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.
In the Netherlands, drug regulatory science is a vibrant national and internationally oriented community. In this review, we present the factors that have contributed to this successful collaboration ...between relevant stakeholders and that led to a surge of activities around how regulatory science became embedded in the ecosystem of medicines research, clinical pharmacology, policymaking and regulation. We distinguished three pivotal episodes: (i) TI Pharma Escher‐project, (ii) Dutch Medicines Evaluation Board as catalyst of the big jump, and (iii) Regulatory Science Network Netherlands and multistakeholder engagement. The research agenda has been influenced by the dynamic evolution of legal frameworks in Europe, such as the EU orphan medicines legislation of 2001 and the EU pharmacovigilance legislation of 2012. All these developments have inspired and have raised pertinent regulatory sciences questions. Furthermore, clinical pharmacology as a discipline has been very influential in shaping regulatory science, contributing to discussions on the level of clinical evidence that is necessary to justify marketing approval of a new medicine. With a growing interest of multiple parties such as academics, European Medicines Agency, national agencies, patient organizations and EFPIA, connecting regulatory science activities is key.
Although the benefits of antithrombotic drugs are indisputable to reduce thrombotic events, they carry a high risk of compromising patient safety. No previous studies investigated the implementation ...and (cost-) effectiveness of a hospital-based multidisciplinary antithrombotic team on bleeding and thrombotic outcomes. The primary aim of this study was to compare the proportion of patients with a composite end point consisting of one or more bleeding episodes or one or more thrombotic event from hospitalization until three months after hospitalization.
A prospective, multicenter before-after intervention study was conducted in two Dutch hospitals. Adult patients hospitalized between October 2015 and December 2017 treated with anticoagulant therapy were included. The primary aim was to estimate the proportion of patients with a composite end point consisting of one or more bleeding episodes or one or more thrombotic event from hospitalization until three months after hospitalization. The intervention was the implementation of a multidisciplinary antithrombotic team focusing on education, medication reviews by pharmacists, implementing of local anticoagulant therapy guidelines based on national guidelines, patient counselling and medication reconciliation at admission and discharge. The primary endpoint was analysed using segmented linear regression. We obtained data for 1,886 patients: 941 patients were included in the usual care period and 945 patients in the intervention period. The S-team study showed that implementation of a multidisciplinary antithrombotic team over time significantly reduced the composite end point consisting of one or more bleeding episodes or one or more thrombotic event from hospitalization until three months after hospitalization in patients using anticoagulant drugs (-1.83% (-2.58% to -1.08%) per 2 month period).
This study shows that implementation of a multidisciplinary antithrombotic team over time significantly reduces the composite end point consisting of one or more bleeding episodes or one or more thrombotic event from hospitalization until three months after hospitalization in patients using anticoagulant drugs.
Trialregister.nl NTR4887.
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.
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.
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.
Real‐world data/evidence (RWD/RWE) may provide insightful information on medicines' clinical effects to guide regulatory decisions. While its contribution has been recognized for safety monitoring ...and disease epidemiology across medicines' life cycles, using RWD/RWE to demonstrate efficacy requires further evaluation. This study aimed to (i) characterize RWD/RWE presented by applicants to support claims on medicines' efficacy within initial marketing authorization applications (MAAs) and extension of indication applications (EoIs), and (ii) analyze the contribution of RWD/RWE to regulatory decisions on medicines' benefit–risk profile. RWD/RWE was included to support efficacy in 32 MAAs and 14 EoIs submitted 2018–2019. Of these, RWD/RWE was part of the preauthorization package of 16 MAAs and 10 EoIs, and was (i) considered supporting the regulatory decision in 10 applications (five MAAs, five EoIs), (ii) considered not supporting the regulatory decision in 11 (seven MAAs, four EoIs), and (iii) not addressed at all in the evaluation of 5 applications (four MAAs, one EoI). Common limitations of submitted RWD/RWE included missing data, lack of representativeness of populations, small sample size, absence of an adequate or prespecified analysis plan, and risk of several types of bias. The suitability of RWD/RWE in a given application still requires a case‐by‐case analysis considering its purpose of use, implying reflection on the data source, together with its assets and limitations, study objectives and designs, and the overall data package issued. Early interactions and continuous dialogues with regulators and relevant stakeholders is key to optimize fit‐for‐purpose RWE generation, enabling its broader use in medicines development.
•Current dialogue between academic researchers and regulators is inadequate.•The STARS project aims to bridge the regulatory knowledge gap in academic research.•Early exchange of information between ...academic researchers and regulators is crucial.•Regulatory science should be implemented in (bio)medical educational programmes.
