European Authorization Research Articles

Advanced Therapy Medicinal Products: Availability, Access and Expenditure in Italy.

Advanced therapy medicinal products (ATMPs) are an innovative output of biomedical research, characterized by a high level of uncertainty on long-term efficacy and safety, elevated price tags and often complex administration. All these elements compounded make their European authorization, national price negotiation for reimbursement and subsequent dispensation and administration to the patient less straightforward and often less successful than for less innovative drugs. To assess if these hurdles have affected patient access and how are ATMPs used in Italy, we have analysed availability, access and expenditure of ATMPs in the period spanning from 2016 to 2023. We have analysed real world data on the duration of ATMP regulatory evaluations for authorisation and reimbursement, time to first patient access and expenditure for ATMPs through the Italian National Health System (INHS) expenditure data flow, as well as information on patient mobility and availability of health facilities specialized in administering ATMPs. Of the 18 ATMPs currently authorized in Europe, 9 are reimbursed by the INHS, but only 6 were actually used, generating a cumulative expenditure of roughly 300 Mln€ from 2016 to 2023, largely owing to CAR-T therapies. Time to patient access reaches an average of 340.6 days from the day publication in the official Gazette of the reimbursement decision to first patient treatment in one of the 107 health facilities authorized for ATMP administration, after an even longer evaluation time by regulatory agencies. Since the first reimbursement decision for an ATMP in Italy, back in 2016, these innovative drugs became progressively more and more available, both in terms of numbers and in terms of coverage across the country. Almost all Italian regions have at least one centre for ATMP administration and has performed a treatment in 2023. Notwithstanding their high per-treatment prices, ATMPs currently have a rather contained expenditure, however it is bound to keep growing in the next few years.

ETIAS system and new proposals to advance the use of AI in public services

Eu-LISA is launching the European Travel Information and Authorization System (ETIAS), which seems an example of a different, human rights-oriented approach to AI within the law enforcement. However, the reality is quite different: the usual problems of the use of AI—lack of transparency, bias, opacity, just to name a few—are still on board. This paper critically assesses these promises of ETIAS and argues that it has serious issues that have not been properly dealt with. So as to argue the need to address these issues, the paper addresses ETIAS within the wider context of human rights and solidarity-based data governance. In this respect, ETIAS is seen as a tool which uses data for high value purposes, such as EU safety and security, yet it also calls for serious risk mitigation measures. Indeed, the risks related to law enforcement on the borders and in migration management are extremely serious due to the vulnerability of people who escape from poverty, wars, regimes, and other disasters. In the third part of this article, we articulate three proposals of such risk mitigation measures. We argue in favour of strengthening critical general safeguards in ETIAS, then elaborate a principle that should guide AI-based public service development (P4P principle) and end with a few IPR-related requirements for private sector involvement in such services. Adopting these measures could contribute to reduce the risk of building EU AI expertise upon data coming from the most vulnerable social groups of our planet.

Balancing ethical norms and duties for the introduction of new medicines through conditional marketing authorization: a research agenda.

The European Medicines Agency's conditional marketing authorization (CMA) aims to expedite patient access to medicines for unmet medical needs by shifting a part of the drug development process post-authorization. We highlight ethical issues surrounding CMA, comprising (i) the complexity of defining unmet medical need; (ii) poor understanding of CMA and its impact on informed consent; (iii) hope versus unrealistic optimism; (iv) implications of prolonged post-authorization studies and potential patient harm; (v) rights and duties of patients surrounding participation in post-authorization studies; (vi) access to previously authorized CMA medicines; and (vii) the "benefit slippage" phenomenon, defined as the gradual shift of strict criteria to less strict criteria. We propose a comprehensive research agenda to address these ethical issues, and stress the need for multi-stakeholder engagement to ensure patient-centered use of CMA.

