Celebrating 25 Years of Orphan Drugs

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Pharmaceutical Technology, Pharmaceutical Technology-07-02-2008, Volume 32, Issue 7

New scientific discoveries promise to expand treatments for rare and neglected diseases.

The US orphan-drug (OD) program has demonstrated that economic incentives and regulatory flexibility can spur development of treatments for small patient populations that were previously considered unprofitable. Before the enactment of the Orphan Drug Act (ODA) in 1983, pharmaceutical companies had produced only a handful of drugs for rare diseases. This situation changed when patient advocates pushed for legislation that encourages industry to bring ODs to market.

Jill Wechsler

The results are cause for celebration. The US Food and Drug Administration's OD program is a "tremendous triumph," commented Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), at a May conference commemorating ODA's 25th anniversary sponsored by the Drug Information Association (DIA). FDA has awarded OD status to 1850 products over the past 25 years. The awards have resulted in 326 approved medications that are used by about 12 million patients worldwide. Yet roughly 6000 to 8000 rare diseases still exist, Woodcock noted, so "we still have a very long way to go."

Woodcock expressed optimism that the emergence of molecular medicine will provide knowledge that can help identify more orphan conditions. Recent genomic discoveries can expand scientists' understanding of many serious conditions. In addition, personalized medicine promises more effective treatment and fewer side effects for many medicines. At the same time, high prices for many ODs, which reflect their development and production costs, create challenges for insurance coverage and patient access.

Success story

Before the ODA, pharmaceutical companies did not invest resources in developing drugs that were unlikely to make a profit, noted Abbey Meyers, prime mover behind ODA and founder of the National Organization for Rare Disorders (NORD). Patient groups thus looked to academia and the National Institutes of Health (NIH) for new treatments. But mention of the rare-disease problem on the popular TV show Quincy and new approaches to spur industry involvement prompted policymakers to examine the problem seriously.

The result was legislation sponsored by Rep. Henry Waxman (D-CA) that offered powerful economic incentives for drug companies to produce ODs. Most important in the legislation is the seven years of exclusivity for an approved OD. During the exclusivity period, no other company may sell the same drug to treat the same rare disease. In addition, there is a 50% tax credit for clinical-study costs as well as grants to support clinical research and FDA protocol assistance. These benefits are particularly important for small companies. Patients who were unable to participate in clinical trials also gained access to experimental treatments. Additional legislation in 1985 added biologics to the program and more clearly defined ODs as treatments for diseases that affect fewer than 200,000 people in the US.

Jason Reed/Getty Images

But the incentives for industry also generated controversy. Some orphan therapies such as human growth hormone became immensely profitable, raising questions about exclusivity and manufacturer "salami slicing," a strategy by which sponsors would seek OD status for a narrow indication and then promote the drug to much broader populations. "Many of the controversies over drugs that became profitable were spurred by competitors who lost the race to approval," Meyers commented. "NORD's greatest service has been to protect ODA from changes."

The search for orphans

ODA gave FDA the job of defining orphan diseases and proposed treatments. In 1983, we knew there were many rare diseases, but "we were clueless" about the scope of the problem, recalled Marlene Haffner, former head of FDA's OD office. The emergence of AIDS, which was then an orphan disease, put the program on the map.


During the past 25 years, FDA's Office of Orphan Products Development (OOPD) has received 2622 requests for OD designation 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. More than three-fourths of approved orphans are conventional drugs, but approvals are now shifting toward biologics, noted OOPD Associate Director Debra Lewis.

OD designation carries important benefits such as a 50% tax credit for clinical-research expenses. The credit can apply to past taxes or be carried forward for as long as 20 years. Designated orphan products also are exempt from the user fee for filing a new drug application (NDA), which is currently more than $1 million.

A designation application should be brief, says OOPD Director Timothy Cote. It should provide a scientific rationale that is consistent with accepted medical knowledge and demonstrate how the test treatment will be used to treat a rare condition. The application also must provide disease-prevalence criteria to document that the drug will treat a population smaller than 200,000 US patients. FDA recognizes that it must provide more clarity and guidance to applicants and make the designation process more efficient. The European Union processes 90% of designation applications in 60 days, while FDA processes 40% in 60 days. "We can do better than that," Cote said.

In Washington This Month

OOPD also provides grants for orphan-product development and assists sponsors in designing research protocols that will meet FDA requirements. FDA has awarded more than 400 grants (of 1500 applications), which generally amount to $400,000 per year for four years. OOPD makes about 15–20 new grants each year and has about 70 active grants at any one time.

Another OOPD assignment is to identify medical devices that qualify under "humanitarian use" provisions to encourage the development of medical devices to treat rare conditions. Products for conditions affecting fewer than 4000 Americans may receive FDA approval if they demonstrate safety and "probable benefit." These criteria are less burdensome than documenting full effectiveness. This process may become more important to pharmaceutical companies as more combination products emerge, Lewis commented.

Global impact

In addition to spurring OD development in the US, ODA has inspired similar strategies around the world, Cote commented at the 2008 meeting of the International Conference on Rare Diseases and Orphan Drugs (ICORD), which also took place in Washington in May. The many participants from foreign regulatory agencies, research organizations, and pharmaceutical companies supported international collaboration and investment in rare-disease research, particularly on the many third-world diseases that are orphan conditions in the US and EU.

