January 1995
FDA Consumer special report

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Alice Parker remembers well the time not long ago when her eyes closed and didn't reopen.

It was like her body had pulled shades over her sight and wouldn't let them go. Her eyes still worked fine, but, blocked by locked-shut eyelids, they couldn't perform. At age 49, afflicted with the rare muscle disorder blepharospasm, she became, in essence, blind.

"I was unable to function normally," says Parker (not her real name). "I was bumping into things." Her only relief came from wearing uncomfortable glasses with special devices that pry the eyelids open. Her bout with blepharospasm, which began in 1985 as overactive blinking, eventually became so debilitating she had to quit her job.

But today, thanks in part to a law passed 12 years ago, Parker has regained her sight and is working again. She's not cured, but an injectable biological product made possible by the Orphan Drug Act of 1983 allows her to lead a life close to normal.

Blepharospasm is an "orphan" disease--a rare disorder affecting a small population. According to the Benign Essential Blepharospasm Research Foundation, about 25,000 people have the disease in this country. Traditional treatments such as surgery haven't always worked and have left patients disfigured. Many sufferers once resigned themselves to a life of functional blindness.

But now, the biologic Botox (botulinum toxin type A), aided in development by the Food and Drug Administration's Orphan Products Program, has rescued many patients with blepharospasm and other muscle disorders. Approved in 1989, Botox is derived from the same deadly bacterium that causes botulism. Yet, injected in the proper dosage, it relaxes certain muscles seized by spasms.

Mitchell Brin, M.D., a New York neurologist who conducted pre-market clinical trials of botulinum toxin, says, "Before the toxin, less than 10 to 20 percent of [blepharospasm] patients could be helped. Now we can help more than 90 percent."

Adopting 'Orphans'

The Orphan Drug Act defines orphan products as ones used to treat diseases or conditions affecting fewer than 200,000 persons in the United States. Such small patient populations reduce profit potential for sponsors, so the act grants special privileges and marketing incentives. In the case of Botox, Allergan Pharmaceuticals "adopted" the biologic from San Francisco ophthalmologist Alan Scott, M.D., and now markets it to patients nationwide.

Blepharospasm is one of more than 5,000 known rare disorders that together affect as many as 20 million Americans, according to estimates from rare-disease groups. For years, these conditions condemned patients to a life of pain and suffering. People with diseases such as hemophilia, multiple sclerosis, cystic fibrosis, rare cancers, and scores of other disorders could see little relief in sight. Companies were reluctant to invest the time and money necessary to develop treatments because the market was so small. Other outlets, such as research hospitals and universities, often lacked the capital and business expertise to develop treatments for limited patient groups. Today, approved treatments are available for all these conditions (see accompanying article).

To be sure, pharmaceutical manufacturers were not completely inactive in the orphan arena. Through the 1960s and 1970s, industry pursued development of numerous drugs of limited commercial value and even provided some at little or no charge. For example, industry developed the pharmaceuticals Mithracin (plicamycin), which treats testicular cancer, and the fungicide flucytosine before the Orphan Drug Act was passed.

By the early 1980s, however, the list of true orphan advancements still was woefully short, says Marlene Haffner, M.D., director of FDA's Office of Orphan Products Development. The plight of orphan-disease patients remained largely unaddressed. Clearly, the only way to change things was for all parties--industry, government, medical professionals, patients, and legislators--to find a way to bolster orphan products development. The catalyst for action was the Orphan Drug Act.

Orphans Bounce Back

With the act's passage, Congress had, for the first time, given research groups and drug companies financial incentives to develop and adopt orphans. Just as importantly, the act focused intense public, government and industry attention on the plight of rare-disease sufferers.

Today, new orphan products come on the market regularly. Some companies have even sprung up to develop and market orphan drugs exclusively. Since the act's passage, FDA has approved 108 orphan products (see Table, or Chart if your browser doesn't support tables), a number some say will at least double in the next decade. "I wouldn't be surprised if there are 200 approved orphan drugs by 2003," says Abbey Meyers, executive director of the National Organization for Rare Disorders (NORD), a grassroots cooperative of more than 100 nonprofit agencies. NORD played a major part in getting the act passed and now offers services such as an extensive database through which rare-disease sufferers and their families can learn more about orphan disorders.

The drug industry also made important strides to boost development of orphan products. In 1981, the Pharmaceutical Research and Manufacturers Association of America (PhRMA) established the Commission on Drugs for Rare Diseases to seek out promising orphan drug candidates and bring them to the attention of companies willing to develop them into useful products. Says Tom Copmann, Ph.D., a PhRMA assistant vice president, the commission canvasses sources such as medical journals, medical schools, and individual researchers to find orphan hopefuls. "Then," he says, "we endeavor to find [each orphan] a 'parent.'"

Markets and Incentives

Though Congress defined a patient limit of 200,000 for orphan disorders, most of these conditions occur at well below this statutory ceiling. In 1992, 47 percent of designated orphan diseases affected an estimated 25,000 or fewer people. Some disorders, such as infant botulism and severe combined immunodeficiency syndrome, have patient populations of less than 100. Such numbers underscore how small the market--and the moneymaking potential--can be. But add in the act's incentives, and the picture changes dramatically.

