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Winter 2024 - Critical Care

The Future of Orphan Drugs: Advancements, Challenges and Hope

An orphan drug is a pharmaceutical agent developed to treat medical conditions deemed rare diseases because they only affect a small percentage of the population.

An orphan drug is a pharmaceutical agent developed to treat medical conditions deemed rare diseases because they only affect a small percentage of the population. The term “orphan” signifies the limited patient population these drugs target. In terms of numbers, a rare disease in the United States is defined as one that affects fewer than 200,000 people. Historically, the development of drugs for these rare diseases was often neglected by pharmaceutical companies because of the low potential return on investment. All that changed when advocates rallied together and governments and regulatory bodies around the world introduced incentives and policies to spur the development of orphan drugs and improve the treatment outcomes and quality of life for impacted patient populations.

The origins of the orphan drug movement date back to the 1960s, when patients with rare diseases and their families began advocating for research into their conditions.1 Fast forward to the early 1980s, when families, advocates and leaders of several rare disease patient organizations formed an ad hoc coalition that became instrumental in passage of the 1983 Orphan Drug Act, a landmark bill that created financial incentives for the development of treatments for rare diseases.2 That coalition became the National Organization for Rare Disorders, or NORD, which celebrated its 40th anniversary in 2023.

The Orphan Drug Act’s initial incentives included a seven-year market exclusivity, tax credits for clinical research, research grants and waived U.S. Food and Drug administration (FDA) fees.3 The impact of these incentives was significant, leading to a boom in orphan drug approvals. Since the passage of the Orphan Drug Act, FDA has approved more than 500 orphan products and rare disease therapies, and orphan drugs currently make up more than 50 percent of new FDA drug approvals.2

Scientific Advancements Drive Development

The past decade has witnessed a surge in orphan drug development, driven by scientific advancements, increased understanding of rare diseases and regulatory incentives. Following are some key advancements in the field:

• Precision medicine: The era of precision medicine has ushered in a new approach to orphan drug development. Researchers are increasingly tailoring treatments to the specific genetic mutations or mechanisms underlying rare diseases, leading to more effective therapies with fewer side effects.3

• Gene therapy: Once considered a distant dream, gene therapy has become a reality in orphan drug development. One example is the groundbreaking treatment Luxturna, which targets a specific gene mutation that causes blindness. Its FDA approval hints at the potential of gene therapy for the treatment of rare diseases.4

• Advancements in rare disease diagnostics: Improved diagnostic tools such as Next-Generation Sequencing and biomarker identification have facilitated the identification of rare diseases and enabled more targeted drug development.5

Additionally, pharmaceutical companies are using recent advances in digital technologies to improve care strategies and provide hope for rare disease patients across thousands of different diagnoses. Thanks to growing sophistication in the use of data analytics and artificial intelligence, the industry is seeing improved diagnostics, accelerated research and development, and improved patient identification and tracking of disease progression. As a result, the rare disease industry is now on the brink of maturity and prepared for a period of sustained growth.6

Access to enhanced analytics also has the potential to decrease diagnosis time for patients who sometimes spend years waiting for a diagnosis and targeted treatment plan. Recent advances in analytics, coupled with greater accessibility of large data sets, give pharmaceutical companies an opportunity to identify and spotlight patient groups more quickly. Case in point: One global pharmaceutical company with a sizable rare disease operation deployed digital and analytic tools to improve its patient identification approach for one of its rare disease treatments. Using multiple core data sets of potential patients, the company built a predictive model to estimate the likelihood of any given individual having the targeted rare disease. They then used this model to identify a large population of undiagnosed patients and the physicians who were disproportionately likely to oversee patients with the disease. This more precise engagement of physicians enabled an increase of more than 40 percent in the number of patients who could benefit from earlier and better access to diagnosis and care in the five years following treatment launch.6

Assessing the Challenges with Clinical Trials

One of the key challenges in the development of orphan drugs is limited ability to enroll, engage and retain patients for clinical trials. Because patients are few and often geographically scattered, it can be hard to recruit enough candidates for trials and expensive to arrange the logistics. By necessity, many rare disease clinical trials are often multinational for sufficient patient recruitment, even in Phase I and II trials. This can challenge the defining of protocols, ethical reviews, organization of clinical services and standards of care. Language differences and working across varied time zones adds further complications. Potential participants may also be discouraged by trial requirements such as taking additional medication, completing diaries and recording symptoms or side-effects — tasks that add to the daily disease burden that patients already face.7

“Assembling enough patients to conduct longitudinal studies and clinical trials is challenging when so few people live with a specific disease,” said James Wilson, MD, PhD, who directs the Orphan Disease Center at the University of Pennsylvania. “For genetic diseases caused by a single gene defect, between two-thirds and three-quarters of affected individuals reside beyond the United States. We have to broaden our horizon outside of the U.S., not only to make sure we gain access to enough patients, but we also want to make sure that any advances that happen are distributed globally so that there’s global access and global impact.”8

