Artificial intelligence integration in the drug lifecycle and in regulatory science: policy implications, challenges and opportunities.

Artificial intelligence tools promise transformative impacts in drug development. Regulatory agencies face challenges in integrating AI while ensuring reliability and safety in clinical trial approvals, drug marketing authorizations, and post-market surveillance. Incorporating these technologies into the existing regulatory framework and agency practices poses notable challenges, particularly in evaluating the data and models employed for these purposes. Rapid adaptation of regulations and internal processes is essential for agencies to keep pace with innovation, though achieving this requires collective stakeholder collaboration. This article thus delves into the need for adaptations of regulations throughout the drug development lifecycle, as well as the utilization of AI within internal processes of medicine agencies.

Monitoring Adverse Drug Events in Web Forums: Evaluation of a Pipeline and Use Case Study.

BACKGROUND: To mitigate safety concerns, regulatory agencies must make informed decisions regarding drug usage and adverse drug events (ADEs). The primary pharmacovigilance data stem from spontaneous reports by health care professionals. However, underreporting poses a notable challenge within the current system. Explorations into alternative sources, including electronic patient records and social media, have been undertaken. Nevertheless, social media's potential remains largely untapped in real-world scenarios. OBJECTIVE: The challenge faced by regulatory agencies in using social media is primarily attributed to the absence of suitable tools to support decision makers. An effective tool should enable access to information via a graphical user interface, presenting data in a user-friendly manner rather than in their raw form. This interface should offer various visualization options, empowering users to choose representations that best convey the data and facilitate informed decision-making. Thus, this study aims to assess the potential of integrating social media into pharmacovigilance and enhancing decision-making with this novel data source. To achieve this, our objective was to develop and assess a pipeline that processes data from the extraction of web forum posts to the generation of indicators and alerts within a visual and interactive environment. The goal was to create a user-friendly tool that enables regulatory authorities to make better-informed decisions effectively. METHODS: To enhance pharmacovigilance efforts, we have devised a pipeline comprising 4 distinct modules, each independently editable, aimed at efficiently analyzing health-related French web forums. These modules were (1) web forums' posts extraction, (2) web forums' posts annotation, (3) statistics and signal detection algorithm, and (4) a graphical user interface (GUI). We showcase the efficacy of the GUI through an illustrative case study involving the introduction of the new formula of Levothyrox in France. This event led to a surge in reports to the French regulatory authority. RESULTS: Between January 1, 2017, and February 28, 2021, a total of 2,081,296 posts were extracted from 23 French web forums. These posts contained 437,192 normalized drug-ADE couples, annotated with the Anatomical Therapeutic Chemical (ATC) Classification and Medical Dictionary for Regulatory Activities (MedDRA). The analysis of the Levothyrox new formula revealed a notable pattern. In August 2017, there was a sharp increase in posts related to this medication on social media platforms, which coincided with a substantial uptick in reports submitted by patients to the national regulatory authority during the same period. CONCLUSIONS: We demonstrated that conducting quantitative analysis using the GUI is straightforward and requires no coding. The results aligned with prior research and also offered potential insights into drug-related matters. Our hypothesis received partial confirmation because the final users were not involved in the evaluation process. Further studies, concentrating on ergonomics and the impact on professionals within regulatory agencies, are imperative for future research endeavors. We emphasized the versatility of our approach and the seamless interoperability between different modules over the performance of individual modules. Specifically, the annotation module was integrated early in the development process and could undergo substantial enhancement by leveraging contemporary techniques rooted in the Transformers architecture. Our pipeline holds potential applications in health surveillance by regulatory agencies or pharmaceutical companies, aiding in the identification of safety concerns. Moreover, it could be used by research teams for retrospective analysis of events.

Rapid Review on Publicly Available Datasets for Health Misinformation Detection.

