Orphan Drug R&D Challenges Sponsors

The U.S. 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, the Food and Drug Administration has approved more than 300 medicines for some 12 million patients around the world. However, there are some 6000 to 8000 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 that was sponsored by the Drug Information Association (DIA).

Jill Wechsler

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 treatments. More partnering between industry and patient groups and growing demand for pediatric treatments should spur development of more treatments for rare conditions.

Before 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-CA) offering powerful incentives for orphan drug development. Most important is seven years of exclusivity for an approved orphan product; that blocks other companies from selling the same drug to treat the same rare disease. There also is a 50% tax credit for clinical study costs, grants to support clinical research, and FDA protocol assistance—particularly important for small companies and investigators. Further legislation in 1985 added biologics to the program and more clearly defined orphan drugs as treatments for diseases affecting fewer than 200,000 people in the United States.

The incentives for industry have generated controversy. Some orphan therapies such as human growth hormone became highly profitable, raising questions about exclusivity and "salami slicing" by companies seeking orphan status for a very narrow indication with an eye to promoting the drug to broader populations. And continued high prices for certain orphan drugs create challenges for payers and for patients seeking access to vital medicines.

Identifying orphans

The ODA gave FDA the job of defining orphan diseases and potential treatments. In the last 25 years, FDA's Office of Orphan Products Development (OOPD) has received 2622 requests for OD designations and has awarded that status to 1850 products. Of those, 326 ODs have been approved, and 41 of those approvals were supported by FDA grants. OOPD has awarded more than 400 grants (of 1500 applications), about 15 to 20 new grants each year that add up to 70 active grants at any one time.

A designation application should be brief, says OOPD Director Timothy Cote. The main purpose is to provide a medical rationale for how the test treatment's effects fit accepted medical knowledge. And the application should present disease prevalence criteria to document that the drug is intended for a patient population under 200,000.

OOPD also encourages development of medical devices to treat rare conditions by identifying products that qualify under the "humanitarian use" provision. That permits FDA to approve devices for conditions affecting less than 4000 patients based on a demonstration of safety and "probable benefit," which is less costly and less complex than documenting full effectiveness.

Once OOPD designates a drug an orphan product, it's up to CDER's new drug review offices to evaluate clinical protocols and approve resulting market applications, as with any new medical product. Cote acknowledges differences among drug review staffs in how much leeway they grant sponsors seeking to modify clinical study protocols to accommodate small patient populations. He makes an effort to prevent the rejection of products that might have some modest effect, but OOPD doesn't "meddle" in safety and efficacy assessments, Cote notes. His office often provides input requested by review divisions and works to educate review staffs on orphan drug issues.

Russell Katz, director of CDER's Division of Neurology Products, said that reviewers aim to be flexible 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. Postapproval studies and registries can augment limited preapproval safety studies. But trials must have some minimum number of patients for the study, he said. "The last thing a sponsor wants is to invest in a study that's fated to fail because it does not have enough patients."

Promoting harmonization

The benefits of the U.S. orphan drug program have inspired similar efforts around the world, a subject explored in depth at the 2008 meeting of the International Conference on Rare Diseases and Orphan Drugs (ICORD), which also took place in Washington in May. Participants from regulatory agencies, research organizations, and biopharmaceutical companies emphasized their desire to promote international collaboration and research on new treatments for rare diseases.

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. The harmonization process was achieved in a record six months, largely because both regions already had similar approaches, noted Kerstin Westermark, chair of EMEA's Committee for Orphan Medicinal Products (COMP), and the political winds were very supportive of "trans-Atlantic administrative simplification" strategies.

The common application may simplify the designation process for sponsors, but each regulatory agency still does its own assessment based on policies that differ on some key points. EMEA requires manufacturers to show that a new orphan drug will have "significant benefit" over any available alternative therapy. And there us variation in standards for determining the prevalence threshold for an orphan disease: It can affect only 200,000 patients in the United States, but the EU uses a formula that sets the threshold at about 240,000 to reflect expanded population levels.

Further harmonization may involve developing a common annual report on orphan drug development, which aims to reduce the paperwork burden on small companies and investigators. There is interest in common guidelines on orphan drug designation and terminology. And similar standards for clinical data requirements in designation applications would allow sponsors to submit results from the same studies to different regulatory authorities—an important consideration when working with very small patient populations.

FDA and EMEA also recognize the need for more common understanding of how they categorize medical conditions, which is key in calculating disease prevalence and orphan qualification. It makes a difference, for example, if a drug treats all B-cell non-Hodgkins lymphomas or a specific subset of that disease class.

Moving forward

No one is eager to make substantive changes in the Orphan Drug Act, but fuller implementation is on the table. Patient groups want to expand the OD grants program, which has been stuck at a $14 million budget level for years and suffers from eroded buying power. Congress regularly authorizes additional funding only to see the number cut by appropriators.

Another FDA project is to "rescue" abandoned orphan drugs. FDA has designated 1850 orphan products and approved 326, which means that some 1500 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.

A new assignment for OOPD is to implement the priority review voucher program established by the FDA Amendments Act. That aims to spur development of drugs to treat tropical diseases. A company that develops a treatment for a listed neglected disease would receive a voucher good for a speedy, six-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. It's a complicated program, but could help spur innovative approaches for tackling neglected diseases around the world.

FDA also sees a need for more outreach to academia, small biotech, and big pharma, says Cote. Most orphan drug designations and approved products have come from small operators. But leading pharmaceutical companies are looking at the rare disease field more positively as an important "stepping stone" between block buster drugs and personalized medicine.

Jill Wechsler is the Washington editor of Applied Clinical Trials, (301) 656-4634 jwechsler@advanstar.com