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.

Precision medicine in regulatory decision making: Biomarkers used for patient selection in European Public Assessment Reports from 2018 to 2020.

Biomarkers can guide precision medicine in clinical trials and practice. They can increase clinical trials' efficiency through selection of study populations more likely to benefit from treatment, thus increasing statistical power and reducing sample size requirements or study duration. We performed a narrative synthesis to explore biomarker utilization for patient selection to guide precision medicine trials in marketing authorization dossiers of centrally approved medicines in Europe between 2018 and 2020 and analyzed in-depth those that eventually included biomarkers in the medicines' indications. From 119 eligible products, 26 included a biomarker in the indication, of which most were oncology products (n = 15). Included biomarkers were often known from literature or from previously approved products in the European Union or the United States. Additionally, 52 dossiers mentioned one or more biomarkers for patient selection in their clinical efficacy and safety information. Although these were not always included in the medicines' indication, they were often implicitly embedded in condition definitions adopted from clinical guidelines or practice. In 15 out of the 26 medicines with a biomarker-guided indication, only biomarker-positive populations were included in the main clinical studies supporting the marketing authorization. These studies were mostly randomized controlled trials or single-arm trials; only two products were studied for multiple indications in an innovative basket trial. Definitions of biomarkers could be subject of debate and needed adaptation after post hoc analyses requested by the assessment committee in four cases, stressing the importance of thorough justification of these definitions to include the right population for an optimal benefit-risk balance, enabling precise medicine.

The role of stakeholder involvement in the evolving EU HTA process: Insights generated through the European Access Academy's multi-stakeholder pre-convention questionnaire.

Involvement of all relevant stakeholders will be of utmost importance for the success of the developing EU HTA harmonization process. A multi-step procedure was applied to develop a survey across stakeholders/collaborators within the EU HTA framework to assess their current level of involvement, determine their suggested future role, identify challenges to contribution, and highlight efficient ways to fulfilling their role. The 'key' stakeholder groups identified and covered by this research included: patients', clinicians', regulatory, and Health Technology Developer representatives. The survey was circulated to a wide expert audience including all relevant stakeholder groups in order to determine self-perception by the 'key' stakeholders regarding involvement in the HTA process (self-rating), and in a second, slightly modified version of the questionnaire, to determine the perception of 'key' stakeholder involvement by HTA bodies, payers, and policymakers (external rating). Predefined analyses were conducted on the submitted responses. Fifty-four responses were received (patients 9; clinicians: 8; regulators: 4; HTDs 14; HTA bodies: 7; Payers: 5; policymakers 3; others 4). The mean self-perceived involvement score was consistently lower for each of the 'key' stakeholder groups than the respective external ratings. Based on the qualitative insights generated in the survey, a RACI Chart (Responsible/Accountable/Consulted/Informed) was developed for each of the stakeholder groups to determine their roles and involvement in the current EU HTA process. Our findings suggest extensive effort and a distinct research agenda are required to ensure adequate involvement of the key stakeholder groups in the evolving EU HTA process.

Safety-Related Drug Label Changes Following Large Post-Marketing Cardiometabolic Trials: A Review of European Public Assessment Reports.

Selective safety data collection may simplify late-stage clinical trials and improve their feasibility. However, the impact on increasing overall drug safety knowledge is unknown. The aim of this study is to evaluate how much safety information is added to the drug label based on large trials after initial authorization. Changes made to the "undesirable effects" section of the drug label of cardiometabolic agents approved between 2000 and 2020 based on the results of large (> 1,000 patient) clinical trials submitted to the European Medicines Agency (EMA) were evaluated. The study focused on glucose lowering, antithrombotic, and lipid-modifying agents. The primary outcome was the number of changes in adverse drug reactions in the drug label. The EMA reviewed 55 large trials concerning 25 cardiometabolic agents after the initial marketing authorization, which included 402,444 patients. Ultimately, 38 trials (69%) resulted in a safety section update, whereas 17 trials (31%) did not. Changes in listed adverse drug reactions were made following 19 trials (35%) for 12 agents: 77 adverse drug reactions were added, 11 were deleted, and the frequencies of 43 were changed. Most changes in adverse drug reactions arose from trials with antithrombotic agents (88%) and trials performed in a new population (92%). Large trials for cardiometabolic agents reported after authorization add limited new safety information on adverse drug reactions, especially when performed in the population studied prior to approval. This suggests that selective safety data collection does not reduce learnings from late stage cardiometabolic trials in populations comprehensively studied before.

