Rare diseases in Chile: challenges and recommendations in universal health coverage context

In Chile, a country with 17,5 million inhabitants [12], the overall prevalence of RDs is unknown. Epidemiological information is primarily based on the National Health Survey that does not collect information on RDs. There is data showing that congenital anomalies are the second cause of infant mortality, with many of them presenting in the context of RDs [13].

The Chilean Healthcare System is composed of two sectors, public and private, covering about 95% of the population [14]. The government-run National Health Fund (FONASA) is funded by salary-based mandatory contributions (7%) and taxes. It provides healthcare for approximately 78% of the population, including the rural and urban poor, the lower middle class and the retirees, mainly through the National System of Healthcare Services. The private sector (twelve insurers called ISAPREs) is financed by mandatory and voluntary contributions (on average 10% of salary). ISAPREs cover approximately 14% of the population belonging to the higher income social groups and provide services mainly through private facilities. The remainder of the population is either covered under other plans (e.g., Armed Forces) or has no insurance [15].

Healthcare reform in 2005 introduced a Universal System with Explicit Guarantees in Health (GES). This system assures timely access to quality healthcare services and financial protection for a prioritized set of 80 programs, diseases or health conditions based on prevalence, severity, cost, and impact on quality of life [16]. These include pediatric cancers, breast cancer, chronic heart disorders, HIV/AIDS and diabetes among others. GES also covers treatment for two RDs: cystic fibrosis and hemophilia (Table 1). However, healthcare financing in Chile remains inefficient and inequitable [17, 18], with marked differences in access and health outcomes between the private and public systems [19].

An additional financial protection system for high-cost diagnoses and treatments was recently established, Law 20.850, or Ricarte Soto Law (RSL), which, through general taxes, funds medications, medical devices or nutrition for 29 health conditions including 14 RDs like Gaucher and Fabry disease, multiple sclerosis, epidermolysis bullosa, amyotrophic lateral sclerosis and Huntington disease (Table 1) [20]. Patients with other RDs do not have guaranteed access to diagnosis or treatments [21].

There are 33 practicing clinical geneticists in Chile [25]. This is a third less than the recommended ratio of 0.75 full-time equivalents per 250,000 inhabitants [26]. Since the country lacks formal professional genetic counseling training program, this intervention is primarily provided by clinical geneticists. There are no genetic counseling training programs in Chile, and there is only one professional genetic counselor trained abroad, who focuses mainly on hereditary cancer risk assessment and counseling [27]. This evidences the lack and necessity of these healthcare professionals who play an important role in addressing psychosocial dimensions of RD diagnoses [28]. Chile also faces a shortage of trained and certified laboratory geneticists. Indeed, genetic counseling and laboratory genetics are not recognized as specialties in the Chilean healthcare system.

Regarding molecular diagnosis, over 15 clinical cytogenetic laboratories offer karyotype and fluorescence in situ hybridization (FISH) analysis and only 3 laboratories offer molecular genetic tests such as multiplex ligation-dependent probe amplification (MLPA), microarrays and targeted Sanger sequencing for a limited number of genetic diseases. FONASA partially covers these tests for some genetic RDs (Table 2) [29] but they have a low diagnostic rate for RDs, leaving patients with complex genetic conditions without coverage for adequate testing and consequently without a diagnosis that can inform therapeutic decisions. Even some covered diseases (Table 1) lack of a proper diagnostic approach to molecular testing and genetic counseling. Only one clinical next-generation sequencing (NGS) panel for Rasopathies is available locally, but none for other RDs or complex undiagnosed genetic conditions. Therefore, more comprehensive NGS based genetic tests (e.g. whole-exome sequencing (WES)) are typically sent to international clinical laboratories and paid out-of-pocket by families who can afford them, generating substantial inequalities in access.

Finally, the reduced availability and extremely high prices of orphan drugs constitute another barrier for therapies, and patients are bringing their cases of lack of coverage from insurers to court, which has led to an increasing trend in the judicialization of healthcare services [30].

