Medicinal Products For Human Use Research Articles

Unleashing the Power of Reliance for Post-Approval Changes: A Journey with 48 National Regulatory Authorities.

Post-approval changes (PACs) to marketed products are routinely introduced to continuously enhance the product lifecycle management. However, bringing a chemistry, manufacturing and control (CMC) change through the global health authorities can be a complex and lengthy process taking up to several years, therefore negatively impacting supply continuity. In order to accelerate the review and approval of regulatory submissions and ensure continuous supply to patients, the World Health Organization (WHO) is strongly supporting the implementation of reliance among National Regulatory Authorities (NRAs). While some promising developments have been made with the use of reliance pathways for initial marketing authorizations, reliance is still not widely used for PACs. With the support of the European Medicines Agency (EMA) and WHO, Roche launched a reliance pilot based on EMA approval to file a supply critical variation for a monoclonal antibody. The variation constitutes major changes to the approved manufacturing process. Sameness of the product is ensured by submitting to all participants the same variation package as in the EU. The objectives of the pilot are to ensure continuous supply of this critical medicine by targeting global approval in 6.5 months, to promote regulatory convergence by waiving country specific requirements, and enhance greater transparency by sharing EMA Committee for Medicinal Products for Human Use (CHMP) final assessment report and Q&As to participating NRAs. Globally 48 NRAs have agreed to join the pilot. This article outlines the process of establishing the pilot project, including a planning phase and an engagement phase with the EMA, WHO and the participating NRAs.

Contact allergy to neomycin in consecutively patch tested Danish eczema patients from 2000 to 2023: A cross-sectional study.

Neomycin is an aminoglycoside antibiotic that may cause contact allergy. It was withdrawn as a medicine for human use in Denmark in October 2009 but is still found in some vaccines. To identify time trends in contact allergy to neomycin in the period from 2000 to 2023. A cross-section study of patients ≥18 years consecutively patch-tested with neomycin sulfate (20% in pet.) at Gentofte Hospital, Denmark, during the period 2000-2023 was conducted. The overall prevalence of contact allergy to neomycin was 1.4%. The prevalence was significantly lower in the period '2010-2023' (1.2%) than in '2000-2009' (1.8%) (p < 0.005). Contact allergy to neomycin was significantly positively associated with facial dermatitis and age >40 years, and significantly negatively associated with occupational dermatitis and hand dermatitis. No changes in sex, occupational dermatitis, atopic dermatitis, hand dermatitis, leg dermatitis, facial dermatitis, or age > 40/≤40 (the MOAHLFA-index) were identified when comparing neomycin contact allergic-patients in the two periods '2010-2023' and '2001-2009'. Neomycin is a rare cause of contact allergy in Denmark with a significantly lower prevalence following its withdrawal as a medicinal product for human use in Denmark in 2009.

Scalable microfluidic method for tunable liposomal production by a design of experiment approach

Liposomes constitute a widespread drug delivery platform, gaining more and more attention from the pharmaceutical industry and process development scientists. Their large-scale production as medicinal products for human use is all but trivial, especially when parenteral administration is required. In this study an off-the-shelf microfluidic system and a methodological approach are presented for the optimization, validation and scale-up of highly monodisperse liposomes manufacturing. Starting from a Doxil®-like formulation (HSPC, MPEG-DSPE and cholesterol), a rational approach (Design of Experiments, DoE) was applied for the screening of the process parameters affecting the quality attributes of the product (mainly size and polydispersity). Additional DoEs were conducted to determine the effect of critical process parameters “CPPs” (cholesterol concentration, total flow rate “TFR” and flow rate ratio “FRR”), thus assessing the formulation and process robustness. A scale-up was then successfully accomplished. The procedure was applied to a Marqibo®-like formulation as well (sphingomyelin and cholesterol) to show the generality of the proposed formulation, process development and scale-up approach. The application of the system and method herein presented enables the large-scale manufacturing of liposomes, in compliance with the internationally recognized regulatory standards for pharmaceutical development (Quality by Design).

