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Understanding Rare Diseases and Orphan Drugs

Some health conditions, such as heart disease, cancer, arthritis, and diabetes, affect millions of people worldwide. These diseases are prevalent in the population, and they have traditionally attracted significant economic and research resources from pharmaceutical companies, public and private institutions, and organizations. Simultaneously, a large number of diseases and conditions affect a relatively small number of patients. "Rare disease" is a term used for diseases whose prevalence is very low in the population. It is believed that over 5,000 rare diseases have already been described, but still few drugs, known as orphan drugs (i.e., drugs developed to treat rare diseases), hit the market every year. Rare diseases can also be orphan diseases in the sense that industry has no interest in producing medicines to treat these conditions because there are not sufficient patients, even globally, to make manufacturing and marketing attractive. The history of medicine has been marked by several examples of rare diseases, and in this article, we will explore some concepts and challenges related to rare diseases and orphan drug development.

Background and General Concepts

Rare diseases refer to a heterogeneous group of conditions with a very low frequency of cases in the population. There is no effective treatment for many of these conditions, which are referred to as "orphans". Thus, the term orphan disease lies in its inherent lack of appeal to pharmaceutical companies, who are more interested in developing medicines for common diseases that affect millions of people (Rinaldi, 2005). These diseases have traditionally been neglected by the pharmaceutical industry and the scientific, medical, and political communities due to their low prevalence (Rinaldi, 2005).

Rare diseases are generally chronically debilitating or potentially fatal diseases that occur in relatively small groups of the population. In the European Union (EU), the definition of a rare disease was established in the 1999 EU Orphan Medicines Regulation as conditions whose prevalence is at most 50 cases per 100,000 individuals (European Union, 1999). In 1983, the American Orphan Drug Act defined these diseases as disorders that affect fewer than 200,000 people in the United States (National Institute of Health, 1983). Definitions from other countries translate into a prevalence that varies between 5 and 76 cases per 100,000 inhabitants (Nguengang Wakap et al., 2020). It is estimated that between 5,000 and 8,000 rare diseases have already been cataloged (Denis, Mergaert, Fostier, Cleemput, & Simoens, 2010). Around 80% of these diseases have genetic origins as the main cause and affect between 3% and 4% of births (EURORDIS, 2005). Other rare diseases may be due to degenerative and proliferative causes. Some examples of rare diseases, whose main symptoms may appear at birth or in childhood, include progressive muscular dystrophy, retinoblastoma, mitochondria-related diseases, and osteogenesis imperfecta (also known as fragile bone disease) (Zhao, Du, Yang, & Wang, 2023). Other rare diseases can appear during adulthood, such as Huntington's disease, Spinocerebellar Ataxias, and thyroid cancer (EURORDIS, 2005).

Figure 1: Rare Diseases facts (Kent, 2021).

Unfortunately, only a small portion of rare disease treatment needs are covered. Fewer than 6% of all rare diseases have an approved treatment option, highlighting the significant unmet needs in drug development for these conditions (Roessler, Knoers, van Haelst, & van Haaften, 2021). Indeed, according to the European Organization for Rare Diseases (EURORDIS), patients with rare diseases face a lack of access to correct diagnosis, associated with a lack of information and public awareness (EURORDIS, 2005). Furthermore, these patients still need to face reduced scientific knowledge and expertise, low investments in therapeutic research and development, a lack of adequate healthcare, a high cost for most of the few existing medicines, as well as inequalities in access to treatment and care (EURORDIS, 2005). Therefore, governments have implemented specific policies on rare diseases in order to improve the quality of life and life expectancy of rare disease patients and encourage research and development of orphan drugs. The rationale behind such policies is to compensate the pharmaceutical companies for risks, guaranteeing a return on investment. The prevalence of rare diseases is relatively low and, consequently, represents a small market size.