Another challenge impacting clinical trial development is the overall lack of information about any given rare disease and its likely path of progression. “For rare diseases, oftentimes, there’s not enough known about the natural history to design a proper clinical trial because you have to select, in most study designs, a single primary endpoint on which the trial hinges. How do you pick the right one if you don’t know very much about the disease or its rate of progression or its main features?” asked Edward Neilan, MD, PhD, chief medical and scientific officer of NORD.8

To address these and other challenges, researchers at the Orphan Disease Center initiated a global study of individuals with Lesch-Nyhan disease, an extremely rare and severe neurological disorder caused by a single gene defect that affects approximately one in 300,000 people. Using a specialized rare disease data platform, the team is compiling medical records and analyzing motor function and behavioral symptoms in people of different ages to construct a picture of the evolution of the disease over time.8

Rare Diseases Facts and Statistics

  • Any disease affecting fewer than 200,000 people in the United States is considered rare.
  • Currently, more than 7,000 rare diseases have been identified.
  • Twenty-five to 30 million Americans are living with a rare disease.
  • Many rare diseases may result in the premature death of infants or can be fatal in early childhood.
  • All pediatric cancers are rare.
  • There are more than 500 types of rare cancers.
  • More than 90 percent of rare diseases are still without an FDA-approved treatment.
  • Rare diseases affect an estimated 35 million people worldwide.
  • Men, women, children and the elderly are all impacted. In actuality, rare diseases are not so rare!
  • Rare Disease Day is celebrated globally on the last day of February each year (the most rare day on the calendar) to raise awareness about rare diseases and the issues patients face.

Source: National Organization for Rare Diseases. Rare Disease Facts & Statistics. Accessed at

Five Rare Diseases People Never Knew Existed

    1. Stoneman syndrome: Fibrodysplasia ossificans progressiva (FOP), colloquially known as Stoneman syndrome, slowly turns connective tissue such as tendons, muscles and ligaments into bone. Frequency: one in two million people
    2. Alice in Wonderland syndrome: The most prominent and often most disturbing symptom is that of altered body image (confusion as to the size and shape of their body parts, usually the head and hands); the second major symptom is the distortion of visual perception (the eyes themselves are normal, but the sufferer ‘sees’ objects with the wrong size or shape and/or finds that perspective is incorrect). Frequency: currently known<
    3. Hutchinson-Gilford progeria syndrome: A genetic condition in which there is a rapid dramatic appearance of aging beginning in childhood. The characteristic facial appearance includes prominent eyes, a thin beaky nose, thin lips, small chin and protruding ears. Frequency: one in four million
    4. Alkaptonuria (or black urine disease): This is a very rare inherited disorder that prevents the body from fully breaking down two protein building blocks (amino acids) called tyrosine and phenylalanine, resulting in a buildup of a chemical called homogentisic acid in the body. Frequency: one in one million people globally
    5. Chronic focal encephalitis (Rasmussen’s encephalitis): Usually occurring in children under the age of 10 (more rarely in adolescents and adults), it is characterized by frequent and severe seizures, loss of motor skills and speech, paralysis on one side of the body (hemiparesis), inflammation of the brain (encephalitis) and mental deterioration. It can lead to the destruction or removal of a part of the affected child’s brain. Frequency: In Germany, 2.4 cases per 10 million people; in the United Kingdom, 1.7 per 10 million people

Source: Five Rare Diseases You Never Knew Existed. Open Access Government, Feb. 28, 2023. Accessed at

To enable similar studies for the entire spectrum of rare diseases, NORD has launched the IAMRARE registry program through which patients complete surveys about their experiences living with rare diseases. Since its launch, more than 13,000 people representing approximately 40 rare diseases have participated in the registry. At its most basic level, the registry helps identify patients with a rare disease that may enroll in a clinical trial. “The real desire of the IAMRARE platform is to do patient-led natural history studies,” Dr. Neilan said, noting that while there are about 7,000 rare diseases, the pharmaceutical industry has focused on only 100 or 200 of them. “That uneven attention is another problem that we’re trying to solve.”8

The Rare Diseases Clinical Research Network through the National Institutes of Health also shares the goal of laying the groundwork necessary to prepare rare disease indications for clinical trials. Currently, researchers and patient advocates come together to form consortia for related rare diseases and work together to determine the “who, what, where, when and how” of clinical trial design.8

Orphan Drug Success Stories

The success stories of orphan drugs are a testament to the incredible impact they can have on patient populations and their families. Among some of the standouts:9

• Coagulation factor IX (FIX) (BeneFIX/Rixubis/Alprolix) is approved to help control and prevent bleeding in people with hemophilia B. Coagulation FIX reached the U.S. market in 1997 and represented a shift in standard of care. Prior to recombinant coagulation FIX, patients received FIX from human plasma, which had the risk of passing on infectious disease. Coagulation FIX is on the World Health Organization list of essential medicines and has one of the highest volumes of orphan drugs in the United States.

