Understanding orphan drugs: Definitions, examples, and legislative support for the treatment of rare diseases

What is a rare disease?

To understand orphan drugs (also called orphan medicines), it is important to provide some background about rare diseases. The definition of a rare disease varies around the world, but in the EU it is defined as a disease affecting no more than 1 in 2000 people [], while in the USA, a disease is called rare if fewer than 200,000 Americans are affected by it at any time [].

Although each rare disease affects only a small number of people, it is estimated that there are over 7000 rare diseases. This means that regardless of the small number of people affected by each disease, the global impact of rare disease is huge, with up to 5.9% of the global population affected []. Despite this, 95% of rare diseases do not currently have an FDA-approved treatment [].

What is an orphan drug?

Simply put, an orphan drug is one that is for the treatment of rare diseases. Unfortunately, the prevalence of each rare disease means that drugs for these conditions are unlikely to offer significant financial rewards to the pharmaceutical company that develops them. Therefore, orphan drugs are those developed due to humanitarian need rather than financial gain [].

Furthermore, orphan drugs are used for the treatment of a broader category of diseases called orphan diseases. This includes not only rare diseases, but also those illnesses neglected or ignored by pharmaceutical companies, often due to their relatively low prevalence in the developed world. Examples include tuberculosis, cholera and malaria [].

Additionally, a medicine developed for the treatment of a more common illness or withdrawn from the market due to economic, therapeutic or safety concerns can also have orphan indications when found to be efficacious against a rare or orphan disease [].

The scale of the drug development process

In order to appreciate why developing treatment for rare diseases is not financially viable for a pharmaceutical company, it helps to have a brief understanding of the scale and process of drug development.

The drug development process can be broken down into five broad steps [].

• Research, discovery and development: a potential molecule is developed into a medicine for subsequent testing.
• Preclinical research: laboratory and animal testing to assess general safety.
• Clinical research: a series of clinical trials increasing in size and often complexity, designed to assess the dosage and safety profile in healthy volunteers as well as patients; later trials are designed to study efficacy and safety in a large number of patients and often last many years.
• Regulatory agency review: if a medicine is successful in clinical trials, a pharmaceutical company submits all the data collected to regulatory agencies for a comprehensive review with the aim of receiving a license (also known as marketing authorisation) for it. This indicates that a medicine has undergone a thorough review and any safety risks are thought to be outweighed by the potential benefits.
• Post-marketing safety monitoring and surveillance: regulatory agencies continue to collect safety information about medicines after licensing to find out how the medicine performs under real-life conditions. They also review applications affecting changes to a medicine’s formula, labeling, or dosage instructions, or larger changes such as dose strength, a new form of administration, or new data that affect the licensed indication.

The entire process can take 10-15 years and cost a pharmaceutical company more than 2 billion USD []. Furthermore, a potential medicine may not make it through the entire process. Clinical trials can fail due to a lack of efficacy (in up to 50% of cases), unacceptable safety profile, or even inadequate planning, causing development to be discontinued. In fact, it is estimated that as many as 90% of potential medicines that enter clinical trials fail []. In the USA where licensing approval and monitoring is carried out by the U.S. , it is estimated that about 12% of medicines that undergo clinical trials eventually receive FDA approval [].

The regulatory authority in the United Kingdom is the , and in Europe, it is the .

Legislation supporting orphan drug development

Several countries have introduced legislation and incentives in order to encourage pharmaceutical companies to develop treatments for rare diseases, and thus make life-changing medications available to patients.

United States of America

The Orphan Drug Act was passed on 4 January 1983. It is applicable to diseases affecting less than 200,000 individuals in the USA (7.5 per 10,000 individuals) or more than 200,000 individuals where it is not possible to cover the cost of development and sales in the USA. The law applies to drugs, medical devices, and dietary products, and offers companies incentives for research (50% tax credit for clinical trials), help filing applications (including written recommendations, reduced waiting times, simplified and fast-tracked procedures), and seven-years marketing exclusivity [].

Marketing exclusivity prevents similar competitor medicines from being brought to market for the period of exclusivity. This is designed to give pharmaceutical companies the chance to recoup some of the costs involved in the drug development [].

Europe

Regulation (EC) No 141/2000 of the European Parliament and of the Council on orphan medicinal products came into force on 16 December 1999, and applies across the territory. It is applicable only to medicine for human use, for the treatment, prevention or diagnosis of a disease that is life threatening or chronically debilitating with a maximum prevalence of 5 per 10,000 individuals.