Evaluation of the EMA log kow trigger for fish BCF testing based on data for several human pharmaceuticals

In the European Medicines Agency (EMA) “Guideline for Environmental Risk Assessment of Medicinal Products for Human Use,” a fish bioconcentration factor (BCF) study is triggered in Phase I for pharmaceuticals having log Kow >4.5, to support Persistence, Bioaccumulation and Toxicity (PBT) screening, and in Phase II to assess secondary poisoning and bioaccumulation (‘B’) potential when log Kow ≥3. The standard sampling schedule outlined in OECD Test Guideline 305 (TG305) may require assessment of approximately 200 fish following exposure to low- and high-test concentrations and a negative control. We report experimental log Kow and BCF values for 64 human pharmaceuticals that were used to evaluate the current BCF testing trigger of log Kow ≥3, and whether a single BCF exposure concentration allows accurate classification of bioaccumulation potential. Our data support raising the BCF testing trigger to log Kow ≥4, and use of a single test concentration. The resulting reduction in the use of fish is consistent with the 3 R s principle and did not adversely affect classification accuracy. An assessment of potential risk of secondary poisoning was also conducted for three drugs classified as either B or vB, and no risks were identified.

Unvaccinated employees during Covid-19 emergency: Debating the Italian labour court referral

This contribution examines the inadmissibility of a preliminary reference order submitted by the Court of Padua, Italy to the Court of Justice of the European Union (CJEU). The case involved the suspension of a worker, who, while legally obliged, declined to have the Covid-19 vaccine. The Italian court temporarily halted proceedings initiated by the worker's appeal. The author provides a comprehensive analysis facts of the case, the applicable national legislation, and the content of the preliminary reference order. The order scrutinised the compatibility of the conditional authorisation issued by the European Commission for the release of vaccines in circulation at that time. Additionally, it explored potential discrimination against workers who, by refusing vaccination, faced suspension from work without pay, as per explicit legal provisions. The contribution concludes by addressing the specific details of the inadmissibility ruling from the CJEU. Case: Judgment of the Court (Second Chamber) of 13 July 2023. D. M. v Azienda Ospedale-Università di Padova. Request for a preliminary ruling from the Tribunale Ordinario di Padova. Reference for a preliminary ruling – Public health – National legislation imposing a vaccination obligation on health professionals – Suspension from duty without pay for personnel refusing the vaccine – Regulation (EC) No 726/2004 – Medicinal products for human use – Vaccines against Covid-19 – Regulation (EC) No 507/2006 – Validity of conditional marketing authorisations – Regulation (EU) 2021/953 – Prohibition of discrimination between vaccinated and unvaccinated persons – Inadmissibility.

Real-World Evidence to Support the Registration of a New Osteoporosis Medicinal Product in Europe

AbstractReal-World Evidence (RWE), which has historically been used to support post-approval safety studies, has recently gained acceptance for new drug applications as supportive evidence or as new clinical evidence for medicinal products with orphan designation and/or in disease areas with high unmet need. Here, we present a case study for the use of RWE in the approval of abaloparatide in the European Union (EU) under the tradename Eladynos. In addition to data from the pivotal Phase 3 study, the marketing authorization application (MAA) included clinical data from additional interventional and observational studies, as well as post-marketing data obtained from the United States (US) market since approval of abaloparatide by the Food and Drug Administration (FDA) in 2017. The new interventional studies were not designed to assess fracture efficacy and cardiovascular safety which were topics of concern raised by the Committee for Medicinal Products for Human Use (CHMP) during their review of the initial MAA submitted in 2015. However, these studies taken together with the RWE formed the basis for a new MAA. Prior to the planned resubmission in the EU, national Scientific Advice (SA) was sought on the proposed clinical program, specifically on the relevance of Real-World Data (RWD) derived from an observational study to support and complement the efficacy and safety data already available from prospective randomized clinical trials. This case study demonstrates successful use of RWE to address a previously identified gap raised by the CHMP during the review of an earlier MAA, which led to the approval of Eladynos for the treatment of osteoporosis in the EU.