Comparative analysis of tabelecleucel and current treatment in patients with Epstein-Barr virus-positive post-transplant lymphoproliferative disease following hematopoietic cell transplant or solid organ transplant

Aims With recent European Union marketing authorization, tabelecleucel is the first off-the-shelf, allogeneic Epstein-Barr virus (EBV)-specific T-cell immunotherapy approved for the treatment of relapsed/refractory EBV-positive post-transplant lymphoproliferative disease (EBV+ PTLD). In the absence of a control arm, real-world evidence can provide a comparative benchmark for single-arm studies in ultra-rare populations. This study assessed the treatment effect of tabelecleucel in the single-arm phase 3 ALLELE study (NCT03394365) versus a treatment group from a multinational, multicenter retrospective chart review study (RS002) of patients with EBV+ PTLD. Methods In ALLELE, patients had disease relapsed/refractory to rituximab ± chemotherapy and received tabelecleucel 2x106 cells/kg on days 1, 8, and 15 in 35-day cycles. Patients in RS002 had disease relapsed/refractory to rituximab ± chemotherapy and received next line of systemic therapy between January 2000 and December 2018. Propensity score-based standardized mortality/morbidity ratio weighting was used to achieve balance between treatment and comparator arms. Kaplan-Meier estimators and Cox regression models were used to compare overall survival (OS) in the re-weighted sample. Results 30 patients (n = 14 hematopoietic cell transplant [HCT], n = 16 solid organ transplant [SOT]) from ALLELE (data cutoff: November 2021) and 84 patients (n = 36 HCT, n = 48 SOT) from RS002 (data lock: January 2021) were included. Median time from diagnosis to first tabelecleucel dose (ALLELE) or start date of next line of systemic therapy (RS002) was 3.6 months. Tabelecleucel was associated with a substantial OS benefit compared with current treatment, with an unadjusted HR of 0.47 (95% confidence interval [CI] 0.25–0.88) and adjusted HR of 0.37 (95% CI 0.20–0.71) when using the start date of the next line of therapy as the index date. Sensitivity analyses yielded consistent results. Conclusions In this study of real-world data, tabelecleucel was associated with an OS benefit among patients with R/R EBV+ PTLD for whom there is high unmet need.

Evaluation of the Scientific Quality and Usability of Digital Dietary Assessment Tools

The importance of digital tools for dietary assessment has increased in recent years, both commercially and scientifically. In the field of nutrition research, the digitization of dietary assessment methods presents many opportunities and risks. One of the main challenges is ensuring scientific quality while maintaining good usability. In this context, an evaluation tool was developed based on the guidelines of the European Food Safety Authorization (EFSA; 2009 and 2014), complemented by the usability aspect of health-related applications. This was followed by a literature search concerning the available dietary assessment tools, which were analyzed according to the evaluation criteria. Eight applications were included in the study after reviewing the inclusion and exclusion criteria for the digital tools. A total of thirty-eight requirements in eight main categories were defined for the evaluation, which the best possible dietary assessment tool should meet. The evaluation showed that none of the tested tools currently meet all the defined requirements or categories. The aspects of usability and the accuracy of data collection showed a positive correlation, suggesting a direct link between the two categories and providing an important approach for future developments.

Limits to discretion and automated risk assessments in EU border control: Recognising the political in the technical

AbstractThis article analyses how the automation of border control challenges the rule of law requirement on sufficient limits to discretion by using the idea expressed by the Court of Justice of the European Union (CJEU) non‐delegation doctrine that it is possible to make a clear distinction between technically complex assessments and political discretion. To illustrate these challenges, the article uses the examples of the European Travel Information and Authorisation System (ETIAS) and the conferral of discretionary powers to EU agency Frontex to establish pre‐determined risk criteria. The article argues that not recognising the inherent political aspects of exercising technical powers leads to insufficient limits to discretionary powers in the context of automated risk assessments. Beyond raising serious rule of law concerns of arbitrary exercise of power, the idea that technical assessments and policy choices can be clearly separated enables ‘algorithmic discretion’ as a new form of administrative discretion.