Modified Delphi procedure-based expert consensus on endpoints for an international disease registry for Metachromatic Leukodystrophy: The European Metachromatic Leukodystrophy initiative (MLDi).

BACKGROUND: Metachromatic Leukodystrophy (MLD) is a rare lysosomal disorder. Patients suffer from relentless neurological deterioration leading to premature death. Recently, new treatment modalities, including gene therapy and enzyme replacement therapy, have been developed. Those advances increase the need for high-quality research infrastructure to adequately compare treatments, execute post-marketing surveillance, and perform health technology assessments (HTA). To facilitate this, a group of MLD experts started the MLD initiative (MLDi) and initiated an academia-led European MLD registry: the MLDi. An expert-based consensus procedure, namely a modified Delphi procedure, was used to determine the data elements required to answer academic, regulatory, and HTA research questions. RESULTS: Three distinct sets of data elements were defined by the 13-member expert panel. The minimal set (n = 13) contained demographics and basic disease characteristics. The core set (n = 55) included functional status scores in terms of motor, manual, speech and eating abilities, and causal and supportive treatment characteristics. Health-related quality of life scores were included that were also deemed necessary for HTA. The optional set (n = 31) contained additional clinical aspects, such as findings at neurological examination, detailed motor function, presence of peripheral neuropathy, gall bladder involvement and micturition. CONCLUSION: Using a modified Delphi procedure with physicians from the main expert centers, consensus was reached on a core set of data that can be collected retrospectively and prospectively. With this consensus-based approach, an important step towards harmonization was made. This unique dataset will support knowledge about the disease and facilitate regulatory requirements related to the launch of new treatments.

Capturing Data in Rare Disease Registries to Support Regulatory Decision Making: A Survey Study Among Industry and Other Stakeholders.

INTRODUCTION: In rare diseases, registry-based studies can be used to provide natural history data pre-approval and complement drug efficacy and/or safety knowledge post-approval. OBJECTIVE: The objective of this study was to investigate the opinion of stakeholders about key aspects of rare disease registries that are used to support regulatory decision making and to compare the responses of employees from industry to other stakeholders. METHODS: A web-based survey was used to gauge the importance of (1) common data elements (including safety outcomes), (2) data quality and (3) governance aspects that are generic across different rare diseases. The survey included 47 questions. The data were collected in the period April-October 2019. RESULTS: Seventy-three respondents completed ≥ 80% of the survey. Most of the respondents were from the industry (n = 42, 57%). For safety data, 31 (42%) respondents were in favour of collecting all adverse events. For data quality, the respondents found a level of 30% reasonable for source data verification. For missing data, a level of 20% was considered acceptable. Compared to responders from industry, the other stakeholders found it less relevant to share data with industry and found it less acceptable if the registry is financed by industry. CONCLUSIONS: This study showed that the opinion towards data and governance is well aligned across parties, and issues of data and governance on their own should not pose a barrier to collaboration. This finding is supportive of the European Medicines Agency's efforts to encourage stakeholders to work with existing registries when collecting data to support regulatory decision making.

Future of the drug label: Perspectives from a multistakeholder dialogue.

Regulating drugs does not end when market access has been granted. Monitoring drugs over the life cycle has become state of the art, inherent to evolving legislation and societal need. Here, we explore how the drug label could move along in a changing playing-field and become a sustainable label for the future. A dialogue between academia, government, the pharmaceutical industry and patient/societal organizations was organized by the Regulatory Science Network Netherlands. This is their view.

Patient Registries: An Underused Resource for Medicines Evaluation : Operational proposals for increasing the use of patient registries in regulatory assessments.