Registries or non-pharmacological observational studies? An operational attempt to draw the line and to provide some suggestions for the ethical evaluation of rare disease registries.

Originally established to evaluate the ethical aspects of clinical trials, Ethics Committees (ECs) are now requested to review different types of projects, including, among others, observational studies and disease registries. In Italy, clinical trials on medicinal products for human use and on medical devices are regulated by EU Regulation 536/2014, EU Regulation 2017/745, and 2017/746 while pharmacological observational studies are regulated by the Italian Medicines Agency guidelines of 2008 and by Ministerial Decree of November 30th, 2021. The other types of studies are not strictly regulated, causing discrepancies in their definition and assessment by the ECs, and slowdowns in the start of projects. The present contribution aims to propose definitions and distinctions between non-pharmacological observational studies and disease registries, which constitute different entities but are often assimilated by ECs, and to formulate suggestions for the evaluation of rare disease registries, which are an expanding research area of interest.

Development and validation of an UPLC-MS/MS method for the determination of irinotecan (CPT-11), SN-38 and SN-38 glucuronide in human plasma and peritoneal tumor tissue from patients with peritoneal carcinomatosis

Irinotecan (CPT-11), an antineoplastic drug, is used for the treatment of colorectal and pancreatic cancer due to its topoisomerase I inhibitory activity. CPT-11 is a prodrug which is converted to its active metabolite SN-38 by carboxylesterases. SN-38 is further metabolized to its inactive metabolite SN-38 glucuronide. When evaluating the pharmacokinetic properties of CPT-11 and its metabolites, it is important to accurately assess the concentrations in both plasma as well as tumor tissues. Therefore, the aim of the current study was to develop and validate a robust and sensitive ultra-high performance liquid chromatography-tandem mass spectrometry method to quantify the concentration of CPT-11 and its metabolites (SN-38 and SN-38 glucuronide) in human plasma and peritoneal tumor tissue. The sample preparation of plasma and tumor tissue consisted of protein precipitation and enzymatic digestion/liquid–liquid extraction, respectively. Chromatographic separation was achieved with an Acquity UPLC BEH C18 column combined with a VanGuard pre-column. The mobile phases consisted of water +0.1 % formic acid (mobile phase A) and acetonitrile +0.1 % formic acid (mobile phase B). Mass analysis was performed using a Xevo TQS tandem mass spectrometer in the positive electrospray ionization mode. Method validation was successfully performed by assessing linearity, precision and accuracy, lower limit of quantification, carry over, selectivity, matrix effect and stability according to the following guidelines: “Committee for Medicinal Products for Human use, Guideline on Bioanalytical Method Validation”. A cross-validation of the developed method was performed in a pilot pharmacokinetic study, demonstrating the usefulness of the current method to quantify CPT-11 and its metabolites in the different matrices.

Dose Selection for Clinical Development in the Treatment of Hypertension: The Aprocitentan Case and Lessons from the Past

Dose selection plays a critical role in the clinical development of a drug. This current review highlights the lessons learned from previous dose finding studies (DFSs) of antihypertensive drugs and from the recent example of aprocitentan, a novel endothelin receptor antagonist for the treatment of resistant hypertension. Based on these, the authors provide 10 key recommendations for an efficient DFS for a new antihypertensive medication. These recommendations respect critical comments repeatedly made by the U.S. Food and Drug Administration (FDA) Division of Cardiology and Nephrology over the last 5 decades and go beyond the more limited recommendations made in the 2016 Committee for Medicinal Products for Human Use (CHMP) guideline on the development of new antihypertensive medications. The added value of a dose-response modelling approach enriches prior regulatory advice on DFSs.

Requesting conflicts of interest declarations from the European Medicines Agency: 3-year follow-up status.

