Conducting Research in Rare Diseases

Romina Iusem, Clinical Research Associate/Regulatory Manager, Blanchard & Asociados

Clinical Researcher—February 2018 (Volume 32, Issue 2)


Romina Iusem

[DOI: 10.14524/CR-17-0029]

Rare diseases are defined by their low prevalence in a population. Diseases are considered rare if the prevalence is lower than one in 2,000. There are about 7,000 rare diseases, so even though each one may affect few patients, there are millions of people worldwide who have rare diseases. It is estimated that about 30 million people in the European Union, about 30 million people in the United States, and about 42 million people in Latin America are affected with rare diseases.

Conducting research in rare diseases involves many challenges, in part due to the low prevalence of these conditions. Therefore, a global approach may be a good strategy in order to achieve the research objectives. Information regarding the status of research in rare diseases in Latin America and some resources available to help conduct such studies will be included in this article, since many readers in other parts of the world may not be familiar with activities in that region.

Rare Diseases Characteristics

Although there are different causes of rare diseases, the majority are thought to be genetic (e.g., adrenoleukodystrophy).1 Other causes of rare diseases can be an infection or allergy. There also are rare autoimmune diseases (e.g., Addison’s disease)2 and some rare cancers (e.g., Kaposi sarcoma).3

Usually, rare diseases are difficult to diagnose due to the low prevalence. In general, they are chronic and progressive with disabling consequences, having a great impact in terms of quality of life for patients and their families.

Treatment for rare diseases and the access to treatment are also challenging. Many rare diseases have no specific treatment, and when there is one, it’s usually focused on improving the quality of life and not on curing the disease. Therefore, the development of orphan drugs to treat rare diseases has benefits for gaining marketing authorization, including financial incentives.

Orphan drugs are drugs developed for rare diseases and conditions and are not developed for economic reasons, but in response to public health need. In 1983, the Orphan Drug Act was issued in the U.S. so that such treatments would acquire the orphan drug designation to encourage their development.4 In the first 30 years following the Orphan Drug Act publication, 177 approvals by the U.S. Food and Drug Administration (FDA) were granted to orphan drugs for rare cancers,5 14 approvals for orphan drugs for lysosomal storage disorders,6 and 14 approvals for orphan drugs for rare rheumatic disorders.7

Some Statistics on Research in Rare Diseases

Rare diseases are defined in the Rare Diseases Act of 2002 as diseases that affect small patient populations—typically populations smaller than 200,000 individuals in the United States.8

During a look in July 2017 by the author at studies registered at, there were 729 studies in “rare diseases.” The purpose of many of these studies is to obtain information about the natural history of the diseases, to review diverse registries, to better understand problems and conditions related to the diseases, or to improve quality of life for patients. From the total, nearly 60% (434) of the studies are interventional, and from those 84 were active in July 2017. Fortunately, research in rare diseases is increasing: 63 studies were registered in 2016 (see Figure 1 for trends).

The Challenges

Among the challenges inherent in conducting studies in rare diseases, the most important is the number of patients—especially in terms of how to standardize the implementation of the protocol procedures across very few patients in a very long time by diverse team of professionals. Robust protocol design is critical to assure statistical significance of the data.9

As the prevalence of any given rare disease is low, the geographical dispersion of patients is very common. This presents difficulties for conducting centralized clinical evaluation and handling the logistics of specialized testing.

Another challenge is finding medical experts and sites that specialize in the disease of interest. Limited clinical experience in the indication or poor validation of protocol clinical monitoring criteria by the investigators may lead to invalid clinical evaluation.

Finding sites and patients seems to be a common and obvious challenge for these types of studies. One way to overcome this difficulty is for sponsors to work with local partners who can connect them with testing sites, local public registries, and patient advocacy organizations.

Another challenge is to obtain the financial resources to carry out the research programs. Incentives from competent authorities and dedicated organizations can help, but often render insufficient aid to complete the development of the treatment under assessment.

Global studies seem to be a good opportunity to concentrate both funding and potential subjects in pursuit of understanding, diagnosing, and treating these low-prevalence conditions.

Key Element for Success: Collaboration

Rare disease studies are collaborative studies in which each party contributes specific strengths and adds value toward making the project implementation successful as a team.10 The joint efforts of the sponsor/contract research organization/vendor companies, governments and their agencies, institutional review boards/ethics committees, investigators/site staff, patients, and their families and support groups are crucial.

Key Opinion Leaders

Key opinion leaders (KOLs) are experts in their fields who wield significant influence on others in those fields. In the context of rare diseases, KOLs are usually local experts in a specific disease. Due to the abovementioned characteristics of rare diseases, physician networks are crucial for the conduct of studies. Also, centralized reading or centralized training may be helpful in managing high-quality data in rare disease studies (e.g., certifying evaluators across the study).

The contact between KOLs and patient advocacy group is a strength that needs to be taken into account. Often, a KOL in a specific disease will be the reference expert of patients’ organizations in a country, and will have contact with other regional experts.

Patient Advocacy Groups

Once informed of the diagnosis, many patients with rare diseases and their families become very familiar with the condition and the possibilities for accessing available treatments. If there are no available treatments, or if available treatments have limited efficacy, patients will naturally seek out other treatment alternatives and may join together in advocating for new research programs to address these needs. Members of such patient populations are more intimately aware of the natural evolution of their diseases and can contribute to research with their knowledge. In addition, patient advocacy groups can spread information about new findings and research projects to affected patients and potential sponsors and investigators around the world.11

Clinical Trials Team and Logistics

In the typical rare disease scenario, management skills are important to achieving the coordination of all the different stakeholders involved. In the case of global studies, access to local physicians with experience in the disease, contacts within local or regional patient advocacy groups, and a thorough understanding of a country’s logistics requirements for any rare disease project will be decisive toward success in a clinical trial’s implementation.

The Status in Latin America

Latin America is an interesting region in which to conduct research, with a large and diverse population, serious quality standards, and Good Clinical Practice–compliant regulations. Also, it’s a region with strong patient-doctor relationships, which could be very important in treating and following up on cases of rare diseases.

There are different regulations in each country that provide the local frameworks intended to support subjects with rare diseases. Further, there are organizations in Latin America that gather patient advocacy groups for different diseases (see Table 1). However, the activities of these organizations do not cover all rare diseases in their countries, and they are still working on how to best articulate support for research projects. Consulting with these organizations and local research teams experienced in rare diseases may be the best way to find out about the diseases in each country, and they can help with making recruitment plans for eligible patients for research projects.

Local experts can provide crucial knowledge about local regulations, study implementation tactics, and treatment coverage in each country. These organizations may be the best source of information for research planning and about how new studies will benefit scientific understanding of the natural history, diagnosis, or treatment of rare diseases.

Table 1: Rare Disease Umbrella Organizations in Latin America

Country Organization Website
Argentina Fadepof – Argentine Foundation of Rare Diseases
Brazil AFAG – Associação dos Famíliares, Amigos e Portadores de Doenças Graves.
Chile Chilean Foundation of Rare Diseases
Colombia FECOER – Colombian Federation of Rare Diseases
México FEMEXER – Mexican Federation of Rare Disorders
Perú FEPER – Peruvian Organization of Rare Diseases


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Romina Iusem ( is a Clinical Research Associate and Regional Regulatory Manager with Blanchard & Asociados in Argentina.