This study aimed to evaluate the potential of Hedera colchica as an alternative to Hedera helix species for the treatment of mild inflammatory conditions of the upper respiratory tract and chronic inflammatory bronchial diseases. The H. colchica extract with the highest saponin content (C3S; 468.19 ± 16.01 mg HE/g dry weight) and the extract with the highest total phenol content (C1F; 108.60 ± 5.61 mg GAE/g dry weight). Chemical analysis and standardisation of the extract with the highest selective COX-2 inhibitory effect was performed using the LC-MS/MS technique. It was determined that the substances found in the highest ratio in the C1F extract were quinic acid (45.909 µg/g extract) and hesperidin (37.077 µg/g extract). As a result, secondary metabolites, in addition to saponins, found in Hedera species may also contribute to the extract\'s effectiveness, more potent extracts can be obtained compared to the total extract-containing preparations available in the market.

Introduction: Over the preceding decade, an increasing number of drugs have been approved by the European Medicines Agency (EMA) with limited knowledge of their relative efficacy. This is due to the utilization of non-randomized, single-arm studies, surrogate endpoints, and shorter follow-up time. The impact of this trend on the accessibility and affordability of newly approved drugs in Europe remains uncertain. The primary objective of this study is to provide insights into the issues of accessibility and affordability of new drugs in the Norwegian healthcare system. Method: The presented study entails an analysis of all reimbursement decisions for hospital drugs in Norway spanning 2021-2022. The included drugs were approved by the EMA between 2014 and 2022, with the majority (91%) receiving approval between 2018 and 2022. The drugs were categorized based on the level of documentation of relative efficacy. Approval rates and costs (confidential net-prices) were compared. Results: A total of 35% (70/199) of the reimbursement decisions were characterized by limited certainty regarding relative efficacy and as a consequence the Norwegian Health Technology Assessment (HTA) body did not present an incremental cost-effectiveness ratio (ICER) in the HTA report. Within this category, a lower percentage of drugs (47%) gained reimbursement approval compared to those with a higher certainty level, which were presented with an ICER (58%). On average, drugs with an established relative efficacy were accepted with a 4.4-fold higher cost (confidential net-prices). These trends persisted when specifically examining oncology drugs. Conclusion: Our study underscores that a substantial number of recently introduced drugs receive reimbursement regardless of the level of certainty concerning relative efficacy. However, the results suggest that payers prioritize documented over potential efficacy. Given that updated information on relative efficacy may emerge post-market access, a potential solution to address challenges related to accessibility and affordability in Europe could involve an increased adoption of market entry agreements. These agreements could allow for price adjustments after the presentation of new knowledge regarding relative efficacy, potentially resolving some of the current challenges.

In this chapter, we discuss production requirements for therapeutic bacteriophage preparations. We review the current regulatory expectancies and focus on pragmatic production processes, implementing relevant controls to ensure the quality, safety, and efficacy of the final products. The information disclosed in this chapter can also serve as a basis for discussions with competent authorities regarding the implementation of expedited bacteriophage product development and licensing pathways, taking into account some peculiarities of bacteriophages (as compared to conventional medicines), such as their specificity for, and co-evolution with, their bacterial hosts. To maximize the potential of bacteriophages as natural controllers of bacterial populations, the implemented regulatory frameworks and manufacturing processes should not only cater to defined bacteriophage products. But, they should also facilitate personalized approaches in which bacteriophages are selected ad hoc and even trained to target the patient\'s infecting bacterial strain(s), whether or not in combination with other antimicrobials such as antibiotics.

Diverse terms have been used in the literature to refer to the health benefits obtained from the administration of non-viable microorganisms or their cell fragments and metabolites. In an effort to provide continuity to this emerging field, the International Scientific Association of Probiotics and Prebiotics (ISAPP) convened a panel of experts to consider this category of substances and adopted the term postbiotic, which they defined as a \"preparation of inanimate microorganisms and/or their components that confers a health benefit on the host.\" This definition does not stipulate any specific health benefit, finished product, target population or regulatory status. In this perspective article, we focused on postbiotics developed for pharmaceutical uses, including medicinal products and medical devices. We address how this field is regulated for products based on inanimate microorganisms, marketing considerations and existing examples of postbiotics products developed as cosmetics for the skin, for vaginal health, and as orally consumed products. We focus on the European Union for regulatory aspects, but also give examples from other geographical areas.

When a medicinal product (MP) and a medical device (MD) are combined, their correct classification implies discrimination among different possible scenarios, based on the nature of the combination and the principal mechanism of action. In the European Union (EU), stakeholders deal with a lack of harmonization, which can represent an obstacle toward the development of these products, and a complex nomenclature, emerging from two divergent regulatory philosophies (i.e., that of MPs and that of MDs). In the USA, where the US Food and Drug Administration (FDA) supervises MDs, drugs, and biological products, stakeholders interact with a single authority, where any issue is addressed internally.