INTRODUCTION: Patient registries, 'organised systems that use observational methods to collect uniform data on a population defined by a particular disease, condition, or exposure, and that is followed over time', are potentially valuable sources of data for supporting regulatory decision-making, especially for products to treat rare diseases. Nevertheless, patient registries are greatly underused in regulatory assessments. Reasons include heterogeneity in registry design and in the data collected, even across registries for the same disease, as well as unreliable data quality and data sharing impediments. The Patient Registries Initiative was established by the European Medicines Agency in 2015 to support registries in collecting data suitable to contribute to regulatory assessments, especially post-authorisation safety and effectiveness studies. METHODS: We conducted a qualitative synthesis of the published observations and recommendations from an initiative-led multi-stakeholder consultation and four disease-specific patient registry workshops. We identified the primary factors facilitating the use of registry data in regulatory assessments. We generated proposals on operational measures needed from stakeholders including registry holders, patients, healthcare professionals, regulators, marketing authorisation applicants and holders, and health technology assessment bodies for implementing these. RESULTS: Ten factors were identified as facilitating registry use for supporting regulatory assessments of medicinal products. Proposals on operational measures needed for implementation were categorised according to three themes: (1) nature of the data collected and registry quality assurance processes; (2) registry governance, informed consent, data protection and sharing; and (3) stakeholder communication and planning of benefit-risk assessments. CONCLUSIONS: These are the first explicit proposals, from a regulatory perspective, on operational methods for increasing the use of patient registries in medicines regulation. They apply to registry holders, patients, regulators, marketing authorisation holders/applicants and healthcare stakeholders broadly, and their implementation would greatly facilitate the use of these valuable data sources in regulatory decision-making.

Communication on Safety of Medicines in Europe: Current Practices and General Practitioners' Awareness and Preferences.

INTRODUCTION: National competent authorities (NCAs) for medicines coordinate communication relating to the safety of medicines in Europe. The effectiveness of current communication practices has been questioned, particularly with regard to reaching general practitioners (GPs). OBJECTIVE: The aim of this study was to assess current European NCA safety communication practices and to investigate European GPs' awareness of and preferences for safety communications on medicines. METHODS: Web-based surveys were distributed among European NCAs and healthcare professionals (HCPs). The survey among regulators was emailed to a representative of each of the 27 European countries participating in the Strengthening Collaboration for Operating Pharmacovigilance in Europe (SCOPE) Joint Action. HCPs from nine European countries (Denmark, Spain, Croatia, Ireland, Italy, The Netherlands, Norway, Sweden, and the UK) were asked about their preferences through a link to the survey on websites, in newsletters, and/or in a direct email. From this survey, data from GPs were used and descriptive analyses were conducted. RESULTS: Current NCA practices were reported for 26 countries. In 23 countries (88%), NCAs published direct healthcare professional communications (DHPCs, i.e. urgent communication letters for serious safety issues) on their website in addition to distribution to individual HCPs. Educational materials were available on the NCA's website in 10 countries (40%), and 21 NCAs (81%) indicated they had their own bulletin/newsletter, which is often presented on the NCA's website (15 countries; 60%). More than 90% of the 1766 GPs who completed the survey were aware of DHPCs. The most preferred senders of safety information were NCAs and professional bodies, while the preferred channels for keeping up to date with safety information were medicines reference books and clinical guidelines. GPs found the repetition of safety issues useful (range of 80% in the UK to 97% in Italy). Preference for an electronic copy rather than a hardcopy varied per country (36% in Sweden to 72% in Spain). CONCLUSIONS: NCAs use similar methods for safety communications on medicines. Most GPs were aware of urgent communications and preferred similar senders of safety communications; however, their preferences towards the format differed per country.

[The new pharmacovigilance legislation in practice]. / Nieuwe wetgeving geneesmiddelenbewaking in de praktijk.

Recent European legislation has provided new tools to enhance the overseeing of medicinal products in the postmarketing phase. Package leaflets of newly approved medicines contain a black inverted triangle as a signal for enhanced monitoring. The leaflets also have clear instructions on how to report possible adverse drug reactions. Databases of drug reactions are accessible by the public. The most important change is the establishment of the Pharmacovigilance Risk Assessment Committee (PRAC) within the European Medicines Agency (EMA). This Committee will review safety signals of medicinal products arising in the member states of the European Union. The Committee could recommend adaptation of the package leaflet, or suspension or revocation of the marketing authorisation. The PRAC is also involved in the assessment of risk management plans for medicinal products and post-authorisation efficacy and safety studies.