Challenges in the Diagnosis and Treatment of Rare Diseases

The diagnosis of rare diseases is difficult and may require very specialized centers where there is a multidisciplinary and comprehensive approach for effective diagnosis and treatment. Usually, there is a great demand for a well-trained medical team, including general practitioners, pediatricians, neonatologists, and neurologists, ready to refer patients to these centers. Furthermore, a multidisciplinary team may require very well-trained geneticists, nutritionists, biochemists, and social workers, in addition to sufficient laboratory support to provide real solutions to patients (Barrera & Galindo, 2010). Due to the low incidence of rare diseases, healthcare professionals' awareness and knowledge of how to treat these diseases may be limited (Rinaldi, 2005). Furthermore, there is a lack of scientific knowledge about rare diseases. As these diseases are not prevalent, access to patients by health professionals and researchers is restricted. In addition, in many of these diseases, the diagnosis requires special tests not commonly available (Cote, Xu, & Pariser, 2010). In this sense, it is important to implement government actions in the development of alternatives and tools to provide access to knowledge and expertise. These actions can comprise the inclusion of databases, the development of skills in specialized centers (improving the referral of patients with rare diseases to specialized centers), and increasing value through international cooperation. All these actions together can contribute to a more efficient therapeutic approach for patients with rare diseases, as well as the optimization of the diagnosis (Denis et al., 2010).

Figure 2: Challenges related to treatment and diagnosis of Rare Diseases (McMullan, et al., 2021).

Development of Medicines for Rare Diseases: Orphan Drugs

Historically, research and development efforts focused on the most prevalent diseases and conditions. Usually, the discovery of a new drug for a prevalent disease takes 10–17 years and comprises the steps of basic discovery, drug design, in vitro (cells and tissues) and in vivo experimentation (animals), clinical trials (humans), and finally drug registration and availability on the market (Zhang et al., 2020).

During drug development, studies on humans, called clinical studies, aim to evaluate the safety and effectiveness of new pharmaceutical medicines that will reach the market. These studies ensure that the new medicine is safe (does not have harmful effects on the patient) and efficient in treating the disease for which it is being proposed to treat. Clinical studies typically comprise the following phases:

  1. Phase I: the new drug is first tested in a small group of people (e.g., 20-100) in order to assess its safety (e.g., identify side effects, safe dosage range). Approximately 70% of drugs move to the next phase.

  2. Phase II: In this stage, the safety and efficacy of the drug (optimal dosing regimen) are evaluated in a large cohort (hundreds of individuals), including individuals with the target condition, in order to confirm the effectiveness of the drug. Around 33% of drugs move on to the next phase.

  3. Phase III: efficacy is then studied in large groups of participants (300 to 3,000 volunteers who have the disease or condition). The new drug is compared with standard or similar treatments, adverse effects are monitored, and substantial evidence of efficacy and safety is collected for regulatory approval. Approximately 25-30% of drugs move to the next phase.

  4. Phase IV: also called post-marketing surveillance, occurs after the medicine is approved and made available to the public. At this stage, researchers monitor the safety of medications in the general population and the adverse effects associated with widespread use (Zhang et al., 2020).

Figure 3: Stages of clinical trials (Stony Brook Medicine, n.d.).

Developing orphan drugs is challenging because these diseases are rare, resulting in a limited number of patients available for studies. Furthermore, the knowledge available regarding disease heterogeneity, manifestations, and progression is limited (Cote et al., 2010). Therefore, there are guidelines specifically related to clinical trials in small populations that must be followed by clinical trial centres (EMA, 2006). Another challenge is related to the profits of pharmaceutical industries. Usually, getting a new drug to market costs between US$2 billion and $3 billion on average, and this investment needs to be recovered in sales (Nosengo, 2016). Thus, for rare diseases, governments have offered incentives to encourage companies to investigate and develop medicines that would not otherwise be developed. During the research and development of orphan medicine, the company can benefit from incentives such as fee reductions, scientific advice on study protocols, and access to funding. Furthermore, medicines designated as orphans that eventually reach the market are granted 10 years of market exclusivity. To access these incentives, pharmaceutical companies can request orphan drug designation for their medicines, as long as certain criteria are met. For instance, the drug must treat, prevent, or diagnose a life-threatening or chronically debilitating disease, or the drug is unlikely to generate sufficient returns to justify the investment required for its development. Also, the disease should be considered rare (not affect more than 5 in every 10,000 people across the EU or > 200,000 people in the US). Finally, there is no satisfactory method of diagnosis, prevention, or treatment; if such a method already exists, the drug must provide a significant additional benefit to those affected by the disease (Aartsma-Rus, Dooms, & Le Cam, 2021; Seoane-Vazquez, Rodriguez-Monguio, Szeinbach, & Visaria, 2008). Thus, the measures adopted by governments in different countries can facilitate and encourage pharmaceutical industries and institutions to invest in the research and development of orphan drugs.

