Round tables

Abstract

Antoni Vallano Ferraz

Medicines Department, Catalan Healthcare Service, Barcelona, Spain; Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain; Healthcare Management of Hospitals, Catalan Institute of Health, Barcelona, Spain

The evolving landscape of drug authorization processes in the European Union (EU), with several actions to accelerate regulatory process and the access to innovative medicines, has been a response to the pressing need for increased access to innovative medicines, particularly for rare diseases, and unmet medical conditions. While this flexibility has undoubtedly expedited the availability of potentially life-saving treatments, based more in expectative that in robust evidence, it has concurrently ushered in a host of challenges that warrant careful consideration.

One of the foremost concerns pertains to the level of uncertainty tolerated during the approval of new medications. Notably, the approval of numerous oncological drugs based on surrogate endpoints, without concrete evidence of meaningful improvements in overall survival or quality of life, underscores the delicate balance between expediency and robust evidence. Furthermore, the emergence of additional toxicities associated with many of these approved drugs raises pertinent questions about the net clinical benefit conferred by these treatments.

The adoption of methodologies in clinical trials that permit early termination in response to favourable interim analyses introduces a layer of complexity, as premature cessation can inadvertently overestimate treatment effects, especially in the absence of rigorous blinding or controlled designs. This underscores the imperative for stringent scrutiny of trial data to ensure the reliability and generalizability of findings.

In parallel, drugs catering to niche patient populations, such as orphan medicinal products (OMPs) and advanced therapy medicinal products (ATMPs), often grapple with methodological limitations in clinical trials, resulting in approvals that are underpinned by scant evidence of efficacy and safety. This poses a considerable challenge for healthcare providers tasked with the management of the intricacies of treatment decisions in such contexts.

The pricing and reimbursement (P&R) landscape, too, is fraught with complexities, as stakeholders endeavour to strike a delicate balance between ensuring equitable access to innovative therapies and safeguarding the fiscal sustainability of healthcare systems. Manufacturers' propensity to overestimate the cost-effectiveness of their products often leads to disparate pricing and reimbursement decisions across jurisdictions, exacerbating disparities in patient access.

Addressing these multifaceted challenges necessitates an approach based on multiple factors. Enhancing the scientific rigour of clinical trials through robust methodologies and transparent reporting practices is paramount. Moreover, the implementation of post-market surveillance mechanisms to capture real-world outcomes and inform decision-making represents a critical linchpin in navigating clinical uncertainties.

Equally imperative is the need for a transparent, evidence-driven framework for pricing and reimbursement decisions that balances the imperatives of access, affordability and sustainability. This may entail the adoption of innovative pricing models, such as value-based pricing or risk-sharing agreements, to align reimbursement with the demonstrated clinical value of therapies while mitigating uncertainties.

In summary, while several actions developed by European Medicines Agency aim to accelerate regulatory process and access to innovative medicines in the EU, which has undoubtedly expanded access to innovative therapies, it has also engendered a concomitant rise in clinical and economic uncertainties. Effectively managing these complexities demands a concerted effort to enhance the quality of evidence for medicine approvals, foster transparency and collaboration across stakeholder groups and implement adaptive pricing and reimbursement mechanisms based on fair pricing that more accurately estimate the real value of medicines.

Reference

Vallano, A, Pontes, C, Agustí, A. The challenges of access to innovative medicines with limited evidence in the European Union. Front Pharmacol 2023; 14:1215431. Accessed May 9, 2024. doi:10.3389/fphar.2023.1215431/.

Federico Martinón-Torres ([email protected] [email protected])

Translational Paediatrics and Infectious Diseases Section, Paediatrics Department, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain; Genetics, Vaccines, and Infections Research Group (GENVIP), Healthcare Research Institute of Santiago de Compostela, University of Santiago de Compostela, Santiago de Compostela, Spain; CIBER of Respiratory Diseases (CIBERES), Instituto de Salud Carlos III, Madrid, Spain

The paediatric population has been, until the past decade, the most excluded group from clinical research due to their vulnerability, which kept them away from most medical advances. For years, children were considered ‘small adults’ in the medical field, so few therapeutic strategies were specifically designed for them. In most cases, the dosage of treatments was calculated directly by extrapolation from the data available for the adult population, and formulations were not adapted to the most suitable pharmaceutical form for paediatric age. Compassionate or off-label use has been the norm for most of the newest drugs when used in children.

