Marketing Authorization Holders Research Articles

A Critical Review of the Drug Promotional Literature Published in Scientific Medical Journals and Available at Outpatient Departments: A Cross-Sectional Observational Study.

Background A vital method used by pharmaceutical companies to make physicians aware of new drugs and increase the prescription and sale of the same is through drug promotion literature (DPL) published in scientific journals and distributed in outpatient departments (OPDs). It is important that drug promotion is done ethically to avoid the spread of false information for which guidelines are available at the international level by the World Health Organization (WHO) and at the national level by the Organisation of Pharmaceutical Producers of India (OPPI). In this study, we aim to review the DPLs used for promotion by market authorization holders (pharmaceutical businessentities) in scientific healthcare journals and OPDs for their compliance with the "Ethical criteria for medicinal drug promotion" of the WHO and OPPI Code of Ethics Practice. In addition, we compare the ethical standard of the DPL available in scientific journals and OPDs with respect to existing norms and guidelines. Methodology A cross-sectional, observational study was conducted at a tertiary care teaching institute in Navi Mumbai, India. DPLs were collected from journals available at the institute library nearby published from January-June 2022 and from the outpatient departments of our hospital and other clinics nearby during the same time duration.Analysis was done according to the criteria given in WHO and OPPI guidelines. Each point in the criteria was scored as 1 or 0 based on whether the DPL was compliant or not respectively. DPLs were graded into 3 categories based on percentage compliance: Grade A (>70%), Grade B (35-70%), and Grade C (<35%). Results A total of 370 DPLs were collected, of which 191 (51.6%) were collected from scientific journals and 179 (48.4%) from OPDs. DPLs collected from journals showed that only 7.85% belonged to Grade A (WHO guidelines). According to the OPPI guidelines, 57.59% of the same DPLs belonged to Grade A. DPLs from OPDs showed similar results by both guidelines with >90% belonging to Grade B. Approximately less than 5% of the DPLs belonged to Grade C from both scientific journals and OPDs. Conclusions None of the DPLs were found to be entirely compliant with either of the guidelines. Most of the DPLs from both sources belong to Grade B, withinformation about adjuvants, adverse drug reactions, contraindications, drug interaction, and references to scientific literature missing from them. DPLs belonging to Grade C even had information about active ingredients missing from them which can lead to serious harm due to the wrong prescription of drugs.

Spotlight commentary: Navigating between financial risks and improved treatment outcomes with immune checkpoint inhibitors in cancer patients: The need for biomarker identification and dose optimization.

Spotlight commentary: Navigating between financial risks and improved treatment outcomes with immune checkpoint inhibitors in cancer patients: The need for biomarker identification and dose optimization.

Recommendations on Informational Monitoring of the Safety and Efficacy of Medicinal Products in the Russian Federation as Part of Pharmacovigilance

Monitoring of information on the safety and efficacy of medicinal products that involves searching for data on benefits and risks of the post-approval use of medicinal products is one of the most important pharmacovigilance processes. The aim of the study was to summarise instruments and recommendations for effective monitoring of information on the safety and efficacy of medicinal products. The article presents the results of the analysis of the regulatory framework and modern tools for scientific literature and Internet information monitoring as part of routine pharmacovigilance. The main resources recommended for information monitoring are open-source scientific and medical bibliographic databases; scientific journals; websites of regulatory authorities and international organisations that monitor the efficacy and safety of medicines; social networks; and online patient communities. Drawing upon current regulatory documents and international good pharmacovigilance practices, the article presents recommendations on the number of resources needed for conducting qualitative monitoring and on the formulation and revision of a search strategy. It describes modern technological solutions in the field of information monitoring, substantiating the suitability of new achievements in such areas as Data Science and natural language processing (NLP) for marketing authorisation holders to collect and analyse data on the safety and efficacy of medicinal products. Regular updates of the search strategy and information channels, the use of software products for the automatic collection and analysis of data from various sources, and the creation of a continuous training system for pharmacovigilance specialists will allow for high-quality monitoring of information on the safety and efficacy of medicines.

