospital-based researchers participated. We also analyzed the international bioprinting market. Results: Digital readiness is more advanced in some hospitals and countries, which have noticed the strategic relevance of bioprinting. Furthermore, it is strengthened by the reformulation of the relations between hospitals and other institutions, a phenomenon that is here interpreted with the concept of interfaces

Biomodifying the ‘Natural’: from adaptive regulation to adaptive societal governance

Biomodifying technologies—such as gene editing, induced pluripotent stem cells and bioprinting— are being developed for a wide range of applications, from pest control to lab-grown meat. In medicine, regulators have responded to the challenge of evaluating modified ‘natural’ material as a therapeutic ‘product’ by introducing more flexible assessment schemes. Attempts have also been made to engage stakeholders across the globe on the acceptable parameters for these technologies, particularly in the case of gene editing. Regulatory flexibility and stakeholder engagement are important, but a broader perspective is also needed to respond to the potential disruption of biomodification. Our case-study technologies problematize basic ideas — such as ‘nature,’ ‘product’ and ‘donation’— that underpin the legal categories used to regulate biotechnology. Where such foundational concepts are rendered uncertain, a socially responsive and sustainable solution would involve exploring evolutions in these concepts across different societies. We suggest that the global observatory model is a good starting point for this ‘Adaptive Societal Governance’ approach, in which a self-organising network of scholars and interested parties could carry out the multi-modal (meta)analyses needed to understand societal constructions of ideas inherent to our understanding of ‘life.

Eukariotic phytoplankton biomass and its availability for the food web at Riogrande II reservoir (Antioquia, Colombia)

RESUMEN: Con el objetivo de establecer la biomasa de carbono contenida en el fitoplancton eucariota del embalse Riogrande II (Antioquia, Colombia), entre agosto de 2011 y agosto de 2012, la porción de esa biomasa disponible para el zooplancton filtrador y la calidad de alimento que podría representar para dicho grupo, el fitoplancton se clasificó en dos rangos de longitud correspondientes a nanoplancton (5 a 20 μm) y microplancton (>20 μm). Para ambos grupos se calculó el contenido de carbono celular y la biomasa total en contenido de carbono. Además, para el nanoplancton, el cual corresponde a la fracción filtrable, se estimaron las concentraciones de nitrato y de fosfato. Los altos niveles de biomasa de organismos fototróficos evidenciaron el papel fundamental del fitoplancton eucariótico en la fijación de carbono. Sin embargo, debido a la eutrofización del sistema y a que la talla del zooplancton dominante es pequeña, el flujo de carbono y de nutrientes parece estar dirigido principalmente hacia la vía detrítica y las sustancias disueltas, y no directamente al zooplancton filtrador, cuya principal fuente de alimento en el fitoplancton eucariótico la constituyen los organismos nanoplanctónicos mixotróficos (Cryptophyta y Euglenophyta), que en función de un mayor volumen poseen concentraciones más elevadas de nitrato y fosfato y, por lo tanto, pueden proveer alimento de mejor calidad que el resto del nanoplancton.ABSTRACT: In order to establish the carbon biomass content in the eukaryotic phytoplankton at Riogrande II reservoir (Antioquia, Colombia) from August 2011 to August 2012, as well as the portion of this available biomass for filter-feeding zooplankton and the quality of food it could represent for each group, we classified phytoplankton considering two length ranges corresponding to nanoplankton (5 to 20 μm) and microplankton (>20 μm). We estimated the cellular carbon content and the total biomass represented as carbon content for both groups. We also estimated nitrate and phosphate concentrations for the nanoplankton, which corresponds to the filterable fraction. The high levels of phototrophic organisms biomass showed the essential role of eukaryotic phytoplankton in carbon fixation; however, due to the eutrophication of this reservoir and to the small size of dominant zooplankton, the carbon flux and nutrients seemed to be directed mainly to the detrital track and to dissolved substances and not directly to the filter-feeding zooplankton, whose main food source among eukaryotic phytoplankton is constituted by mixotrophic nanoplanktonic organisms (such as Cryptophyta and Euglenophyta), that according to their greater volume have higher concentrations of nitrate and phosphate and, therefore, can provide better quality food than the remaining nanoplankton

Eukariotic phytoplankton biomass and its availability for the food web at Riogrande II reservoir (Antioquia, Colombia)

Con el objetivo de establecer la biomasa de carbono contenida en el fitoplancton eucariota del embalse Riogrande II (Antioquia, Colombia), entre agosto de 2011 y agosto de 2012, la porción de esa biomasa disponible para el zooplancton filtrador y la calidad de alimento que podría representar para dicho grupo, el fitoplancton se clasificó en dos rangos de longitud correspondientes a nanoplancton (5 a 20 μm) y microplancton (>20 μm). Para ambos grupos se calculó el contenido de carbono celular y la biomasa total en contenido de carbono. Además, para el nanoplancton, el cual corresponde a la fracción filtrable, se estimaron las concentraciones de nitrato y de fosfato. Los altos niveles de biomasa de organismos fototróficos evidenciaron el papel fundamental del fitoplancton eucariótico en la fijación de carbono. Sin embargo, debido a la eutrofización del sistema y a que la talla del zooplancton dominante es pequeña, el flujo de carbono y de nutrientes parece estar dirigido principalmente hacia la vía detrítica y las sustancias disueltas, y no directamente al zooplancton filtrador, cuya principal fuente de alimento en el fitoplancton eucariótico la constituyen los organismos nanoplanctónicos mixotróficos (Cryptophyta y Euglenophyta), que en función de un mayor volumen poseen concentraciones más elevadas de nitrato y fosfato y, por lo tanto, pueden proveer alimento de mejor calidad que el resto del nanoplancton.In order to establish the carbon biomass content in the eukaryotic phytoplankton at Riogrande II reservoir (Antioquia, Colombia) from August 2011 to August 2012, as well as the portion of this available biomass for filter-feeding zooplankton and the quality of food it could represent for each group, we classified phytoplankton considering two length ranges corresponding to nanoplankton (5 to 20 μm) and microplankton (>20 μm). We estimated the cellular carbon content and the total biomass represented as carbon content for both groups. We also estimated nitrate and phosphate concentrations for the nanoplankton, which corresponds to the filterable fraction. The high levels of phototrophic organisms biomass showed the essential role of eukaryotic phytoplankton in carbon fixation; however, due to the eutrophication of this reservoir and to the small size of dominant zooplankton, the carbon flux and nutrients seemed to be directed mainly to the detrital track and to dissolved substances and not directly to the filter-feeding zooplankton, whose main food source among eukaryotic phytoplankton is constituted by mixotrophic nanoplanktonic organisms (such as Cryptophyta and Euglenophyta), that according to their greater volume have higher concentrations of nitrate and phosphate and, therefore, can provide better quality food than the remaining nanoplankton.Facultad de Ciencias Naturales y Muse