Paediatric clinical research is the tool that ensures that children are not exposed to safety issues due to very high doses or to efficacy issues due to insufficient doses. The entry into force of the European regulation governing research with medicines for paediatric use brought about a paradigm shift in pediatric clinical research, assuming that the only way to ensure the protection of the paediatric population is to have medicines previously studied and adapted to the needs of children. Since then, there has been a considerable increase in the number of paediatric investigation plans (PIPs) implemented. Despite the progress made in this regard, efforts have been insufficient, and only 30% of the medicines marketed in Europe include paediatric authorization, and less than 50% of the drugs authorized for children have been adequately tested in the paediatric population. This scenario highlights the numerous deficiencies and shortcomings that still exist and makes us reflect on the need to invest more time and resources to carry out safe and high-quality paediatric clinical research. The changes proposed in the new regulations aim to promote access to medicines quickly and equitably among the entire population, so paediatric patients will be direct beneficiaries of this new regulatory framework since, additionally, they are one of the populations with the highest number of unmet medical needs.

The regulatory framework, in turn, should not hinder the agility and competitiveness of the process and should adapt to clinical-epidemiological contexts and new forms of clinical research: adaptive designs, in vitro trials, challenge trials or pragmatic trials, among other. We have the example of vaccine research and how, during the recent pandemic, the regulatory framework allowed the rapid development of safe and effective vaccines, considerably reducing the time needed for their implementation. It is also necessary to promote solutions to the logistical challenges of conducting paediatric research, ensuring that trials reach where the patient is and vice versa. An example in this regard is rare diseases, which, according to data from the Spanish Federation of Rare Diseases, affect between 6% and 8% of the world's population, being mostly chronic and degenerative diseases, severe and disabling in up to 65% of cases, with onset before the age of 2 in two out of three cases. The creation of specialized networks such as the Spanish Network of Paediatric Clinical Trials (RECLIP) or the European Network of Paediatric Clinical Trials (Conect-4-children) aims to minimize these barriers, allowing the location of patients and appropriate centres intime and form and adapting study designs to real needs, considering the perspectives of children and their families.

Paediatric medicine and clinical research have undergone a complex and exciting revolution in recent years: New technologies, personalized medicine and active patient involvement have changed the traditional landscape, and regulation must move in that direction swiftly, without losing sight of the need to ensure the highest quality standards and patient safety. More drugs, and faster, for the paediatric population, but with all guarantees.

Luís León Mateos

Medic Oncology Service, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain

Cancer is the leading cause of death in advanced countries and a real challenge for contemporary societies. A fundamental pillar in the treatment of both solid and haematological tumours are systemic therapies, whether chemotherapy, hormone therapy, immunotherapy, tyrosine kinase inhibitors or cell therapy. In order to improve survival results in oncology patients, early access to the innovation that is being developed with new clinical trials is necessary. In fact, one of the main complaints of scientific societies and patient associations is the long approval period for many oncology drugs in our country, which clearly exceeds the averages of other countries in our environment.

In Spain, 40% of all clinical trials are carried out in oncology, which in itself is an advantage as it allows patients to have access to drugs that are not yet commercially available. In addition, the possibility of using drugs through early access programmes also offers new opportunities for patients with advanced or aggressive cancers for which existing treatment options are limited.

In the case of cancer patients, the relaxation of the drug authorization process with the new European regulations may offer several advantages. Firstly, shortening the drug evaluation processes, avoiding the repetition of European and national technical reports, could allow faster access to new drugs or new indications for existing treatments. Another positive aspect of the new regulation is to grant more opportunities for patient participation and collaboration in the drug authorization process.

However, the new regulation introduces changes in the exploitation of patent times, a point of concern for the pharmaceutical industry, which could have the undesired effect of displacing the commitment to clinical trials in our country and in the rest of Europe to other more attractive environments. Another challenge we face is to adapt the evaluation processes to a scenario of change: Most of the new drugs in oncology will be advanced cell therapies, with study designs that differ from the classic ones in oncology, smaller sample sizes, and often without the identification of biomarkers that allow predicting the benefit of the therapy.

All these factors will have to be considered in the development and implementation of the new regulations in order to achieve the highest possible quality in the response to the needs of professionals and patients, with the highest ethical standards and guaranteed accessibility to new drugs that can have an impact on survival and quality of life.