The European Travel Information and Authorization System (ETIAS): Enhancing Counterterrorism and Counterintelligence Efforts

The European Travel Information and Authorization System (ETIAS) is set to revolutionize border security in the European Union. Scheduled for operation in 2025, it will screen travelers from visa-exempt countries, enhancing security by identifying potential threats such as terrorism, organized crime, and illegal migration. Regulated by EU legislation and involving a detailed application process, the system collects and cross-references traveler data with various databases to assess security, public health, and migration risks. While ETIAS is a powerful tool for counterterrorism, preventing entry of potential terrorists, it is also an advanced counterintelligence asset, employing intelligence capabilities to detect espionage and Intelligence related activities and act as a deterrent to potential spies. With a comprehensive approach, the present paper describes the ETIAS promises to bolster EU security.

Artículo traducido] Abemaciclib en adyuvancia para el tratamiento del cáncer de mama precoz de alto riesgo

ObjectiveTo adapt the GHEMA report of abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6. European Medicines Agency authorisation (April 2022) includes, in combination with endocrine therapy, the adjuvant treatment of adult patients with hormone receptor positive, human epidermal growth factor receptor 2 negative, node-positive, early breast cancer at high risk of recurrence. MethodThe efficacy and safety of abemaciclib were evaluated in a randomized, open-label and multicenter phase III study. A total of 5,637 patients diagnosed with early breast cancer with hormone receptor positive, human epidermal growth factor receptor 2 negative, node positive and high risk of recurrence were included. High risk was defined as patients with 4 or more positive axillary lymph nodes, or 1-3positive axillary lymph nodes and at least one of the following: tumor size ≥5 cm, histologic grade 3 or Ki-67 ≥ 20%. Patients were randomized (1:1) to receive adjuvant abemaciclib + endocrine therapy (n = 2,808) or endocrine therapy alone (n = 2,829) for 2 years, with endocrine therapy prescribed for at least 5 years. ResultsWith a median follow-up of 15.5 months, abemaciclib + endocrine therapy demonstrated a statistically significant improvement in invasive disease-free survival versus endocrine therapy alone (HR = 0.747 [95% CI 0.598-0.932], p = 0.0096); achieving an absolute improvement of 3.5% invasive disease-free survival rate at 2-years. These results were maintained, with a median follow-up of 27.7 months: absolute improvement of 2.7% and 5.4% in invasive disease-free survival rate at 2 and 3-years, respectively. All-causality grade 3 or 4 adverse events were 45.9% for abemaciclib and 12.9% for endocrine therapy, and included neutropenia (19.6% vs. 0.8%), leukopenia (11.4% vs. 0.4%) and diarrhea (7.8% vs. 0.2%). ConclusionsThe results of the pivotal trial are sufficient to consider abemaciclib as adjuvant treatment for high-risk early breast cancer in highly selected patients. However, in order to the efficacy results present less uncertainty, we must wait for a evaluation later, in which we can have a mature determination at 3 years (with more patients at risk).

Pricing and reimbursement mechanisms for advanced therapy medicinal products in 20 countries

Introduction: Advanced Therapy Medicinal Products are a type of therapies that, in some cases, hold great potential for patients without an effective current therapeutic approach but they also present multiple challenges to payers. While there are many theoretical papers on pricing and reimbursement (P&R) options, original empirical research is very scarce. This paper aims to provide a comprehensive international review of regulatory and P&R decisions taken for all ATMPs with centralized European marketing authorization in March 2022.Methods: A survey was distributed in July 2022 to representatives of 46 countries.Results: Responses were received from 20 countries out of 46 (43.5%). 14 countries reimbursed at least one ATMP. Six countries in this survey reimbursed no ATMPs.Conclusion: Access to ATMPs is uneven across the countries included in this study. This arises from regulatory differences, commercial decisions by marketing authorization holders, and the divergent assessment processes and criteria applied by payers. Moving towards greater equality of access will require cooperation between countries and stakeholders, for example, through the WHO Regional Office for Europe’s Access to Novel Medicines Platform.

