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June 29, 2022

Rare Disease Spotlight – tracing the rise of orphan drug designations over almost 40 years

In the first edition of Pharmaceutical Technology’s series on the FDA’s orphan drug program, we examine how its popularity has grown over the years.

By Irena Maragkou

This year has already been eventful when it comes to the development of therapies for rare diseases. The US Food and Drug Administration (FDA) put a high-profile bluebird bio trial for sickle cell disease on partial clinical hold, and advisory panels deliberated over decisions involving gene therapies for amyotrophic lateral sclerosis (ALS), cerebral adrenoleukodystrophy (CALD), and beta-thalassemia. Additionally, pricing and access for rare disease therapies continue to be scrutinized closely.

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Most, if not all, of these therapies used the FDA’s Orphan Drug Designation to aid their development plans. So far this year, 176 drugs have already received this designation.

Almost 40 years since it was instituted, some have described the FDA’s orphan drug program, which is meant to foster innovation, as “one of the most successful US legislative actions in recent history”. Others judge its success based on the fact that 95% of rare diseases still have no available therapies and patient needs remain unmet. Research and drug development for rare diseases has shifted from “niche” to conventional, aided by multiple drivers of growth in the field and favorable legislation.

In a series of data-driven deep dives, we will examine how the development of orphan drug therapies has evolved over the years, and use the FDA’s orphan drug program as a barometer of these advances. For example, while orphan drug designations have more than doubled in the last decade compared to the previous one, only 16% of therapies with orphan tags have managed to gain FDA approval in some indications.

In order to examine the impact of the FDA’s program on research for rare diseases, Pharmaceutical Technology analyzed the number of orphan drug designations assigned since the establishment of the Orphan Drug Act, using GlobalData’s proprietary database. GlobalData is the parent company of Pharmaceutical Technology.

Have orphan drug designations increased in recent years?

The Orphan Drug Act was established in 1983 to promote the development of drugs for rare diseases with limited or no available treatment options. Prior to the program, only 10 drugs were approved for a rare disease.

Orphan drug designations provide financial incentives for companies and developers, including “tax credits for qualified clinical testing”, “a Waiver of the Prescription Drug User Fee” that is currently at almost $3 million for a new drug, and “potential seven years of market exclusivity”. However, extended market exclusivity is often associated with high drug pricing and limited patient access. Apart from financial uncertainty, inherent scientific risks also hinder rare disease research since the lack of understanding about the underlying pathophysiology of rare diseases and the fact that a small patient population makes designing clinical trials complicated.

In the US, over 30 million patients (roughly 1 out of 10 Americans) suffer from more than 7,000 rare diseases. A rare disease is defined by the Orphan Drug Act as a disease or condition that affects less than 200,000 individuals in the US. A drug can also be considered for an orphan drug designation if a pharmaceutical company is unlikely to reclaim the research, development, and approval costs in addition to reasonable profit for a drug within seven years of an FDA approval.

Since the Orphan Drug Act was passed, many pharmaceutical companies have been motivated by these incentives to develop drugs for rare diseases, and the number of orphan drug designations being awarded has rapidly increased, especially in the last 20 years.

Based on Pharmaceutical Technology’s analysis, between 1983 and 2000, only 568 drugs received their first orphan drug designation for a specific therapeutic indication. During 2001–10, the number of granted designations almost tripled, with 1,527 drugs receiving their first  orphan drug designation. The total number of designations more than doubled during 2010–21 compared to those given in the preceding decade.

Based on the upward trajectory in the number of orphan drug designations in recent years, the rare disease drug market is experiencing rapid growth. However, this increased interest in rare diseases cannot only be attributed only to the impact of the Orphan Drug Act and its incentives, as the understanding of the underlying disease pathophysiology has greatly improved due to advances in genomic research in the last 20 years. The identification of new disease subtypes and their molecular etiology, the development of personalized medicine, the use of technology, and artificial intelligence (AI) tools in research and treatment have also helped accelerate the development of orphan drugs.

What happens after a drug gets an orphan drug designation?

An orphan drug designation does not automatically translate into approval. Since the inception of the program, approximately 16% of therapies that received the designation later gained FDA approval, but 23% are now classified as inactive. 

Moreover, almost 9% of expensive therapies with orphan drug designations were later discontinued for certain indications after they received marketing authorization. An additional 2.67% of therapies with orphan designations were completely withdrawn from the markets, such as Eli Lilly’s Lartruvo (olaratumab). Lartruvo was approved in 2016 for the treatment of rare soft tissues sarcoma and was withdrawn from the global markets three years later due to the failure of the Phase III ANNOUNCE trial, which did not confirm improved patient survival.

Most pipeline orphan therapies are currently in Phase II clinical trials (18%), while 11% of orphan drugs are in the preclinical stage, 9% are in Phase III, and 8% are in Phase I.

Since one drug may be under development or marketed for multiple indications, our analysis looked at all indications in which a drug has received a designation.

However, to establish whether the Orphan Drug Act has been successful in stimulating research in rare diseases and fostering innovation, it is necessary to take an in-depth look into the distribution of the rare disease burden, as well as the therapeutic areas and indications with orphan drug designations. Approximately 10.9% of the most prevalent rare diseases account for 98.6% of the total patient population suffering from rare diseases.

In the next installment of the series, we will take a look at orphan drug designations that have been granted in specific therapeutic areas to identify the top disease indications with the highest number of designations. Watch this space for more.

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How is the Biopharmaceutical industry evolving?

2021 was a year of continued innovation and change in the Biopharmaceutical industry. As the COVID-19 pandemic continues to take its toll on businesses worldwide, it’s time to look for new ways to create value, prepare for the future, and remain competitive in the ever-changing landscape. GlobalData’s expansive report examines the business environment and trends that shape the Biopharmaceutical industry. We highlight the most impactful emerging technologies, as well as the industry, regulatory, and macroeconomic factors that influence growth prospects. Access the report to:
  • Benchmark the impact of major themes on the Biopharmaceutical industry.
  • Gain a deeper "on the ground" perspective through exclusive opinions and analysis from industry respondents.
  • Evaluate the effects of COVID-19 on the sector.
Download the full report to understand what to expect and how to align your strategies for success.
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Enter your details here to receive your free Report.

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