A cumulative impact assessment on the marine capacity to supply ecosystem services.

Ecosystem services link the status of biodiversity and its functioning to societal goods and benefits contributing to human wellbeing. As such, they can play a key role in preserving the environment and managing natural resources and ecosystems to conserve nature's contributions to people. Identification of the main threats acting on the natural environment, and how these may impact its capacity to supply ecosystem services, is fundamental to the maintenance of these services. To that end, we present a novel approach based on a cumulative impacts assessment that 1) covers all relevant human activities and their pressures, 2) links impacts to the biotic groups that make up biodiversity and 3) provides an estimation of the Service Supply Potential based on the functioning of these biotic groups. Key proxy metrics to estimate this Service Supply Potential were identified from a literature review and quantified using a food web model (Ecopath with Ecosim). In addition to this quantitative information, the assessment of the capacity to supply ecosystem services was supplemented with expert judgement-based information to reflect the societal preferences that drive the allocation of human capital and turn these services into societal goods and benefits. As a proof of concept, the method was applied to the North Sea ecosystem. Results showed that, overall, the capacity of the North Sea to supply Cultural ecosystem services was most threatened, with an average potential decline of 50 % compared to an undisturbed situation. This was followed by the Provisioning ecosystem services with 46 % and the Regulation & Maintenance with 38 %. The main anthropogenic threats (excluding climate change) to the North Sea capacity to supply ecosystem services come primarily from fishing contributing to 51 % of the overall threat. Of the remaining 18 sectoral activities another 23 % was contributed by mining, non-renewable energy, tourism, and agriculture.

Determining a risk-proportionate approach to the validation of statistical programming for clinical trials.

BACKGROUND: The contribution of the statistician to the design and analysis of a clinical trial is acknowledged as essential. Ability to reconstruct the statistical contribution to a trial requires rigorous and transparent documentation as evidenced by the reproducibility of results. The process of validating statistical programmes is a key requirement. While guidance relating to software development and life cycle methodologies details steps for validation by information systems developers, there is no guidance applicable to programmes written by statisticians. We aimed to develop a risk-based approach to the validation of statistical programming that would support scientific integrity and efficient resource use within clinical trials units. METHODS: The project was embedded within the Information Systems Operational Group and the Statistics Operational Group of the UK Clinical Research Collaboration Registered Clinical Trials Unit network. Members were asked to share materials relevant to validation of statistical programming. A review of the published literature, regulatory guidance and knowledge of relevant working groups was undertaken. Surveys targeting the Information Systems Operational Group and Statistics Operational Group were developed to determine current practices across the Registered Clinical Trials Unit network. A risk-based approach was drafted and used as a basis for a workshop with representation from statisticians, information systems developers and quality assurance managers (n = 15). The approach was subsequently modified and presented at a second, larger scale workshop (n = 47) to gain a wider perspective, with discussion of content and implications for delivery. The approach was revised based on the discussions and suggestions made. The workshop was attended by a member of the Medicines for Healthcare products Regulatory Agency Inspectorate who also provided comments on the revised draft. RESULTS: Types of statistical programming were identified and categorised into six areas: generation of randomisation lists; programmes to explore/understand the data; data cleaning, including complex checks; derivations including data transformations; data monitoring; or interim and final analysis. The risk-based approach considers each category of statistical programme against the impact of an error and its likelihood, whether the programming can be fully prespecified, the need for repeated use and the need for reproducibility. Approaches to the validation of programming within each category are proposed. CONCLUSION: We have developed a risk-based approach to the validation of statistical programming. It endeavours to facilitate the implementation of targeted quality assurance measures while making efficient use of limited resources.

Regulatory Aspects for Approval of Advanced Therapy Medicinal Products in the EU.

In the European Union (EU), advanced therapy medicinal products (ATMPs) undergo evaluation by the European Medicines Agency's (EMA) Committee for Advanced Therapies (CAT) to obtain marketing authorization under the centralized procedure. Because of the diversity and complexity of ATMPs, a tailored approach to the regulatory process is required that needs to ensure the safety and efficacy of each product. Since ATMPs often target serious diseases with unmet medical need, the industry and authorities are interested in providing treatment to patients in a timely manner through optimized and expedited regulatory pathways. EU legislators and regulators have implemented various instruments to support the development and authorization of innovative medicines by offering scientific guidance at early stages, incentives for small developers and products for rare diseases, accelerated evaluation of marketing authorization applications, different types of marketing authorizations, and tailored programs for medicinal products with the orphan drug designation (ODD) and the Priority Medicines (PRIME) scheme. Since the regulatory framework for ATMPs was established, 20 products have been licenced, 15 with orphan drug designation, and 7 supported by PRIME. This chapter discusses the specific regulatory framework for ATMPs in the EU and highlights previous successes and remaining challenges.