We have previously described the European Medicines Agency's (EMA) and the US Food and Drug Administration's guidelines, each for a specific psychiatric indication, on how to design pivotal drug trials used in new drug applications. Here, we report on our efforts over 3years to retrieve conflicts of interest declarations from EMA. We wanted to assess potential internal industry influence judged as the proportion of guideline committee members with industry conflicts of interest. We submitted Freedom of Information requests in February 2020 to access EMA's lists of committee members (and their declared conflicts of interest) involved in drafting the 13 'Clinical efficacy and safety' guidelines available on EMA's website pertaining to psychiatric indications. In our request, we did not specify the exact EMA committees. Here, we describe the received documents and report the proportion of members with industry interests (i.e.defined as any financial industry relationship). It is a follow-up paper to our first report (http://doi.org/10.1017/S2045796021000147). After 2years and 9months (November 2022), the EMA sent us member lists and corresponding conflicts of interest declarations from the Committee for Medicinal Products for Human use (CHMP) from 2012, 2013 and 2017. These member lists pertained to 3 of the 13 requested guidelines (schizophrenia, depression and autism spectrum disorder). The 10 remaining guidelines were published before 2011 and EMA stated that they needed to require permission from their expert members (with unknown retrieval rate) and foresaw excessive workload and long wait. Therefore, we withdrew our request. The CHMPs from 2012, 2013 and 2017 had from 34 to 36 members; 39%-44% declared any interests and we judged 14%-18% as having industry interests. For the schizophrenia guideline, we identified two members with industry interests to companies who submitted feedback on the guideline. We did not receive declarations from the Central Nervous System (CNS) Working Party, the CHMP appointed expert group responsible for drafting and incorporating feedback into the guidelines. After almost 3years, we received information, which only partly addressed our request. We recommend EMA to improve transparency by publishing the author names and their corresponding conflicts of interest declarations directly in the 'Clinical efficacy and safety' guidelines and to not remove conflicts of interest declarations after 1year from their website to reduce the risk of stealth corporate influence during the development of these influential guidelines.

Gloss to the Judgment of the Court of Justice of the European Union (Third Chamber) of 25 November 2021 in Case C‑488/20, Delfarma SP. Z o.o. v. Prezes Urzędu Rejestracji Produktów Leczniczych, Wyrobów Medycznych i Produktów Biobójczych

Medicinal products are a special type of goods due to their importance for human health and life, and their trade is generally under the scope of Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use. The preamble to this act states that the essential aim of the rules governing the production, distribution and use of medicinal products must be to safeguard public health. Hence, in the above-mentioned directive, the rules related to the authorisation of medicinal products for marketing and pharmacovigilance are very important. At the same time, it should be noted that parallel import of medicinal products as a form of trade in an EU Member State in connection with their authorisation for marketing in another Member State, although it has a long tradition, has not had a clear normative pattern, and has not been subject to the scope of Directive 2001/83/EC. It is based on the achievements of the acquis communautaire developed in this area and the principle of free movement of goods (Article 34 TFEU) and its exceptions set out in Article 36 TFEU concerning the protection of human health and life. The commented judgment sets an example of one more verdict confirming the interpretation of Articles 34 and 36 TFEU, according to which national provisions of a Member State should be considered unacceptable, according to which the withdrawal of the marketing authorisation for the reference medicinal product in the country of import has the automatic effect of expiring the parallel import authorisation. At the same time, new circumstances affecting the safety of the medicinal product on the market were analysed to give the conclusion as declared in the sentence.

Advertising of medicinal products in Polish law in the light of Directive 2001/83/EC on the Community code relating to medicinal products for human use

Advertising of medicinal products in Polish law in the light of Directive 2001/83/EC on the Community code relating to medicinal products for human use

A full-document analysis of the semantic relation between European Public Assessment Reports and EMA guidelines using a BERT language model

