The importance of patient registries for rare diseases

1. Background

Rare diseases (RD) are defined as diseases affecting no more than 1:2,000 individuals in the European Union (EU) and no more than approximately 1:1,250 individuals in the USA; although any one condition is rare, the cumulative public health burden associated with RD is substantial, with 6 – 8% of people experiencing a RD at some point in their lifetime [1,2]. There are approximately 7000 known RD, 80% of which have a genetic etiology. These diseases are very heterogeneous in their clinical expression, with a wide variability between the conditions themselves as well as between patients with the same disease [1,2].

The signs and symptoms of RD are often peculiar in their clinical presentations, which can range from chronic, permanent and progressive and are generally poorly understood by physicians; the signs and symptoms of some RDs can be more common than others, but are similarly misunderstood by physicians due to their lack of knowledge of RDs. Additionally, the age of onset and the symptoms at onset can vary greatly. Onset can occur during the embryologic period (as a cause for miscarriage), during the perinatal or neonatal period, childhood, adolescence or adult life. A survey of 8 RD (Crohn's disease, cystic fibrosis, Duchenne muscular dystrophy, Ehlers Danlos syndrome, Marfan syndrome, Prader-Willi syndrome, tuberous sclerosis and Fragile X syndrome) showed that the time between the appearance of first symptoms and diagnosis was 5 – 30 years in 25% of patients, that 40% of these patients received an incorrect diagnosis, that the genetic nature of the diseases was not communicated to the family in 25% of the cases and that genetic counseling only occurred in 50% of the cases [1].

Public awareness of RD has increased in recent years because of the efforts undertaken by patients' support groups. Established in 1983, the National Organization of Rare Disorders (NORD) in the USA was instrumental in the approval of the Organ Drug Act [3]. The role of patients' and parents' support groups is growing beyond the boundaries of initiatives aimed at raising public awareness and promoting social care and benefits [4]. These aims are very important because patients with RD in most health-care systems face inadequate social and health care [4].

There is very little documented information on the epidemiology of RD, the majority of which have no cure. The advances in our understanding of the mechanisms of many diseases and the explosion of knowledge in genetic medicine indicate that it is time for a leap forward [4]. Within this context, registries are useful in gathering information about patients with RD, achieving a sufficient sample size for epidemiological and/or clinical research [5].

2. Global RD registries

Patient registries are organized systems that use observational research methods to collect data for scientific, clinical or policy purposes. These registries do not generally have restrictive inclusion or exclusion criteria nor do they specify what therapy the health care provider must adhere to. Registries are a valuable component of randomized controlled trials in determining real-world outcomes in the practice of medicine. They can be used to evaluate outcomes for diverse purposes ranging from the natural history of a disease, to the safety of drugs or devices, to the real-world effectiveness of therapies [6,7].

Most RD still have no medical therapy, and because of their rarity, no single institution and, in many cases, no single country has sufficient numbers of patients to conduct generalizable clinical and translational research. Registries enable the formation of infrastructures for various types of research, education and outcome improvement [8].

Most of RD registries are operated by patient organizations or researchers, and less than 1/5 of RD has registries. Only 347 RD have registries in the US National Institute of Health Database (http://www.clinicaltrials.gov). In a recent publication [9], EU countries were reported to have patients enrolled in 588 different RD registries. Thus, the USA and EU called for the wide expansion of access to registries for patients with RD [5], and recent agreements made by both the USA and EU support the establishment of registries for research and public health purposes as one of the priorities for the call launched in 2011 by the International Rare Disease International Research Consortium (IRDIRC) [10].

Registries of patients treated with orphan drugs are particularly relevant because they allow for the gathering of evidence regarding the effectiveness of a treatment and the possible side effects, keeping in mind that marketing authorization is usually granted at a time when evidence is still limited although already somewhat convincing [9]. Because pharmacovigilance in RD faces many challenges (that is, limited knowledge of safety profiles at authorization, insufficient knowledge regarding the epidemiology of a disease, few patients in each country), registries are a valuable resource in orphan drug pharmacovigilance and risk management [10].

It is important to understand that registries can serve multiple purposes and, therefore, require different elements. With the increasing use of registries, the requirements for each specific purpose are now better defined. For example, registries that serve a public health purpose, such as those that are developed for population surveillance, do not need clinical data beyond diagnosis or follow-up data. On the other hand, registries that are being used to assess the effectiveness and safety of agents after authorization require more stringent elements. For these regulatory drug registries, completeness of case ascertainment, high-quality data, verification of data validity and follow-up are mandatory [11].