In Chile, both GES and RSL consider several criteria in their prioritization processes to decide which health conditions and interventions each program will cover, according to criteria established by law [20, 22]. GES broadly includes the burden of disease, budget impact, social preferences, and cost-effectiveness evaluations, while RSL uses the evidence-to-decision methodology, which considers the cost of diagnoses or treatments (must exceed a threshold defined by law) and the rating evidence of interventions using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach [31]. The latter may entail drawbacks for RDs, often lacking high-quality evidence and might also affect the cost-effectiveness analyses of treatments for these disorders [32]. Furthermore, the high prices of these treatments impact the cost of such analyses [9, 33‐35], which justifies the need for a higher willingness to pay for RD interventions [34]. Unfortunately, traditional economic evaluation methods do not necessarily capture a complete notion of the social value and societal preferences, leaving RD patients without coverage and proper healthcare. All these issues regarding prioritization criteria, added to the minimal amount of resources allocated to LRS constitute significant downside for access to diagnosis and treatments, especially when considering the substantial economic impact they pose for patients, families, communities, the healthcare system, and society [9].

Other Latin-American countries, such as Argentina, Colombia, and Peru have specific laws for RDs that recognize them as having a special status or be national interest or that guarantee access to treatment or social protection (Fig. 1) [2]. In Chile, although the legislators have recognized a minimum level of access to the essential material components of the constitutional right to health through the GES law [36], RDs were not considered. Therefore, the coverage of RDs was later complemented with another national program oriented toward high-cost drugs through the RSL, which is not specifically focused on RDs either [37]. RDs were left without their own legal structure to guarantee financial coverage and must compete with other common high-cost diseases that more easily satisfy the prioritization criteria mentioned earlier.

Patients and patient advocacy groups play an important role in the establishment and adoption of healthcare policies for RDs and orphan drugs. Patient groups can provide prevalence data, estimates on the uptake of treatments, and valuable insights into what they consider to be important regarding quality of life [38]. They can also indicate barriers in drug access and treatments for both patients and caregivers, which are crucial for studies on the proper use of healthcare resources [39]. Associations from Latin-American countries have been involved in awareness campaigns, providing legal advice, and informing patients about referral centers if the country has them (for example, the Federation of Uncommon Diseases Argentina). Also, Latin America RDs associations lead the formation of work teams with scientists, clinicians and politicians for law development, such as the screening of rare metabolic diseases in newborns (Federation of Rare Diseases Colombia). In Chile, the Federation for Rare Diseases (FECHER) and the Federation of Uncommon Diseases Chile (FENPOF) are the main patient advocacy groups, composed of patients and their relatives/caregivers, healthcare professionals, and citizens who understand these issues. FECHER actively contributed to the development of the RSL and currently aims to be the official channel for all patients, supporting and defending their rights in health committees where regulations or bills related to RDs are discussed. FENPOF is an emerging organization addressing collaborative work with leaders of RD groups seeking treatment accessibility and legislators. Both organizations aim at increasing awareness and communication about RD to the general public and policymakers in the Ministry of Health and Congress for the development of RD regulations. They also establish alliances with Chilean healthcare providers, scientific research centers, and universities to promote RD research.

In Chile, biomedical research occurs almost exclusively in universities and is funded primarily by competitive peer-reviewed grants awarded by the National Research and Technology Funding Program (CONICYT), according to the scientific merit of each proposal. Investigator-driven collaborations with foreign research groups also play an important role. Nevertheless, neither special support nor national or private initiatives have arisen to promote research or clinical trials on specific RDs, and RD projects must compete with other, more prevalent conditions that are often more recognized by the community. In a retrospective analysis of CONICYT funds granted from 1999 to 2017, only 37 of them focused on different aspects of RDs, out of 11,588; that is only 0.32% of government-funded projects. Also, only few research groups are actively working in certain rare diseases in Chile (e.g., Epidermolysis bullosa, lysosomal storage diseases, 22q11.2 microdeletion syndromes [40‐42]). Two other research groups, namely Chile Genómico [43] and 1000 Genomas Chile [44], are focused on ancestry and genomic variation. Regarding clinical trials, the current state of RSL contains specific provisions intended to protect the enrolled patients against any unwanted effects or unforeseen accidents. RSL establishes civil liability insurance and the presumption that any harm to the health of a patient participating in a clinical trial occurred due to the research, which has significantly increased costs and barriers to conducting a trial in Chile [45]. All of the above indicates that the limited research in RDs, sustained by the efforts of a few research groups, has not been supported by a scientific policy that prioritizes research with societal impact. The newly established Ministry of Science, Technology, Knowledge, and Innovation [46], one of whose functions is to coordinate the stakeholders of the national science system, should play a key role when discussing public policies for RDs.