Total neoadjuvant therapy in rectal cancer: the evidence and expectations.

Current management of locally advanced rectal cancer achieves high cure rates, distant metastatic spread being the main cause of patients' death. Total neoadjuvant therapy (TNT) employs (chemo)radiotherapy and combined chemotherapy prior to surgery to improve the treatment outcomes. TNT has been shown to reduce significantly distant metastases, increase disease-free survival by 5 - 10% in 3 years, and finally also overall survival (≈ 5% in 7 years). It proved to double the rate of pathologic complete responses, making it an attractive strategy for non-operative management to avoid permanent colostomy in patients with distal tumors. In addition, it endorses adherence to the therapy due to better tolerance and, potentially, shortens its overall duration. A number of questions related to TNT remain currently unresolved including the indications, preferred radiotherapy and chemotherapy regimens, their sequence, timing of surgery, and role of adjuvant therapy. A stratified approach may be the optimal way to go.

Marketing Regulatory Oversight of Advanced Therapy Medicinal Products in Europe.

Advanced therapy medicinal products (ATMP) in the European Union (EU) are regulated by Regulation 1394/2007 and comprise gene and cell therapy and tissue-engineered products. Under this framework, ATMP are authorised by the centralised procedure, coordinated by the European Medicines Agency (EMA), whereas clinical trial authorisations remain at the remit of each National Competent Authority. The Committee for Advanced Therapies is responsible for the scientific evaluation of the marketing authorisation applications and for generating a draft opinion that goes to the Committee for Human Medicinal Products for a final opinion. For every application, data and information relating to manufacturing processes and quality control of the active substance and final product have to be submitted for assessment together with data from non-clinical and clinical safety and efficacy studies. Technical requirements for ATMP are defined in the legislation, and guidance for different products is available through several EMA/CAT guidelines.Due to the diverse and complex nature of ATMP, a need for some regulatory flexibility was recognised. Thus, a risk-based approach was introduced in Regulation 1394/2007 allowing adapted regulatory requirements. This has led, for instance, to the development of good manufacturing practice (GMP) guidelines specific for ATMP. This, together with enhanced regulatory support, has allowed an increasing number of successful marketing authorisation applications resulting in 25 licensed ATMP in the EU, mainly gene therapy medicinal products. The promise of messenger RNA and genome editing technologies as therapeutic tools make the future for these innovative medicinal products look even brighter.This chapter reviews the regulatory landscape together with some of the support initiatives developed for ATMP in the EU.

Regulatory Oversight of Cell, Tissue, and Gene Therapy Products in Singapore.

The Health Sciences Authority of Singapore has implemented a fit-for-purpose regulatory framework for Cell, Tissue, and Gene Therapy Products (CTGTPs) on 1 March 2021. A total of 11 pieces of subsidiary legislation for CTGTP are gazetted under the Health Products Act as Health Products (CTGTP) Regulations 2021. The CTGTPs are stratified into lower-risk Class 1 CTGTP or moderate- to higher-risk Class 2 CTGTP based on their degree of manipulation, intended use, and if they are combined or used with therapeutic products or medical devices. The regulatory controls are calibrated to the different risk profiles of the products. This risk-based regulatory approach aims to facilitate successful product development and registration in Singapore for innovative CTGTP with a least burdensome regulatory framework while ensuring reasonable safeguards on the safety, quality, and efficacy of the products. This chapter describes the regulatory oversight of CTGTP in Singapore.

3D intraoral scan and diagnostic plaster model under General Data Protection Regulation - Legal protection.

