Finding Homes for Orphans

The unique challenges of researching, managing, and developing orphan drugs for rare diseases

Rare diseases are having a moment, and not just in the field of hematology, where most of the “orphan diseases” find their home.

In 2017, the U.S. Food and Drug Administration (FDA) approved 80 agents with an orphan indication (a drug intended to treat any disease that affects fewer than 200,000 patients), and that number climbed to 90 in 2018. Most of those approvals are for the treatment of rare hematologic disorders, which account for a large portion of the disorders hematologists see every day: Between 2008 and 2017, more than half of the drugs granted orphan status were for the treatment of hematologic malignancies or blood disorders.1

Despite the name, rare diseases are not so rare. The National Organization for Rare Disorders (NORD) lists more than 7,000 rare diseases and disorders, which affect approximately 30 million Americans, or 10 percent of the U.S. population.2 The record number of new drug approvals and growing attention being paid to these disorders reflect concerted efforts by doctors, researchers, pharmaceutical companies, patient advocacy groups, and the FDA to raise awareness about their profound impact on patients’ – and caregivers’ – lives.

By some measures, these stakeholders have been enormously successful; by others, they still have a long way to go. “Rare diseases have received more attention in the media, but I think it’s been harder to reach that same level of attention in terms of research,” said Neil Zakai, MD, MSc, a hematologist at the University of Vermont Medical (UVM) Center and an associate professor at UVM’s Larner College of Medicine.

ASH Clinical News spoke with Dr. Zakai and other clinicians and researchers about the recent attention being paid to these disorders – and how to translate the seeming popularity of rare diseases into meaningful progress for patients.

What Is a Rare Disease?

The FDA defines a rare disease as one that affects fewer than 200,000 patients, and any drug or biologic intended to treat, diagnose, or prevent such diseases as an “orphan drug.”3 Other countries have similar definitions, although the number of affected persons can vary. Regardless of the exact threshold applied, rare diseases are given this special distinction to promote awareness of – and eventually improve the diagnosis and treatment of – these conditions.

However, the limited number of patients suffering from each rare disease has led to myriad research and treatment challenges, explained David Fajgenbaum, MD, MSc, assistant professor of medicine at the University of Pennsylvania’s Perelman School of Medicine. Dr. Fajgenbaum also is executive director of the Castleman Disease Collaborative Network (CDCN), which brings together scientists, patient groups, academic institutions, and other organizations to improve the diagnosis and treatment of Castleman disease – a rare lymph node disorder he was diagnosed with during his third year of medical school.

Foremost among the challenges Dr. Fajgenbaum outlined is the difficulty of running studies with so few patients available to participate in trials. “Of course, the fewer patients, the fewer data are going to exist,” he said. And the patients who can supply data are likely to be spread out geographically, making collecting samples and running tests exceptionally expensive and time-consuming.

Rare diseases also have complex presentations: Approximately 80 percent of rare diseases are genetic and continue throughout a patient’s life. And, while some patients don’t display symptoms until adulthood, about 50 percent of rare diseases affect children. Symptoms can vary from patient to patient and can change as patients age.

The limited information about the natural progression of rare diseases, combined with a variation in symptoms and severity, mean that designing ideal endpoints for clinical trials for these conditions is challenging. According to a report from the Tufts Center for the Study of Drug Development, the average time from first patent filing to marketing approval of an orphan drug is 15.1 years – 2.3 years longer (an 18% increase) than for therapies for more common diseases.4

Still, Dr. Fajgenbaum is optimistic about the future of rare disease drug development. “So much work has already been done for the more common diseases, so there is just more low-hanging fruit and more opportunity for major strides in the rare disease space,” he said. Discoveries in rare diseases can dramatically change patients’ lives, he suggested, while discoveries in more common diseases are likely only to lead to incremental improvements in known treatment strategies.

The Rarity of Rare Disease Specialists

Even as rare diseases gain more attention, physicians like Courtney Fitzhugh, MD, a Lasker Clinical Research Scholar at the National Institutes of Health’s (NIH’s) National Heart, Lung, and Blood Institute, said there remains a shortage of providers who specialize in rare diseases. This is true even for more common rare diseases like sickle cell disease (SCD), Dr. Fitzhugh’s specialty.

“There are not many adult providers taking care of patients with sickle cell,” she said, explaining that the scarcity of clinicians trained in the management of SCD means pediatric hematologists are stretched thin. “It’s hard to find doctors for older pediatric patients who need to transition to adult care.”

It also is common for institutions to struggle to find clinical trial participants, according to Mitchell Cairo, MD, chief of pediatric hematology, oncology, and stem cell transplantation at New York Medical College.