Healthcare Cost Concerns

Despite the challenges associated with developing orphan drugs, when manufacturers invest in research and development of treatment options for rare diseases, market prices can be extremely high, resulting in higher profit but reduced access for patients (Roessler et al., 2021).

The cost of care for rare diseases poses an important economic burden. In general, the cost of orphan drugs is much higher than the cost of treating common diseases, mainly due to inpatient care and prescription drugs. The average healthcare cost per patient with rare diseases varies significantly by patient and disease characteristics, but the costs of treatment can reach thousands of dollars. Life-threatening health conditions and the lack of therapeutic alternatives create an inelastic demand for orphan drugs, leading to high prices in a market with already limited competition (Roessler et al., 2021). The price of orphan drugs is often the most significant barrier for patients to access care. Thus, reimbursement programs are offered by governments in order to improve the quality of life and life expectancy of patients. However, this scenario may not be economically sustainable for long periods as the price of orphan drugs tends to be high, being easily impacted by budget constraints and the growing number of orphan drugs approved by regulatory agencies such as the FDA (Food and Drug Administration) and the EMA (European Medicines Agency) due to incentive programs (Rodriguez-Monguio, Spargo, & Seoane-Vazquez, 2017). This scenario has therefore still been debated so that other alternatives may also be explored.

Figure 4: Rare diseases are associated with higher health costs (NIH, 2021).
Drug Repurposing May Be a Cheaper and Faster Option

Drug repurposing (also known as drug repositioning or drug reprofiling) is the process of redeveloping a compound for use in a different disease for which the drug was initially approved (Roessler et al., 2021). Rather than developing a new medicine from scratch, researchers and pharmaceutical companies explore the potential of existing medicines, whose safety for use has already been established, to treat different diseases or medical problems. This strategy can be highly advantageous, as it reduces costs and time associated with drug development. While the discovery of a new drug takes 10–17 years, drug repurposing can take only 3–9 years. These can be explained by the rapid progression of these drugs into Phase II and Phase III clinical studies, which also can significantly reduce the development costs associated with drug development (Zhang et al., 2020). For more information about drug repurposing, please visit

Figure 5: Principle of drug repurposing (Masuda et al., 2020).

In fact, any compound classified as safe for human use is likely to have multiple therapeutic applications. For instance, compounds tend to trigger multiple targets, which can also lead to the appearance of undesired adverse events (Roessler et al., 2021). However, these effects might be of advantage for other indications, like for example aspirin, pain relief, and anti‐inflammatory compounds that can be administered at low doses to prevent cardiovascular disorders, such as stroke and heart attacks (Jourdan, Bureau, Rochais, & Dallemagne, 2020). Repositioning can increase the chances of introducing the drug onto the market by 150% compared to a new medicine, in addition to the development costs being more than 80% cheaper (Jourdan et al., 2020). In the case of rare diseases, drug repositioning can be effective, being a faster and cheaper alternative, facilitating access to treatments and reducing costs for the patient.


Rare diseases constitute a very heterogeneous group of diseases with little in common other than their rarity. These diseases are usually poorly understood by health professionals and researchers, and diagnosis is often complex and time-consuming. Many of these disorders are serious, chronic, and progressive, with patients having few or no treatment options, which increases the urgency of developing new treatments. Regulatory initiatives and government efforts over the past few years have resulted in the development and approval of medicines for rare diseases and conditions, but it is still not enough. Although orphan drugs improve patients' health status and quality of life, the associated cost also limits patients' access to treatment. Thus, additional initiatives to accelerate the development of new drugs to treat rare diseases and reduce treatment costs are still necessary. In this sense, alternatives such as drug repositioning must be considered.