No legal subsumption of dental impressions, plaster models and intraoral scanning has been attempted yet. It should be examined to what extent the General Data Protection Regulation (GDPR) applies to them. The aim of this study is to legally classify 3D intraoral scans and plaster models prepared on the basis of alginate impressions within the context of personal data safety and determination of legal protection applicable to their use. The authors set the deliberations concerning legal protection of plaster models and 3D intraoral scans in the light of recently published articles regarding palatal rugae pattern stability, thus enabling accurate personal identification regardless of age or dental treatment. The deliberations concerning legal protection will be based on the analysis of the international legal acts, in particular GDPR. The intraoral scan constitutes biometric data, because it is information about a natural person - a patient is identifiable on the basis of elements defining physical identity. The plaster model itself does not constitute personal data. However, both of them constitutes medical documentation. The biometric data must be processed in a manner compliant with the GDPR provisions. The GDPR shapes only aims which should be attained. When creating a data safety system, ISO or NIST standards may help to ensure the proper level of protection against possible liability resulting from breaches in the scope of personal data processing.

Analysis of the problems of drug sampling and testing programme under tripartite system reform in China.

RATIONALE: To ensure that quality medicines are available to the populace. AIM AND OBJECTIVE: To provide a new perspective for drug sampling and testing using a risk-based approach globally, and provide a reference for improving the efficiency of the drug sampling and testing programme in China. METHOD: This study used a combination of theoretical analysis and problem analysis. First, we analysed the high-risk drugs that should be given attention to theoretically in the drug sampling testing programme based on the healthcare reform in China. Second, this study leveraged on data on the sampling and testing of drugs extracted from self-constructed data by the China Food and Drug Administration (CFDA). The integrated and structured data sets were used to conduct an innovative analysis that identifies the actual content of the drug sampling and testing programme and contrasts them with the theoretical content to understand the problems. This study used quantitative and qualitative approaches for data analysis. RESULTS: Following analysis, we discovered that there is still a big gap between the reality of drug sampling and testing in China and the ideal state of the objective requirements of healthcare reforms. The major sources of risk are the retail pharmacies or hospital pharmacies in the distribution chain of drugs; however, the CFDA sampled mostly drugs from drug manufacturers. Additionally, the CFDA did not sample adequate essential medicines, bid-winning drugs (especially those with large price drops in centralized procurement), biological products and other high-risk drug varieties. The high-risk drugs produced by companies or enterprises with a history of noncompliance, especially bid-winning enterprises in centralized procurement, were not sampled. CONCLUSION: We suggest that the major content of drug sampling and testing in China should focus on the link of drug utilization, varieties of drugs with large price drops in centralized procurement and bid-winning enterprises with a history of noncompliance.

Identification of potential risk factors for the poor prognosis of neonatal sepsis.

Background and aim: Risk factor-based approach is one of the best approaches employed by middle income countries which are not well facility driven for any disease management. Thus, through this approach, we aim to identify the potential risk factors responsible for the poor outcome in neonatal sepsis. Methods: A case control was conducted retrospectively with neonates admitted to Neonatal Intensive Care Unit during January 2012 to December 2016. Cases were identified using ICD-10 Code from inpatient medical records and demographic, maternal and neonatal details were collected from the medical files. Logistic regression was performed to identify the risk factors associated with mortality in neonatal sepsis. Results: A total of 613 neonates were found to have culture positive sepsis from the 4690 neonates admitted in the Neonatal Intensive Care Unit (NICU). There was a total of 831 episodes in the 613 neonates. The mortality rate in neonates with sepsis was found to be 25.4%. Extremely low birth weight (OR 6.171, CI 3.475-10.957), extreme preterm (OR 5.761, CI 2.612-12.708), very preterm (OR 2.548, CI 1.607-4.042), preeclampsia (OR 1.671, CI 1.091-2.562), acute renal failure (OR 4.939, CI-2.588-9.426), coagulopathy (OR 2.211, CI-1.486-3.289), septic shock (OR 173.522, CI-23.642-1273.59), thrombocytopenia (OR 5.231, CI-3.310-8.268), leukopenia (OR 2.422, CI- 1.473-3.984), CRP > 24 (OR 2.099, CI-1.263-3.487) and abnormal absolute neutrophil count (OR 2.108, CI-1.451-3.062) were some of the significant predictors, identified through risk-based approach, in assessing mortality in neonatal sepsis. Conclusion: Risk-based approach applied was successful in determining plausible important predictors such like extreme low birth weight, extreme preterm, resistance against gram negative infections, preeclampsia, septic shock, hypotension, leukopenia, neutropenia, thrombocytopenia in predicting mortality in neonatal sepsis. These potential risk factors, identified through risk- based approach, can play a pivotal role in assisting clinician to make appropriate and judicious decision.