In the European Union, the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA) develop guidelines to guide drug development, supporting development of efficacious and safe medicines. A European Public Assessment Report (EPAR) is published for every medicine application that has been granted or refused marketing authorisation within the EU. In this work, we study the use of text embeddings and similarity metrics to investigate the semantic similarity between EPARs and EMA guidelines. All 1024 EPARs for initial marketing authorisations from 2008 to 2022 was compared to the 669 current EMA scientific guidelines. Documents were converted to plain text and split into overlapping chunks, generating 265,757 EPAR and 27,649 guideline text chunks. Using a Sentence BERT language model, the chunks were transformed into embeddings and fed into an in-house piecewise matching algorithm to estimate the full-document semantic distance. In an analysis of the document distance scores and product characteristics using a linear regression model, EPARs of anti-virals for systemic use (ATC code J05) and antihemorrhagic medicines (B02) present with statistically significant lower overall semantic distance to guidelines compared to other therapeutic areas, also when adjusting for product age and EPAR length. In conclusion, we believe our approach provides meaningful insight into the interplay between EMA scientific guidelines and the assessment made during regulatory review, and could potentially be used to answer more specific questions such as which therapeutic areas could benefit from additional regulatory guidance.

Implementation of EU legislation into the criminal legislation of Ukraine to ensure criminal legal protection of pharmaceutical activity

The purpose of the article is to determine the specifics of the implementation of EU legislation into the criminal law of Ukraine to ensure the criminal protection of pharmaceutical activity. The methodology includes the author's emphasis on basic international legal guidelines. Directive No. 2001/83/EC of the European Parliament and the Council of the EU on the Community Code on Medicinal Products for Human Use of November 6, 2001 serves as one of the main guidelines here. In the author's opinion, this is important based on the fact that the adopted Law of Ukraine "On Medicinal Products" of July 28, 2022 implemented many provisions of the said Directive, including those that are important for the criminal protection of pharmaceutical activity. The article pays special attention to the issue of determining the "limits" of criminal protection of the circulation of medicinal products, which depend on the specific requirements of Directive 2001/83/EC, which define the concept of "medicinal product" and provide for the limited use of medicinal products, as well as mandatory components circulation of medicinal products (as defined in Article 2 of Directive 2001/83/EC), each of which is related to the state registration procedure and obtaining the necessary permission. The results. Attention is focused on other international legal documents, such as EU Council Directive 85/374/EEC "On the approximation of laws, regulations and administrative provisions of the member states regarding liability for low-quality products" dated July 25, 1985, which contains an independent general declaratory prescription that the "special liability system" created by this Directive is an effective legal means of protecting consumers of pharmaceutical products. Scientific novelty. The author notes that the construction of a "national model" of criminal law protection of pharmaceutical activity must in any case take into account the main international legal standards regarding the "subjects" of pharmaceutical activity and their separate varieties, "accompanying" subjects that ensure the "handling" of pharmaceutical activity products (in particular, accessories, documents), integral components of pharmaceutical products (active substances and excipients, parts and materials), types and varieties of pharmaceutical activity, as well as state regulation of pharmaceutical activity. Practical significance. The results of the research can be used in law-making and law-enforcement activities during the investigation of crimes related to the field of pharmaceutical activity.

Protocol for the Tallaght University Hospital Institute for Memory and Cognition-Biobank for Research in Ageing and Neurodegeneration

IntroductionAlzheimer’s disease and other dementias affect >50 million individuals globally and are characterised by broad clinical and biological heterogeneity. Cohort and biobank studies have played a critical role in advancing...

