Rare and Orphan Diseases


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More than 7,000 rare diseases collectively affect over 25 million people in the U.S. Rare diseases, also known as orphan diseases, are classified as any disease that affects less than 200,000 Americans. Rare diseases include more familiar conditions such as cystic fibrosis, Lou Gehrig’s disease and Tourette’s syndrome, as well as less familiar conditions such as Duncan’s Syndrome, Madelung’s disease and acromegaly/gigantism. These conditions are complex and often not well understood, causing greater challenges to diagnose and treat, and only 5% of rare diseases have a treatment approved by the Food and Drug Administration (FDA).

Potential Causes

While most rare diseases are genetic in origin, many causes are not well understood. Even if the cause is identified, researchers may still not understand how the disease functions or how to properly treat it. The Institute of Medicine’s 2010 report on rare diseases and orphan products outlines four potential causes of rare diseases:

  • Genetic causes: 80% or more of rare diseases are genetic in origin. Sometimes one gene (as in alpha-1 antitrypsin deficiency) or multiple genes (as in Williams-Beuren syndrome) contribute to manifestations of the disorder. They can be inherited or arise in sporadic or chance mutations.
  • Infectious agents: Some infections are thought to be rare worldwide, while others are rare in wealthy countries but common in less economically developed countries. Tuberculosis, for example, was common in wealthy countries before preventive measures and treatments were discovered and widely applied, but remains a major cause of morbidity and mortality in developing countries. Infectious diseases can be rare but well-publicized and feared (such as rabies, botulism and Rocky Mountain spotted fever), while others are truly obscure (such as Lemierre syndrome).
  • Toxic agents: Exposure to natural or manufactured toxic substances can also cause rare diseases. For example, mesothelioma is a cancer typically caused by exposure to asbestos. Many types of poisoning could be listed as rare conditions, but often are not. Disease-causing toxic substances such as cadmium, chromium and phosphine are handled by the Agency for Toxic Substances and Disease Registry (ATSDR) and marine toxins caused by harmful algae blooms that may contaminate food are tracked by the Centers for Disease Control and Prevention.
  • Other causes: Rare conditions have a variety of other causes such as nutritional deficiencies, injuries, adverse effects of treatment and many others.

Effects on Patients and Caregivers

Financial strain from rare diseases can affect both patients and their caregivers. The diagnosis process can be time-consuming and expensive. Medications developed specifically to treat rare diseases can cost families tens or even hundreds of thousands of dollars per year. Many rare conditions are diagnosed in childhood and continue to affect individuals for decades. Orphan drugs tend to have more coverage restrictions than non-orphan drugs, leading to higher per-unit price. Under Medicaid Part D, 85% of plans covered orphan drugs, which were placed in the highest cost-sharing tier, only covering 25% to 33% of the full cost of the drug.

Lost productivity, lost wages or lack of manageable work with crucial benefits can impact individuals living with a rare disease. Caregivers experience financial impacts from caring for patients with rare diseases, with 86% reporting that they cut back on household savings, did not save for long-term goals, used personal savings and took on more personal debt.

Additional barriers to accessing adequate health care services and treatment options exist for patients with rare diseases and their caregivers. These include financial effects such as lower income, limited transportation, leaving jobs to care for a child or spouse, and health care costs such as respite care, home medical equipment, medical or food supplements, and physical and other therapies. Only 27% of caregivers believed their local hospital could handle their patient’s rare disease or they could afford the associated travel and lodging costs to access a center of excellence or a specialist for some rare diseases.

Diagnosis and Treatment

For one-third of individuals with a rare disease, it can take between one and five years to receive a proper diagnosis. Patients with rare diseases often seek treatment in clinics where the condition has never been seen before and symptoms that are absent, masked, misunderstood or confused can also contribute to delayed diagnosis.

Rare disease treatments range from curing the disease, modifying how the disease functions or treating the symptoms. Truly curative treatments are rare. Disease-modifying therapies target the underlying pathology of a disease to prevent it from worsening. Symptomatic treatments seek to temper symptoms or maintain physical, emotional and mental functioning. Treatments may include medications, nutritional agents, surgical procedures, psychotherapy, physical and occupational therapy,  and medical devices. Examples include cardiac valve conduits that expand as a child grows to prevent repeated surgeries throughout their lifetime and nutrition and dietary supplement interventions to promote proper growth and development among patients with inborn errors of metabolism.

Many patients with rare diseases require medical devices to diagnose and treat their conditions, such as genetic tests, pediatric implants that grow with a child and pediatric intrathecal ports for drug delivery. The FDA and the National Institutes of Health’s National Center for Advancing Translational Sciences/Office of Rare Diseases Research reported that 917 clinicians cited unmet medical device needs in 2015, with many noting the need for entirely new diagnostic and therapeutic devices.

Newborn screening: Early detection, diagnosis and intervention is critical to prevent death or disability for many rare diseases. Half of all patients diagnosed with a rare disease are children, and as many as 3 in 10 children with a rare disease will not live to see their 5th birthday. Newborn screening, routinely provided to 4.1 million babies each year in the United States, can identify genetic, endocrine and metabolic disorders. Each year, 4,000 babies are diagnosed as having a congenital disorder, and approximately 1,000 go undetected.

The Recommended Uniform Screening Panel (RUSP) includes 35 core conditions and 26 secondary conditions. Each state decides which conditions to include in its newborn screening program. Most states include those listed in the RUSP, but it can take years to fully implement RUSP recommendations.

Federal Action

In 1983, Congress passed the Orphan Drug Act (ODA), which created financial incentives for drug and biologics manufacturers to research and develop treatments for orphan diseases. These include tax credits for the costs of clinical research, government grant funding, assistance for clinical research, and a seven-year exclusive marketing period for the first sponsor of an orphan-designated product that obtains market approval from the FDA. Since the ODA passed, more than 250 orphan drugs have been developed and made available to more than 13 million Americans. Nonetheless, it can take more than 10 years from initial discovery to entering the market, and less than 12% of drugs that enter clinical testing eventually make it to the market.

For the treatment of rare diseases, the FDA administers three programs to incentivize research and development of pharmaceuticals, biologics and medical equipment. The Orphan Drug Modernization Program was created to eliminate the FDA’s backlog of orphan drugs. The Rare Pediatric Disease Designation and Voucher Program awards priority review vouchers to sponsors of rare pediatric disease product applications. The Humanitarian Use Device Designation Program creates an alternative pathway for getting market approval for medical devices that may help people with rare diseases or conditions. Several bills were introduced in the 116th Congress (2019-2020) addressing the research and development of treatments, medication affordability, and education and awareness of rare diseases.

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