Prescribing of rosiglitazone and pioglitazone following safety signals: analysis of trends in dispensing patterns in the Netherlands from 1998 to 2008.

BACKGROUND: Relevant safety signals in the EU are regularly communicated in so-called 'Direct Healthcare Professional Communications' (DHPCs) or European Medicines Agency (EMA) press releases. Trends of a decrease in the use of rosiglitazone following regulatory safety warnings have been described in the US. In the EU, however, relatively little is known about dispensing patterns following DHPCs or other safety signals such as EMA press releases. OBJECTIVE: The objective of this study was to analyse trends in dispensing patterns of rosiglitazone and pioglitazone following DHPCs and EMA press releases in the EU member state, the Netherlands. METHODS: Data for this study were obtained from the PHARMO Record Linking System, which includes drug dispensing records from community pharmacies of approximately 2.5 million individuals in the Netherlands. Over the period 1998-2008 an auto-regressive, integrated, moving average model (ARIMA) was fitted. The DHPC letters or EMA press releases were used as determinants. Adjustments were made for publication of certain literature. Stratification was performed for dispensings prescribed by general practitioners (GPs) and those prescribed by specialists. RESULTS: For rosiglitazone, four EMA press releases and two DHPCs were issued; for pioglitazone, one DHPC was issued. The number of rosiglitazone dispensings prescribed by GPs decreased significantly after publication of DHPCs and EMA press releases concerning the risk of macular oedema and risk of fractures (both p-values 0.001). The number of rosiglitazone dispensings decreased statistically significantly after publication of EMA press releases 2 and 3 concerning cardiovascular risks but not for EMA press release 4. Adjustment for certain publications in the literature reduced the effect of communicated safety issues on the proportion of dispensings. CONCLUSIONS: Although it is difficult to disentangle the effect of DHPCs and EMA press releases from the effect of reports published in the literature, our results suggest that prescribers may react to such safety communications.

Effect of safety issues with HIV drugs on the approval process of other drugs in the same class: an analysis of European Public Assessment Reports.

BACKGROUND: Knowledge on the safety of new medicines is limited at the time of market entry. Nearly half of all drugs used to treat HIV registered in the EU required ≥1 Direct Healthcare Professional Communication (DHPC) in the past 10 years for safety issues identified post-approval. OBJECTIVE: The aim was to evaluate the extent to which regulators and industry have addressed the risk of safety issues for HIV drugs based on prior experience with other drugs in the same class and whether doing so impacts development time of these drugs. METHODS: HIV drugs receiving ≥1 DHPC in the Netherlands between January 1999 and December 2008 were identified. Each drug with a DHPC ('index' drug) was paired with subsequently approved HIV drug(s) in the same class (Anatomical Therapeutic Chemical [ATC] 4th level) ['follow-on' drugs]. Characteristics of safety issues were extracted from the DHPCs of the 'index' drugs. European Public Assessment Reports (EPARs) were reviewed regarding whether the safety issues had been considered during development and approval. Consideration of previously identified safety issues in 'follow-on' drug applications was assessed regarding attention paid to adverse drug reaction (ADR) symptoms in pre-marketing studies, Summary of Product Characteristics (SmPC) and postmarketing commitments, and whether size of the safety population was in accordance with Regulatory guidelines. 'Index' drugs were also paired with drugs in the same class already on the market ('older' drugs). For 'older' drugs, we identified whether the safety issue led to appropriate changes in the current SmPC (January 2011) compared with the SmPC at the time of marketing authorization. Clinical development time was assessed using time from first patent application to market authorization as proxy, and comparison was made between 'index' and 'follow-on' drugs. RESULTS: For 9 (43%) of the 21 centrally authorized HIV drugs, 11 serious safety issues that required a DHPC were identified. Two drugs were excluded from our analysis (DHPCs related to contamination/medication error). Six 'index' drugs were paired, each with one to six 'follow-on' drugs. Three concerned drug-drug interactions (DDIs); the other three were intracranial haemorrhage, neuromuscular weakness and severe skin/hepatic reactions. All but one 'follow-on' drug had information in the EPAR on that specific ADR (i.e. attention was paid to the ADR). The DDIs were addressed in pre-marketing studies and/or the SmPC. Two of the other ADRs were addressed by postmarketing surveillance commitments; intracranial haemorrhage was not addressed. Three safety issues for two 'index' drugs could not be paired with a 'follow-on' drug as no drug in the same class was approved after the corresponding DHPCs were issued. Five of the nine safety issues were added to at least one of the current SmPCs for the 'older' drugs already on the market at the time of DHPC issue. Two safety issues were already in the SmPC of the 'older' drugs at time of market approval and two were not introduced into the SmPC of 'older' drugs. Population size to assess short-term safety complied with the guidelines for four 'index', seven 'follow-on' and three 'older' drugs; population size to assess long-term safety complied for one, three and two drugs, respectively. For five drugs, EPARs did not provide adequate information on population size. No statistically significant difference in development time between 'index' and 'follow-on' drugs was found. CONCLUSION: Generally, safety issues were taken into account in the approval process of other drugs in the class. The approaches were different and determined by the nature of the ADR. Taking safety issues into account in the approval process did not seem to impact on the time taken to perform the pre-approval clinical programme.