Readability of information imprinted in patient information leaflets (PILs) in Saudi Arabia: The case of antihypertensive medications

BackgroundThe Saudi Food and Drug Authority (SFDA) requires marketing authorization holders to submit a PIL in both Arabic and English language. However, the readability of imprinted and disseminated Patient information leaflets (PILs) was not assessed extensively in Saudi Arabia. This study aims to assess the readability of PIL of antihypertensive drugs in both Arabic and English languages. MethodThis study was a descriptive quantitative analysis conducted in Saudi Arabia in August 2021. PILs of all oral antihypertensive medications in Saudi Arabia were included in the study. The Arabic and English PILs were extracted from the Saudi Drugs Information System (SDI) and pharmaceutical companies' registration documents. The study used Flesch-Kincaid grade level to assess the readability of English and sentence length to assess the Arabic texts. Descriptive analyses were used to assess the readability scores and the mean differences. ResultsIt was found that almost 88% of English PILs were above recommended readability level compared to 79% of Arabic PILs. About 89% of English PILs of generic and 86% of brand-name medications were above the readability cutoff point compared with 83% of Arabic PILs of generic and 68% of brand-name medications. The means of grade level for readability of PILs for the widely used antihypertensive medications including angiotensin II receptor blockers (ARBs), antiadrenergic, diuretics, Beta-blockers (BBs), calcium channel blockers (CCBs), and combination antihypertensive medications, and CCBs were higher than the recommended readability level (p < 0.05). The highest mean grade level for readability among English PILs was for combinations of antihypertensive agents (9.35 ± 1.38, p 0.01) and among Arabic PILs was for ARBs (6.15 ± 1.62, p < 0.01). ConclusionsThe majority of PILs of antihypertensive medications were above the recommended readability level that can be understood by the majority of the public, especially among generic medications and the most widely used antihypertensive medications. The study findings highlight the need of implementing guidelines to improve the readability of information imprinted in PILs and adopt new regulations requiring readability assessment for manufactures before submitting the PILs to the SFDA.

Collaborative reliance in medicine safety and quality regulation: Investigation of experiences in handling N-nitrosamine impurities among ZaZiBoNa participating countries.

IntroductionThe presence of N-nitrosamine impurities in medicines raised concerns globally as they are genotoxic and probable human carcinogens. A review of N-nitrosamine impurities in medicines provides an opportunity for National Regulatory Authorities (NRAs) to ensure that corrective and preventive actions are applied so that safe and good quality medicines are made available to the public. This study aimed to investigate the experiences on reviews conducted by NRAs from various Southern African Development Community countries which participate in the regional work-sharing forum, ZaZiBoNa, on the quality and safety data due to the presence of N-nitrosamine impurities in medicines.MethodsA comparative, descriptive study using mixed methods was conducted. Purposive sampling was applied in selecting research participants based on their participation status in the ZaZiBoNa initiative. A standardized questionnaire structured into five parts was completed by ZaZiBoNa focal persons/nominated individuals to determine the experience of each NRA in addressing the safety and quality issues related to the presence of N-nitrosamine impurities in the affected medicines. Profiled medicines included sartans, ranitidine, metformin, rifampicin, and rifapentine.ResultsSartan medicines had been reviewed by all countries participating in the ZaZiBoNa initiative. Although most NRAs have yet to conduct reviews on other profiled medicines, evaluations have been implemented to ensure access to safe and good quality medicines within the region. Most countries experienced challenges in communicating with applicants or marketing authorization holders (MAHs) on reviewing N-nitrosamine impurities in their medicines. The majority of NRAs agree that there is a need for further collaboration efforts to review N-nitrosamine impurities in medicines.ConclusionThe review of N-nitrosamine impurities in the profiled medicines by NRAs within the region has demonstrated the importance of enhanced regulatory oversight to safeguard against the risks associated with medicines. Collaborative reliance on the review of the safety and quality of medicine, continuous monitoring, implementation and review of processes, testing methods, and regular engagements with stakeholders could be essential in ensuring adequate control of N-nitrosamine impurities in medicines.

