Assessment of the current status of personalized medicine in the “Centro” Region

Comprehensive insights were gained into the current status of 3PM in the “Centro” Region, covering the following key aspects: human and technological resources, research and clinical activities, genome-scale sequencing capabilities, and academic programs offered by universities in the fields of human genetics, bioinformatics, statistics, and advanced computing.

By identifying the resources, competencies, and needs related to 3PM within the “Centro,” a holistic perspective has been developed, which has made it possible to formulate a regional strategy in line with the objectives and aspirations of the Region.

Definition of a regional strategy to strengthen the implementation of 3PM

Administrators responsible for implementing a 3PM program must bear in mind that this process requires high-quality and real-time information on four critical points: health needs of society, financial resources, operation and infrastructure, and clinical outcomes [13].

One of the outputs from this work was a detailed 240-page document presenting a strategy for the “Centro,” articulated with the National and EU strategies for 3PM. This document was developed through reviewing the literature, from scientific articles to policy documents and other strategic plans, listening to diverse stakeholders in focus groups, performing an inventory of existing capacities, and using the tools of strategic analysis (PESTEL, SWOT, idea generation, and selection). The process and the strategy defined for the “Centro” can guide future efforts to develop strategies for 3PM in other regions.

The following points were considered strategic objectives for the definition of a regional strategy aimed at implementing 3PM: improve the population’s health, reinforce citizens’ participation in their own healthcare, promote social cohesion, protect personal information, ensure financial sustainability, promote value creation, and differentiate the “Centro” Region.

A major distinction was considered between capacitation for genome sequencing, focusing on equipment, and capacitation for interpretation of genomic data, focusing on qualified human resources. Interpretation of genomic data was considered the core competence to be developed in the “Centro.” In addition, the potential for innovation in developing vaccines and treatments based on genome research was highlighted, building on some promising examples in the Region.

Moreover, considering the size of the “Centro” Region in the context of the country and the world, much of the discussion was centered on identifying specific areas in which the Region can be the most relevant. The areas of oncology, neurodegenerative diseases, diabetes, cardiovascular diseases, and eye diseases were identified as very relevant, considering both the existing potential and the population’s needs. Some rare diseases were also identified as a niche to be exploited, based on successful examples in the Region.

Strategic axes and strategic initiatives (Table 2) have been organized in terms of networks, data, equipment and infrastructures, professionals, citizens, and research.

Table 2 Strategic axes and objectives for 3PM development in the “Centro” Region. This table summarizes the formulated strategy for 3PM development in the “Centro” Region, presenting the axes that will guide strategy implementation and the main objectives in each of them

Implementing such a strategy will require resources. Thus, policy makers must be aware of their ability to pay, having in mind distributive justice and proportionality, to accomplish accessibility, affordability, and system readiness [13]. More generally, decision makers and health stakeholders wish to know if economic value is provided. Although the economic value of 3PM is still difficult to quantify, a few studies already indicate advantages, compared to more traditional approaches in medicine [14,15,16]. By reducing the waste and costs associated with ineffective treatments and their side effects, 3PM also promotes the rational and efficient use of available resources and has the potential to relieve pressure on national health services [17]. For this reason, the strategy document devoted a chapter to provide an overview of existing evidence, anticipating the benefits that could be expected.

A systematic review found robust evidence for the cost-effectiveness of genotyping before treatment with several common drugs [18]. In the majority of studies, the increased costs of genotyping were more than offset by the positive effects on patients’ life expectancy and quality of life [18], with the reduction of the risk of adverse drug reactions being a key benefit [19]. Nevertheless, some studies (e.g., [19, 20]) show that the cost-effectiveness of implementing pharmacogenomics-guided drug use varies according to the diseases and types of drugs evaluated, which supports our choice of highlighting specific areas in the strategy document. Other studies mentioned cost-effectiveness evidence of using targeted massive parallel sequencing (MPS) as routine screening for allelic variants associated with maturity onset diabetes of the young [21] and the cost-effectiveness of an anticipatory intervention for asthmatics based on a relevant genetic abnormality [22]. Moreover, it is also noted that 3PM is an emerging paradigm in cancer treatment, aiming to tailor cancer therapy to the individual patient and treatment scenario, although cost-effectiveness analyses face several challenges and remain unclear [23].

Training personnel in genomics

Sequencing parts of the genome, the exome or all the whole of an individual genome, is becoming an affordable method to attain significant knowledge regarding rare and common genetic variations, especially those that are functionally significant [24]. Therefore, being proficient in sequencing is crucial to establish expertise in genomics. The training was developed using the laboratory from the university with specific expertise, namely, in cancer, respiratory diseases, and hereditary forms of diabetes.

Deep phenotyping plays a crucial role in cohort stratification for population-based studies, like genome-wide association studies (GWAS) and polygenic risk scores (PRS). This approach significantly improves the predictability of models that solely rely on genetic information.

Training in genomic studies is aimed at ensuring the acquisition of technical skills. Effective training is essential in diagnosis, therapy, and research areas related to 3PM to enable customization of treatment algorithms according to individual patient profiles. Patients with allelic variants that are directly targetable may gain benefits from proven or novel therapies which could enhance their survival and quality of life. Main application fields are stratification of cancer situations, characterization of genetic diseases and pharmacogenomics. By reducing the time required for diagnosis and increasing the accuracy of identifying the molecular mechanism, genomic research facilitates prescribing the most suitable treatment, while also enhancing cost-effectiveness of patient treatments. Additionally, genomic research can assist physicians in predicting a patient's functional status prior to disease onset, or before irreversible conditions emerge, and thus promoting and improving the health of the population. This enhances 3PM by enabling the prioritization of preventative measures and methods of treatment [25].