The proliferation of health misinformation in recent years has prompted the development of various methods for detecting and combatting this issue. This review aims to provide an overview of the implementation strategies and characteristics of publicly available datasets that can be used for health misinformation detection. Since 2020, a large number of such datasets have emerged, half of which are focused on COVID-19. Most of the datasets are based on fact-checkable websites, while only a few are annotated by experts. Furthermore, some datasets provide additional information such as social engagement and explanations, which can be utilized to study the spread of misinformation. Overall, these datasets offer a valuable resource for researchers working to combat the spread and consequences of health misinformation.

Transfer Learning for Early Prediction of Adverse Drug Reactions: Docetaxel and Alopecia in Breast Cancer as a Case Study.

Transfer Learning (TL) is an approach which has not yet been widely investigated in healthcare, mostly applied in image data. This study outlines a TL pipeline leveraging Individual Case Safety reports (ICSRs) and Electronic Health Records (EHR), applied for the early detection Adverse Drug Reactions (ADR), evaluated using of alopecia and docetaxel on breast cancer patients as use case.

An Integrated Care Platform System (C3-Cloud) for Care Planning, Decision Support, and Empowerment of Patients With Multimorbidity: Protocol for a Technology Trial.

BACKGROUND: There is an increasing need to organize the care around the patient and not the disease, while considering the complex realities of multiple physical and psychosocial conditions, and polypharmacy. Integrated patient-centered care delivery platforms have been developed for both patients and clinicians. These platforms could provide a promising way to achieve a collaborative environment that improves the provision of integrated care for patients via enhanced information and communication technology solutions for semiautomated clinical decision support. OBJECTIVE: The Collaborative Care and Cure Cloud project (C3-Cloud) has developed 2 collaborative computer platforms for patients and members of the multidisciplinary team (MDT) and deployed these in 3 different European settings. The objective of this study is to pilot test the platforms and evaluate their impact on patients with 2 or more chronic conditions (diabetes mellitus type 2, heart failure, kidney failure, depression), their informal caregivers, health care professionals, and, to some extent, health care systems. METHODS: This paper describes the protocol for conducting an evaluation of user experience, acceptability, and usefulness of the platforms. For this, 2 "testing and evaluation" phases have been defined, involving multiple qualitative methods (focus groups and surveys) and advanced impact modeling (predictive modeling and cost-benefit analysis). Patients and health care professionals were identified and recruited from 3 partnering regions in Spain, Sweden, and the United Kingdom via electronic health record screening. RESULTS: The technology trial in this 4-year funded project (2016-2020) concluded in April 2020. The pilot technology trial for evaluation phases 3 and 4 was launched in November 2019 and carried out until April 2020. Data collection for these phases is completed with promising results on platform acceptance and socioeconomic impact. We believe that the phased, iterative approach taken is useful as it involves relevant stakeholders at crucial stages in the platform development and allows for a sound user acceptance assessment of the final product. CONCLUSIONS: Patients with multiple chronic conditions often experience shortcomings in the care they receive. It is hoped that personalized care plan platforms for patients and collaboration platforms for members of MDTs can help tackle the specific challenges of clinical guideline reconciliation for patients with multimorbidity and improve the management of polypharmacy. The initial evaluative phases have indicated promising results of platform usability. Results of phases 3 and 4 were methodologically useful, yet limited due to the COVID-19 pandemic. TRIAL REGISTRATION: ClinicalTrials.gov NCT03834207; https://clinicaltrials.gov/ct2/show/NCT03834207. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/21994.

Encouraging Behavior Changes and Preventing Cardiovascular Diseases Using the Prevent Connect Mobile Health App: Conception and Evaluation of App Quality.