Using structural topic modelling to reveal patterns in reports on opioid drugs in a pharmacovigilance database.

Adverse drug reaction (ADR) reports in pharmacovigilance databases often contain coded information and large amounts of unstructured or semi-structured information in plain text format. The unstructured format and sheer volume of these data often render them neglected. Structural topic modelling (STM) represents a potentially insightful way of harnessing these valuable data and to detect grouping or themes in spontaneous reports to aid signal detection. This was an explorative study of the potential for structural topic modelling to identify useful patterns in ADR reports involving opioid drugs in a pharmacovigilance database. A dataset of ADR reports on opioid drugs reported to the Netherlands Pharmacovigilance Centre Lareb from 1991 to December 2020 was used, comprising a total of 3069 unique reports. Qualitative text analysis was combined with STM, an automated text analysis method, to examine these data. In reports submitted directly by patients and healthcare professionals, 11 meaningful topics were identified, whereby patient experience reports, particularly in relation to pain (relief), and the timing of intake and ADRs of tramadol and paracetamol, were the most common. Of the 12 topics identified in reports received via marketing authorization holders, patch and skin-related side effects, addiction and constipation were the most prevalent. The STM-based analysis identified information that cannot always be captured by coding with the Medical Dictionary for Regulatory Activities (MedDRA®). The identified topics reflect findings in the literature on opioids.

The Impact of Patient Support Programs in Europe: A Systematic Literature Review

Background and ObjectivePatient support programs aim to provide solutions beyond the medication itself, by enhancing treatment adherence, improving clinical outcomes, elevating patient experience, and/or increasing quality of life. As patient support programs increasingly play an important role in assisting patients, numerous observational studies and pragmatic trials designed to evaluate their impact on healthcare have been conducted in recent years. This review aims to characterize these studies.MethodsA systematic literature review, supplemented by a broad search of gray literature, was conducted following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and Cochrane recommendations. Observational studies and pragmatic trials conducted in Europe to evaluate the impact of patient support programs, published in English or Spanish between 17/03/2010 and 17/03/2020, were reviewed. Two patient support program definitions were applied starting with Ganguli et al.’s broad approach, followed by the European Medicines Agency definition, narrowed to Marketing Authorization Holders organized systems and their medicines. The quality of publications was assessed using the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement 22-item checklist.ResultsOf the 49 identified studies following the Ganguli et al. definition, 20 studies met the European Medicines Agency definition and were reviewed. Patient support program impact was evaluated based on a wide range of methodologies: 70% assessed patient support program-related patient-reported outcomes, 55% reported clinical outcomes, and 25% reported economic impacts on health resources. Only 45% conducted a comparative analysis. Overall, 75% of the studies achieved their proposed objectives.ConclusionsThe heterogeneity of the observational studies reviewed reflects the complexity of patient support programs that are built ad hoc for specific diseases, treatments, and patients. Results suggest that patient support programs play a key role in promoting treatment effectiveness, clinical outcomes, and satisfaction. However, there is a need for standardizing the definition of patient support programs and the methods to evaluate their impact.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40271-022-00582-y.

An Industry Survey on Managing the Pharmacovigilance System Master File in a Global Environment: The Need for a Pragmatic Approach.

BackgroundLegislative requirements for Marketing Authorisation Holders (MAHs) to maintain a Pharmacovigilance System Master File (PSMF) were introduced in the European Union (EU) in 2010, operationalised in 2012 and subsequently introduced in other territories. There are no internationally agreed standards for the PSMF and country/regional requirements vary, leaving room for interpretation. This creates complexities for MAHs in implementing and maintaining multiple PSMFs.ObjectivesThe approaches taken towards the creation and maintenance of PSMFs in a global environment were investigated using a survey in order to gain a better understanding of the impact of the PSMF for MAHs.MethodsA structured benchmarking survey was conducted during September and October of 2019 and the responses were analysed. A questionnaire with open-ended questions was designed to elicit detailed information on PSMF management and provide insights into company experiences. Companies affiliated to the EU Federation of Pharmaceutical Industries and Associations (EFPIA) and industry stakeholders with experience of PSMFs were contacted ensuring a broad representation including small, medium and large pharmaceutical companies, contract organisations/consultants and research-driven and generic organisations.ResultsThirty companies responded; of these, 29 provided information relating to their PSMF practices. Respondents acknowledged that the PSMF is a valuable document that has helped to create greater awareness of pharmacovigilance within companies. Complex and varying international requirements were recognised as burdensome, especially in the context of consistent development and maintenance of multiple PSMFs. The respondents indicated that companies use the EU PSMF to manage requirements in other territories. Similar areas for standardisation were identified across respondents.ConclusionThe survey results highlight both the value of the PSMF and the challenges in maintaining it. Building on these responses, the paper offers pragmatic solutions to the challenges faced by MAHs and proposes a continued dialogue with key stakeholders in industry and national regulatory authorities about PSMF globalisation, harmonisation and simplification of requirements.

