Clinical research in rare diseases in Brazil: challenges and opportunities

Abstract

This article provides a concise overview of the clinical research landscape concerning Rare Diseases in Brazil. Rare Diseases, affecting a small portion of the population, present a substantial public health concern. Estimates suggest that between 7 to 12 million Brazilians may be affected by these conditions. Despite incomplete epidemiological data on Rare Diseases in Brazil, collaborative efforts among various institutions are underway to address this gap. The Brazilian Policy of Comprehensive Care for People with Rare Diseases was launched in 2014 aiming to enhance diagnosis and follow-up care, thereby facilitating recruitment for clinical trials. The approval process for clinical studies in Brazil involves rigorous ethical evaluation by CEPs—Comitês de Ética em Pesquisa (Research Ethics Committees) and CONEP—Comissão Nacional de Ética em Pesquisa (National Commission on Ethics in Research), along with regulatory assessment by Anvisa—Agência Nacional de Vigilância Sanitária (the Brazilian Health Regulatory Agency). While timelines for approval can be lengthy, recent regulatory changes are streamlining the process. Despite challenges, conducting clinical research on Rare Diseases in Brazil offers unique opportunities for large, inclusive and diverse patient populations. The evolving regulatory landscape and collaborative initiatives hold promise for accelerating clinical trial participation and advancing therapeutic options for Rare Diseases, consequently improving patient outcomes and quality of life.

Introduction

Brazil is a country with great potential for the development of clinical research, given its large population and ethnic and racial diversity. When considering Rare Diseases, this potential needs to be especially taken into account. Although the epidemiology of Rare Diseases in Brazil is not yet completely known, studies are already being developed with the collaboration of numerous institutions to change this reality (Félix et al. 2022). Additionally, the Brazilian Policy of Comprehensive Care for People with Rare Diseases was launched in 2014 aiming to increase access for people with Rare Diseases to diagnosis and appropriate follow-up in reference centers, enhancing the recruitment capacity for clinical trials. Therefore, it is important for researchers, sponsors, patient advocacy groups, and other stakeholders involved in developing new therapeutic alternatives for Rare Diseases to be attentive and to work together to address the challenges and take hold of the opportunities for conducting research in Brazil. So, in this article, we present a brief review of the clinical research landscape on Rare Diseases in Brazil, from the perspective of a research group in this field.

Rare genetic diseases in Brazil

Rare Diseases are conditions that affect only a small number of individuals, and each country or region determines its definition. In Brazil, it is generally adopted the definition that considers rare a disease that affects no more of 65 individuals per 100,000 inhabitants, which means approximately 1.3 individuals per 2,000 people (Brasil 2014). The exact number of Rare Diseases is disputed. There are estimates between 6 to 10 thousand different types of rare diseases (Nguengang Wakap et al. 2020; Ferreira 2019), with around 80% resulting from genetic factors. Although each disease is considered rare, collectively it affects a significant percentage of the population, being so considered a relevant public health problem (Brasil 2014, 2022).

Nguengang Wakap et al. (2020) estimated the global point prevalence of Rare Diseases is at least 3.5% to 5.9%. This point prevalence translates into conservative figures of 263 to 446 million persons affected worldwide by Rare Diseases at any point in time (Wakab et al., 2020). In Brazil, it is estimate that rare diseases affect 6–8% of the population, reaching 13–15 million Brazilians (Giugliani et al. 2016; Interfarma 2024).

Although it has a vast territorial extension and a large population, Brazil is marked by significant regional and social inequality, which affects access to healthcare, with two systems that complement each other. For about 75% of the population, access to healthcare services is provided through the SUS—Sistema Único de Saúde (Unified Health System), where healthcare services are organised and supported by the state. A smaller portion of the population relies on private health insurance (Giugliani et al. 2016; Paim et al. 2011).

There are few reference centres on Rare Diseases around the country. Many of them did not offer a wide portfolio of genetic tests and SUS does not reimburse diagnostic tests for most genetic diseases, so most of the Brazilian population which depends exclusively on the SUS has limited access to comprehensive genetic diagnosis and treatment (Giugliani et al. 2016). However, since the Brazilian Policy of Comprehensive Care for People with Rare Diseases was established in 2014 a list of genetic tests was incorporated into SUS, which can increase the access for people with Rare Diseases to diagnosis and appropriate follow-up in reference centres (Félix et al. 2022; Oliveira et al. 2023). Therefore, we can expect that with an increase in diagnosis, there will be a greater potential for recruitment for clinical trials on Rare Diseases, which can be very advantageous for the development of more clinical research in the country.

Clinical research on rare genetic diseases

Clinical trials are the gold standard for evaluating the safety and effectiveness of medical treatments, interventions, or therapies. It is widely disseminated by health organizations and can be evidenced through scientific literature that there is no specific treatment for the vast majority of Rare Diseases (Aureliano 2018). Thus, the great need for the development of clinical research for these diseases is evident. Additionally, participation in clinical trials can bring real benefits to participants (Poswar et al. 2021). Also, it is important to consider offering participation in a randomized clinical trial as part of the therapeutic alternatives to be offered by a reference service (Kandi and Vadakedath 2023). For many genetic diseases, participation in clinical trials may be the only hope, linked to the possibility of accessing qualified and comprehensive medical care, which is not always possible in routine follow-ups, especially for participants treated in the SUS.