BACKGROUND: Nowadays, the inception of computer modeling and simulation in life science is a matter of fact. This is one of the reasons why regulatory authorities are open in considering in silico trials evidence for the assessment of safeness and efficacy of medicinal products. In this context, mechanistic Agent-Based Models are increasingly used. Unfortunately, there is still a lack of consensus in the verification assessment of Agent-Based Models for regulatory approval needs. VV&UQ is an ASME standard specifically suited for the verification, validation, and uncertainty quantification of medical devices. However, it can also be adapted for the verification assessment of in silico trials for medicinal products.
RESULTS: Here, we propose a set of automatic tools for the mechanistic Agent-Based Model verification assessment. As a working example, we applied the verification framework to an Agent-Based Model in silico trial used in the COVID-19 context.
CONCLUSIONS: Using the described verification computational workflow allows researchers and practitioners to easily perform verification steps to prove Agent-Based Models robustness and correctness that provide strong evidence for further regulatory requirements.

The Summary of Product Characteristics (SmPC) is an obligatory document concerning a medicine required (among other things) for the authorization of a medicinal product. The purpose of the SmPC is to provide product information to healthcare professionals. A necessary condition for this is to ensure that the SmPC is clear and precise. However, neither European nor national legislation obliges marketing authorization holders to review the SmPC in terms of its readability and understandability prior to the registration of a medicine. To date, research on SmPCs has focused on accuracy and completeness; however, the literature lacks information on the extent to which SmPCs meet the needs of healthcare professionals concerning the readability of the information they contain. The main objective of this article is to point out the lack of precision in the legal provisions for the preparation of SmPCs concerning the comprehensibility of the provisions. The article points to the lack of testing of the SmPC in terms of accessibility and transparency for healthcare professionals, highlighting that the document does not meet the needs of healthcare professionals in providing adequate information about medicines. It shows that the current rules and guidelines for the preparation of the registration dossier for a medicinal product are not entirely precise and contain numerous shortcomings.

From its origins as a left-field, experimental, and even \"maverick\" intervention, faecal microbiota transplantation (FMT) is now a well-recognised, accepted, and potentially life-saving therapeutic strategy, for the management of recurrent Clostridiodes difficile infection (rCDI). It is being investigated as a treatment for a growing number of diseases including hepatic encephalopathy and eradication of antimicrobial resistant organisms, and the list of indications will likely expand in the future. There is no universally accepted definition of what FMT is, and its mechanism of action remains incompletely understood; this has likely contributed to the breadth of approaches to regulation depending on interpretation. In the UK FMT is considered a medicinal product, in North America, a biological product, whereas in parts of Europe, it is considered a human cell/tissue product. Regulation seeks to improve quality and safety, however, lack of standardisation creates confusion, and overly restrictive regulation may hamper widespread access and discourage research using FMT. FMT is generally considered safe, especially if rigorous donor screening and testing is conducted. Most short-term risks are associated with the delivery method (e.g. colonoscopy). Longer term risks are less well described but longitudinal follow-up of treated cohorts is in place to assess for this, and no signal towards harm has been found to date. Rarely it has been associated with adverse outcomes including the transmission of antibiotic resistant bacteria, and even death. It is vital patients undergoing FMT are well informed to the currently appreciated risks and benefits before proceeding.

This chapter summarises all relevant aspects of patch testing, closely following recommendations outlined in a recent European, and a German S3 guideline on diagnostic patch testing with contact allergens and medicinal products (drugs). Patch testing is indicated in patients suspected of suffering, or having been suffering, from delayed-type hypersensitivity leading to allergic contact dermatitis or other skin and mucosal diseases. Sections of this chapter include detailed indications, reasons for possibly postponing the test, considerations on choosing haptens (contact allergens) to test, various aspects of the application of patch test allergen preparations (storage, dosing) and of testing with individual materials provided by the patients. Special aspects of patch testing in cutaneous adverse drug reactions, children, or occupational contact dermatitis are outlined. Supplemental test methods, notably the repeated open application test, are briefly described. Finally, the final evaluation in terms of assessment of clinical relevance of reactions and patient counselling are outlined.

Recent years have seen the establishment of several radionuclides as medicinal products in particular in the setting of theranostics and PET. [177Lu]Lutetium Chloride or [64Cu]Copper Chloride have received marketing authorization as radionuclide precursor, [68Ga]Gallium Chloride has received regulatory approval in the form of different 68Ge/68Ga generators. This is a formal requirement by the EU directive 2001/83, even though for some of these radionuclide precursors no licensed kit is available that can be combined to obtain a final radiopharmaceuticals, as it is the case for Technetium-99m. In view of several highly promising, especially metallic radionuclides for theranostic applications in a wider sense, the strict regulatory environment poses the risk of slowing down development, in particular for radionuclide producers that want to provide innovative radionuclides for clinical research purposes, which is the basis for their further establishment. In this paper we address the regulatory framework for novel radionuclides within the EU, the current challenges in particular related to clinical translation and potential options to support translational development within Europe and worldwide.