Incentives outlined in this regulation include technical assistance during applications, fee reductions (including for trial protocol development), accelerated, centralised marketing procedures, 10-year marketing exclusivity, additional incentives for companies classed as micro, small and medium-sized enterprises, and in some cases early access to medicines. Despite a centralised European system, availability and speed of access are not the same across all member states [].

Orphan medicines for pediatric populations may benefit from an additional 2 years of marketing exclusivity [].

Other countries

Japan adopted similar legislation in 1993 and Australia in 1998 [].

A look at terminology: Medicine with orphan designation

In Europe, companies can apply to the for orphan designation for promising medicines, which if granted helps them access the incentives covered by orphan legislation, assisting them with further product development.

The aim of any medicine in development is to achieve a marketing authorisation, making it available for the treatment of patients. COMP also assesses the validity of maintaining the orphan designation after marketing authorisation has been granted, which then offers marketing exclusivity under the European orphan legislation []. This is a medicine marketing authorisation and designated orphan status, also known as an orphan drug/medicine.

For an authorised product, the medical indication for the orphan designation may differ from the official approved indication [].

As will all developmental medicines, not all potential medicines with designated orphan status achieve marketing authorisation. In 2017, the EMA reported that 66% of applicants gained orphan designation for their developmental medicine, but only 8% were ultimately marketed as orphan medicines [].

The maintains a searchable list of products with orphan designation in Europe.

How many orphan drugs are there?

While exact figures for the number of medicines with a marketing authorisation and orphan designation may be hard to find, one document based on data available from the Orphanet database of orphan drugs in Europe, reported that at the end of February 2023, there were 184 drugs with a European marketing authorisation and orphan designation in Europe []. Data from the EMA suggest the number may be slightly higher (over 240) [].

Most of the orphan medicines are antineoplastic (to treat cancer) and immunomodulating (affect the immune system) agents (42.9%), followed by medicinal products for the alimentary tract and metabolism (16.3%), and nervous system (7.6%). 10.3% fall into the category of gene therapy [].

The same Orphanet report, states that 307 rare disorders, or 4.84% (of 6346 rare diseases in the Orphanet database in January 2024) benefit from an orphan medicine in Europe. Many are rare neoplastic disorders (e.g., multiple myeloma, ), rare inborn disorders of metabolism (e.g., , Argininemia), or rare endocrine diseases (e.g., familial isolated [].

As a comparison, as of April 2024, 410 drugs had marketing authorisation for the treatment of rare diseases without designated orphan status. They cover 491 rare disorders [].

Examples of orphan drugs

Example 1: Ivacaftor (Kaftrio)

Kaftrio is a combination regimen containing ivacaftor authorised in the EU to treat pediatric patients with cystic fibrosis and at least one causative mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene [, ]. is a life-threatening, progressive, inherited condition that causes severe damage to the body, particularly the respiratory and digestive systems. It has a prevalence in the general population of 1 in 9,000 [].

Example 2: Nusinersen (Spinraza)

In 2017, Spinraza became the first drug licensed for 5q spinal muscular atrophy [, ]. is a genetic neuromuscular disorder with symptoms including muscle weakness and hypotonia (decreased muscle tone) that affect life quality and life expectancy. It has a prevalence of 1–2 per 100,000 people [].

Example 3: Eculizumab (Soliris)

Soliris was marketed for paroxysmal nocturnal hemoglobinuria in 2007 [, ]. Paroxysmal nocturnal hemoglobinuria is a rare blood disorder with the main symptom of red, brown, or dark colored urine that is especially noticeable at night. This is caused by the immune system breaking down red blood cells. It affects around 6 in 1 million people [].

For more information about orphan medicines, The European Commission maintains a , and Orphanet has a and also publishes a list of in Europe.

Conclusion

Our scientific and medical knowledge of rare diseases is still quite poor, with most knowledge available for the most common rare diseases. However, patients with rare diseases have the same desire and right to treatment as patients with other more common diseases. Area-specific legislation encourages pharmaceutical companies to develop drugs for the treatment of rare diseases, where otherwise the cost may mean they may choose not to.

In Europe, there has been a general trend for an increase in both drugs with marketing authorisation and orphan designation, as well as those with a marketing authorisation for a rare disease without orphan designation []. Although this suggests that supportive legislation is somewhat effective, the number of rare diseases with an approved treatment is only around 5%. Nevertheless, the existence of the legislation and associated incentives for pharmaceutical companies continues to offer hope to patients, their families and carers.

It has been suggested that if an orphan product that would not be cost effective to develop without legislation is used to treat a rare disease, then a rare disease could possibly be defined as one that is not cost effective to treat []. Even so, rare disease treatments can often help alleviate symptoms and improve the quality of life, therefore their research and development should be actively encouraged.