UK veterinary professionals' perceptions and experiences of adverse drug reaction reporting.

Spontaneous reporting of suspected adverse drug reactions (ADRs) is the cornerstone of pharmacovigilance. Despite this, it is believed that there is significant under-reporting in the veterinary setting. Low reporting rates delay marketing authorisation holders (MAHs) and regulators taking mitigating action in the case of safety concerns. We designed a survey to explore the perceptions, attitudes and experiences of UK veterinary professionals towards ADR reporting. The survey was advertised widely through conventional and social media and at several conferences. In total, 260 respondents completed the survey, including 210 veterinary surgeons, 49 veterinary nurses and one suitably qualified person. Respondents generally understood the need to report ADRs. The main barrier to reporting was the suspected ADR being well known, and the most popular potential facilitator identified was the ability to report via the practice management system. Facilitation via education in the form of a pharmacovigilance themed continuing professional development event was particularly popular among veterinary nurses, who reported time as being less of a barrier to reporting than their veterinary surgeon counterparts. Our findings suggest that technological interventions to facilitate reporting and empowerment of veterinary nurses to report through a tailored training event should be explored further.

A 5-year look-back at the notification and management of vaccine supply shortages in Germany.

BackgroundUnavailability of vaccines endangers the overall goal to protect individuals and whole populations against infections.MethodsThe German notification system includes the publication of vaccine supply shortages reported by marketing authorisation holders (MAH), information on the availability of alternative vaccine products, guidance for physicians providing vaccinations and an unavailability reporting tool to monitor regional distribution issues.AimThis study provides a retrospective analysis of supply issues and measures in the context of European and global vaccine supply constraints.Resultsbetween October 2015 and December 2020, the 250 notifications concerned all types of vaccines (54 products). Most shortages were caused by increased demand associated with immigration in Germany in 2015 and 2016, new or extended vaccine recommendations, increased awareness, or changes in global immunisation programmes. Shortages of a duration up to 30 days were mitigated using existing storage capacities. Longer shortages, triggered by high demand on a national level, were mitigated using alternative products and re-allocation; in a few cases, vaccines were imported. However, for long lasting supply shortages associated with increased global demand, often occurring in combination with manufacturing issues, few compensatory mechanisms were available. Nevertheless, only few critical incidents were identified: (i) shortage of hexavalent vaccines endangering neonatal immunisation programmes in 2015;(ii) distribution issues with influenza vaccines in 2018; and (iii) unmet demand for pneumococcal and influenza vaccines during the coronavirus disease (COVID)-19 pandemic.ConclusionVaccine product shortages in Germany resemble those present in neighbouring EU states and often reflect increased global demand not matched by manufacturing capacities.