BACKGROUND: Cardiovascular diseases are a major cause of death worldwide. Mobile health apps could help in preventing cardiovascular diseases by improving modifiable risk factors such as eating habits, physical activity levels, and alcohol or tobacco consumption. OBJECTIVE: The aim of this study was to design a mobile health app, Prevent Connect, and to assess its quality for (1) assessing patient behavior for 4 cardiovascular risk factors (unhealthy eating, sedentary lifestyle, alcohol, and tobacco consumption) and (2) suggesting personalized recommendations and mobile health interventions for risky behaviors. METHODS: The knowledge base of the app is based on French national recommendations for healthy eating, physical activity, and limiting alcohol and tobacco consumption. It contains a list of patient behaviors and related personalized recommendations and digital health interventions. The interface was designed according to usability principles. Its quality was assessed by a panel of 52 users in a 5-step process: completion of the demographic form, visualization of a short presentation of the app, testing of the app, completion of the user version of the Mobile App Rating Scale (uMARS), and an open group discussion. RESULTS: This app assesses patient behaviors through specific questionnaires about 4 risk factors (unhealthy eating, sedentary lifestyle, alcohol, and tobacco consumption) and suggests personalized recommendations and digital health interventions for improving behavior. The app was deemed to be of good quality, with a mean uMARS quality score of 4 on a 5-point Likert scale. The functionality and information content of the app were particularly appreciated, with a mean uMARS score above 4. Almost all the study participants appreciated the navigation system and found the app easy to use. More than three-quarters of the study participants found the app content relevant, concise, and comprehensive. The aesthetics and the engagement of the app were also appreciated (uMARS score, 3.7). Overall, 80% (42/52) of the study participants declared that the app helped them to become aware of the importance of addressing health behavior, and 65% (34/52) said that the app helped motivate them to change lifestyle habits. CONCLUSIONS: The app assessed the risky behaviors of the patients and delivered personalized recommendations and digital health interventions for multiple risk factors. The quality of the app was considered to be good, but the impact of the app on behavior changes is yet to be demonstrated and will be assessed in further studies.

Identifying Actionability as a Key Factor for the Adoption of 'Intelligent' Systems for Drug Safety: Lessons Learned from a User-Centred Design Approach.

INTRODUCTION: Information technology (IT) plays an important role in the healthcare landscape via the increasing digitization of medical data and the use of modern computational paradigms such as machine learning (ML) and knowledge graphs (KGs). These 'intelligent' technical paradigms provide a new digital 'toolkit' supporting drug safety and healthcare processes, including 'active pharmacovigilance'. While these technical paradigms are promising, intelligent systems (ISs) are not yet widely adopted by pharmacovigilance (PV) stakeholders, namely the pharma industry, academia/research community, drug safety monitoring organizations, regulatory authorities, and healthcare institutions. The limitations obscuring the integration of ISs into PV activities are multifaceted, involving technical, legal and medical hurdles, and thus require further elucidation. OBJECTIVE: We dissect the abovementioned limitations by describing the lessons learned during the design and implementation of the PVClinical platform, a web platform aiming to support the investigation of potential adverse drug reactions (ADRs), emphasizing the use of knowledge engineering (KE) as its main technical paradigm. RESULTS: To this end, we elaborate on the related 'business processes' (i.e. operational processes) and 'user goals' identified as part of the PVClinical platform design process based on Design Thinking principles. We also elaborate on key challenges restricting the adoption of such ISs and their integration in the clinical setting and beyond. CONCLUSIONS: We highlight the fact that beyond providing analytics and useful statistics to the end user, 'actionability' has emerged as the operational priority identified through the whole process. Furthermore, we focus on the needs for valid, reproducible, explainable and human-interpretable results, stressing the need to emphasize on usability.

Visualising Patterns Associated with Adverse Drug Reactions in French Forums.

As social media are an interesting source of information for pharmacovigilance, we implemented a novel visualisation method for pharmacovigilance specialists applied to French discussion forums. A word embedding model was trained on posts to facilitate the identification of patterns associated with adverse drug reactions.

Influence of Connected Health Interventions for Adherence to Cardiovascular Disease Prevention: A Scoping Review.