“Participating in clinical research trials can be cumbersome for a patient and a family. Many patients with rare diseases like SCD come from socioeconomic backgrounds that provide overwhelming barriers that can prohibit them from actively being involved, whether it’s family support, transportation, insurance coverage, etc.”

“Rare disease foundations are playing a greater role in raising awareness about diseases, pushing forward guidelines, and bringing together consortia … to make more progress.”

—David Fajgenbaum, MD, MSc

These impediments have contributed to low rates of clinical trial participation, Dr. Cairo added. “I would like to find ways to solve that issue over time, by providing additional funding over and above the regular funding to help families be able to participate.”

On the pharmaceutical development side, inadequate funding is frequently blamed for the lack of treatments for rare diseases: With so few patients to use an approved orphan drug, the return on investment for years of research doesn’t make fiscal sense for most pharmaceutical companies. To address this concern, the FDA’s definition of an orphan drug includes a stipulation that companies can apply for an orphan drug indication if their product is intended for use in diseases that affect more than 200,000 people but are not expected to recover the costs of developing and marketing the drug.3

The Missing Link: Advocacy Groups

The greater focus on rare diseases appears to have coincided with a greater understanding of the human genome and the genetic basis of diseases, according to Dr. Cairo, which “is pointing us in a direction of therapeutic opportunities that really didn’t exist before in these rare diseases.”

Alongside this breakthrough in knowledge, patient advocacy groups – which are primarily known for raising awareness and funds for research – have started stepping up to act as liaisons between researchers and institutes and between patients and pharmaceutical companies. The Cystic Fibrosis Foundation’s partnership with Vertex Pharmaceuticals is a widely cited example of collaboration between advocacy organizations and a pharmaceutical company; the agreement, in which the foundation invests in the for-profit company, has helped produce the first three disease-modifying drug approvals for cystic fibrosis.5

“Rare disease foundations are playing a greater role in raising awareness about diseases, pushing forward guidelines, and bringing together consortia,” Dr. Fajgenbaum said. “These types of proactive efforts from rare disease foundations are getting the attention of physicians and researchers and certainly providing resources to make more progress.”

Dr. Fajgenbaum established the CDCN in 2012 with a goal of accelerating treatments for Castleman disease in four main areas: a research plan, strategic collaborations that span the globe, awareness and fundraising, and patient engagement. The network fills a hole and acts as a “central player between all of the various aspects of the health-care industry,” he noted. In addition to creating a network of researchers and patients, the group has identified key goals for future research and established diagnostic criteria for HHV-8-negative multicentric Castleman disease.6

The American Society of Hematology also has taken a proactive stance in supporting rare diseases research: In September 2018, the Society announced the launch of an SCD clinical trials network, under the auspices of the newly formed ASH Research Collaborative (ASH RC), “to accelerate the development of new therapies for a patient community that has very few treatments and curative options.”7 The network will connect trial locations and sponsors, provide consulting services to each site, and encourage patient input and involvement. Other efforts will focus on reducing inefficiencies and redundancies in the research landscape, like establishing a single institutional review board to serve all research sites and trial sponsors, along with a central data repository – the ASH RC Data Hub – to aggregate and facilitate sharing of clinical data. The group plans to initiate its first study in the fall of 2019.

“Enrollment and completion of clinical trials in SCD have historically been slow and costly,” said 2018 ASH President Alexis Thompson, MD, MPH, of the Ann & Robert H. Lurie Children’s Hospital of Chicago. “Establishing an organized network that will accelerate the completion of clinical research studies and bring new therapeutic options to patients more quickly is one of the most meaningful ways ASH can make a difference in the lives of people with this debilitating, chronic disease.”

Physician Recruitment

Like Dr. Fajgenbaum, many rare disease specialists are drawn to their area of expertise by personal experience. “My connection obviously is personal, and I would say that’s the case for most physicians who get involved in rare disease,” he said. “They treat a patient who has a rare disease, they recognize the challenges or how much work still needs to be done, and they start to look into it a little bit more.”

For example, Dr. Fitzhugh was introduced to SCD at an early age, when her mother’s organization hosted a Christmas party for children living with SCD.

Debra Regier, MD, PhD, a geneticist at Children’s National Health System in Washington, DC, learned about the challenges of treating rare diseases when her nephews were diagnosed with one. Now, Dr. Regier is hoping to nurture young investigators’ interests in rare diseases. She is education director of the Rare Disease Clinical Research Network’s Rare Disease Training Program, which launched in 2015 with the goal of teaching the “characteristics that we see in people who succeed and stay in rare disease research.”8

Over eight weeks, program workshops introduce researchers to strategies for conducting statistical analyses in studies with few patients, fostering trust in patients and families, building patient networks, and obtaining funding. “We started with 20 people, and last year, we had almost 40 applications,” said Dr. Regier. “Now, we’re accepting 30 people a year into the program.”

