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What to keep in mind as a developer of Drugs for Rare Diseases?

The definition of rare disease varies across countries and jurisdictions, but it usually takes into account disease prevalence, severity and existing therapeutic options.

  • In the United States, rare disease is defined as a disease or condition that affects fewer than 200,000 People.

  • In the EU, disease is defined as rare when it affects fewer than 5 in 10,000 people.

There are approximately 7,000 different rare diseases known today, with many more still to be identified. Rare diseases currently affect 3.5% - 5.9% of the worldwide population. Although most rare diseases impact relatively few people, their impact on public health is far-reaching. It is currently estimated that 80% of rare diseases have identified genetic origins and affect between 3% and 4% of births. Other rare diseases are due to degenerative and proliferative causes.

Examples of rare diseases include:Duchenne Muscular Dystrophy, Cystic Fibrosis, Amyotrophic Lateral Sclerosis (ALS), Pompe Disease, Sickle Cell Anemia, and many types of cancer.

Orphan Drugs

According to the European Medicines Agency (EMA), Orphan medicine is “a medicine for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition that is rare or where the medicine is unlikely to generate sufficient profit to justify research and development costs.”

There are various incentives, depending on the national orphan drug legislation, intended to provide support to companies developing orphan drugs, with the goal to minimize the effect of the anticipated low sales due to the rarity of the disease.

In the US the “Orphan Drug Act” (ODA) was established in 1983 and it was the first major piece of legislation of its kind, followed by Japan and Australia. It the EU the Regulation (EC) No 141/2000 was implemented in 2000.

The ODA acknowledged that “because so few individuals are affected by any one rare disease or condition, a pharmaceutical company which develops an orphan drug may reasonably expect the drug to generate relatively small sales in comparison to the cost of developing the drug and consequently to incur a financial loss“. With this act, the need for incentives for orphan drug development and other changes has been officially recognized.

From 1967 to 1983, only 34 drugs approved by the Food and Drug Administration (FDA) were for rare diseases, and only 10 of the products brought to market by the pharmaceutical industry in the decade before 1983 would have qualified under today’s ODA as orphan drugs.

Since the passage of the ODA, over 770 orphan drug approvals have been granted, bringing treatments and cures to rare disease patients in need.

Regulatory challenges – practical aspects

Being involved for many years in all aspects of orphan drug development we have collected some universally applicable guidance tips that developers of orphan drugs should take into consideration when preparing their development plans:

  • Learn from previously approved orphan drug products:

There is a considerable knowledge gathered since Orphan drug regulations have come into force in various regions. Followed by mandatory publications of marketing authorization reports, it is now extremely important for developers of orphan drugs to perform a thorough research on previously approved products in same or similar indications and/or same or similar compounds.

  • Orphan Drug designations must be renewed before MA is granted

Very important aspect to know is that if a certain product received an ODD in 2015 it might not qualify for it in 2025, either due to higher disease prevalence or other aspects. In addition, competitors could register and bring their product earlier on the market. Next to the impact on market share developers will need to discuss significant benefit over this newly registered product, which can get complicated. It is important to monitor your competitors along the way using publicly available databases (e.g. ,, or

  • Orphan Drug Designation is granted based on at least some data with the product in question

It will be difficult to EMA/FDA to grant an ODD without seeing at least some in vitro or preclinical data involving your product, in the indication of interest. References to published literature is accepted but ODD request cannot rely solely on published literature, some proprietary data must be available.

  • Medical plausibility for indication in question must be carefully elaborated

This assumes an adequate definition of an indication and avoidance of narrowing the indication to a subset, if not scientifically and medically justified. This aspect is carefully reviewed by the EMA/FDA.

  • Research all other regulations that might be triggered by your orphan drug development

As an example, a requirement for a Pediatric Investigation Plan (PIP) should be clearly understood. In EU it is mandatory to discuss aspects of the PIP for orphan drugs. In US, the situation is a bit different and an agreed Pediatric Study Plan is not needed for orphan drugs (except for oncology products). The aspect of pediatric development is very important since it can trigger a considerable resource and time limitations. It is of crucial importance to be aware of it in a timely manner so you can properly plan.

  • Understand your ways to market

There are various ways how orphan drugs can get to the market. The paramount is to get the most promising orphan drugs as soon as possible to the patients who need them. With that in mind there are various ways how developers can speed up getting to market (e.g. PRIME, Accelerated Assessment, Breakthrough Designation, Priority Review).

Challenges in Orphan Drug Development

  • Only 5% of all rare diseases have an FDA-approved treatment option, although 85% to 90% of rare diseases are considered “serious or life threatening.”

  • As of August 2019, overall development for orphan drugs takes nearly 4 years longer than nonorphan medicines. Reasons vary, but the most prominent are clinical trial recruitment difficulties, choice and execution on study endpoints and surrogates.

  • While rare diseases now account for 31% of the R&D pipeline (up from 18% in 2010), the success rate for orphan drugs in clinical trials is estimated to be only 6%.

  • In 2019, 21 of CDER’s 48 novel drug approvals (44%) were approved to rare disease.

According to the EURODIS, top 3 obstacles to rare disease research are:

  • Lack of public funding

  • Lack of private funding

  • Small patient population

Companies developing orphan drugs deal with many uncertainties.

Limited funding, limited patient populations, complex clinical trial designs, use of biomarkers and surrogate endpoints and complex regulatory interactions are just some of many challenges that companies face while developing orphan drugs.

Pre-clinical testing may be challenging due to the lack of relevant animal rare disease models.

Clinical trials can be extremely hard to properly design, conduct and analyze. Sometimes there are only few medical experts who understand the disease and are willing to conduct clinical trials. Finding appropriate trial sites and patient population is another obstacle.

Double blind, randomized, placebo-controlled trials may not be ethical as no patient would like to receive a placebo for a seriously debilitating disease. Patient recruitment poses a significant challenge due to a very limited and geographically disperse patient population.

Many rare diseases affect disproportionally pediatric population raising additional considerations.

ODA has introduced FDA-administered research grants for orphan drug development, 7-year market exclusivity, tax credits and user fees waivers. Similarly, EU and EU Member States offers also research funds, 10-year market exclusivity and various discounts for interactions with the European Medicines Agency.

Early interaction between sponsor and regulatory agencies is crucial for the timely discussion of the trial design, sample size calculation, meaningful outcomes and other aspects crucial for the orphan drug development.

In case you have any comments you want to share with us or if you have any questions please don’t hesitate to contact us at


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