International Regulatory Collaboration on the Analysis of Nitrosamines in Metformin-Containing Medicines

Recalls of some batches of metformin have occurred due to the detection of N-nitrosodimethylamine (NDMA) in amounts above the acceptable intake (AI) of 96 ng per day. Prior to the recalls, an international regulatory laboratory network had been monitoring drugs for nitrosamine impurities with each laboratory independently developing and validating multiple analytical procedures to detect and measure nitrosamines in metformin drugs used in their jurisdictions. Here, we provide an overview of the analysis of metformin active pharmaceutical ingredients (APIs) and drug products with 1090 samples (875 finished dosage forms (FDFs) and 215 API samples) tested beginning in November of 2019 through July of 2020. Samples were obtained internationally by a variety of approaches, including purchased, received from firms via information requests or selected by regional regulatory authorities (either at wholesalers or during GMP inspections). Only one nitrosamine (NDMA) was detected and was only present in some batches of metformin products. For API samples, 213 out of 215 lots tested had no measurable level of NDMA. For FDF samples tested, the number of batches with NDMA above the AI amount for patient safety was 17.8% (156/875). Based on these data, although the presence of NDMA was of concern, 82.2% of the samples of metformin drug products tested met quality and safety standards for patients. Regulatory agencies continue to collaborate extensively and work with marketing authorization holders to understand root causes of nitrosamine formation and agree on corrective actions to mitigate the presence of NDMA in future metformin batches.Graphical abstract

Chaos to Clarity: Pragmatic Approaches to Overcome Challenges for Successful Implementation of Additional Risk Minimisation Measures in the European Union and the UK by a Marketing Authorisation Holder.

Most national competent authorities issue guidance on the dissemination and implementation of additional risk minimisation measures (aRMMs), like the European Medicines Agency. However, national competent authorities guidance includes additional regulatory requirements, the reasons for which are unclear. The purpose of this study was to identify significant barriers to risk management implementation and methodological challenges encountered by local safety managers in the European Union and the UK owing to differences in country-specific regulations and regional national competent authorities guidance. The European Medicines Agency and national competent authorities guidance for each of the aRMM programme's formative components were compared. A survey was conducted to ascertain the challenges encountered by local safety managers throughout the implementation phases and the responses analysed. Twenty-seven national guidance documents were compared with the European Medicines Agency's guidance, and it was observed that national competent authorities provide additional aRMM dissemination and implementation parameters for the format and layout of aRMM, translation requirements, guidance on aRMM content, submission requirements, monitoring parameters and aRMM update requirements, among others. The survey was completed by 11 out of 21 local safety managers (52.38%). Eight local safety managers rated submission of an implementation plan as the most challenging aspect. Multiple national competent authorities requests, frequent updates, and delayed approval impacted planning and implementation, resulting in modifications and delays. Moreover, the study discovered that managing frequent version updates of digital aRMMs was challenging, and most national competent authorities neglected the post-implementation phase activities. Further, most local safety managers followed both the local and global processes to maintain documentation of aRMM implementation. It was evident that the European Medicines Agency and national competent authorities empower marketing authorisation holders to implement and disseminate aRMM materials tailored to their local healthcare settings. However, this poses a challenge for marketing authorisation holders because of a lack of clarity in guidance in executing an aRMM programme and an added burden of complying with both European Medicines Agency and national competent authority requirements.

Postauthorization safety study of betaine anhydrous

Patient registries for rare diseases enable systematic data collection and can also be used to facilitate postauthorization safety studies (PASS) for orphan drugs. This study evaluates the PASS for betaine anhydrous (Cystadane), conducted as public private partnership (PPP) between the European network and registry for homocystinurias and methylation defects and the marketing authorization holder (MAH). Data were prospectively collected, 2013-2016, in a noninterventional, international, multicenter, registry study. Putative adverse and severe adverse events were reported to the MAH's pharmacovigilance. In total, 130 individuals with vitamin B6 nonresponsive (N=54) and partially responsive (N=7) cystathionine beta-synthase (CBS) deficiency, as well as 5,10-methylenetetrahydrofolate reductase (MTHFR; N=21) deficiency and cobalamin C (N=48) disease were included. Median (range) duration of treatment with betaine anhydrous was 6.8 (0-9.8) years. The prescribed betaine dose exceeded the recommended maximum (6g/day) in 49% of individuals older than 10 years because of continued dose adaptation to weight; however, with disease-specific differences (minimum: 31% in B6 nonresponsive CBS deficiency, maximum: 67% in MTHFR deficiency). Despite dose escalation no new or potential risk was identified. Combined disease-specific treatment decreased mean ± SD total plasma homocysteine concentrations from 203 ± 116 to 81 ± 51 μmol/L (p < 0.0001), except in MTHFR deficiency. Recommendations for betaine anhydrous dosage were revised for individuals ≥ 10 years. PPPs between MAH and international scientific consortia can be considered a reliable model for implementing a PASS, reutilizing well-established structures and avoiding data duplication and fragmentation.

