A decade of marketing approval of gene and cell-based therapies in the United States,European Union and Japan: An evaluation of regulatory decision-making

There is a widely held expectation of clinical advance with the development of gene and cell-based therapies (GCTs). Yet, establishing benefits and risks is highly uncertain. We examine differences in decision-making for GCT approval between jurisdictions by comparing regulatory assessment procedures in the United States (US), European Union (EU) and Japan. A cohort of 18 assessment procedures was analyzed by comparing product characteristics, evidentiary and non-evidentiary factors considered for approval and post-marketing risk management. Product characteristics are very heterogeneous and only three products are marketed in multiple jurisdictions. Almost half of all approved GCTs received an orphan designation. Overall, confirmatory evidence or indications of clinical benefit were evident in US and EU applications, whereas in Japan approval was solely granted based on non-confirmatory evidence. Due to scientific uncertainties and safety risks, substantial post-marketing risk management activities were requested in the EU and Japan. EU and Japanese authorities often took unmet medical needs into consideration in decision-making for approval. These observations underline the effects of implemented legislation in these two jurisdictions that facilitate an adaptive approach to licensing. In the US, the recent assessments of two chimeric antigen receptor-T cell (CAR-T) products are suggestive of a trend toward a more permissive approach for GCT approval under recent reforms, in contrast to a more binary decision-making approach for previous approvals. It indicates that all three regulatory agencies are currently willing to take risks by approving GCTs with scientific uncertainties and safety risks, urging them to pay accurate attention to post-marketing risk management.     

Comparison of requirements in the European Union and United States of America for pre-clinical viral safety testing of veterinary vaccines

Of paramount importance in ensuring the safety of live and inactivated veterinary vaccines is demonstration of freedom from extraneous agents in biological starting materials used in their production. Both the European Union (EU) and United States of America (US) provide regulations and guidelines on extraneous agent testing of veterinary vaccines including guidance from the Committee for Medicinal Products for Veterinary Use (CVMP), the European Pharmacopoeia (Ph. Eur.) and the USDA Code of Federal Regulations, Title 9 (9CFR). There are distinct requirements prescribed in EU and US regulations and guidelines. The differences in EU and US requirements for extraneous agent testing of starting materials are such that there may be occasions when no one test may satisfy both sets of regulations for a given scenario. For compliance with both, for global licensing purposes it may therefore be necessary to perform additional tests and/or to justify methods chosen from one set of regulations over another, based on a variety of factors.     

Comparison of new Brazilian legislation for the approval of advanced therapy medicinal products with existing systems in the USA,European Union and Japan

Background aimsAdvanced therapy medicinal products (ATMPs) are a class of biological products for human use that are based on genes, cells and tissues. The first ATMP received marketing authorization in Europe in 2009, whereas Brazil granted the first authorization in 2020. The objective of this study was to compare the regulatory models adopted by Brazil, the USA, Japan and the European Union, which comprise the member countries of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, with regard to the marketing authorization of ATMPs.MethodsThe authors performed a review of the scientific literature and official documents of the regulatory agencies in the aforementioned countries.ResultsThe legislation and regulatory guidelines adopted by the regulatory agencies exhibit similarities and differences. It was not possible to assess whether these differences can be translated into divergent final recommendations by regulatory authorities upon a request for marketing authorization.ConclusionsIn the future, it will be appropriate to start a progressive process of harmonization between these agencies in terms of terminology, legal recommendations and characterization requirements. This is particularly important for emerging countries such as Brazil. In this sense, some measures can be taken to achieve alignment between regulators.     

Regulatory pathways in the European Union

In principle, there are three defined procedures to obtain approval for a medicinal product in the European Union. As discussed in this overview of the procedures, the decision on which regulatory pathway to use will depend on the nature of the active substance, the target indication(s), the history of product and/or the marketing strategy.     

美国与欧盟的转基因食品安全性政策演变比对

随着转基因食品的研究与发展,人们对待转基因食品的态度表现为主要以美国和欧盟为主的两种代表性政策.美国采取遵循可靠科学原则,坚决反对预防原则,即对转基因食品采取积极支持,自愿标识的宽松政策;欧盟采取谨慎预防原则,必须标识和可追溯.从管理原则出发,结合相应采取的监管措施和相关条例,对两国从开始颁布转基因食品政策到当下态势的发展,并结合最新出台的政策进行跟踪分析,比对美国及欧盟对这些指令和条例的执行情况.     