Arturo González Quintela

Internal Medicine Service, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain

Polypharmacy is largely an indirect consequence of population ageing and the associated increase in the prevalence of chronic diseases. Polypharmacy is becoming a challenge for healthcare systems, especially when it involves potentially inappropriate medications (Payne, 2016).

The prevalence of polypharmacy in the elderly is very high. With the limitations of the definition of polypharmacy (especially when based on simple numerical criteria that may be insufficient), recent studies have shown that more than half of older people were prescribed five or more active substances (a common criterion for polypharmacy) in four of the six European countries studied (Belgium, France, Germany, the United Kingdom, Italy and Spain, in a sample with an average age of 76 years) (Bennie et al., 2024). In many of these countries, the prevalence of having 10 or more prescribed drugs exceeded 10% in this population segment. The figures are similar in other European countries (Morin et al., 2016). In specific studies in Spain, the prevalence of polypharmacy using the same criteria has been estimated at almost a quarter of the total population of people over 65 years of age, the prevalence being higher in women than in men (Cebrino and Portero, 2023). The latter may be influenced by the greater longevity of women. In Spain, the drugs with the most common potentially inappropriate indication in this age group were, in ascending order, antipsychotics, opioids, benzodiazepines and proton pump inhibitors (PPIs) (Bennie et al., 2024). Therefore, the problems inherent in polypharmacy itself are compounded by the fact that some of the prescribed drugs have specific or common side effects in this population. The type of drugs with potentially inappropriate indications varies considerably between European countries (Bennie et al., 2024). In Spain, among older people, the drugs included in polypharmacy are different in women (with a greater frequency of analgesics and anxiolytics) and in men (with a greater frequency of antihypertensives, PPIs and statins) (Cebrino and Portero, 2023).

The evolution of the prevalence of polypharmacy in the elderly in Spain has remained relatively stable in the last 10 years, with a slight decrease in recent times (Cebrino and Portero, 2023), as in other countries. Future studies will be necessary to assess whether the COVID-19 pandemic played a role in this fact. In any case, the stabilization or slight decrease only reflects the inadequacy of the measures taken to date to minimize the frequent public health problem of polypharmacy in elderly people with chronic diseases.

References

Bennie, M, Santa-Ana-Tellez, Y., Galistiani, G.F., Trehony, J., Despres, J., Jouaville, L.S., Poluzzi, E., Morin, L., Schubert, I., MacBride-Stewart, S., Elseviers, M., Nasuti, P., Taxis, K. (2024). The prevalence of polypharmacy in older Europeans: a multi-national database study of general practitioner prescribing. Br J Clin Pharmacol 2024 (in press). DOI: 10.1111/bcp.16113.

Cebrino, J, Portero de la Cruz, S. (2023). Polypharmacy and associated factors: a gender perspective in the elderly Spanish population (2011-2020). Front Pharmacol 14:1189644. DOI: 10.3389/fphar.2023.1189644.

Morin, L, Johnell, K., Laroche, M.L., Fastbom, J., Wastesson, J.W. (2018). The epidemiology of polypharmacy in older adults: register-based prospective cohort study. Clin Epidemiol 10: 289–298. DOI: 10.2147/CLEP.S153458.

Payne, RA. (2016). The epidemiology of polypharmacy. Clin Med (Lond); 16: 465–469, 5. DOI: 10.7861/clinmedicine.16-5-465.

Rosendo Bugarín González

Monforte de Lemos Health Center, SERGAS

The progressive population ageing in our country, and those around us, is associated with an increase in morbidity and chronicity. This leads to a greater number of medication prescriptions and, consequently, a greater probability of adverse events related to the use of these substances. Furthermore, older people have a series of differential characteristics, compared to other age groups, that make them more likely to suffer a problem related to medication.

The higher the level of polypharmacy, the greater the probability of suffering adverse events and drug interactions, the greater the probability of encountering unnecessary medications, and the greater the probability of suffering therapeutic adherence. Thus, polypharmacy can compromise both therapeutic efficacy and patient safety.

Additionally, it has been established that polypharmacy and the use of inappropriate medications is related to various social factors such as living alone, in rural areas and having a low educational and socio-economic level. Medicine self-administration errors at home are frequent and normally caused by incorrect doses or intervals, confusion between medications, duplications, forgetfulness and lack of compliance.