The EU adopted an OD program in 2000, which has resulted in 28 product approvals. Now FDA and the European Medicines Agency (EMEA) seek to spur OD development by harmonizing the relevant regulatory processes. The two authorities have developed a common application for industry to seek OD designation, a process that was achieved in a record six months. Both regions already had similar approaches, as seen in data showing that FDA and EMEA granted OD designations in 90% of applications from 2000 to 2005, pointed out Yann Le Cam, CEO of the European Organization for Rare Diseases, at the DIA conference. Harmonization also was spurred by mutual political support for "trans-Atlantic administrative simplification" strategies, said Kerstin Westermark, chair of EMEA's Committee for Orphan Medicinal Products.

Since the common format was adopted in November 2007, FDA has received 16 OD requests on the new application, and EMEA has received six. The numbers are disappointing, but the cooperative effort should be regarded as the "first stone that will pave the road towards a global orphan-drug approval process," said Caterina Edfjall of Celgene (Summit, NJ) at the ICORD meeting.

Push for tropical disease treatments

The common application may simplify the designation process, but each regulatory agency still performs its own assessment and follows policies that differ on key points. EMEA requires manufacturers to show that a new OD will have "significant benefit" over any available alternative therapy. And standards for determining the prevalence threshold for an orphan disease vary. In the US, an orphan disease can affect only 200,000 patients, but the EU uses a formula that reflects changing population levels that results in a threshold of about 240,000, Le Cam explained.

Further harmonization may involve developing a common annual report on OD development. FDA and EMEA require periodic development reports, which can be burdensome for small companies. Regulators also need common guidelines for OD designation and terminology, plus similar standards for clinical data requirements in designation applications, too. When working with small patient populations, much can be gained if sponsors submit results from the same trials to different regulatory authorities.

FDA and EMEA also recognize the need for a common understanding of how they categorize medical conditions. Categorization is key to determining disease prevalence and orphan criteria. It makes a difference, for example, whether a drug treats all B-cell lymphomas or a specific subset of that class.

In both the US and EU, separate offices review market applications for ODs. The OD office only designates whether a test therapy qualifies as an orphan and thus is eligible for exclusivity and other benefits. New drug-review divisions at FDA differ in how much leeway they grant manufacturers for modifying clinical testing to reflect the small populations available for clinical trials. OOPD doesn't "meddle" in safety and efficacy assessments, Cote says, but his office often provides input requested by review divisions.

Manufacturing challenges

In addition to clinical-research issues, formulation and production challenges can stymie OD development. Many biological orphan treatments require complex production processes and raise problems during scale-up or moves to new facilities. FDA took action in April 2008 to block Genzyme's (Cambridge, MA) plans to shift production of its treatment for Pompe disease to a larger facility, a decision illustrating that life-saving treatments must meet quality standards. FDA determined that "Myozyme" (alglucosidase alfa) produced at Genzyme's 2000-L facility in Allston, Massachusetts, was not sufficiently similar to batches from its 160-L-scale production in Framingham, Massachusetts. The agency cited differences in the carbohydrate structures of the molecules from the two facilities and requested data from larger clinical trials to ensure that the differences do not affect product quality.

The company has filed a new biologics license application for the product, including additional clinical data based on product from the larger plant, which already was approved for use in Europe and other countries. But the delay will cost Genzyme some $50 million in lost sales plus the cost of providing Myozyme for free to patients unable to obtain the drug from the smaller plant. The silver lining for Genzyme and other biotechnology manufacturers, though, is that FDA's demand for additional clinical data to support a shift in manufacturing to a different site highlights the difficulty in gaining market approval for a follow-on biotechnology therapy made by a different company.

The Genzyme scale-up problem also indicates the need to provide researchers and small companies with assistance in product formulation and clinical-supply production. An NIH Rapid Access to Interventional Development project provides toxicology testing, small-molecule synthesis, scale-up production for clinical trial lots, and other services to support development of novel treatments. Similarly, the Center for Orphan Drug Research at the University of Minnesota College of Pharmacy provides assistance in drug synthesis, formulation, pharmacometrics, and bioanalytical support to small companies that lack in-house expertise in these areas. The Keck Center for Rare Diseases in California supports projects to revive potential ODs by identifying barriers to commercialization such as formulation difficulties and bioprocessing challenges.

The way forward

The ODA "is the single most successful piece of drug-development legislation in the history of the planet," and no one wants to change it, Cote says. But fuller implementation is on the table. There is talk of expanding 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 ODs. With 326 approved ODs based on 1850 OD designations, 1500 drugs identified as orphans have never come to market and may be languishing in research laboratories. In light of new scientific discoveries and patient needs, FDA plans to review those abandoned applications to "find the diamonds hidden in all that gravel," Cote said.

OOPD also is implementing a new priority-review voucher program established by the FDA Amendments Act of 2007 as one way to spur development of drugs to treat tropical diseases that are rare in the US (see sidebar, "Push for tropical disease treatments").

FDA sees a need for more outreach to academics, small biotechnology companies, and Big Pharma, says Cote. ODA propelled "little bio" into major expansion, he notes, and now Big Pharma's general disregard for orphan research "is changing" as rare diseases emerge as a "stepping stone" between the blockbuster drug and personalized medicines.

Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, jwechsler@advanstar.com