Sustainability guidelines and forest market response: an assessment of European Union pellet demand in the southeastern United States

Woody biomass from the southeast United States is expected to play an important role in meeting European Union renewable energy targets. In crafting policies to guide bioenergy development and in guiding investment decisions to meet established policy goals, a firm understanding of the interaction between policy targets and forest biomass markets is necessary, as is the effect that this interaction will have on environmental and economic objectives. This analysis increases our understanding of these interactions by modeling the response of southern US forest markets to new pellet demand in the presence of sustainability sourcing or harvest criteria. We first assess the influence of EU recommended sustainability guidelines on the forest inventory available to supply EU markets, and then model changes in forest composition and extent in response to expected increases in pellet demand. Next, we assess how sustainability guidelines can influence the evolution of forest markets in the region, paying particular attention to changes in land use and forest carbon. Regardless of whether sustainability guidelines are applied, we find increased removals, an increase in forest area, and little change in forest inventory. We also find annual gains in forest carbon in most years of the analysis. The incremental effect of sustainability guideline application on forest carbon and pellet greenhouse gas (GHG) balance is difficult to discern, but results suggest that guidelines could be steering production away from sensitive forest types inherently less responsive to changing market conditions. Pellet GHG balance shows significant annual change and is attributable to the complexity of the underlying forest landscape. The manner by which GHG balance is tracked is thus a critical policy decision, reinforcing the importance and relevance of current efforts to develop approaches to accurately account for the GHG implications of biomass use both in the United States and European Union.     

The Energetic Metabolism of the European Union and the United States: Decadal Energy Input Time-Series with an Emphasis on Biomass

This article presents an assessment of energy inputs of the European Union (the 15 countries before the 2004 enlargement, abbreviated EU‐15) for the period 1970–2001 and the United States for 1980–2000. The data are based on an energy flow analysis (EFA) that evaluates socioeconomic energy flows in a way that is conceptually consistent with current materials flow analysis (MFA) methods. EFA allows assessment of the total amount of energy required by a national economy; it yields measures of the size of economic systems in biophysical units. In contrast to conventional energy balances, which only include technically used energy, EFA also accounts for socioeconomic inputs of biomass; that is, it also considers food, feed, wood and other materials of biological origin. The energy flow accounts presented in this article do not include embodied energy. Energy flow analyses are relevant for comparisons across modes of subsistence (e.g., agrarian and industrial society) and also to detect interrelations between energy utilization and land use. In the EU‐15, domestic energy consumption (DEC = apparent consumption = domestic extraction plus import minus export) grew from 60 exajoules per year (1 EJ = 10¹⁸ J) in 1970 to 79 EJ/yr in 2001, thus exceeding its territory's net primary production (NPP, a measure of the energy throughput of ecosystems). In the United States, DEC increased from 102 EJ/yr in 1980 to 125 EJ/yr in 2000 and was thus slightly smaller than its NPP. Taken together, the EU‐15 and the United States accounted for about 38% of global technical energy use, 31% of humanity's energetic metabolism, but only 10% of global terrestrial NPP and 11% of world population in the early 1990s. Per capita DEC of the United States is more than twice that of the EU‐15. Calculated according to EFA methods, energy input in the EU and the United States was between one‐fifth and one‐third above the corresponding value reported in conventional energy balances. The article discusses implications of these results for sustainability, as well as future research needs.     

Time required for approval of new drugs in Canada,Australia, Sweden,the United Kingdom and the United States in 1996-1998

BACKGROUND: The timeliness with which national regulatory agencies approve new drugs for marketing affects health care professionals and patients. An unnecessarily long approval process delays access to new medications that may improve patients'' health status. The author compared drug approval times in Canada, Australia, Sweden, the United Kingdom and the United States. METHODS: Application and approval dates of new chemical or biological substances (excluding diagnostic products, and new salts, esters, dosage forms and combinations of previously approved substances) approved for marketing in the 5 countries from January 1996 to December 1998 were requested from the relevant pharmaceutical companies. Data on new drug approvals during the study period were also obtained from the national drug regulatory agencies in Canada, Australia and Sweden and from publications of the US Food and Drug Administration. RESULTS: A total of 219 new drugs were identified as being approved in at least one of the countries during the study period: 23 (10.5%) in all 5 countries, 23 (10.5%) in 4, 27 (12.3%) in 3, 42 (19.2%) in 2, and 104 (47.5%) in 1 country. By individual nation, 97 drugs were identified as being approved in Canada, 94 in Australia, 107 in Sweden, 55 in the UK and 123 in the US. Approval times in Canada and Australia were similar (medians 518 and 526 days respectively), but both countries had significantly longer approval times than Sweden (median 371 days), the UK (median 308 days) and the US (median 369 days). This pattern was consistent across all 3 years and for the 23 new drugs approved in all 5 countries during the 3-year period. Median approval times in Canada were similar in all of the reviewing divisions of Health Canada''s Therapeutic Product Program (539-574 days) except the Central Nervous System Division (428 days) and the Bureau of Biologics and Radiopharmaceuticals (698 days). INTERPRETATION: Median drug approval times during 1996-1998 decreased by varying amounts from the 1995 values in all 5 countries. However, the median approval time in Canada continues to be significantly longer than the times achieved in Sweden, the UK and the US, and it remains considerably longer than Canada''s own target of 355 days for all new drugs.     