While more and more trainees are learning about rare diseases, Dr. Zakai explained that reaching young trainees is only part of the battle. Once physicians are out of training, their time becomes billable, and it can be difficult to keep them involved in research of any kind, let alone rare disease research.

“From a recruiting perspective, hospitals and universities are very risk-averse, so it’s hard to get them to take a risk on a person to provide the protected time for research nowadays,” he said. “Ten or 15 years ago, it was much easier to justify a decision with protected time to allow physician–scientists to build a research career. Now, it’s much more difficult to get these spots approved without funding already in hand, meaning that young investigators already have a grant that protects their time.”

Federal Support

The FDA has stepped in to address some of these challenges. One approach has been to co-host workshops like the FDA-ASH SCD Clinical Endpoints Workshop in October 2018, with a goal of identifying opportunities to bring uniformity and standards to existing SCD endpoints, identify gaps, and propose development of new endpoints for future research.9 Similarly, the Product Development in Hemophilia workshop, held in December 2018, brought together staff from the FDA’s Oncology Center of Excellence, the Center for Biologics Evaluation and Research, and the Center for Drug Evaluation and Research to discuss the development of patient-experience and patient-reported outcomes for use in trials of novel hemophilia products.10

But, undoubtedly, the agency’s largest impact on rare disease treatments began in the 1980s with the Orphan Drug Act.11 This legislation was designed to incentivize pharmaceutical companies to take the financial risk of developing drugs to treat rare diseases. The act offered three main incentives: federal grants for orphan drug research, a 50-percent tax credit to help cover the cost of clinical trials, and seven years of marketing exclusivity for products approved as orphans.

By some measures, the act has been extraordinarily successful. From 1967 to 1983 (the 16 years immediately before the act was passed), only 34 drugs were approved for rare diseases; since the act was passed, the FDA has approved more than 500 orphan drugs.3

Dr. Cairo, whose research has been supported by an Orphan Products Clinical Trials Grant, said the act has had an “extremely positive” influence on his work. “I can’t say enough about how much and how critical the FDA has been in creating this grant mechanism for orphan diseases,” he stated. “We would not be able to accomplish what we’ve done or cure all the patients we’ve cured without that support.”

Orphan Drug Act Controversies

The incentives, though, may have worked a little too well: So many companies applied for orphan drug designation for their products that the FDA couldn’t keep up, creating a backlog of 138 overdue drug applications by 2017. According to the FDA, reviewers caught up and erased the backlog in September of 2017.12

In the 16 years prior to the Orphan Drug Act’s passage, only 34 drugs were approved for rare diseases; since it was passed, the FDA has approved more than 500 orphan drugs.

The legislation also included a well-known loophole that allowed companies to skip conducting crucial pediatric trials for products designated as orphan drugs. Manufacturers have exploited this exemption, seeking to designate their products as orphan drugs to avoid the pediatric study requirement. In 2018, the FDA effectively closed this loophole, issuing a draft guidance for industry that clarifies orphan drug requirements for pediatric subpopulations of a common disease.13 (Editor’s note: The FDA’s Office of Orphan Products Development [OOPD] was unavailable to comment for this article because of the government shutdown.)

Others believe that the seven-year period has given opportunistic companies the ability to charge exorbitant prices for orphan products. When the seven-year exclusivity for one orphan designation runs out, some companies seek orphan status for the same drug for a different indication, gaining another seven years of market exclusivity. For example, in hematology/oncology, the manufacturers of rituximab, pegfilgrastim, and lenalidomide have been able to gain new approvals. A 2017 Kaiser Health News investigation found that 70 of 450 orphan drug approvals weren’t new; they were already being marketed for common diseases.14

A November 2018 investigation from the Government Accountability Office (GAO) also points to some areas for improvement in the orphan drug program, reporting that many applications were not thoroughly evaluated.15 “GAO’s analysis of 148 designation review templates found that FDA does not consistently record or evaluate background information when making designation decisions,” the authors wrote.

In many cases, applications that were missing important background information were approved, and reviewers did not always verify the information they did have. “Specifically, we found that OOPD granted designation to 11 applications where the reviewer did not record prior orphan designation history, to 13 applications where the reviewer did not document independent verification of the manufacturer’s population estimate, and to two applications where the reviewer did neither,” according to the report.

Critics also have pointed to other oversights in the Orphan Drug Act that could be exploited. For example, pharmaceutical companies can split diseases into smaller populations, suggesting a drug only be used for patients in particular stages of disease, or repeatedly apply for more orphan designations for the same drug. Some of the most widely used drugs also have orphan drug designations, like Humira (adalimumab), the best-selling drug in the world. It initially was approved to treat rheumatoid arthritis but later received orphan designations to treat juvenile rheumatoid arthritis, Crohn disease, and uveitis.16

Prices Reaching Rare Heights

Orphan diseases are getting more attention recently, and so are the prices for their treatment. Despite the financial incentives offered by the Orphan Drug Act, companies continue to price drugs for rare disease in the hundreds of thousands of dollars per patient per year. As part of the Kaiser Health News investigation, EvaluatePharma found that out of the 10 drugs with the highest annual sales (in total dollars), seven were considered orphan drugs.14 By 2020, it is predicted that orphan drugs will account for 20 percent of all drug sales (excluding generics).