Experiences and Perspectives of Marketing Authorisation Holders towards Medication Safety Monitoring during Pregnancy: A Pan-European Qualitative Analysis.

Although marketing authorisation holders (MAHs) are involved in monitoring medication safety, it was unclear how they experience their role and current monitoring activities in pregnancy. Therefore, a qualitative study using online focus groups with MAHs and the Belgian umbrella organisation of MAHs was conducted in June–July 2021. In total, 38 representatives of nine organisations participated. Overall, participants reported multiple difficulties with data collection, including underreporting, collection of incomplete information, and loss to follow-up. The limited number of high-quality data collected, the unknown denominator and the lack of comparator data complicate MAHs’ data processing activities, preventing them to timely provide evidence in the pregnancy label. Three ‘conflicts’ inherent to the specific position of MAHs were identified explaining the difficulties they experience, i.e., (1) mistrust from patients and healthcare professionals (HCPs); (2) MAHs’ legal obligations and regulatory framework; (3) MAHs’ position outside the healthcare context. To overcome these barriers, MAHs suggested that data registration should occur in close collaboration with patients and HCPs, organised within the healthcare context and performed by using a user-friendly system. In conclusion, the reported difficulties and underlying conflicts of MAHs highlight the need for more effective, collaborative data collection strategies to generate new evidence on this topic.

The impact of medicines shortages on pharmaceutical practice

Access to medicines is a fundamental human right and is a vital element of health care. Over the last 10 years, there has been a tendency for the global discontinuation of drug supply to become a major problem, with an increasing exacerbation of this phenomenon in the European Union, with a potential negative impact on patient health care due to multiple causes (manufacturing problems, drug pricing policy, parallel export etc.). National Agency for Medicines and Medical Devices of Romania (NAMMDR) argues, in full agreement with European Medicines Agency, that in this situation effective collaboration between the various stakeholders and regulators is required, and also a good communication between manufacturers, distributors and authorities. It is a point of view that NAMMDR supported in the working meetings with the representatives of the marketing authorization holders/ manufacturers, wholesale distribution, patient associations. According to pharmacists, situations have been reported in which patients tend to stock up on medicines, and this puts additional pressure on existing stocks. In this work, we intended to draw attention to the medicine shortages issue which has a huge impact on national health systems, on patients′ safety, on public health and healthcare professionals.

Analysis and Suggestions on Status Quo of Commissioned Production under Medical Device Marketing Authorization Holder System in China

Sort out and analyze the current status and existing problems of the pilot work of the medical device marketing authorization holder system to provide reference opinions for the full implementation of the medical device marketing authorization holder system. Use literature analysis, comparative analysis and field research to comprehensively analyze the status, advantages and risks of commissioned production under the medical device marketing authorization holder system. The commissioned production under the medical device marketing authorization holder system brings dividends and also brings risks. We should consider improving the medical device marketing authorization holder system from marketing authorization holder, the entrusted manufacturer, and the regulatory authority, and strengthen the quality supervision of the entrusted production of products.

Pharmacovigilance in China: Evolution and future challenges.