BACKGROUND: Recent health care developments include connected health interventions to improve chronic disease management and/or promote actions reducing aggravating risk factors for conditions such as cardiovascular diseases. Adherence is one of the main challenges for ensuring the correct use of connected health interventions over time. OBJECTIVE: This scoping review deals with the connected health interventions used in interventional studies, describing the ways in which these interventions and their functions effectively help patients to deal with cardiovascular risk factors over time, in their own environments. The objective is to acquire knowledge and highlight current trends in this field, which is currently both productive and immature. METHODS: A structured literature review was constructed from Medline-indexed journals in PubMed. We established inclusion criteria relating to three dimensions (cardiovascular risk factors, connected health interventions, and level of adherence). Our initial search yielded 98 articles; 78 were retained after screening on the basis of title and abstract, 49 articles underwent full-text screening, and 24 were finally retained for the analysis, according to preestablished inclusion criteria. We excluded studies of invasive interventions and studies not dealing with digital health. We extracted a description of the connected health interventions from data for the population or end users. RESULTS: We performed a synthetic analysis of outcomes, based on the distribution of bibliometrics, and identified several connected health interventions and main characteristics affecting adherence. Our analysis focused on three types of user action: to read, to do, and to connect. Finally, we extracted current trends in characteristics: connect, adherence, and influence. CONCLUSION: Connected health interventions for prevention are unlikely to affect outcomes significantly unless other characteristics and user preferences are considered. Future studies should aim to determine which connected health design combinations are the most effective for supporting long-term changes in behavior and for preventing cardiovascular disease risks.

Decision Support System for Selection of e-Health Interventions.

The main goal of this work was to design a decision support system for effective personalized cardiovascular risk prevention: i) to identify behavioral groups associated with clinical risk factors, ii) to provide recommendations associated with the objective to be achieved and iii) to determine the decision-making rules assigning each group to the type of mobile health intervention conveying the most appropriate prevention messages, to help patients to achieve attainable goals. The system is based on an existing data prediction model taking into account specific risky behaviors, clinical risk factors and social status, and it is embedded in a new e-health application. The system is operational. The next step will be the design of a large study to assess improvements in patient adherence to prevention messages through e-health interventions selected by the application.

Supporting Active Pharmacovigilance via IT Tools in the Clinical Setting and Beyond: Regulatory and Management Aspects.

Information Technology (IT) could have a prominent role towards the "Active Pharmacovigilance" (AP) paradigm by facilitating the analysis of potential Adverse Drug Reactions (ADRs). PVClinical project aims to build an IT platform enabling the investigation of potential ADRs in the clinical environment and beyond. In this paper, we outline the respective EU regulatory framework and the related Business Processes (BPs), elaborated based on input from clinicians and PV experts as part of the project's "user requirements analysis" phase, highlighting their potential pivotal role in the design of IT tools aiming to support AP.

Localisation, Personalisation and Delivery of Best Practice Guidelines on an Integrated Care and Cure Cloud Architecture: The C3-Cloud Approach to Managing Multimorbidity.

BACKGROUND: C3-Cloud is an integrated care ICT infrastructure offering seamless patient-centered approach to managing multimorbidity, deployed in three European pilot sites. Challenge: The digital delivery of best practice guidelines unified for multimorbidity, customized to local practice, offering the capability to improve patient personalization and benefit. METHOD: C3-Cloud has adopted a co-production approach to developing unified multimorbidity guidelines, by collating and reconciling best practice guidelines for each condition. Clinical and technical teams at pilot sites and the C3-Cloud consortium worked in tandem to create the specification and technical implementation. RESULTS: C3-Cloud offers CDSS for diabetes, renal failure, depression and congenital heart failure, with over 300 rules and checks that deliver four best practice guidelines in parallel, customized for each pilot site. CONCLUSIONS: The process provided a traceable, maintainable and audited digitally delivered collated and reconciled guidelines.

Classification of the Severity of Adverse Drugs Reactions.

This poster presents a non-exhaustive study of machine learning classification algorithms on pharmacovigilance data. In this study, we have taken into account the patient's clinical data such as medical history, medications taken and their indications for prescriptions, and the observed side effects. From these elements we determine whether the patient case is considered serious or not. We show the performances of the different algorithms by their precision, recall and accuracy as well as their learning curves.

Ontological and Non-Ontological Resources for Associating Medical Dictionary for Regulatory Activities Terms to SNOMED Clinical Terms With Semantic Properties.