The rationale behind pricing is that orphan drugs take longer to bring to market, accruing more in research-and-development costs. However, a December 2016 report prepared for Congress suggested that the average cost to develop an orphan drug was less than half that of a drug for more common diseases – $1 billion compared with $2.6 billion.16

A 2017 study commissioned by NORD appears to allay concerns about the pricing of orphan drugs, however: Only 7.9 percent ($36 billion) of drug spending in the U.S. went toward orphan designations of orphan drugs, while another $100 billion was spent on nonorphan uses of drugs with orphan designations, suggesting that the Orphan Drug Act has not been a significant driver of health-care spending in the U.S.17

There are no concrete plans for lowering the costs of orphan drugs, but not for lack of trying. Dr. Fajgenbaum pointed to several bills attempting to control pharmaceutical pricing that have failed to or are unlikely to pass. For example, the Open Act, which has been under review for about two years, seeks to lower prices by incentivizing off-label studies of approved drugs by offering market exclusivity, but only for six months.18

Still, parents are unlikely to refuse a drug that could save their child’s life because the price tag is too high. “It’ll be important to see what pediatric patients choose to do as they grow up,” Dr. Regier remarked. Pharmaceutical companies occasionally offer copay assistance, though, so patients themselves may not struggle to cover the cost of the drug. Instead, only insurance companies shoulder the burden of the astronomical price.

Nonetheless, Dr. Regier said she was “impressed that the FDA is thinking about rare diseases as well as they are.” To her, the most effective strategy will be to continue to decrease the cost of getting a drug to market. “That’s going to help us have more justification for saying this drug shouldn’t be this expensive.” —By Emma Yasinski


  1. Kaiser Health News. “Government investigation finds flaws in the FDA’s orphan drug program.” November 30, 2018. Accessed January 14, 2019.
  2. National Organization for Rare Disorders. “Rare Disease Information.” Accessed January 14, 2019.
  3. S. Food and Drug Administration. “Office of Orphan Products Development.” Accessed January 14, 2019.
  4. Tufts Center for the Study of Drug Development. “Tufts CSDD Impact Report May/June 2018.” May 29, 2018. Accessed January 14, 2019.
  5. Cystic Fibrosis Foundation. “CF Foundation Venture Philanthropy Model.” Accessed January 14, 2019.
  6. Fajgenbaum DC, van Rhee F, Nabel CS. HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy. Blood. 2014;123:2924-33.
  7. American Society of Hematology. “American Society of Hematology to Launch Sickle Cell Disease Clinical Trials Network.” September 29, 2018. Accessed January 14, 2019.
  8. Rare Disease Clinical Research Network. “Rare Disease Research Training Program.” Accessed January 14, 2019.
  9. American Society of Hematology. “FDA-ASH Sickle Cell Disease (SCD) Clinical Endpoints Workshop.” Accessed January 14, 2019.
  10. S. Food and Drug Administration. “Orphan Drug Act – Relevant Excerpts.” Accessed January 14, 2019.
  11. National Organization for Rare Disorders. “Trends in Orphan Drug Costs and Expenditures Do Not Support Revisions in the Orphan Drug Act: Background and History.” Accessed January 14, 2019.
  12. S. Food and Drug Administration. “FDA unveils plan to eliminate orphan designation backlog.” June 29, 2017. Accessed January 14, 2019.
  13. S. Food and Drug Administration. “FDA In Brief: FDA takes step to close orphan drug loophole that let drug developers sidestep pediatric studies.” December 19, 2017. Accessed January 14, 2019.
  14. Kaiser Health News. Drugmakers manipulate orphan drug rules to create prized monopolies.  January 17, 2017. Accessed January 14, 2019.
  15. S. Government Accountability Office. “Orphan Drugs: FDA Could Improve Designation Review Consistency; Rare Disease Drug Development Challenges Continue.” Accessed January 14, 2019.
  16. S. Department of Health and Human Services. “Prescription Drugs: Innovation, Spending, and Patient Access.” December 7, 2016. Accessed January 14, 2019.
  17. National Organization for Rare Disorders. “New Study Examines Use and Cost of Orphan Drugs.” October 17, 2017. Accessed January 14, 2019.
  18. gov. “H.R.1223 – OPEN Act.” Accessed January 14, 2019.