Bibliographical References

Aartsma-Rus, A., Dooms, M., & Le Cam, Y. (2021). Orphan Medicine Incentives: How to Address the Unmet Needs of Rare Disease Patients by Optimizing the European Orphan Medicinal Product Landscape Guiding Principles and Policy Proposals by the European Expert Group for Orphan Drug Incentives (OD Expert Group). Frontiers in Pharmacology, 12, 744532.

Barrera, L. A., & Galindo, G. C. (2010). Ethical aspects on rare diseases. Advances in Experimental Medicine and Biology, 686, 493-511.

Cote, T. R., Xu, K., & Pariser, A. R. (2010). Accelerating orphan drug development. Nature Reviews Drug Discovery, 9(12), 901-902.

Denis, A., Mergaert, L., Fostier, C., Cleemput, I., & Simoens, S. (2010). Issues surrounding orphan disease and orphan drug policies in Europe. Applied Health Economics and Health Policy, 8(5), 343-350.

European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). Guideline on clinical trials in small populations. 2006.

European Union. Regulation (EC) N°141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products. 2000.

EURORDIS. Rare diseases: understanding this public health priority. 2005.

Jourdan, J. P., Bureau, R., Rochais, C., & Dallemagne, P. (2020). Drug repositioning: a brief overview. Journal of Pharmacy and Pharmacology, 72(9), 1145-1151.

National Institute of Health. Public Law 97–414 97th Congress. Jan 4, 1983 .

Nguengang Wakap, S., Lambert, D. M., Olry, A., Rodwell, C., Gueydan, C., Lanneau, V., . . . Rath, A. (2020). Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. European Journal of Human Genetics, 28(2), 165-173.

Nosengo, N. (2016). Can you teach old drugs new tricks? Nature, 534(7607), 314-316.ª

Rinaldi, A. (2005). Adopting an orphan. EMBO Reports, 6(6), 507-510.

Rodriguez-Monguio, R., Spargo, T., & Seoane-Vazquez, E. (2017). Ethical imperatives of timely access to orphan drugs: is possible to reconcile economic incentives and patients' health needs? Orphanet Journal of Rare Diseases, 12(1), 1.

Roessler, H. I., Knoers, N., van Haelst, M. M., & van Haaften, G. (2021). Drug Repurposing for Rare Diseases. Trends in Pharmacological Sciences, 42(4), 255-267.

Seoane-Vazquez, E., Rodriguez-Monguio, R., Szeinbach, S. L., & Visaria, J. (2008). Incentives for orphan drug research and development in the United States. Orphanet Journal of Rare Diseases, 3, 33.

Zhang, Z., Zhou, L., Xie, N., Nice, E. C., Zhang, T., Cui, Y., & Huang, C. (2020). Overcoming cancer therapeutic bottleneck by drug repurposing. Signal Transduction and Targeted Therapy, 5(1), 113.

Zhao, H., Du, C., Yang, G., & Wang, Y. (2023). Diagnosis, treatment, and research status of rare diseases related to birth defects. Intractable & Rare Diseases Research, 12(3), 148-160.

Visual Sources

Cover Image: NHIR BioResource (n.d.). Rare Diseases BioResource, [Image]. Retrieved October 4, 2023.

Figure 1: Kent, A. (2021). Why a diagnosis is so important for rare disease patients. [Image]. Retrieved October 4, 2023.

Figure 2: McMullan, et al., (2021). Perceptions and experiences of rare diseases among General Practitioners: an exploratory study. [Image]. Retrieved October 4, 2023.

Figure 3: Stony Brook Medicine, (n.d.). Clinical Research. [Image]. Retrieved October 18, 2023.

Figure 4: NIH, 2021. NIH Study Suggests People with Rare Diseases Face Significantly Higher Health Care Costs. [Image]. Retrieved October 4, 2023.

Figure 5: Masuda, T., Tsuruda, Y., Matsumoto, Y., Uchida, H., Nakayama, K. I., & Mimori, K. (2020). Drug repositioning in cancer: The current situation in Japan. Cancer Science, 111(4), 1039-1046. [Image].


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Juliana Priscila Vago

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