Background: Formal definitions allow selecting terms (e.g., identifying all terms related to "Infectious disease" using the query "has causative agent organism") and terminological reasoning (e.g., "hepatitis B" is a "hepatitis" and is an "infectious disease"). However, the standard international terminology Medical Dictionary for Regulatory Activities (MedDRA) used for coding adverse drug reactions in pharmacovigilance databases does not beneficiate from such formal definitions. Our objective was to evaluate the potential of reuse of ontological and non-ontological resources for generating such definitions for MedDRA. Methods: We developed several methods that collectively allow a semiautomatic semantic enrichment of MedDRA: 1) using MedDRA-to-SNOMED Clinical Terms (SNOMED CT) mappings (available in the Unified Medical Language System metathesaurus or other mapping resources, e.g., the MedDRA preferred term "hepatitis B" is associated to the SNOMED CT concept "type B viral hepatitis") to extract term definitions (e.g., "hepatitis B" is associated with the following properties: has finding site liver structure, has associated morphology inflammation morphology, and has causative agent hepatitis B virus); 2) using MedDRA labels and lexical/syntactic methods for automatic decomposition of complex MedDRA terms (e.g., the MedDRA systems organ class "blood and lymphatic system disorders" is decomposed in blood system disorders and lymphatic system disorders) or automatic suggestions of properties (e.g., the string "cyclic" in preferred term "cyclic neutropenia" leads to the property has clinical course cyclic). Results: The Unified Medical Language System metathesaurus was the main ontological resource reusable for generating formal definitions for MedDRA terms. The non-ontological resources (another mapping resource provided by Nadkarni and Darer in 2010 and MedDRA labels) allowed defining few additional preferred terms. While the Ci4SeR tool helped the curator to define 1,935 terms by suggesting potential supplemental relations based on the parents' and siblings' semantic definition, defining manually all MedDRA terms remains expensive in time. Discussion: Several ontological and non-ontological resources are available for associating MedDRA terms to SNOMED CT concepts with semantic properties, but providing manual definitions is still necessary. The ontology of adverse events is a possible alternative but does not cover all MedDRA terms either. Perspectives are to implement more efficient techniques to find more logical relations between SNOMED CT and MedDRA in an automated way.

Mapping the Hyperlink Structure of Diabetes Online Communities.

Diabetes is one of the largest global health emergencies of the 21st century. As a chronic disease, diabetes requires continuous medical care and constant patient self-management. Such care involves several stakeholders to improve health outcome and patient quality of life. This paper makes use of World Wide Web network analysis to highlight how stakeholders, providing information about online diabetes communities, link to each other. To achieve this, we capture the network of diabetes related websites as a digital trace of a non-digital phenomenon. Furthermore, this helps us to understand the current situation of diabetes organizations from a digital perspective. The methodology involves state-of-the-art tools to crawl (Hyphe) and visualize (Gephi) topic-sensitive networks. While neither of these tools is new in itself, their combination provides a promising way to analyze chronic disease stakeholders, organizations and communities, representing a large proportion of the knowledge and support diabetes patients have access to nowadays.

User-Centered Design of the C3-Cloud Platform for Elderly with Multiple Diseases - Functional Requirements and Application Testing.

The number of patients with multimorbidity has been steadily increasing in the modern aging societies. The European C3-Cloud project provides a multidisciplinary and patient-centered "Collaborative Care and Cure-system" for the management of elderly with multimorbidity, enabling continuous coordination of care activities between multidisciplinary care teams (MDTs), patients and informal caregivers (ICG). In this study various components of the infrastructure were tested to fulfill the functional requirements and the entire system was subjected to an early application testing involving different groups of end-users. MDTs from participating European regions were involved in requirement elicitation and test formulation, resulting in 57 questions, distributed via an internet platform to 48 test participants (22 MDTs, 26 patients) from three pilot sites. The results indicate a high level of satisfaction with all components. Early testing also provided feedback for technical improvement of the entire system, and the paper points out useful evaluation methods.