3. RD registries in Latin America

Searching the LILACS (Latin America and Caribbean Health Science Literature Database) and MEDLINE databases using the keywords ‘rare disease' and ‘registry' and ‘Latin America', we could retrieve only publications on primary immunodeficiency [12] and lysosomal storage disorders [13,14]. Thus, it appears that there is no method for collecting data in an organized manner. Furthermore, there is not yet a wide cooperative relationship between patient organizations and researchers, and a lack of information on the epidemiology of RD from government health care persists. We have experience with certain international lysosomal storage disorders registries, inputting the data of some patients who are under our care.

The Gaucher Registry (GR) is funded and supported by pharmaceutical companies due to the Food and Drug Administration's approval of the specific medications that are produced by these companies for the treatment of patients with RD. Large, prospective, randomized trials are difficult to conduct, given the circumstances of these diseases; thus, a long-term registry was established to expand the knowledge that has been gained from the smaller clinical trials that have been conducted during the drug development process. Long-term observational studies are also extremely important because of the progressive evolution of RD. These studies help us to better understand the natural history and genotype–phenotype relationship of these diseases to assist in assessing the responses to treatments (for patients who have this option) and to assist physicians by providing the best available scientific evidencein counseling patients in clinical and therapeutic decision-making. The population of patients in registries is heterogeneous. Thus, registries are representative of patients, whereas clinical assays employ a controlled and homogeneous population with restricted eligibility criteria and by uniform and systematic data collection [15].

The GR has an advisory board that is composed of independent experts who treat patients throughout the world and collaborate to ensure the overall integrity of the program.

The quality of data and the number of patients in registries are very important. Gaucher disease is the most frequent disorder of lysosomal storage, and more than 6,000 patients with this disease are enrolled in the GR. Thus, publications from this registry have great value in guiding physicians with respect to therapeutic recommendations, treatment expectations and severe complications that may occur during the evolution of the disease. For example, the manuscript, ‘Therapeutic goals in the treatment of Gaucher's disease' [15] has been used both in clinical practice and in clinical trials of new therapeutic options for Gaucher's disease. This type of document may only be produced using a registry with a representative number of patients, as well as high-quality, consistent and clinically meaningful data.

RD registries in Latin America help build our knowledge of the natural history and phenotypic variability of diseases. They also enhance treatment responses to these diseases in our specific population [13].

A Latin American publication using GR data observed that the majority of Latin patients were younger than 20 years of age (68%) at diagnosis, that 48% of Latin Gaucher's disease patients had bone pain and that splenomegaly in these patients was more severe than that in patients from the rest of the world [14].

The GR data show that the Brazilian population appears to have a more severe form of the disease with a lower mean age at diagnosis, more anemia, more bone pain, more bone crises and more lytic lesions compared with the rest of the world. Approximately 50% of the Brazilian patients had a N370S/L444P genotype versus 16% in the rest of world; thus, we now know that this genotype is associated with a more severe form of the disease. These data can be used to encourage Brazilian physicians to be sensitive to early diagnosis and bone complications in their Gaucher's disease patients [16].

The quality of data inputted into registries should be periodically assessed through the verification of source documents [17]. It is also important to avoid biases in the collection of registry data due to the great heterogeneity of the diseases registered. These biases may be minimized using case-control pairing in analyses [6].

4. Conclusion

There is a worldwide awareness of the urgency of establishing internet-based platforms for RD registries [18], due to the geographic spread of patients and the ease of data handling. Such platforms would provide a critical infrastructure through which to integrate information from existing RD registries and establish registries for patient organizations currently with no registry or for patients with no affiliation to a support group looking to belong to a registry [18].

We agree with authors' statements that some of the greatest hurdles to be overcome in the development of RD registries is not the technical but rather the cultural obstacles to collaboration and data sharing across academic institutions and international boundaries [5,10], as well as funding sources. Thus, collaboration between academics and pharmaceutical industries is one way to overcome this hurdle [10]. This partnership solely functions for post-marketing commitments with regulatory agencies, but we postulate that RD registries must have a long-term existence.

RD registries are highly recommended and should be established in accordance with the principles of the International Conference for Harmonization – Good Clinical Practice (http://www.ich.gov). The largest possible geographic coverage, a set minimum amount of required data, the inclusion of data directly reported by patients together with data reported by health professionals and maintaining more focus on a certain disease or group of diseases than on therapeutic interventions [1] all contribute to enhancing the quality of these registries.

We believe that these registries can also operate as a collaborative network of researchers, patients and their relatives because as regards data input, sometimes the patients are monitored more closely by different physicians.

Declaration of interest

AM Martins has been a Coordinator for a Fabry Registry supported by Genzyme in Brazil. SO Kyosen has nothing to disclose.