Decontamination of High-Containment Laboratories for Demolition: A Risk-Based Approach.

Introduction: Decontamination of redundant laboratories, contained plant space, and support buildings used to handle high consequence animal pathogens (North America BSL-3Ag, UK SAPO4) was required before demolition to mitigate the risk that infectious material was released into the environment. Methods: Given the age of the buildings and their construction, bespoke qualitative risk-based methods were developed by biorisk personnel, in consultation with specialist contractors where applicable. This approach was to give assurance that suitable decontamination was achievable, sometimes through multilayered approaches to disinfection. Time was considered as a contributing factor in decontamination. Different means of achieving decontamination were employed, and waste management was considered as part of the overall process ensuring a "cradle to grave" approach. Summary: This article describes the challenges and solutions, faced by a UK facility licensed to work on high hazard pathogens, including foot-and-mouth disease virus and African swine fever virus. The risk-based approach (and methods described herein) may also be applicable to routine decontamination of younger buildings, that is, during renovations or temporary derestriction.

R.Graph: A new risk-based causal reasoning and its application to COVID-19 risk analysis.

Various unexpected, low-probability events can have short or long-term effects on organizations and the global economy. Hence there is a need for appropriate risk management practices within organizations to increase their readiness and resiliency, especially if an event may lead to a series of irreversible consequences. One of the main aspects of risk management is to analyze the levels of change and risk in critical variables which the organization's survival depends on. In these cases, an awareness of risks provides a practical plan for organizational managers to reduce/avoid them. Various risk analysis methods aim at analyzing the interactions of multiple risk factors within a specific problem. This paper develops a new method of variability and risk analysis, termed R.Graph, to examine the effects of a chain of possible risk factors on multiple variables. Additionally, different configurations of risk analysis are modeled, including acceptable risk, analysis of maximum and minimum risks, factor importance, and sensitivity analysis. This new method's effectiveness is evaluated via a practical analysis of the economic consequences of new Coronavirus in the electricity industry.

A roadmap towards quantitative cumulative impact assessments: Every step of the way.

Currently most Cumulative Impacts Assessments (CIAs) are risk-based approaches that assess the potential impact of human activities and their pressures on the ecosystem thereby compromising the achievement of policy objectives. While some of these CIAs apply actual data (usually spatial distributions) they often have to rely on categorical scores based on expert judgement if they actually assess impact which is often expressed as a relative measure that is difficult to interpret in absolute terms. Here we present a first step-wise approach to conduct a fully quantitative CIA based on the selection and subsequent application of the best information available. This approach systematically disentangles risk into its exposure and effect components that can be quantified using known ecological information, e.g. spatial distribution of pressures or species, pressure-state relationships and population dynamics models with appropriate parametrisation, resulting in well-defined assessment endpoints that are meaningful and can be easily communicated to the recipients of advice. This approach requires that underlying assumptions and methodological considerations are made explicit and translated into a measure of confidence. This transparency helps to identify the possible data-handling or methodological decisions and shows the resulting improvement through its confidence assessment of the applied information and hence the resulting accuracy of the CIA. To illustrate this approach, we applied it in a North Sea CIA focussing on two sectors, i.e. fisheries and offshore windfarms, and how they impact the ecosystem and its components, i.e. seabirds, seabed habitats and marine mammals through various pressures. The results provide a "proof of concept" for this generic approach as well as rigorous definitions of several of the concepts often used as part of risk-based approaches, e.g. exposure, sensitivity, vulnerability, and how these can be estimated using actual data. As such this widens the scope for increasingly more quantitative CIAs using the best information available.

Overview of "The Study in Risk-Based Manufacturing Environmental Control for Non-Sterile Drug Products".

To develop a guide of best practices for establishing appropriate controls on nonsterile manufacturing environments for pharmaceutical manufacturers, the Kansai Study Group of the Parenteral Drug Association Japan Chapter explored relevant issues in-depth and published the results of their study, "The Study in Risk-Based Manufacturing Environmental Control for Non-Sterile Drug Products" in the PDA Journal of GMP and Validation in Japan. This review summarizes the background of that study and the structure of the published article and, to help readers make the most of the contents, provides a table displaying the category, subject, problem statement, and points to consider of each topic discussed in the article, as well as examples of central topics (Appendices 1-3).

