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Advanced therapy medicinal products (ATMPs) are innovative therapies that mainly target orphan diseases and high unmet medical needs. The uncertainty about the product's benefit-risk balance at the time of approval, the limitations of nonclinical development, and the complex quality aspects of those highly individualized advanced therapies are playing a key role in the clinical development, approval, and post-marketing setting for these therapies. This article reviews the current landscape of clinical development of advanced therapies, its challenges, and some of the efforts several stakeholders are conducting to move forward within this field. Progressive iteration of the science, methodologically sound clinical developments, establishing new standards for ATMPs development with the aim to ensure consistency in clinical development, and the reproducibility of knowledge is required, not only to increase the evidence generation for approval but to set principles to achieve translational success in this field., Graphical abstract, Most authorized ATMPs are based on small, open-label, uncontrolled, and single-arm pivotal trials using single and intermediate variables to evaluate outcomes. Health authorities are demanding methodologically sound clinical development to guide higher-quality evidence generation and decision-making. New standards for ATMP development are required to ensure consistency in clinical development.

BACKGROUND: Given the uncontrolled increase of those affected by the SARS-CoV-2 Coronavirus, COVID-19, and the possibility of the health system collapsing in Spain, the Royal Decree 463/2020, of March 14th, declared a state of alarm for the management of this health crisis. The whole population, despite their social background, were confined inside their homes during this arduous situation. There are numerous articles that endorse the idea that their home conditions, the number of people with whom they coexist with, their employment, gender, amount of physical exercise, as well as their body mass index and their diagnosis in COVID-19 are characteristics that may represent an increased risk of suffering pain and changes in their quality of life. We proposed a study to determine the impact of the confinement on pain, quality of life and public health of the Spanish population due to the COVID-19 pandemic. METHODS: An observational study was carried out during April and May 2020 through an online survey. It was statistically analysed through descriptive analysis and inferential analysis by bivariate logistic regression, ordinal logistic and Pearson's chi square. RESULTS: A total of 225 questionnaires were obtained between April and May 2020. For subjects suffering pain before confinement, significant relationships were drawn between experiencing pain and work-related activities (P=0.006), as well as, physical activity or the absence of it (P=0.033). In addition, an important association between experiencing pain and gender was discovered, both for people suffering pain before and during confinement (P=0.007 and P=0.011). Furthermore, the confinement has affected the quality of life of those affected, particularly in relation with suffering pain before and during confinement (P=0.001 and P=0.000), Job type (P=0.016) and BMI (P=0.025) and affecting more Physical Role, Emotional Role and Mental Health, followed by Physical Function. CONCLUSIONS: The presence of pain in subjects undergoing confinement is persistent, with varying intensity and frequency based on age, gender, physical activity, and work status. In any of these conditions, the quality of life of the subjects in confinement has been severely affected, which to this day creates a severe public health problem.

Background: Trigeminal neuralgia is a chronic disease characterized by intense facial pain that is caused by trigeminal nerve affectation. It usually affects adults from 50 years of age, and is more frequent in women. Additionally, it presents serious psychological effects that often lead to depression, which is why it is considered highly disabling. The therapeutic approach is based on the modification of nerve activity through electrical, surgical or chemical stimulation in specific regions of the nervous system. Objective: To perform a meta-analysis of the scientific literature related to invasive and non-invasive electrical neuromodulation of trigeminal neuralgia, in order to assess their effects over pain and adverse effects. Methods: A literature search was conducted in 4 databases, followed by a manual search of articles on invasive or non-invasive electrical neuromodulation to control the pain of trigeminal neuralgia, including the last 15 years. Results: Regarding non-invasive methods, clinical trials did not present enough results in order to perform a meta-analysis. Regarding invasive methods, clinical trials meta-analysis showed no statistical differences between different treatment methods. In all cases, improvements in patients' pain were reported, although results regarding adverse effects were variable. Conclusion: In the treatment of trigeminal neuralgia, the continuous radiofrequency provides better short and medium-term results, but pulsed radiofrequency shows less adverse effects after treatment, and has better results in the long-term.

A new category of products, i.e. regenerative medicine products (RPs), has been defined for advanced therapies medicinal products in Japan, as well as a legislative and regulatory framework to promote their clinical development. This review analyses the most relevant features of the regulatory strategies and clinical development that led RPs to their approval in Japan. As of 31st September 2021, a total of 14 RPs were approved for 16 indications. From a regulatory standpoint, the available designations allow attractive benefit packages that promote the development of innovative products in Japan and is one of the key points to consider when the global regulatory strategy for the product is being developed. RPs regulations in Japan allow adaptive licensing and constitute shortcut through the clinical development to the approval. RPs have been mainly approved so far based on small studies with inconclusive and limited evidence of efficacy and safety, prioritizing the unmet medical needs of the target diseases, and therefore, the early access for patients. This review also compares the regulatory and clinical development for the current approved RPs in Japan with the development trends in the European Union and United States of America.