Augustine and collaborators (2013) summarize several obstacles to clinical trials in Rare Diseases, such as the proper understanding of the natural history of the disease, which will result in the appropriate choice of protocol outcomes and follow-up timeline; the need for alternatives to controlled and randomized clinical trials since these diseases are highly heterogeneous and there is a small sample size, being necessary to adequate the statistical data analysis; the difficulty of recruitment due to the low prevalence of the diseases; the need for participant retention strategies in research, as these diseases often impose significant physical limitations on patients, making visits to research centres very hard. Additionally, there is the challenge of finding qualified human resources to conduct clinical studies, including regulatory aspects.

Many of the Brazilian medical genetics services and reference centres in Rare Diseases are working in networks for several diseases, to collaborate with academic researchers and also to improve access to patient diagnosis. In this way, it is possible to generate epidemiological data about Rare Diseases as well as allow patients assisted all over the country to have access to participate in international multicentre clinical research protocols (Giugliani et al. 2016; Poswar et al. 2021; Félix et al. 2022).

Poswar et al. (2021) suggest researchers can enhance awareness among research subjects by involving patients with genetic diseases in scientific meetings, maintaining close ties with genetic disease awareness associations, and ensuring sufficient time for an informed consent process. Therefore, it is expected to increase the capacity for recruitment. Effective recruitment could be supported through partnerships with patient families and patient advocacy associations, access to patient contact registries, and clinical education to increase disease recognition and reduce the time to diagnosis (DeWard et al. 2014; Augustine et al. 2013; Poswar et al. 2021).

Approval of clinical studies in Brazil

Before any research procedure is carried out, the project must be submitted and undergo a careful ethical evaluation by research ethics committees. In Brazil, the CEPs—Comitês de ética em pesquisa (Research Ethics Committees and CONEP—Comissão Nacional de Ética em Pesquisa (National Commision on Ethics in Research are responsible for this ethical evaluation, and the regulatory evaluation is carried out by Anvisa—Agência Nacional de Vigilância Sanitária (the Brazilian Health Regulatory Agency). Only after the study has received all the appropriate approvals it can be initiated and start including participants (Gouy et al. 2018).

The ethical assessment should mainly take into account the following aspects: the risks should be minimized in relation to the possible benefits; the choice of research participants should be equitable; free and informed consent should be collected from all research participants, or their guardians (where applicable), except in situations where the waiver of this consent is legally justified; additional safeguards are required in the case of vulnerable participants; during the collection of study data, monitoring should take place to ensure the safety of participants, protecting their privacy and maintaining the confidentiality of data. The ultimate goal of this assessment is to demonstrate that the research is relevant and necessary, with an acceptable risk–benefit ratio, guaranteeing the rights and well-being of the participants. (Kim 2012).

In Brazil, the ethics submission process takes place through a platform called “Plataforma Brasil”, which works as a system for collecting and exchanging information. This is a specific platform in which research projects must be included before they are started, so that they can be assessed by the CEPs and CONEP. There is a wide heterogeneity among CEPs timelines, but with can say that usually, after submitting the project and all the documents related to the study on the Plataforma Brasil, the CEP takes around 10 days to review the documentation submitted and accept it for evaluation, changing the status of the study to"under ethical appraisal". Once accepted, the CEP has 30 days to issue its first opinion on the study. If applicable, the CEP will forward the project to CONEP. CONEP has 15 days to review the documentation, and then 60 days to issue an opinion. (Brasil 2013).

If a pending opinion is issued by either CEP or CONEP, the researcher has 30 days to respond, counting from the date the opinion is issued. After submission, the deadlines for evaluating responses are the same: 10 + 30 days for CEP, 15 + 60 days for CONEP. Therefore, the time needed to approve the protocol can be even longer depending on the outstanding issues raised (Box 1), which a point of concern, especially in the case of competitive recruitment studies (Brasil 2013).

Box 1: Deadlines for the ethical submission process actions.

Actions	Maximum time for each step when queries are raised	Maximum time if there is no pending queries are raised
Documentary review by the CEP after initial submission	10 days	10 days
Release of opinion after ethical review by CEP	30 days	30 days
Investigator’s response to CEP’s pending decision	30 days	-
Documentary review by the CEP	10 days	-
Release of opinion after ethical review by CEP	30 days	-
Documentary review by CONEP	15 days	15 days
Release of opinion after ethical review by CONEP	60 days	60 days
Investigator’s response to CONEP’s pending decision	30 days	-
Documentary review by CONEP	15 days	-
Release of opinion after ethical review by CONEP	60 days	-
Total	290 days	115 days

Brasil 2013

Clinical research involving drugs must also undergo an evaluation by Anvisa before being started, and this process can take place concurrently with the ethical evaluation process, minimizing the impact on the overall approval time of the study. This evaluation by Anvisa takes place through the submission of a DDCM—Dossiê de Desenvolvimento Clínico de Medicamento (Clinical Drug Development Dossier), which should be made up of the drug development plan, investigator's brochure and dossier for the experimental drug. After receiving the DDCM, Anvisa has 90 days to issue an opinion in the case of rare diseases (180 days in other conditions) (Brasil 2017a, 2015).