Reliability of the assessment of preventable adverse drug events in daily clinical practice.

PURPOSE: To determine the reliability of the assessment of preventable adverse drug events (ADEs) in daily practice and to explore the impact of the assessors' professional background and the case characteristics on reliability. METHODS: We used a combination of the simplified Yale algorithm and the National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) scheme to assess on the one hand the causal relationship between medication errors (MEs) and adverse events in hospitalised patients and on the other hand the severity of the clinical consequence of MEs. Five pharmacists and five physicians applied this algorithm to 30 potential MEs. After individual assessment, the pharmacists reached consensus and so did the physicians. Outcome was both MEs' severity (ordinal scale, NCC MERP categories A-I) and the occurrence of preventable harm (binary outcome, NCC MERP categories A-D vs. E-I). Kappa statistics was used to assess agreement. RESULTS: The overall agreement on MEs' severity was fair for the pharmacists (kappa = 0.34) as well as for the physicians (kappa = 0.25). Overall agreement for the 10 raters was fair (kappa = 0.25) as well as the agreement between both consensus outcomes (kappa = 0.30). Agreement on the occurrence of preventable harm was higher, ranging from kappa = 0.36 for the physicians through kappa = 0.49 for the pharmacists. Overall agreement for the 10 raters was fair (kappa = 0.36). The agreement between both consensus outcomes was moderate (kappa = 0.47). None of the included case characteristics had a significant impact on agreement. CONCLUSIONS: Individual assessment of preventable ADEs in real patients is difficult, possibly because of the difficult assessment of contextual information. Best approach seems to be a consensus method including both pharmacists and physicians.

Improving compliance with hospital antibiotic guidelines: a time-series intervention analysis.

OBJECTIVES: This study investigated the impact of a combined intervention strategy to improve antimicrobial prescribing at University Hospital Groningen. For the intervention, the antimicrobial treatment guidelines were updated and disseminated in paperback and electronic format. The credibility of the guidelines was improved by consultation with users. In a second phase, academic detailing (AD) was used to improve specific areas of low compliance with the guidelines. MATERIALS AND METHODS: Prescribing data were prospectively collected for 2869 patients receiving 7471 prescriptions for an antimicrobial for an infection covered by the guidelines between July 2001 and September 2003. After collection of baseline data, the guidelines were actively disseminated in February 2002. Next, after a 5 month interval, a second intervention, i.e. an AD approach, addressed suboptimal prescribing of ciprofloxacin and co-amoxiclav. Segmented regression analysis was used to analyse the interrupted time-series data. RESULTS: At baseline, compliance with the drug choice guidelines was 67%. The first intervention showed a significant change in the level of compliance of +15.5% (95% CI: 8%; 23%). AD did not lead to statistically significant additional changes in already high levels +12.5% (95% CI:-3%; 28%) of compliance. Post-intervention compliance was stable at 86%. CONCLUSIONS: Updating the guidelines in close collaboration with the specialists involved followed by active dissemination proved to be an efficient way to improve compliance with guideline recommendations. An 86% compliance level was achieved in this study without compulsory measures. A ceiling effect may have limited the added value of AD.