Industry One-Voice-of-Quality Solutions Management Review of Post-Approval Changes Guide.

Post-approval changes (PACs) are inevitable and necessary throughout the life of a drug product. Because many PACs require prior approval by individual regulatory agencies each having their own reporting requirements and approval timelines, this results in companies having to manage several versions of a manufacturing process at the same time. The global regulatory complexity increases risk of drug shortages. Chief quality officers and heads of quality from more than 20 global pharmaceutical companies have come together to speak with One-Voice-of-Quality (1VQ) and develop solutions to this problem by developing a science and risk-based approach to manage more PACs in the pharmaceutical quality system (PQS) rather than submitting these as prior approval supplements. Pharmaceutical companies already conduct management review (MR) according to the International Conference on Harmonization (ICH) Q10. This One-Voice-Of-Quality paper is a practical guide on how companies can expand the MR to also evaluate and demonstrate the effectiveness of their PQS in specifically managing PACs to achieve regulatory flexibility as stated in ICH Q10, Annex 1. Examples of PQS key performance indicators (KPIs) that may be used to assess, plan, implement, and monitor PACs are described. The intent is to provide assurance through MR that PACs can be managed effectively in the PQS, thereby resulting in a reduced need for regulatory prior approval of certain low risk changes that enhance product availability, reduce the risk of drug shortages, and/or facilitate timely innovation and continual improvement in the pharmaceutical industry. This document is endorsed by 1VQ chief quality officers and heads of quality.

Managing multiple pressures for cetaceans' conservation with an Ecosystem-Based Marine Spatial Planning approach.

Despite the recognized important ecological role that cetaceans play in the marine environment, their protection is still scarcely enforced in the Mediterranean Sea even though this area is strongly threatened by local human pressures and climate change. The piecemeal of knowledge related to cetaceans' ecology and distribution in the basin undermines the capacity of addressing cetaceans' protection and identifying effective conservation strategies. In this study, an Ecosystem-Based Marine Spatial Planning (EB-MSP) approach is applied to assess human pressures on cetaceans and guide the designation of a conservation area in the Gulf of Taranto, Northern Ionian Sea (Central-eastern Mediterranean Sea). The Gulf of Taranto hosts different cetacean species that accomplish important phases of their life in the area. Despite this fact, the gulf does not fall within any area-based management tools (ABMTs) for cetacean conservation. We pin down the Gulf of Taranto being eligible for the designation of diverse ABMTs for conservation, both legally and non-legally binding. Through a risk-based approach, this study explores the cause-effect relationships that link any human activities and pressures exerted in the study area to potential effects on cetaceans, by identifying major drivers of potential impacts. These were found to be underwater noise, marine litter, ship collision, and competition and disturbance on preys. We draw some recommendations based on different sources of available knowledge produced so far in the area (i.e., empirical evidence, scientific and grey literature, and expert judgement) to boost cetaceans' conservation. Finally, we stress the need of sectoral coordination for the management of human activities by applying an EB-MSP approach and valuing the establishment of an ABMT in the Gulf of Taranto.

A novel systematic, risk based approach to support the designation of aquatic disposal sites.

Humans rely fundamentally on the marine environment, which is at the same time subject to an increasingly broad range of anthropogenic pressures, leading to growing concerns and the need for effective management for marine protection. One activity is the dredging of ports and harbours which is necessary to maintain safe channels for commercial and recreational navigation. Regulatory authorities in developing countries have few resources to conduct full EIAs for determining dredged material disposal sites but are required to do so under international obligations. The Tool in this paper provides an effective, pragmatic, transparent, consistent, and robust approach to protect the environment whilst using limited technical and scientific resources through a risk based approach to defining need, characterising and designating disposal sites at sea for dredged material. Whilst this approach for dredged material disposal sites was developed for use in UK, this process is equally applicable to other waste types, worldwide.

Status of risk-based approach and national framework for safe drinking water in small water supplies of the Nordic water sector.