RESUMEN Introducción y objetivos: El diagnóstico de hiperparatiroidismo primario en pacientes sin criterio quirúrgico es cada vez más frecuente. Material y métodos: Revisión narrativa. Resultados: Aunque la evidencia de calidad es escasa en algunos casos. Conclusiones: Cada vez se dispone de más datos que nos permiten conocer el efecto de los distintos fármacos sobre la calcemia, la afectación ósea y renal en pacientes sometidos a ellos durante periodos prolongados de tiempo. ABSTRACT Introduction: The diagnosis of primary hyperparathyroidism in patients without surgical criteria is increasingly frequent. Material and methods: Narrative review. Results: Although quality evidence is scarce in some cases. Conclusions: Last years there are more data available that allow us to know the effect of different drugs on calcemia, bone and kidney involvement in patients undergoing them for prolonged periods of time.

Background aims Regulatory agencies in the European Union (EU) and in the United States of America (USA) have adapted and launched regulatory pathways to accelerate patient access to innovative therapies, such as advanced therapy medicinal products (ATMPs). The aim of this study is to analyze similarities and differences between regulatory pathways followed by the approved ATMPs in both regions. Methods A retrospective analysis of the ATMPs approved by EU and US regulatory agencies was carried out until May 31, 2020. Data were collected on the features and timing of orphan drug designation (ODD), scientific advice (SA), expedited program designation (EP), marketing authorization application (MAA) and marketing authorization (MA) for both regions. Results In the EU, a total of fifteen ATMPs were approved (eight gene therapies, three somatic cell therapies, three tissue-engineered products and one combined ATMP), whereas in the USA, a total of nine were approved (five gene therapies and four cell therapies); seven of these were authorized in both regions. No statistical differences were found in the mean time between having the ODD or EP granted and the start of the pivotal clinical trial or MAA in the EU and USA, although the USA required less time for MAA assessment than the EU (mean difference, 5.44, P = 0.012). The MAA assessment was shorter for those products with a PRIME or breakthrough designation.. No differences were found in the percentage of ATMPs with expedited MAA assessment between the EU and the USA (33.3% versus 55.5%, respectively, P = 0.285) or in the time required for the MAA expedited review (mean difference 4.41, P = 0.105). Approximately half of the products in both regions required an Advisory Committee during the MAA review, and 60% required an oral explanation in the EU. More than half of the approved ATMPs (67% and 55.55% in the EU and the USA, respectively) were granted an ODD, 70% by submitting preliminary clinical data in the EU. The mean number of SA and protocol assistance per product conducted by the European Medicines Agency was 1.71 and 3.75, respectively, and only 13% included parallel advice with health technology assessment bodies. A total of 53.33% of the products conducted the first SA after the pivotal clinical study had started, reporting more protocol amendments. Finally, of the seven ATMPs authorized in both regions, the type of MA differed for only two ATMPs (28.6%), and four out of eight products non-commercialized in the USA had a non-standard MA in the EU. Conclusions The current approved ATMPs mainly target orphan diseases. Although EU and US regulatory procedures may differ, the main regulatory milestones reached by the approved ATMPs are similar in both regions, with the exception of the time for MAA evaluation, the number of authorized products in the regions and the type of authorization for some products. More global regulatory convergence might further simplify and expedite current ATMP development in these regions.

Attempts to streamline environmental procedures for those products containing or consisting of genetically modified organisms (GMOs) among the European Union (EU) Member States are ongoing but still need to be further developed. These procedures can be complex, resource-intensive and time-consuming. Some candidate vaccines currently under development for COVID-19 include genetically modified viruses, which may be considered GMOs. Given the public health emergency caused by the COVID-19 outbreak, on July 15, 2020, the European Parliament approved a temporary derogation of the European environmental requirements to facilitate that those clinical trials with GMOs intended to treat or prevent COVID-19 can start as soon as possible in Europe. This measure has been very controversial, since it could entail risks to human health and the environment, and could be seen as unfair for other products targeting unmet medical needs. With the adoption of this measure, the bottlenecks and obstacles for the development of innovative GMO-based medicines in the EU that the environmental legislation entails have become even more evident.

An environmental risk assessment (ERA) consists of an analysis of the risks to human health and the environment that a medicinal product may cause due to its release during clinical development or after entering the market. Regulators in European Union (EU) and the United States (US) require that advanced therapy medicinal products (ATMPs) that are also genetically modified organisms (GMOs) undergo an ERA in order to be approved for marketing authorization. This work aims to review the regulatory issues that need to be taken into consideration for carrying out an ERA, comparing the EU and the US. The European regulatory framework for environmental procedures and the dissimilarities in its implementation across the Member States and its implications at a logistical level are analyzed in detail. In addition, this review provides a brief insight into the non-clinical and clinical assessments that should be carried out during the development of the product in order to conduct a successful ERA, and thus facilitate its marketing authorization and post-marketing monitoring. Finally, the need for a European harmonization regarding environmental procedures for ATMPs is discussed.