The EMA Assessment of Asciminib for the Treatment of Adult Patients With Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase Who Were Previously Treated With at Least Two Tyrosine Kinase Inhibitors

Asciminib is an allosteric high-affinity tyrosine kinase inhibitor (TKI) of the BCR-ABL1 protein kinase. This kinase is translated from the Philadelphia chromosome in chronic myeloid leukemia (CML). Marketing authorization for asciminib was granted on August 25, 2022 by the European Commission. The approved indication was for patients with Philadelphia chromosome-positive CML in the chronic phase which have previously been treated with at least 2 TKIs. Clinical efficacy and safety of asciminib were evaluated in the open-label, randomized, phase III ASCEMBL study. The primary endpoint of this trial was major molecular response (MMR) rate at 24 weeks. A significant difference in MRR rate was shown between the asciminib treated population and the bosutinib control group (25.5% vs. 13.2%, respectively, P=.029). In the asciminib cohort, adverse reactions of at least grade 3 with an incidence≥5% were thrombocytopenia, neutropenia, increased pancreatic enzymes, hypertension, and anemia. The aim of this article is to summarize the scientific review of the application which led to the positive opinion by the European Medicines Agency's Committee for Medicinal Products for Human Use.</p

Current european regulatory perspectives on insulin analogues

Insulin analogues are increasingly considered as an alternative to human insulin in the therapy of diabetes mellitus. Insulin analogues (IAs) are chemically different from human insulin and may have different pharmacokinetic or pharmacodynamic properties. The significance of the modifications of the insulin molecule for the safety profile of IAs must be considered. This review describes the regulatory procedure and the expectations for the scientific content of European marketing authorization applications for innovative IAs submitted to the European Medicines Agency. Particular consideration is given to a potential cancer hazard. Specific regulatory guidance on how to address a possible carcinogenic or tumor promoting effect of innovative IAs in non-clinical studies is available. After marketing authorization, the factual access of patients to the new product will be determined to great extent by health technology assessment bodies, reimbursement decisions and the price. Whereas the marketing authorization is a European decision, pricing and reimbursement are national or regional responsibilities. The assessment of benefit and risk by the European Medicines Agency is expected to influence future decisions on price and reimbursement on a national or regional level. Collaborations between regulatory agencies and health technology assessment bodies have been initiated on European and national level to facilitate the use of the European Medicines Agency's benefit risk assessment as basis on which to build the subsequent health technology assessment. The option for combined or joint scientific advice procedures with regulators and health technology assessment bodies on European level or on a national level in several European Member States may help applicants to optimize their development program and dossier preparation in regard of both European marketing authorization application and reimbursement decisions

Development of Innovative Medicines for European Patients and Impact of Brexit

European patients may benefit from innovative medicines only at the end of a complex process with a sequence of positive decisions on different levels by different stakeholders. The decision of the industry to invest in a usually global clinical development must be followed by a European marketing authorization decision and a mostly national decision on price and reimbursement until finally patients and their physicians can make an individual treatment decision. Development strategies must consider the evolution of scientific and procedural requirements. Current trends are characterized by an enhanced cooperation of regulators and health technology assessment-bodies. The increasing availability of innovative personalized or precision medicines is reflected in the new procedural tools like European Medicines Agency’s priority medicines scheme and adaptive pathways concept. The UK decision to leave the EU will have consequences for their contribution to the European regulatory and health technology assessment network. Current strategies for the successful development of innovative medicines may need adjustments to address both scientific and political changes

The new EU regulation on in vitro diagnostics: potential issues at the interface of medicines and companion diagnostics

The new European regulation for in vitro diagnostics (IVD) divides the certification of IVD including companion diagnostics (CDx) by notified bodies (NB) from the market authorization of medicines. With the new regulation, CDx will require conformity assessment which is expected to include clinical evidence by NB. This is a significant change from the current situation: until now most IVD have been certified based on their manufacturers’ assessment. For one medicine assessed by the EMA, certification of several different CDx by different NB is possible. As the benefit–risk balance of the medicine may depend on the performance (e.g., sensitivity and specificity) of its CDx, a close cooperation of EMA and NB will be necessary. The availability of detailed information on CDx used in the pivotal clinical trials for the medicine’s authorization will become crucial for the assessment of alternative or competing CDx

Comparative toxicity and cell-tissue distribution study on nanoparticular iron complexes using avian embryos and HepG2-cells

In this study the toxicity and intracellular availability of iron from iron dextran (FeD), iron sucrose (FeS), and iron gluconate (FeG) was compared in organs of avian (turkey) embryos and in isolated cells (HepG2) in cell culture. Iron uptake was more pronounced in embryonic liver than in renal tissue. Cellular iron uptake in liver and kidney was more or less similar for the different compounds. Only some experiments showed slightly greater iron concentrations in liver and kidney with FeG compared with FeD and FeS. Significant differences were found in the survival ratios of the eggs and the embryo weights depending on the type of iron complex administered. The rank order of toxicities was FeG>FeS>FeD. Iron accumulation in HepG2-cells was extremely high with FeS and FeG, whereas FeD did not lead to a relevant iron uptake by HepG2 cells. The excessively high iron content of the cells is an in vitro phenomenon found neither in the in ovo model with the turkey embryos nor in the clinical use of the compounds. The rank order of toxicities in HepG2 cells was FeS>FeG>FeD. Iron uptake in cell culture does not reflect the in vivo situation. The in ovo model is more suitable to assess the cellular iron uptake and iron toxicity in cells and tissues than the in vitro model. In both in ovo and in vitro experiments, FeD seemed to be superior in terms of toxicity