Reliable safe water supply is a pillar of society and a key to public health. The Nordic countries have an abundance of clean fresh water as a source for drinking water supplies. They have followed developments in safeguarding water, both the recommendations of the World Health Organization framework for safe drinking water and European legislation. Worldwide, including the Nordic countries, small water supplies are less compliant with water safety regulation. The forthcoming EU directive on drinking water require risk-based approaches and improved transparency on water quality. This research looks at the Nordic frameworks for safe water supply, with emphasis on risk-based approaches and smaller systems. We analyzed the legal frameworks for safe water, the structure of the water sector across the Nordic countries and explored how prepared these countries are to meet these requirements. Our findings show that, while legal requirements are mostly in place, delivery of information to the public needs to be improved. Most Nordic countries are in the process of implementing risk-based management in large and medium size water supplies, whereas small supplies are lagging. We conclude that a key to success is increased training and support for small supplies. We suggest wider adoption of the Nordic model of cooperation with benchmarking of safe water for all to transfer knowledge between the countries. This work provides insights into challenges and opportunities for the Nordic countries and provides insights relevant to countries worldwide in their effort towards realization of SDG Target 6.1.

Good design practices for an integrated containment and production system for advanced therapies.

Advances in molecular biology and the possibility of differentiating stem cells have opened up new scenarios in therapies that use progenitor or variously differentiated cells. Regardless of the choice of the system, designing a plant for producing advanced therapies requires a clear understanding of the final objective (the product), taking into account all the regulatory, environment, process, risk assessment, asepsis, and validation aspects involved until its implementation. Good Manufacturing Practice (GMP) compliant procedures are a prerequisite for cell production in clinical application, and clean rooms are zones for producing cell therapies. Clean rooms for clinical application require high running and maintenance costs and need trained operators and strict procedures to prepare the rooms and the people involved in the processes. While today production mainly occurs in open systems (clean rooms), there is evidence of processes in closed systems (isolators). The isolator is a Grade A aseptic closed system that requires a controlled environment and at least a Grade D environment in the case of sterile productions (A in D closed system). The use of isolators can ensure a very high level of protection against the risk of product contamination and, at the same time, provide the operators with a very safe working environment. Furthermore, working with closed systems can optimize and facilitate the production of Advanced Therapy Medical Products in GMP environments, by providing an easily reproducible working tool even for large-scale production, with generally lower costs compared to a classical clean room approach. In conclusion, the isolator workstation as a possible alternative to the classic clean room, due to its small size and the simplification of the working and maintenance operational procedures, may represent an interesting solution in the perspective of the increasingly more stringent requests for cost reductions of GMP in clinical application.

Industry One-Voice-of-Quality (1VQ) Solutions: Effective Management of Post-Approval Changes in the Pharmaceutical Quality System (PQS)-through Enhanced Science and Risk-Based Approaches.

Post-approval changes are inevitable and necessary throughout the life of a drug product-to implement new knowledge, maintain a state of control, and drive continual improvement. Many post-approval changes require regulatory agency approval by individual countries before implementation. Because of the global regulatory complexity, individual post-approval changes usually take years for full worldwide approval even when they reduce patient risk, improve compliance, or enhance the manufacturing process or test methods. This global complexity slows down continual improvement and innovation and can cause drug shortages and current good manufacturing practices compliance issues. Manufacturers that market products globally experience the greatest challenge and risks in their daily operations because of this post-approval change complexity. A global problem needs a global solution. This paper has been sponsored and endorsed by senior quality leaders (Chief Quality Officers/Heads of Quality) from >20 global pharmaceutical companies who have collaborated to speak with "One-Voice-Of-Quality" (1VQ). The paper provides two specific solutions that lay the foundation for an aligned and standardized industry position on the topic of effective management of post-approval changes in the pharmaceutical quality system (PQS). This document represents the 1VQ standard approach for the steps necessary to establish and demonstrate an effective quality system to fully leverage a risk-based approach to post-approval changes as laid out by ICH Q10 Annex 1. Implementation of the solutions presented in this paper can help achieve a transformational shift with faster implementation of new knowledge, continual improvement, and innovation through post-approval changes. The Chief Quality Officers/Heads of Quality are inviting other companies to join the 1VQ (contact either Emma Ramnarine or Anders Vinther) and other stakeholders to join the dialog.