AVAILABILITY OF MEDICINES AS A RESULT OF REIMBURSEMENT MECHANISMS AND MEDICAL INSURANCE IS AN ISSUE FOR DISCUSSION

Availability of medicines, their quantity, quality, and appropriate documentation organization regarding distribution, storage, and sales – is one of the priority tasks of the healthcare system of each country. In European Union countries, a significant portion of expenditures for ensuring pharmaceutical supplies is covered by the state, implementing the principle of equal access of the population to effective medicines at an affordable price, which underlies the mechanisms of pricing and reimbursement. To achieve these goals, requirements are outlined in Directive 89/105/EEC of December 21, 1989, «On the transparency of measures regulating the pricing of medicinal products for human use and their inclusion in the system of national health insurance», aimed at promoting the development of the pharmaceutical industry both in the direction of developing expensive innovative drugs and in providing patients with quality generics. Thus, the main mechanism for ensuring the availability of medicinal products and medical devices for the population is the reimbursement program – the complete or partial refunding to entities engaged in retail trade of medicinal products, of the cost of medicinal products or medical devices dispensed to patients based on prescriptions, at the expense of the State Budget of Ukraine. The main objective of regulatory activities remains comprehensive regulation. Individual healthcare questions, including the provision of medicinal products, have been explored in the works of Yu. Bytiak, V. Kolpakov, R. Maidanyk, O. Myronets, I. Seniuta and others. The purpose of this publication is to review the normative and legal regulation of the reimbursement mechanism and practical implementation issues. Different countries establish their own reimbursement mechanisms, which vary in terms of funding sources, reimbursement conditions, price regulation methods, selection criteria for medicinal products, and key nosologies for treatment. The recipients of such systems may include socially vulnerable segments of the population, individuals suffering from severe or chronic illnesses, as well as various types of pharmaceutical assistance such as inpatient and outpatient care. Depending on the specifics of healthcare systems in different countries, different compensation mechanisms may be used. For example, this may involve the reimbursement of the cost of medicines for insured individuals, where the patient’s treatment expenses are covered by the insurance company or compensated to pharmacy establishments, with settlements being made between the insurance fund, healthcare facility, and pharmacy based on contracts. In Ukraine, in the absence of a mandatory medical insurance system, the reimbursement process operates in the form of the state program «Accessible Medicines», where the state compensates pharmacy establishments for the full or partial cost of medicines from the respective list.

Oncolytic Viruses: An Inventory of Shedding Data from Clinical Trials and Elements for the Environmental Risk Assessment.

Attenuated and/or genetically modified oncolytic viruses (OV) gain increasing interest as a promising approach for cancer therapy. Beside the assessment of subject safety, quality and efficacy aspects of medicinal products for human use, genetically modified viruses are also governed by EU regulatory frameworks requiring an environmental risk assessment (ERA). An important element to be assessed as part of the ERA is the incidence of exposure to OV of individuals, other than the trial subjects, and the environment. The evidence-based evaluation of shedding data is considered to be decisive in that context, as it may impact the OV capacity to be transmitted. This is particularly true for OV still able to (conditionally) replicate as opposed to replication-defective viral vectors commonly used in gene therapy or vaccination. To our knowledge, this article presents the most extensive and up-to-date review of shedding data reported with OV employed in clinics. Besides the identification of a topical need for improving the collection of shedding data, this article aims at providing an aid to the design of an appropriate shedding study, thereby relying on and further complementing principles described in existing guidelines issued by European and international institutions.

Methodological Approaches to Risk Management of Advanced Therapy Medicinal Products

Introduction. Advanced therapy medicinal products (ATMPs) rely on recent advances in medical science, but alongside with potential benefits they may also bring safety concerns for patients. The inherent complexity of the ATMP production and use calls for special approaches to risk management throughout their lifecycle, from obtaining the raw materials to administration to the patient.Aim. The aim of the present study was to develop approaches to risk management for ATMPs, using the example of CAR T-cell therapy.Materials and methods. The study analysed the relevant regulatory frameworks currently in force in the European Union and the United States of America, namely the regulations and guidelines adopted by the Center for Biologics Evaluation and Research of the U.S. Food and Drug Administration and the Committee for Medicinal Products for Human Use of the European Medicines Agency.Results and discussion. The paper provides a classification of patient risks, which was developed based on the European risk-based approach. It formulates the principles of risk management for each of the risks, depending on the stage of the product life cycle. Each type of risk was considered separately. The following risk minimization strategies were determined: compliance with the good practices, ensuring the necessary qualifications or expertise of all parties involved in the product life cycle. The main element of risk control is the detailed description of the medicinal product use in the summary of product characteristics and patient information leaflet.Conclusion. The study identified the main stages at which ATMP risks may occur, and each type of risk was considered separately. The following requirements should be put in place in order to manage the ATMP risks: requirements for distributors on how to perform the product transportation and storage and to keep records for the marketing authorisation holder; requirements for healthcare facilities on how to perform the product storage, its preparation for use, advising and informing the patients on the treatment risks, symptoms of adverse events, preparatory and follow-up medical procedures, and on how to keep records for the marketing authorisation holder; requirements for the qualifications of healthcare professionals who are in charge of the product storage, its preparation for use, treatment procedures, advising and informing the patients on the treatment risks, symptoms of adverse events, and follow-up medical procedures. The data obtained will be used in the preparation of recommendations for ATMP developers.