A Knowledge-Based Platform for Assessing Potential Adverse Drug Reactions at the Point of Care: User Requirements and Design.

Even though Adverse Drug Reactions (ADRs) constitute a significant public health issue, there is a lack of Information & Communication Technologies (ICT) tools supporting Pharmacovigilance activities at the point of care. In this paper, we present the rationale of a Web-based platform to address this need. The driving user scenario of the proposed platform refers to a clinician who investigates information for a possible ADR as part of a specific patient treatment. The goal is to facilitate this assessment through appropriate tools for searching various relevant data sources, analysing the acquired data, aggregating the obtained evidence, and offering follow-up ADR monitoring over time in a systematic and user-friendly way. In this regard, we describe the adopted user requirements engineering methodology and illustrate the use of Knowledge Engineering (KE) as the platform's main technical paradigm to enable heterogeneous data integration and handle the complexity of the underlying information processing workflow.

User Driven Design: First Step in Involving Healthcare Consumers and Clinicians in Developing a Collaborative Platform to Prevent Cardiovascular Diseases.

To prevent cardiovascular diseases, eHealth solutions may be used as tools, involving health care consumers in the set-up of their prevention plan, a fundamental condition for improving their long-term adherence to the plan. This paper presents the first step in a web platform design aiming to support the co-elaboration by health care consumers and clinicians of personalized prevention plans. Applying a user driven innovation approach, first, a questionnaire and semi-structured interviews were combined to identify clinicians' needs. Then, three focus group sessions with consumers and clinicians were organized to identify their needs, creating the system workflows, its graphical user interface, and its navigation paths, with the best ideas shaped by paper mockups. An interactive mockup was designed including 30 screens (ex. user dashboards, desk for co-elaborating plan). This user driven approach enabled to design not only the technology and its graphical user interface, but also a prevention plan design process.

Computational Advances in Drug Safety: Systematic and Mapping Review of Knowledge Engineering Based Approaches.

Drug Safety (DS) is a domain with significant public health and social impact. Knowledge Engineering (KE) is the Computer Science discipline elaborating on methods and tools for developing "knowledge-intensive" systems, depending on a conceptual "knowledge" schema and some kind of "reasoning" process. The present systematic and mapping review aims to investigate KE-based approaches employed for DS and highlight the introduced added value as well as trends and possible gaps in the domain. Journal articles published between 2006 and 2017 were retrieved from PubMed/MEDLINE and Web of Science® (873 in total) and filtered based on a comprehensive set of inclusion/exclusion criteria. The 80 finally selected articles were reviewed on full-text, while the mapping process relied on a set of concrete criteria (concerning specific KE and DS core activities, special DS topics, employed data sources, reference ontologies/terminologies, and computational methods, etc.). The analysis results are publicly available as online interactive analytics graphs. The review clearly depicted increased use of KE approaches for DS. The collected data illustrate the use of KE for various DS aspects, such as Adverse Drug Event (ADE) information collection, detection, and assessment. Moreover, the quantified analysis of using KE for the respective DS core activities highlighted room for intensifying research on KE for ADE monitoring, prevention and reporting. Finally, the assessed use of the various data sources for DS special topics demonstrated extensive use of dominant data sources for DS surveillance, i.e., Spontaneous Reporting Systems, but also increasing interest in the use of emerging data sources, e.g., observational healthcare databases, biochemical/genetic databases, and social media. Various exemplar applications were identified with promising results, e.g., improvement in Adverse Drug Reaction (ADR) prediction, detection of drug interactions, and novel ADE profiles related with specific mechanisms of action, etc. Nevertheless, since the reviewed studies mostly concerned proof-of-concept implementations, more intense research is required to increase the maturity level that is necessary for KE approaches to reach routine DS practice. In conclusion, we argue that efficiently addressing DS data analytics and management challenges requires the introduction of high-throughput KE-based methods for effective knowledge discovery and management, resulting ultimately, in the establishment of a continuous learning DS system.