Good practices handbook on genomic studies

The writing of a good practices handbook on genomic studies was based on the following assumptions [26,27,28]:

Next-generation sequencing (NGS) has revolutionized our ability to decode genome-scale DNA information, ushering rapid advancements in both fundamental research and clinical applications

The adoption of NGS has compelled laboratories to embrace greater complexity in their workflows, accompanied by an increased demand for sophisticated bioinformatics analysis

Although ongoing advances in technology and equipment have gradually reduced the cost of NGS, it still remains a relatively expensive technology, limiting its accessibility to a few laboratories

The effectiveness of NGS protocols hinges heavily on precise sample preparation and meticulous data analysis. To optimize cost-efficiency and time savings, it is imperative to provide comprehensive training to all professionals involved and adhere to best practices, techniques, and methodologies

This handbook was entitled “Sequenciação de DNA—NGS” and published as an open access publication in Portuguese [29].

Good practices handbook on ethical and legal issues of genetic information

A good practice handbook was conceived as a guide dedicated to ethical and legal concerns generated by the rapid advances of health and healthcare in the framework of 3PM utilizing genomic tools. High quality of ethical standards is a prerequisite for successful implementation of 3PM in healthcare systems [7]. The handbook, based on national and international legislation, produced ethical thinking aimed at health professionals. As many of the challenges arising from this new paradigm of medicine and healthcare provision do not find neither sufficiently clear answers at the regulatory level, nor established ethical thinking, the handbook also presents new thinking and proposals on ethical and legal challenges generated by 3PM.

The handbook addresses issues in the fields of biobanks and DNA profile databases; conflicting interests between family members regarding access to genetic information and the duty of secrecy; automated decision systems; genomic-based digital health and medicine; impacts of personalized medicine on public health, social justice, and personal discrimination on the grounds of genetic heritage; the role of EU as a driver of personalized medicine; and implications of personalized medicine in health professions. The handbook was entitled “Medicina Personalizada de Base Genómica, Boas Práticas, Ética e Direito” and published as an open access publication in Portuguese [30].

Biolaw, ethics, and biobanks in the framework of 3PM utilizing genomic tools

Using individual’s genomic information in disease prevention, diagnosis, and personalized treatment requires physicians to know more than simple genetic bases to develop genetic rationales underlying an adequate selection of genetic or genomic testing, interpretation of test results, and clinical decision. That implies specific education, skills and experience, and mastery of the “state of the art,” this is understood as the generally accepted clinical practice.

Using genomic information has particular implications for healthcare professions [31]. For this reason, medical genetics services should be installed in hospitals and healthcare institutions that must be aware of the increased responsibility of physicians dealing with genetic information, namely, in the field of genetic counseling. Adequate training of health professionals must be ensured.

Relevant aspects concerning the process of introducing genomic studies in the field of public health should be considered [32,33,34]. The process must be progressive and cautious, always ensuring that all decisions are taken based on scientific evidence and minimizing any threats and risks to the human and fundamental rights of citizens. It is necessary to promote health and genomic literacy, to empower citizens to make truly informed decisions regarding their health status, with clear advantages in terms of public health. Despite the aspiration for the broadest possible introduction of 3PM into the National Health Service, special care is needed to ensure equitable and non-discriminatory access for all citizens.

In 3PM, the physician–patient relationship is often solely guided by obtaining and knowing the diagnosis, with the transmission of genetic information about diagnosis playing the main role. Additionally, ethical concerns are overwhelming.

Physicians failing to follow the “state of the art” can fall under legal liability and be sued due to negligence or personal injury. However, evidence based on genetic/genomic information is, frequently, insufficient to support the definition of a general accepted clinical practice or a standard to provide physicians guidance [31].

In order to avoid any liability for possible diagnostic errors, two issues are paramount. One is the provision of reinforced informational duties, which are the basis for obtaining duly informed consent, especially regarding the lack of immediate therapeutic benefit. Another one is to comply with the “state of the art” when making a diagnosis, considering any and all obvious symptoms and recording a well-made and detailed analysis of all tests, procedures, and resources on available devices and instruments [35, 36].

Besides the production of a good practices handbook on ethical and legal concerns of genetic information, the biolaw team was still involved in the preparation of proposals for legislative changes at national and European level, in the development of adequate procedures to obtaining informed consents; in the analysis of ethical, legal, and social aspects of personalized medicine; and in initiatives dedicated to health literacy promotion and to empowering patients organizations.

In the field of biobanks [37], the biolaw team defined the legal regime that establishes the conditions for treatment of biological samples of human origin (from collection, processing, analysis, availability and use, storage, and destruction) for the purposes of fundamental, applied, or translational scientific research; established that a financing guarantee should exist to avoid compromising the essential ethical and scientific exemption of structures dedicated to biobanking activities for scientific research purposes; and established that technical measures should ensure the safety and quality of procedures, by monitoring compliance with them.

Concerning automated decision systems in 3PM, the biolaw team identified as essential [38, 39]: to pay attention to basic principles of General Data Protection Regulation; the indispensability of subjective analysis of patient’s condition and human supervision, action, and recommendation of the predictions achieved by automated systems; and an urgent social debate, mainly involving people working within the health system.