Cost-effectiveness model of trastuzumab deruxtecan as second-line treatment in HER2-positive unresectable and/or metastatic breast cancer in Finland

ObjectivesTrastuzumab deruxtecan (T-DXd) was recently recommended by the Committee for Medicinal Products for Human Use as a treatment for adult patients with unresectable or metastatic HER2-positive breast cancer, who had received a prior anti-HER2-based regimen. In our study, we evaluated the cost-effectiveness of T-DXd compared with ado-trastuzumab emtansine (T-DM1) for this indication in Finland.MethodsA three-state partitioned survival analysis model was developed with a payer’s perspective. Time to event data from the DESTINY-Breast03 (DB-03) trial were extrapolated over a lifetime horizon either directly—for progression-free survival and time to treatment discontinuation—or using an alternative approach utilizing long-term T-DM1 survival data and DB-03 data—for overall survival. Discount rates of 3% were applied for costs and effects. Inputs were sourced from the Medicinal Products Database from Kela, Helsinki University Hospital service price list, Finnish Medicines Agency assessments, clinical experts, and DB-03. Sensitivity analyses were performed to characterize and demonstrate parameter uncertainties in the model.ResultsTotal quality-adjusted life years (QALYs) and life years (LYs) gained for T-DXd compared with T-DM1 were 1.93 and 2.56, respectively. Incremental costs for T-DXd compared with T-DM1 were €106,800, resulting in an ICER of €55,360 per QALY gained and an ICER of €41,775 per LY gained. One-way sensitivity analysis showed the hazard ratio of T-DXd vs T-DM1 for OS was the most influential parameter. The probabilistic sensitivity analysis showed similar results to the base case.ConclusionsT-DXd is cost-effective based on surrogate WTP thresholds of €72,000 and €139,000 per QALY.

Review of the Certification Procedure for Qualified Persons of Manufacturers of Medicines for Human Use in Russia

Scientific relevance. In December 2020, the Russian Federation adopted the Eurasian Economic Union (EAEU) requirements. This has significantly changed the certification procedure for qualified persons (QPs) of manufacturers of medicinal products for human use in the Russian Federation. To accommodate these changes, the Russian regulatory framework needs further improvement.Aim. This study aimed to review the changes made to the mechanism of state regulation of medicines and to evaluate the impact on the pharmaceutical industry two years after the adoption of the current QP certification procedure.Discussion. This review compares two QP certification procedures established by Order No. 7n of the Ministry of Health of the Russian Federation dated 12 January 2021. The first is an abbreviated one for QPs certified under the previous procedure, and the second is an initial one for QPs being certified for the first time, having an expired certificate, or wishing to extend their professional qualification profiles. The article illustrates common mistakes made by certification applicants when preparing their documents. Furthermore, the authors describe the most prevalent knowledge gaps identified by testing. The abbreviated certification procedure ensured a sufficiently smooth transition to the EAEU requirements. For example, by 1 February 2023, 506 QPs were recertified for the next five-year period according to this procedure. This accounts for slightly more than half of all QPs certified in the Russian Federation according to the previous requirements. The total number of QPs certified according to the EAEU requirements in Russia in 2021–2022 is approximately 1.5 times higher than the number of QPs certified during the same period in 2014–2015.Conclusions. The updated procedure for QP certification has noticeably changed the occupational group of QPs formed in the Russian Federation in the last decade. The implementation of the new QP certification procedure has revealed several procedural issues that require additional explanation and clarification by the Ministry of Health of the Russian Federation.