Drug-related adverse reactions are among the main reasons for harm to patients under care worldwide and even their deaths. The pharmacovigilance system has been proven to be an effective method of avoiding or alleviating such adverse events. In 2019, after two decades of implementation of the drug-related adverse reaction reporting system, China formally implemented a pharmacovigilance system with the Pharmacovigilance Quality Management Standards and a series of supporting technical documents created to improve the safety of medication given to patients. China's pharmacovigilance system has faced many problems and challenges during its implementation. This spontaneous reporting system is the main source of data for China's medication vigilance activities, but it has not provided sufficiently powerful evidence for regulatory decision-making. In conformity with the health-centred drug regulatory concept, the Chinese government has accelerated the speed of examination and approval of urgently needed clinical drugs and orphan drugs along with the requirement to improve the safety supervision of these drugs after their listing. China's marketing authorization holders (MAHs) must strengthen their pharmacovigilance capabilities as the primary responsible departments for drug safety. Chinese medical schools generally lack professional courses on pharmacovigilance. The regulatory authorities have recognized such problems and have made efforts to improve the professional capacity of pharmacovigilance personnel and to strengthen cooperation with stakeholders through the implementation of an action plan of medication surveillance and the establishment of a patient-based adverse events reporting system and active surveillance systems, which will help China bridge the gap to bring its pharmacovigilance practice up to standards.

Practical and Science-Based Strategy for Establishing Acceptable Intakes for Drug Product N-Nitrosamine Impurities.

The potential for N-nitrosamine impurities in pharmaceutical products presents a challenge for the quality management of medicinal products. N-Nitrosamines are considered cohort-of-concern compounds due to the potent carcinogenicity of many of the structurally simple chemicals within this structural class. In the past 2 years, a number of drug products containing certain active pharmaceutical ingredients have been withdrawn or recalled from the market due to the presence of carcinogenic low-molecular-weight N,N-dialkylnitrosamine impurities. Regulatory authorities have issued guidance to market authorization holders to review all commercial drug substances/products for the potential risk of N-nitrosamine impurities, and in cases where a significant risk of N-nitrosamine impurity is identified, analytical confirmatory testing is required. A key factor to consider prior to analytical testing is the estimation of the daily acceptable intake (AI) of the N-nitrosamine impurity. A significant proportion of N-nitrosamine drug product impurities are unique/complex structures for which the development of low-level analytical methods is challenging. Moreover, these unique/complex impurities may be less potent carcinogens compared to simple nitrosamines. In the present work, our objective was to derive AIs for a large number of complex N-nitrosamines without carcinogenicity data that were identified as potential low-level impurities. The impurities were first cataloged and grouped according to common structural features, with a total of 13 groups defined with distinct structural features. Subsequently, carcinogenicity data were reviewed for structurally related N-nitrosamines relevant to each of the 13 structural groups and group AIs were derived conservatively based on the most potent N-nitrosamine within each group. The 13 structural group AIs were used as the basis for assigning AIs to each of the structurally related complex N-nitrosamine impurities. The AIs of several N-nitrosamine groups were found to be considerably higher than those for the simple N,N-dialkylnitrosamines, which translates to commensurately higher analytical method detection limits.

The Quality and Reliability of Information in the Summaries of Product Characteristics.

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.

Nonsteroidal anti-inflammatory drugs’ adverse drug reactions: 10 years of national database data

The group of non-steroidal anti-inflammatory drugs has occupied one of the leading positions in terms of demand by the population over the past decade. This fact is explained by non-prescription sale, a wide range of purposes and an affordable price range. The lack of proper control over the use of non-steroidal anti-inflammatory drugs (NSAIDs) greatly complicates the assessment of safety, timely detection and prevention of events associated with patient’ safety. Target. Evaluation of data from the national pharmacovigilance database of the safety of non-steroidal anti-inflammatory drugs. Materials and methods. This is a cross-sectional study covering the period from 2010 till 2020. The assessment of the safety profile of international non-proprietary names (INN) from the group of NSAIDs at the post-registration stage was carried out according to the data of uploading the national database (Automated Information System of Roszdravnadzor; AIS RZN), as well as PubMed, Medline, Google Scholar, Elibrary databases. Conclusions. Over a ten-year period, the number of registered spontaneous messages was 8,334. With regard to the three international generic names, the number of adverse drug reactions prevails - this is metamizole (1875 (22.5 %)), acetylsalicylic acid (1716 (20.6 %)), diclofenac (979 (11.7 %)). The main system organ class with safety-related events are described for skin and subcutaneous structures. This fact is not consistent with the data of reference sources of information, which indicates the ineffectiveness of post-marketing observations by marketing authorization holders.