Abemaciclib as adjuvant treatment for high-risk early breast cancer

ObjectiveTo adapt the GHEMA report of abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6. European Medicines Agency authorization (April 2022) includes, in combination with endocrine therapy, the adjuvant treatment of adult patients with hormone receptor positive, human epidermal growth factor receptor 2 negative, node-positive, early breast cancer at high risk of recurrence. MethodThe efficacy and safety of abemaciclib were evaluated in a randomized, open-label, and multicenter phase III study. A total of 5637 patients diagnosed with early breast cancer with hormone receptor positive, human epidermal growth factor receptor 2 negative, node positive, and high risk of recurrence were included. High risk was defined as patients with 4 or more positive axillary lymph nodes, or 1–3 positive axillary lymph nodes and at least one of the following: tumor size ≥5 cm, histologic grade 3, or Ki-67≥20%. Patients were randomized (1:1) to receive adjuvant abemaciclib+endocrine therapy (n = 2808) or endocrine therapy alone (n = 2829) for 2 years, with endocrine therapy prescribed for at least 5 years. ResultsWith a median follow-up of 15.5 months, abemaciclib+endocrine therapy demonstrated a statistically significant improvement in invasive disease-free survival versus endocrine therapy alone [HR = 0.747 (95% CI 0.598–0.932), P = 0.0096]; achieving an absolute improvement of 3.5% invasive disease-free survival rate at 2-years. These results were maintained, with a median follow-up of 27.7 months: absolute improvement of 2.7% and 5.4% in invasive disease-free survival rate at 2 and 3 years, respectively. All-causality grade 3 or 4 adverse events were 45.9% for abemaciclib and 12.9% for endocrine therapy, and included neutropenia (19.6% vs. 0.8%), leukopenia (11.4% vs. 0.4%), and diarrhea (7.8% vs. 0.2%). ConclusionsThe results of the pivotal trial are sufficient to consider abemaciclib as adjuvant treatment for high-risk early breast cancer in highly selected patients. However, in order to the efficacy results present less uncertainty, we must wait for a evaluation later, in which we can have a mature determination at 3 years (with more patients at risk).

Rule of Law Challenges of ‘Algorithmic Discretion’ & Automation in EU Border Control

Abstract The European Travel Information and Authorisation System (ETIAS) will profile visa- exempt third-country nationals using a screening rules algorithm to make automated predictive risk assessments. By using the screening rules algorithm as a case study, this article analyses if the ETIAS Regulation, and the legal safeguards it establishes for the decision-making process, comply with formal and substantive legality requirements as defined by the Venice Commission and the Court of Justice of the European Union. Three legality challenges are identified: [1] The regulatory design of ETIAS raises issues in relation to the foreseeability, clarity and accessibility of law, as well as insufficient limits to discretion. [2] The ETIAS screening rules algorithm represents a development towards a new form of arbitrariness through ‘algorithmic discretion’. [3] The safeguard of manual (human) processing in case of a ‘hit’ is not a panacea for the identified legality challenges.

Current and Future Landscape in Genetic Therapies for Leber Hereditary Optic Neuropathy.

Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial genetic disease that causes blindness in young adults. Over 50 inherited mitochondrial DNA (mtDNA) variations are associated with LHON; however, more than 95% of cases are caused by one of three missense variations (m.11778 G > A, m.3460 G > A, and m.14484 T > C) encoding for subunits ND4, ND1, and ND6 of the respiration complex I, respectively. These variants remain silent until further and currently poorly understood genetic and environmental factors precipitate the visual loss. The clinical course that ensues is variable, and a convincing treatment for LHON has yet to emerge. In 2015, an antioxidant idebenone (Raxone) received European marketing authorisation to treat visual impairment in patients with LHON, and since then it was introduced into clinical practice in several European countries. Alternative therapeutic strategies, including gene therapy and gene editing, antioxidant and neurotrophic agents, mitochondrial biogenesis, mitochondrial replacement, and stem cell therapies are being investigated in how effective they might be in altering the course of the disease. Allotopic gene therapies are in the most advanced stage of development (phase III clinical trials) whilst most other agents are in phase I or II trials or at pre-clinical stages. This manuscript discusses the phenotype and genotype of the LHON disease with complexities and peculiarities such as incomplete penetrance and gender bias, which have challenged the therapies in development emphasising the most recent use of gene therapy. Furthermore, we review the latest results of the three clinical trials based on adeno-associated viral (AAV) vector-mediated delivery of NADH dehydrogenase subunit 4 (ND4) with mitochondrial targeting sequence, highlighting the differences in the vector design and the rationale behind their use in the allotopic transfer.