• Imatinib (Gleevec) is a ground-breaking drug that revolutionized the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors. It is considered one of the most successful orphan drugs to date. Prior to imatinib, allogeneic stem cell transplantation was the only treatment for long-term control of CML. In one eight-year follow up study, the estimated overall survival of all patients randomized to receive imatinib was 85 percent.

• Cystic fibrosis modulator drugs such as ivacaftor (Kalydeco) and its combinations have transformed the treatment of cystic fibrosis, significantly improving the quality of life for patients. Prior to the approval of ivacaftor in 2012, only one other therapy was available to cystic fibrosis patients. The availability of ivacaftor, along with ivacaftor/lumacaftor (Kalydeco) and dornase alfa (Pulmozyme) has increased the life expectancy of cystic fibrosis patients.

• Rucaparib (Rubraca) was approved to treat women with advanced ovarian cancer who had been treated with two or more chemotherapies and whose tumors had a specific gene mutation (deleterious BRCA) as identified by an FDA-approved companion diagnostic test. Approximately 15 to 20 percent of patients with ovarian cancer have a BRCA gene mutation. FDA approved rucaparib under its 2017 accelerated approval program.

As far as breakthroughs and success stories on the horizon, there are a number of biotech companies actively making strides in developing rare disease therapies and treatments. Worth noting: London-based Alchemab Therapeutics is a biotechnology company working on harnessing the power of the immune system to create the next generation of antibody therapeutics for hard-to-treat diseases that do not yet have disease-modifying therapies. By studying the naturally-occurring antibody response in individuals who are resistant to or have overcome a certain disease, the company aims to develop antibodies into therapies for people who don’t have the same protective response. Also notable is Horizon Therapeutics, led by CEO Tim Walbert, who has a rare disease that causes inflammation throughout his body along with chronic pain. The company’s vision is to achieve medical breakthroughs for people with rare, autoimmune and severe inflammatory diseases, and they already have several in the pipeline.10

What the Future Holds

According to data in Evaluate’s 2022 Orphan Drug report detailed on, the orphan drug market is growing more than twice as fast as the non-orphan market, with a 2021-2026 compound annual growth rate of 12 percent. That means orphans will account for 20 percent of all prescription drug sales and almost one-third of the global drug pipeline’s value by 2026.9 The report goes on to state that orphans are forecast to match or outsize several mass-market drugs for chronic, widespread diseases, despite dramatically smaller patient numbers. Citing just one example, AbbVie/Johnson & Johnson’s chronic lymphocytic leukemia drug Imbruvica (ibrutinib) is expected to be the biggest orphan drug in 2026 with $13 billion in worldwide sales.11

Orphans also have strength in numbers: More than half of the FDA’s Center for Drug Evaluation and Research approvals in 2021 had orphan designations. In the first three months of 2022 alone, the administration approved seven rare disease drugs compared to just four for non-rare conditions. In fact, new medicines for chronic, widespread and highly complex conditions such as diabetes, heart disease or kidney disease are now in the minority.11

If these statistics are any indication, the future of orphan drugs is a promising one, driven by scientific advancements, regulatory incentives and collaborative efforts. These drugs have the potential to transform the lives of individuals affected by rare diseases, offering hope where there was once despair. As research continues to advance and access to treatments improves, the future looks bright.


  1. Mikami, K. Orphans in the Market: The History of Orphan Drug Policy. Social History of Medicine, 2019 Aug; 32(3): 609–630. Accessed at
  2. National Organization of Rare Diseases. History of NORD. Accessed at
  3. Mueller, CM, Rao, GR, and Needleman, KIM. Precision Medicines’ Impact on Orphan Drug Designation. Clinical and Translational Science, V.12(6); 2019 Nov. Accessed at
  4. FDA Approves Novel Gene Therapy to Treat Patients with a Rare Form of Inherited Vision Loss. U.S. Food and Drug Administration news release, Dec. 18, 2017. Accessed at
  5. Fernández-Marmiesse, A, Gouveia, S, and Couce, ML. NGS Technologies as a Turning Point in Rare Disease Research, Diagnosis and Treatment. Current Medicinal Chemistry, 2018 Jan; 25(3): 404–432. Accessed at
  6. Treating Rare Diseases: How Digital Technologies Can Drive Innovation. McKinsey & Co., Feb. 27, 2023. Accessed at
  7. Mellerio, JE. The Challenges of Clinical Trials in Rare Diseases. British Journal of Dermatology, Oct. 3, 2022. Accessed at
  8. Anderson, S. Finding a Home for Orphan Diseases. The Orphan Disease Center, May 2, 2023. Accessed at
  9. Orphan Drugs in the United States: Providing Context for Use and Cost. QuintilesIMS Institute, October 2017. Accessed at
  10. Shah-Neville, W. Ten Biotech Companies Making a Difference in Rare Diseases. Labiotech, Feb. 28, 2023. Accessed at
  11. Senior, M. Orphan Drugs: From Niche to Mainstream. PharmaExec, June 15, 2022. Accessed at
Trudie Mitschang
Trudie Mitschang is a contributing writer for BioSupply Trends Quarterly magazine.