Orphan drug program continues to yield treatments for serious conditions

The US orphan drug program has demonstrated that economic incentives and regulatory flexibility can spur development of treatments for small patient populations. Since enactment of the Orphan Drug Act (ODA) in 1983, FDA has approved >300 medicines for approximately 12 million patients around the world. However, there are approximately 6,000 to 8,000 rare diseases, so “we still have a very long way to go,” commented Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), at a May conference commemorating ODA’s 25th anniversary, which was sponsored by the Drug Information Association (DIA).

The US orphan drug program has demonstrated that economic incentives and regulatory flexibility can spur development of treatments for small patient populations. Since enactment of the Orphan Drug Act (ODA) in 1983, FDA has approved >300 medicines for approximately 12 million patients around the world. However, there are approximately 6,000 to 8,000 rare diseases, so “we still have a very long way to go,” commented Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), at a May conference commemorating ODA’s 25th anniversary, which was sponsored by the Drug Information Association (DIA).

Woodcock noted that genomic discoveries can expand understanding of the science behind many serious conditions, and personalized medicine promises an increased treatment effect and decreased side effects for many therapies. Additional partnerships between industry and patient groups and growing demand for pediatric treatments should spur development of more treatments for rare conditions, she said.

Before passage of the ODA, biomedical companies seldom invested in products unlikely to make a profit, recalled Abbey Meyers, prime mover behind ODA and founder of the National Organization for Rare Disorders (NORD). That changed with legislation sponsored by Rep Henry Waxman (D–Calif) offering powerful incentives for orphan drug development. Perhaps the most important of these incentives is 7 years of exclusivity for an approved orphan product; this exclusivity blocks other companies from selling the same drug to treat the same rare disease. Other incentives include a 50% tax credit for clinical study costs, grants to support clinical research, and FDA protocol assistance, which are particularly important for small companies. Further legislation passed in 1985 added biologics to the program and more clearly defined orphan drugs as treatments for diseases affecting <200,000 people in the United States.

These incentives for manufacturers have generated some controversy. Certain orphan therapies such as human growth hormone became highly profitable, raising questions about exclusivity and “salami slicing,” a practice in which companies seek orphan status for a drug for a very narrow indication with an eye to promoting the drug to broader populations. Continued high prices for certain orphan drugs also create challenges for payors and for patients seeking access to vital medicines. In most cases, however, strong evidence of efficacy for targeted patient populations has led insurers and plans to cover these treatments.

Identifying orphans


Through the ODA, FDA has the task of defining orphan diseases and potential treatments. In the past 25 years, FDA’s Office of Orphan Products Development (OOPD) has received 2,622 requests for orphan drug designations and has awarded that status to 1,850 products. Of those, 326 orphan drugs have been approved, and 41 of those approvals were supported by FDA research grants.

Manufacturers submit a designation application to OOPD that provides a medical rationale for how the effects of the agent fit accepted medical knowledge, explained OOPD director Timothy Cote. The application also presents disease prevalence criteria to document that the drug is intended for a patient population <200,000.

Once OOPD designates a drug an orphan product, FDA’s new drug review offices must then evaluate clinical protocols and approve resulting market applications, as with any new medical product. Russell Katz, director of CDER’s Division of Neurology Products, said that reviewers aim to be flexible in dealing with treatments for small patient populations, especially where no other therapy is available. He noted that randomized withdrawal studies and trial enrichment strategies can be useful when testing orphan drugs. Sponsors may identify more patients by revising eligibility criteria and by expanding trials internationally. Postmarket studies and registries, moreover, can augment limited preapproval safety studies. However, trials must have a minimum number of patients to power the study, he explained. “The last thing a sponsor wants is to invest in a study that’s fated to fail because it does not have enough patients.”

The benefits of the US orphan drug program have inspired similar efforts around the world. The European Union adopted an orphan drug program in 2000, which has resulted in 28 product approvals. Now FDA and the European Medicines Agency (EMEA) seek to establish common regulatory processes, starting with a joint application for orphan drug designation. Further harmonization may involve developing a common annual report on orphan drug development and common guidelines on orphan drug designation and terminology. FDA and EMEA also recognize the need for better understanding of how they categorize medical conditions, which is key in calculating disease prevalence and orphan qualification. There is a difference, for example, between a drug that treats all B-cell non-Hodgkin’s lymphomas and a drug that treats a specific subset of that disease class.

Moving forward
Proposals to more fully implement the ODA are under discussion. Patient groups want to expand the orphan drug grants program, which has remained at a $14 million budget level for years. Congress regularly authorizes additional funding only to see these funds cut by appropriators.

Another FDA project is to “rescue” abandoned orphan drugs. FDA has designated 1,850 orphan products and approved 326, which means that approximately 1,500 potential therapies have never come to market and may be languishing in research labs. FDA plans to cull through those abandoned applications to “find the diamonds hidden in all that gravel,” Cote said.

FDA also sees a need for further outreach to academia, small biotechnology companies, and major pharmaceutical manufacturers, says Cote. Most orphan drug designations and approved products have come from small companies. However, leading pharmaceutical companies now are looking at the rare disease field more positively as an important “stepping stone” between blockbuster drugs and personalized medicine.

An additional assignment for OOPD is to implement a priority review voucher program established by the FDA Amendments Act. This program aims to spur development of drugs to treat tropical diseases such as malaria, dengue fever, and tuberculosis. A biopharmaceutical company that develops a treatment for a listed neglected disease would receive a voucher that promises a 6-month review of any NDA. The sponsor may use the voucher for another drug application or sell it to another company and use the revenue to offset R&D costs. This is a complicated program, but it could encourage innovative approaches for tackling neglected diseases around the world.

Despite broad support for the orphan drugs program, some clouds loom on the horizon. Heightened fears about drug safety could expand postmarket study demands and impose limited distribution programs that could overwhelm the sponsor of a rare disease treatment. And such requirements will “significantly add to the cost of drugs,” noted Marlene Haffner, previous head of OOPD, now with Amgen. The cost of drugs, she adds, “is a very real issue.”