European Sitting Championship: Prevalence and Correlates of Self-Reported Sitting Time in the 28 European Union Member States

Objective

Sedentary behaviour is increasingly recognized as an important health risk, but comparable data across Europe are scarce. The objective of this study was to explore the prevalence and correlates of self-reported sitting time in adults across and within the 28 European Union Member States.

Methods

This study reports data from the Special Eurobarometer 412. In 2013, 27,919 randomly selected Europeans (approximately 1000 per Member State) were interviewed face-to-face. Sitting time on a usual day was self-reported and dichotomised into sitting less- and more than 7.5 hours per day. Uni- and multivariate odds ratios of sitting more than 7.5 hours per day were assessed by country and socio-demographic variables using binary logistic regression analyses. The analyses were stratified by country to study the socio-demographic correlates of sitting time within the different countries.

Results

A total of 26,617 respondents were included in the analyses. Median sitting time was five hours per day. Across Europe, 18.5 percent of the respondents reported to sit more than 7.5 hours per day, with substantial variation between countries (ranging from 8.9 to 32.1 percent). In general, northern European countries reported more sitting than countries in the south of Europe. ‘Current occupation’ and ‘age when stopped education’ were found to be the strongest correlates of sitting time, both across Europe and within most Member States. Compared to manual workers, the odds ratio of sitting more than 7.5 hours per day was 5.00 for people with white collar occupations, 3.84 for students, and 3.65 for managers.

Conclusions

There is substantial variation in self-reported sitting time among European adults across countries as well as socio-demographic groups. While regular surveillance of (objectively measured) sedentary behaviour is needed, the results of this study provide entry points for developing targeted interventions aimed at highly sedentary populations, such as people with sedentary occupations.     

Intake assessment of L-ergothioneine in some European countries and in the United States

L-ergothioneine is an amino acid synthetized by fungi and mycobacteria that cannot be synthesized by other species. It has been detected in plants, animals, and the human body. In the last few years, it has been recognized as a good antioxidant and, recently, it has also been related to other properties besides antioxidant properties. Even though few studies on the toxicity of L-ergothioneine have been carried out, evidence suggests that L-ergothioneine is not harmful to health. Considering that L-ergothioneine has increasingly been linked to positive effects on human health, coupled with the fact that it seems to be safe for human consumption, this molecule may be suitable for use as an ingredient in foods. On the other hand, despite the positive effects reported for this molecule, no estimate of L-ergothioneine intake has been carried out until now. Thus, the aim of this work is to estimate the intake of L-ergothioneine through food consumption of several European countries and the United States. Values were estimated by using the deterministic and probabilistic approach. Results show that the populations with the highest intake of L-ergothioneine correspond to Italian population, both for children and adults.     

Charging up Battery Recycling Policies: Extended Producer Responsibility for Single‐Use Batteries in the European Union,Canada, and the United States

Extended producer responsibility (EPR) policies have proven effective at raising consumer awareness, expanding waste collection infrastructure, and shifting costs of end‐of‐life (EOL) management from municipalities to stewardship organizations. Yet, such policies have been less successful in advancing waste management programs that ensure a net environmental benefit. This article analyzes how EPR policies for single‐use batteries in the European Union (EU), Canada, and the United States address the environmental costs and benefits of EOL management. Considering these EPR policies is instructive, because single‐use batteries have high collection costs and are of relatively low economic value for waste processors. Without deliberate planning, the environmental burdens of collecting and recycling such batteries may exceed the benefits. This article considers how EPR policies for single‐use batteries integrate performance requirements such as collection rates, recycling efficiencies, and best available techniques. It argues that for such policies to be effective, they need to be extended to address waste collection practices, the life cycle consequences of EOL management, and the quality of recovered materials. Such strategies are relevant to EPR policies for other products with marginal secondary value, including some textiles, plastics, and other types of electronic waste.     

Jewish Hearts: A Study of Dynamic Ethnicity in the United States and the Soviet Union

Jewish Hearts:. Study of Dynamic Ethnicity in the United States and the Soviet Union. Betty N. Hoffman. Albany: State University of New York Press, 2001. 282 pp.     

The role of ECVAM in promoting the regulatory acceptance of alternative methods in the European Union. European Centre for the Validation of Alternative Methods

The roles played by the European Centre for the Validation of Alternative Methods (ECVAM) and its advisory committee, the ECVAM Scientific Advisory Committee (ESAC), in the evolution of alternative methods are described. Particular emphasis is given to the process by which ECVAM and the ESAC assess the scientific validities of alternative methods, and, in appropriate cases, initiate the progression of scientifically validated methods toward regulatory acceptance.