Effectiveness and safety outcomes in patients with EBV+ PTLD treated with allogeneic EBV-specific T-cell immunotherapy (tabelecleucel) under an expanded access program (EAP) in Europe.

7521 Background: Pts with relapsed or refractory (r/r) EBV+ post-transplant lymphoproliferative disease (PTLD) in Europe have had historically poor overall response rates and median overall survival (OS) with no approved treatment options. Tabelecleucel, an off-the-shelf, allogeneic EBV-specific T-cell immunotherapy has shown clinical benefit and favorable safety profile in the treatment of EBV+ PTLD failing rituximab ± chemotherapy (Prockop EBMT 2021, ATC 2021, ASH 2022). Its recent European marketing authorization (EMA) represents the first approval of an allogenic T-cell immunotherapy globally. Methods: Atara Bio supported expanded access requests for tabelecleucel in Europe. Here we report updated effectiveness and safety data for r/r EBV+ PTLD pts who provided consent for research between Sep 2020 and Dec 2022. Results: 74 EAP requests were received from 10 countries for pts with r/r EBV+ diseases. 27 EBV+ PTLD pts consented to secondary use of data and 24 pts had received ≥1 dose of tabelecleucel, including 4 pts with primary central nervous system (PCNS) PTLD. 16 of 24 (66.7%) PTLD pts achieved a partial (PR) (33.3%) or complete (CR) (33.3%) response, with median time to response (TTR) of 1.0 mo (0.8–2.2). Response rate for PCNS PTLD pts was 75% (1 CR, 2 PR). 1-yr OS Kaplan–Meier (KM) estimate rates were 73.7% (95% CI: 47.3, 88.3) overall, 87.5% in allogeneic hematopoietic stem cell transplant (HCT) and 66.5% in solid organ transplant (SOT), with a median follow-up time of 9.9 (2.4–13.9) and 6.0 (0.7–18.0) mo, respectively. Serious treatment-emergent adverse events (TESAEs) were reported in 7 (29.2%) pts, including 1 fatal event of disease progression. Predefined risks for tabelecleucel were reported in 3 pts; 1 (4.2%) SOT pt had a TESAE of liver transplant rejection (grade 2) and 2 (8.3%) HCT pts had non-serious TEAEs of chronic graft-versus-host disease (grade 1 and 2). No cases of cytokine release syndrome or tumor flare reaction were reported. No AEs were reported as related to tabelecleucel by the treating physician. Conclusions: These updated real-world results for pts with r/r EBV+ PTLD post-HCT or post-SOT treated in the European EAP continue to reinforce the favorable risk:benefit profile of tabelecleucel and are in line with clinical study data supporting its recent EMA approval. [Table: see text]

Efficacy of fungoid chitosans from Aspergillus niger and Agaricus bisporus in controlling the oxidative browning of model white wines