The most powerful incentive is the act's marketing exclusivity clause, says FDA's Haffner. Once an orphan drug is approved, exclusivity gives sponsors legal protection against introduction of an identical competing product for seven years. This "shelter" is critical to keeping many companies interested in orphans, she says.

"Large firms need exclusivity to convince management to invest capital," she explains. "And small-to-medium-sized companies need it to ensure stockholders that the product won't be infringed upon by competitors."

Among other provisions for orphan-designated products are:

• Grants--The act funds a total of $12 million worth of clinical research grants annually. Each grant may cover as much as $200,000 of direct costs per year for up to three years. The grants provision is aimed not at large companies but at smaller, research-oriented organizations. So far, six approved orphan drugs have come from the grants program, and several more are in clearance. Since 1983, FDA has awarded $67 million in research grants (another $12 million is earmarked for fiscal 1995 distribution).
• Protocol assistance--FDA helps orphan sponsors design research that conforms to regulatory requirements and shows them how to deal with the FDA review system. Sponsors, especially small companies with little regulatory experience, can save time and money using this service.
• Tax credits--A sponsor may claim 50 percent of clinical trial costs as a credit against taxes owed.

The act also bolstered orphan development by "lessening disincentives," says PhRMA's Copmann. For example, he says, pharmaceutical firms may use the act's marketing exclusivity provisions to enter these smaller, "niche" markets. "When [manufacturers have] the capability of finding a niche and have market protection, you've removed a disincentive."

In another example, Copmann cites biotechnology companies whose products are unpatentable under current law. These firms can gain a "quasi-patent" under the Orphan Drug Act's marketing exclusivity provision. Without this protection, many of these companies probably would not pursue orphans.

On the Horizon

Typically, FDA approves orphan products much more quickly than products aimed at potentially huge markets. "Because orphans serve a smaller population, they require less data; thus it's possible to have a fairly quick approval," says Haffner. She says the agency hopes to speed things up even more in the future, while still making sure safety and efficacy requirements are met. She points to the December 1993 approval of the cystic fibrosis treatment Pulmozyme (dornase alfa), which was approved in eight months, as an example of how the process can be "amazingly rapid."

Some in the orphan diseases community say FDA approval still takes too long. To that, Haffner responds that the agency may aim to speed approvals, but it won't take shortcuts. "You have to know why evaluation can take time," she says. "The bottom line is that the American public will not forgive FDA if we send out a potentially harmful drug."

NORD's Meyers says she'd like to see "a bigger dent" made in the number of orphan diseases that have no treatments. Still, she says she is pleased that orphan development is progressing steadfastly. NORD, she says, will continue to participate in legislative issues, to monitor health reform, and to work with the pharmaceutical industry and government to promote orphan concerns.

Copmann also sees orphan development advancing steadily. PhRMA's Commission on Drugs for Rare Diseases, he says, currently has eight promising orphan drugs "looking for parents." Copmann says new technologies may prompt novel treatments for orphan disorders.

FDA's Office of Orphan Products Development plans over the next three years to help sponsors develop treatments for very small patient populations, including those with rare genetic diseases, says Haffner. The next decade, she adds, should bring a broadening of the act's scope. "Often, pregnant women, children, senior citizens, and others are excluded from usual clinical trials when orphan products are being developed. Our goal is to include these individuals so we can increase the number of patients benefiting from the act and ensure that the number of approved orphan products continues to grow."

John Henkel is a staff writer for FDA Consumer.

For More Information

FDA's Office of Orphan Products Development (OPD) can give information about orphan diseases and products to patients, families and physicians. It can help with:

• Patient Information--OPD maintains the National Information Center for Rare Diseases (NICODARD), designed to answer professional practitioner inquiries as well as patient and family queries about orphan products. NICODARD will send a general information packet or a two-page "Rare Disease Information Directory" with additional contacts; telephone (1-800) 300-7469.
• Drug Lists--A cumulative list of designated orphan products, updated monthly, includes product sponsors, designated or approved use, and dates of product designation and marketing; telephone (1-800) 300-7469.
• Research Grants--Applications are accepted on Jan. 15 and Oct. 1 of each year for grants to fund clinical patient research; telephone (301) 443-4903 (program information) or (301) 443-6170 (grant applications).

Other organizations that can help consumers include:

• Alliance of Genetic Support Groups--Refers patients and families to support groups and offers advice on subjects such as insurance and informed consent; telephone (1-800) 336-GENE.
• Rare Disorder Network of General Clinical Research Centers--Maintains a database of clinical trials for rare diseases. Will refer patients and families to appropriate medical care and conduct literature searches on rare diseases; telephone (1-800) 428-6626.
• National Organization for Rare Disorders--A coalition of more than 100 rare-disease organizations, NORD has an extensive database on orphan diseases and offers a newsletter and numerous publications; telephone (1-800) 999-NORD.