When trials involve genetic modified organisms, additional approval should be granted by the Institution’s Biosafety Committee and the National Biosafety Committee (CTNBio), but this usually does not impact the timeline as it can be performed in parallel with CEP and CONEP reviews (Fig. 1). Also, the contract negotiation between sponsor and clinical research group can be performed in parallel and do not impact the final approval time.

Fig. 1.

Road map for clinical trial protocol review in Brazil. NOTE: Dashed lines indicate processes needed just for protocols involving genetic therapies

Conduct of studies in Brazil

Of the 5,700 clinical studies related to genetic diseases started between 2010 and 2019, more than 200 involved Latin American countries, including Brazil, which is responsible for conducting 127 studies, most of them phase III. The studies have the collaboration of specialized centres, such as hematology, neurology, pediatrics, genetics, among others, and are mostly sponsored by international companies (Poswar et al. 2021).

Unlike other countries, in Brazil it is forbidden to pay research participants (with the exception of Phase I studies and bioequivalence studies), which can be considered a negative point in the search for subjects. They must participate voluntarily, but they must not have any expenses associated with their participation. All expenses that participants may have related to their participation in the research must be reimbursed by the sponsor. In the case of rare diseases, where it is not possible to find a significant number of patients diagnosed in the same region, the costs of these reimbursements become high for the sponsor, considering situations of displacement between states distributed over the great Brazilian territorial extension, plus the costs of food and lodging (Brasil 2013; Félix et al. 2022).

Another unfavourable factor from the sponsors'point of view is the legal obligation they have to provide the medication indefinitely after the study, if it proves to be effective. In 2017, a specific rule was created for ultra-rare diseases, reducing this period to 5 years after the establishment of the pharmaceutical product’s market price by Câmara de Regulação do Mercado de Medicamentos—CMED (Chamber for the Regulation of the Medicines Market). Despite being exclusive to a specific group of conditions, this can be considered a step forward, making protocols in this area less expensive. However, from the point of view of the research participant, this obligation becomes a very positive factor, as they are guaranteed their right to the best treatment (Brasil 2017b).

The opportunity given to patients with rare diseases to access innovative experimental therapies, combined with specialized medical care, with access to qualified medical examinations and evaluations, is one of the great benefits when it comes to conducting clinical studies in Brazil. In addition, clinical practice also ends up being influenced by the high-quality standards that must be followed in clinical protocols, brought about by the professionals who work on the projects and also have their work cut out for them in health care services (Giugliani et al. 2019).

Final considerations

Despite a significant portion of the population is affected by these conditions, they individually affect a not so significant number of patients, thus making it less attractive for the pharmaceutical industry to develop new therapies for rare diseases. At the same time, as Brazil has such a big and heterogeneous population from an ethnic, racial, cultural, and social point of view, it can guarantee clinical studies handle diversity and inclusive samples.

The ethical evaluation of studies conducted in Brazil is careful and effective, which protects research participants, but it is still reasonably time-consuming, which can hinder the inclusion of participants in the case of studies with competitive inclusion. It is necessary to consider this factor when planning the submission of projects in Brazil, also with a view to being more competitive in relation to other countries.

Considering the vast territory and large population of Brazil, which generates significant regional and social inequalities and affects access to healthcare, participation in clinical research protocols enables this access for people who probably wouldn't have it easily through the public health system, as well as improving patient care, considering the knowledge acquired by professionals when they participate as a team in these projects.

Finally, also with the publication of Brazilian Policy of Comprehensive Care for People with Rare Diseases, it is hoped that new rare disease centres will be qualified in Brazil, which could boost the creation of new clinical research centres focused on rare genetic conditions or they can also serve as referral of patients to already established research centers. We can have more studies and consequently more technologies for diseases that for the most part still have no treatment, thus improving the quality of life of this rare but significant portion of our population.

Conducting clinical research projects into rare genetic diseases in Brazil is complex and challenging, and some changes have made the process more attractive, with faster approval timeline and more realistic post-study obligations. However, recently, Law No. 14.874, was published, which establishes principles, guidelines and rules for conducting research with human beings by public or private institutions and establishes the National System of Ethics in Research with Human Beings. The law is not yet fully in force, but it is already dividing opinions. On the one hand, it protects and benefits research participants, but it is also being seen as harmful by sponsors, and some believe that unfortunately the number of research projects brought to Brazil will decrease (Brasil 2024).

Authors’ contribution

LPS: Conceptualization, literature review, and writing. TAV: Conceptualization, literature review, and writing. GLS: Literature review, and editing. RG: Review and approval of the manuscript before submission for publication.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of Interest

The authors declare no competing interests.