The efficacy of two water-insoluble chitosans from Aspergillus niger and Agaricus bisporus, in controlling the browning of model white wine solutions was assessed and compared with respect to sulfite addition (70 mg/L). A water-soluble oligomeric preparation from Agaricus bisporus was also included to test the effect of solubility and reduced molecular weight on the antibrowning capability of the polysaccharide. Chitosans were added at 0.5 g/L and 1 g/L. Color development, iron oxidoreductive equilibrium and generation of phenolic intermediates were monitored. Results demonstrated a significant and comparable anti-browning efficacy of both insoluble formulations (up to 85% reduction in browning development with respect to control samples), which mainly acted by chelating iron (up to around 4.4 mg/g of chitosan) and shifting its oxidoreductive equilibrium toward the reduced form. Oligomeric chitosan was ineffective for this purpose as it completely lacked chelating activity, which it is proposed, depended on its negligible interaction with tartaric acid. Data on browning and oxidation-related phenolic intermediates also revealed that sulfite promotes browning once it is completely oxidized.Industrial relevance: Following its very recent European authorization as novel food, chitosan from Agaricus bisporus has been evaluated for the first time and compared in wine-like conditions with the already known water-insoluble chitosan from Aspergillus niger. A further novelty are the data on water-soluble chitosan preparations, not yet permitted in wine but potentially interesting due to the potentially higher specific surface once in solution. The results, apart from providing information on a recently introduced source for enological chitosan, can be useful to producers and winemakers in deciding among fungoid preparations aimed to control the browning of products.

European Conditional Marketing Authorization in a Rapidly Evolving Treatment Landscape: A Comprehensive Study of Anticancer Medicinal Products in 2006-2020.

Since 2006, the European conditional marketing authorization (CMA) aims to facilitate timely patient access to medicinal products for which there is an unmet medical need by accepting less comprehensive data than normally required. The granting of CMA requires a positive benefit-risk balance, unmet medical needs to be fulfilled, likely submission of comprehensive data postauthorization, and the benefit of immediate availability to outweigh the risks of data noncomprehensiveness. Since its first use, more than half of all CMAs represent (hemato-)oncology indications. Therefore, we aimed to investigate the conditions in which CMA has been applied for anticancer medicinal products and whether they have changed over time. We retrospectively assessed the European public assessment reports of the 30 anticancer medicinal products granted CMA in 2006-2020 (51% of all 59 CMAs). Comparison of 2006-2013 to 2014-2020 highlighted increased proportions of proactively requested CMAs (+40%), medicinal products that addressed unmet medical needs by providing a major therapeutic advantage over authorized treatments (+38%), and orphan designated indications (+32%). In contrast, it showed decreased proportions of medicinal products for which a scientific advisory group was consulted (-55%) and phase III randomized controlled trial data were available (-38%). This suggests that applicants and the European Medicines Agency have learned how to use the CMA as a regulatory tool, among others, through better planning and proactive interaction. However, the increasing number of granted CMAs complicates the establishment of unmet medical need and the benefit-risk balance, especially in crowded indications and when only phase II uncontrolled trials are available.

Environmental exposure assessment of co-formulants in plant protection products under REACH.

It is a regulatory requirement to assess co-formulants in plant protection products (PPP) under the European Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) legislation. The standard environmental exposure assessment framework for chemicals under REACH is a multicompartmental mass-balanced model and, at the local scale, is designed for use with urban (wide dispersive) or industrial (point source) emissions. However, the environmental release of co-formulants used in PPP is to agricultural soil and indirectly to waterbodies adjacent to a field and, for sprayed products, to the air. The Local Environment Tool (LET) has been developed to assess these specific emission pathways for co-formulants in a local-scale REACH exposure assessment, based on standard approaches and models used for PPP. As such, it closes a gap between the standard REACH exposure model's scope and REACH requirements to assess co-formulants in PPP. When combined with the output of the standard REACH exposure model, the LET includes an estimate of the contribution from other nonagricultural background sources of the same substance. The LET is an improvement over the use of higher tier PPP models for screening purposes because it provides a simple standardized exposure scenario. A set of predefined and conservatively selected inputs allows a REACH registrant to conduct an assessment without requiring detailed knowledge of PPP risk assessment methods or typical conditions of use. The benefit to the co-formulant downstream user (formulators) is a standardized and consistent approach to co-formulant assessment, with meaningful and readily interpretable conditions of use. The LET can serve as an example to other sectors of how to address possible gaps in the environmental exposure assessment by combining a customized local-scale exposure model with the standard REACH models. A detailed conceptual explanation of the LET model is provided here together with a discussion on its use in a regulatory context. Integr Environ Assess Manag 2023;19:1544-1554. © 2023 BASF SE, Bayer AG et al. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Economic interests cloud hazard reductions in the European regulation of substances of very high concern