Truly disruptive medicine innovation and new treatment paradigms tend to start in non-commercial research institutions. However, the lack of mutual understanding between medicine developers and regulators when it comes to medicine development significantly delays or even prevents the access of patients to these innovations. Here, we outline what regulatory-related barriers hamper the translational development of novel products or new treatment paradigms initiated in academia, and propose key steps towards improved regulatory dialogue among academia, funding bodies and regulatory authorities. Moreover, we briefly describe how the STARS (Strengthening Training of Academia in Regulatory Science) project aims to reach out to medicine innovators in academia to bridge the regulatory knowledge gap and enhance this dialogue to facilitate the implementation of academic research findings in clinical practice.
Important discoveries by academic drug developers hold the promise of bringing innovative treatments that address unmet medical needs to the market. However, the drug development process has proved ...to be challenging and demanding for academic researchers, and regulatory challenges are an important barrier to implementing academic findings in clinical practice. European regulators offer varying degrees of support services to help drug developers meet regulatory standards and requirements. “Strengthening Training of Academia in Regulatory Sciences and Supporting Regulatory Scientific Advice” (STARS) is a European Commission–funded consortium aiming to strengthen the training of academics in regulatory science and requirements. Here, we report the results of four surveys that investigated the awareness and utilization of support tools offered by European regulators and identified the regulatory challenges and support needs of researchers. The surveys targeted four main European stakeholders in academic medicines research: academic research groups (706 respondents), academic research centers (99), funding organizations (49), and regulators (22). The results show that while European regulators provide various regulatory support tools, less than half of the responding academic researchers were aware of these tools and many experienced challenges in reaching a sufficient level of regulatory knowledge. There was a general lack of understanding of the regulatory environment that was aggravated by poor communication between stakeholders. The results of this study form a foundation for an improved European medicines regulatory network, in which regulatory challenges faced by academia are tackled.
Medication adherence is a key factor impacting efficacy and safety of medicines, yet how it is dealt with in European registration trials is unknown. A cross‐sectional analysis of European Medicines ...Agency (EMA) marketing authorization dossiers for new medicines approved through centralized procedures in the European Union between 2010 and 2020 was performed. Data were extracted from European Public Assessment Reports and Clinical Study Reports. Clinical trials covering five therapeutic areas were included: diabetes, respiratory conditions, cardiovascular diseases, infectious diseases, and oncology. Outcomes included adherence assessment, measurement methods, and rates. Overall, 102 medicines studied in 253 clinical trials were reviewed. All but one study reported measuring adherence. Two hundred twenty trials (87%) measured adherence using quantitative methods, while 32 (13%) trials monitored adherence but did not further quantify. Reported adherence rates were high (> 90%) across trials yet marked disparities in measurement methods and definitions were found. The most frequently used adherence measurement method was pill/dose count (single method: 52.7%; in combination: 37.7%; with patient diary/report: 17.3%; electronic methods: 1.4%; bioanalytical methods: 4.1%). Patient diary/report (6.4%) and electronic methods (2.7%) were also used as single methods. Electronic methods were more often used in respiratory and anti‐infective trials, while bioanalytical methods were more frequently used in diabetes. Overall, adherence is measured in EMA registration trials, yet the methods used and the way in which adherence rates are presented vary widely between trials and therapeutic areas. To better understand and compare efficacy of medicines, standardization of adherence definitions and measurement methods is needed.
Aims
We aimed to assess and characterize sex differences in adverse drug reactions (ADRs) reported to the national pharmacovigilance centre in the Netherlands while considering differences in drug ...use.
Methods
ADRs spontaneously reported by healthcare professionals and patients to the Netherlands pharmacovigilance centre Lareb were used. Drug–ADR combinations reported at least 10 times between 2003–2016 for drugs used by ≥10,000 persons in that period were included. Data about the number of drug users was obtained from the National Health Care Institute. Sex‐specific ADRs, like gynaecological problems, were excluded. Sex differences in specific drug–ADR combinations were tested using bivariate logistic regression analyses in which the number of drug users per sex was taken into account.
Results
In total, 2483 drug–ADR combinations were analysed. Possibly relevant sex differences were shown in 363 combinations (15%). Most of these drug–ADR combinations were reported more often for women (322 combinations). Drugs with the highest number of ADRs that were more often reported for women included thyroid hormones (32 combinations) and antidepressants (16 combinations for the centrally acting sympathomimetics; 14 combinations for other antidepressants). Some ADRs were predominantly reported for women across a range of drugs such as headache and dizziness whereas other ADRs such as tendon ruptures and aggression were reported more often for men.
Conclusions
Identified sex differences in reported ADRs often referred to women. These differences may have various causes, including pharmacological and behavioural causes, which need to be further assessed. The results may ultimately lead to sex‐specific prescribing or monitoring recommendations.
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