For all these reasons, it is essential to adopt multidisciplinary strategies that aim to promote the effective and safe use of medications, both in the prevention and early detection of adverse effects and in guaranteeing adequacy and improving therapeutic adherence. As a result, the Galician Health Service (SERGAS) has developed several complementary programmes that review the medication during hospital discharge in primary care in coordination with hospital care, promote safe practices in chronic use medications and improve therapeutic adherence through the preparation and delivery of personalized dosing systems (1).

At the beginning of the interventions, it was observed that in the Galician community, there were around 9500 patients with more than 15 medications, 34 300 with more than 12 and 74 500 with more than 10 chronically prescribed medications. The demographic pattern of these patients corresponded mainly to women (60%) and patients over 70 years of age (70%), highlighting 995 patients with ages between 91 and 103 years. After 6 months of implementing these multidisciplinary programmes and a subsequent implementation time until reaching 100% of the population, a reduction of 47%, 32.7% and 22% was observed in the number of patients with more than 15, more than 12 and more than 10 chronically prescribed drugs, respectively. In 6% of cases, at least one START criterion was detected, and in 27%, at least one STOPP criterion was detected (2).

Moreover, it was evident that the number of patients with potential safety problems reached to 59 668 in 2017 compared to 29 807 in 2023, which means a reduction of 50%.

In conclusion, the implementation of multidisciplinary medication review processes results in an improvement in the quality of care by articulating measures that allow adequate pharmacotherapeutic monitoring for polymedicated chronic patients in Galicia. Thus, the next steps would be to measure the impact of the implementation such multidisciplinary programmes on morbidity and mortality.

1. Xunta de Galicia. Consellería de Sanidade. https://www.sergas.es/Asistencia-sanitaria/Programa-de-mellora-da-calidade-da-atencion-ao-paciente-cronico-polimedicado?idioma=es. [Fecha de acceso: 01/06/2024].

2. Reboredo-García S, González-Criado C, Casal-Llorente C. Implantación de un programa de polimedicados en el marco de la Estrategia Gallega de Atención Integral a la Cronicidad. Aten Primaria2014;46(3):33–40, DOI: 10.1016/S0212-6567(14)70063-0.

Miguel Angel Maciá Martínez

Coordinator of the Pharmacoepidemiologic Research in Public Health Systems Database, Head of the Pharmacoepidemiology Area, Pharmacoepidemiology and Pharmacovigilance Division, Spanish Agency of Medicines and Medical Devices

The Pharmacoepidemiologic Research in Public Health Systems Database (BIFAP) is a programme by the Spanish Agency of Medicines and Medical Devices (AEMPS). Initially created to support pharmacovigilance activities of the AEMPS, since 2015, it has been accessible to independent researchers in the public sector. BIFAP is an innovative example of the secondary use of data generated within the National Health System (SNS) for research purposes.

BIFAP is fuelled by electronic health records (EHR) provided by the participating autonomous communities (CCAA) through collaboration agreements and an advisory committee. A scientific committee ensures the scientific feasibility and quality of each research project. To date, 12 CCAA have already signed agreements with the AEMPS.

BIFAP includes records of 22 million patients attended in primary care centres across CCAA, including medications and hospital discharge diagnoses, with an average follow-up of over 10 years per patient.

A public governance document on data access outlines the data flow, involved parties and technologies, as well as procedures to comply with data protection regulations and the commitments researchers must adhere to. The Service Web offers tools to request and conduct studies. The data, pseudonymized and standardized, are housed in a single data space, available to public sector researchers in pharmacoepidemiology and public health (http://www.bifap.org/learn-more?lang=en).

Technological tools within the broad concept of artificial intelligence (AI) are being explored to address various issues related to the analysis of big data from EHR like those in BIFAP.

One of the primary areas where AI can assist is the standardization of diagnosis/clinical episodes recorded by primary care physicians (GPs). In BIFAP, these data should be mapped to internationally interoperable common data models (CDM), specifically OMOP (https://www.ohdsi.org/data-standardization/). This is necessary for participation in collaborative networks like the DARWIN EU programme (https://www.darwin-eu.org/) established by the European medicines regulatory network (https://www.ema.europa.eu/en/about-us/how-we-work/european-medicines-regulatory-network). Most of these diagnoses/clinical episodes are recorded by GPs using locally modified ICPC-2 terminologies and free text. To make this crucial data interoperable, we map the text descriptors of primary care diagnoses recorded by GPs in BIFAP's database to SNOMED-CT codes.