Here we investigate how the conflicts between hazard reduction and economic interests have shaped the regulation of substances of very high concern (SVHCs) under the Authorization program of the European chemical regulation Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH). Since regulation starts with listing SVHCs on the Candidate List, we analyze the relative importance of toxicological properties, economic motivations, and available scientific knowledge on the probability of inclusion on the Candidate List. We find that the most important factor in whether a substance is listed is whether it is being produced in, or imported into, the European Economic Area (EEA), with the regulators less likely to place a substance on the list if it is currently being produced or imported in the EEA. This evidence suggests that regulators have listed chemicals of secondary importance leading to lesser than anticipated hazard reductions, either because production and imports had already ceased before the listing, or because the compound has never been produced or imported in the EEA at all.

PERFORMANCE EVALUATION OF COMMERCIAL SCINTILLATION COCKTAILS FOR LOW-LEVEL TRITIUM COUNTING BY HIGH-CAPACITY LIQUID SCINTILLATION COUNTER.

Low-background liquid scintillation counter is one of the popular measuring instruments used to investigate tritium radioactivity in environmental media. These instruments require the liquid sample and organic solvent to be mixed for tritium measurement. In the European Union, the registration, evaluation, authorization and restriction of chemicals regulation was established to control the use of chemical substances of very high concern. It is important to find continuously available alternative reagents. In this paper, a performance evaluation was conducted using four scintillation cocktails according to Japanese conventional procedure; although one of them, Gold Star LT2, contains nonylphenol ethoxylate, it will continue to be available for research and development. From the evaluation results it was confirmed that Gold Star LT2 would be a satisfactory alternative scintillator, which is similar performance of Ultima Gold LLT.

Autologous Chondrocyte Implantation (ACI) for Cartilage Defects of the Knee Using Novocart 3D and Novocart Inject

Ever since autologous chondrocyte implantation (ACI) has been introduced, there have been important advancements and progress leading to a more reliable and more standardized application of this technology. While first-generation ACI followed the principle of a cell-suspension being injected under an autologous periosteum patch, second and third generation of ACI are characterized by the use of biomaterials, either using a cell-suspension (2 nd generation) or a combination of cells and the biomaterial (3 rd generation). Due to easier handling and improved clinical outcome, 3 rd generation ACI has become the gold standard for the use of ACI at this time. The present chapter focuses on the Novocart® 3 rd generation ACI products. While Novocart® 3D uses a collagen membrane and therefore a implantable biomaterial, Novocart® Inject is a hydrogel-based ACI product which can be injected into the cartilage defects. Both products are currently under way for central European market authorization by the European Medicinal Agency (EMA), additionally a FDA-approval trial is under way for Novocart® 3D. Products characteristics, indication, surgical technique and clinical outcome are summarized in the present chapter.

Semi-automated harmonization and selection of chemical data for risk and impact assessment.

Chemical data for thousands of substances are available for safety, risk, life cycle and substitution assessments, as submitted for example under the European Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) Regulation. However, to widely disseminate reported physicochemical properties as well as human and ecological exposure and toxicological data for use in various science and policy fields, systematic methods for data harmonization and selection are necessary. In response to this need, we developed a semi-automated method for deriving appropriate substance property values as input for various assessment frameworks with different requirements for resolution and data quality. Starting with data reported for a given substance and property, we propose a set of aligned data selection and harmonization criteria to obtain a representative mean value and related confidence intervals per chemical-property combination. The proposed method was tested on a set of octanol-water partition coefficients (Kow) for an illustrative set of 20 substances, reported under the REACH regulation as example data source. Our method is generally applicable to any set of substances, and can assess specific distributions in quality and variability across reported data. Further research can likely extend our method for mining information from text fields and adapt it to available data reported or collected from other sources and other substance properties to improve the reliability of input data for risk and impact assessments.