Although a large percentage of the diagnoses in the database are straightforwardly mapped, around 10%–20% of the text descriptors are not easily converted into SNOMED codes. Since this percentage is unevenly distributed across the spectrum of medical conditions, ensuring inclusiveness at the study variable level requires the completion of this process before the study begins, as detailed in the study protocol.

To manage this normalization process to SNOMED CT, a proprietary tool has been developed, providing a framework to explore and validate techniques for maintaining the consistency and quality of standardized clinical data, including algorithms that utilize natural language processing (NLP) technologies.

NLP tools are also useful for extracting, summarizing and classifying clinical records registered in free text by GPs or copied from hospitalization reports available to GPs. The BIFAP team is currently exploring various human-supervised procedures integrating NLP and other AI techniques.

Finally, NLP is being explored to ensure the complete anonymization of unstructured texts. This would allow the protection of data and privacy conditions for pharmacoepidemiology researchers, providing access to a broader spectrum of individual-level health data within a secure processing environment.

In conclusion, pharmacoepidemiology research using real-world data is a relevant use case for AI to expand the scope of research, increase efficiency, interoperability and quality.

María J. Carreira

Centro Singular de Investigación en Tecnoloxías Intelixentes (CiTIUS), Universidade de Santiago de Compostela, Fundación Instituto de Investigación Sanitaria de Santiago de Compostela (FIDIS)

In recent years, artificial intelligence (AI) has become an integral part of our lives, particularly in the social sphere. However, we are now faced with the challenge of assessing its implementation in high-risk scenarios, such as healthcare. As with any disruptive technology that has transformed our lives, we must capitalize on the opportunities offered by AI to enhance our healthcare system. This encompasses personalization in the delivery of care, optimizing hospital efficiency and improving access to healthcare through decision-making tools. Another aspect to consider is the vast quantity of health data currently available. This includes medical records, DNA data, images and data from health apps on mobile phones. It is therefore necessary to develop systems that can handle this vast amount of data securely and identify the information that is useful and critical to our health.

There remains a significant disparity between the utilization of AI at the individual level by the entire population and its comprehensive deployment in a high-risk context such as healthcare. Although there is a multitude of successful research in its application, there is a significant gap between the proposals of researchers and their implementation in health systems. A study funded by the European Union [1] involved surveys with key players in the healthcare ecosystem, including healthcare professionals, managers and advisors of start-up companies. One of the principal conclusions of this report is that the integration of AI into the healthcare system will not result in the replacement of healthcare professionals. Instead, it will enhance their capabilities to impact patients and healthcare systems. This will be made possible by the introduction of AI into the healthcare system, which will enable healthcare professionals to focus on patients, spending less time on administrative tasks and more time on direct care delivery. It is anticipated that certain activities will become more efficient and/or produce better outcomes. It is also expected that intelligent machines will assume responsibility for more physical, repetitive and basic cognitive tasks. Furthermore, it is assumed that the average patient visiting a hospital will have more complex needs. Finally, it is assumed that the acceptance and integration of new professional profiles with expertise in AI and data science in healthcare will occur. The second part of the report examines the necessary changes to facilitate the introduction and scale-up of AI in healthcare. It identifies eight key action points, including the need for collaboration to deliver quality AI in healthcare, rethinking education and skills, strengthening data quality, governance, security and interoperability, managing change, investing in new talent and creating new roles, working at scale, regulation, policy development and accountability and risk management and funding.

This is consistent with the report on AI and health by the Office of Science and Technology of the Spanish Congress of Deputies in November 2022 [2], which identifies the challenges to achieving trusted AI in healthcare systems. These include the development of quality and unbiased databases, the development of reliable and secure AI systems, the establishment of clear regulatory frameworks, the explainability and reliability of systems and the professional transformation of people working in healthcare systems.

In conclusion, although preliminary steps have been taken to integrate AI into healthcare systems, it is imperative that governments assume a leadership role to ensure that this implementation is safe, reliable and accessible to the entire population. Furthermore, there is a pressing need for both patients using the technology and medical students in universities to possess the requisite literacy in order to navigate the complexities of AI-driven healthcare.

References

[1] EIT Health and McKinsey & Company. Transforming healthcare with AI. The impact on the workforce and organisations. 2020. https://eithealth.eu/think-tank-topic/artificial-intelligence-in-healthcare/ (consultado 12-june-2024).

[2] Oficina de Ciencia y Tecnología del Congreso de los Diputados. Informe C: Inteligencia artificial y salud. 2022. DOI:10.57952/tcsx-b678.