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FDA Consumer magazine
November-December 2003 Issue

Orphan Products: Hope for People With Rare Diseases

By Carol Rados

Jumping Frenchmen of Maine sounds like an uproarious, modern-day stage show or even a new wave rock group. But it's neither. It's the name of an unusual disorder that causes an extreme startle reaction to unexpected noises or sights. Though little is known about Jumping Frenchmen of Maine, the disorder and more than 6,000 other rare or "orphan" diseases are receiving increasing attention from government, patient groups, and the pharmaceutical industry.

An orphan disease is defined as a condition that affects fewer than 200,000 people nationwide. This includes diseases as familiar as cystic fibrosis, Lou Gehrig's disease, and Tourette's syndrome, and as unfamiliar as Hamburger disease, Job syndrome, and acromegaly, or "gigantism." Some diseases have patient populations of fewer than a hundred. Collectively, however, they affect as many as 25 million Americans, according to the National Institutes of Health (NIH), and that makes the diseases--and finding treatments for them--a serious public health concern.

Most Inherit Orphan Diseases

New rare diseases are discovered every year. Most are inherited and caused by alterations or defects in genes (mutations). Others can be acquired as a result of environmental and toxic conditions. Genes are pieces of DNA, part of the code that determines the traits and individual characteristics of all living things. Each human cell contains around 30,000 genes. Besides influencing features such as eye and hair color, genes also can play a role in the development of diseases and in their transmission from parent to child.

As disparate as rare diseases are, patients share many common frustrations. For example, for one-third of people with a rare disease, getting an accurate diagnosis can take one to five years. And people often are so isolated that they may never know anyone else with the same disease. Patients often must travel long distances to visit the few doctors knowledgeable about their illnesses, and the costs involved with diagnosis, treatment and other related expenses can be exorbitant.

Stephen C. Groft, Pharm.D., director of the NIH Office of Rare Diseases (ORD), says that in understanding health and diseases, scientists must study rare diseases that affect smaller portions of the population as readily as those, such as cancer, for which research and treatment can result in benefits to a greater number of people.

"Many advances are not only the direct result of years of rare disease research," Groft says, "but also from the emphasis that NIH places on both basic and clinical research." The course that a rare disease takes often may represent an exaggerated form of a common disease pathway, he says, and studying one helps scientists learn about the other.

A genetic lung disease known as alpha-1-antitrypsin deficiency, for example, produces a form of emphysema that develops 10 to 30 years earlier than the more prevalent form common to smokers. Because it affects young people, it can be studied apart from any complicating factors, such as the aging process, to enhance what researchers already know about the disease.

Managing Rare Diseases

Many rare diseases or conditions can be difficult to diagnose and manage because in their early stages, symptoms may be absent or masked, misunderstood, or confused with other diseases.

In Doug Bermel's case, the misdiagnosis 21 years ago of multiple sclerosis (MS) led to delayed and inappropriate treatment of his true disease--adrenomyeloneuropathy (AMN). AMN is a milder form of adrenoleukodystrophy (ALD), one of a group of genetically determined progressive disorders known as "leukodystrophies" that affect the brain, spinal cord and peripheral nerves. Bermel, 48, of Corcoran, Minn., raised a red flag for his doctor when he mentioned that not only had his grandfather been diagnosed with MS--and in fact had died from it--but also that he had lost two brothers and several cousins to the same disease.

According to the United Leukodystrophy Foundation (ULF), the leukodystrophies are often misdiagnosed as MS because diagnosis of neurological conditions relies on subtle and circumstantial evidence, and, "even the most experienced clinicians may have difficulty" distinguishing between the two.

Because MS is not hereditary, Bermel's doctor suspected that the disease that had befallen his family members, and now him, was not MS because of its genetic pattern of inheritance. An in-depth family history revealed that Bermel and his brothers had a 50 percent chance of getting either ALD or AMN because their mother was a carrier of the gene. Following his diagnosis of AMN, two more of Bermel's brothers died of the disease.

For rare disease patients there may be no cures, but treatments of the symptoms can help. Having the support of family and friends, patient advocacy groups, and disease associations like ULF is also helpful.

"I had to learn to accept help from other people," admits Bermel, who uses a wheelchair and sometimes walks with a cane. "Now, when somebody helps me, I know they feel good about it, and that makes me feel better."

In addition to finding emotional and educational support, participating in a clinical trial may be a way to receive the most advanced care for some diseases (see "Clinical Trials: Testing Medical Products in People," September-October 2003 FDA Consumer).

People who experience unexplained symptoms, recurrent infections, and pain that have gone undiagnosed for a long period of time might want to visit a referral center that is experienced in diagnosing patients with rare diseases.

Some rare diseases do not have clearly defined treatment guidelines and require the specific skills of an expert physician. Be sure to go to a hospital that is familiar with treating people with multiple problems.

Adopting the 'Orphans'

Before the passage of rare disease laws in the United States, patients diagnosed with a rare disease were denied access to effective medicines because prescription drug manufacturers rarely could make a profit from marketing drugs to such small groups. Consequently, the prescription drug industry did not adequately fund research for orphan product development. Other potential sources, such as research hospitals and universities, also lacked the capital and business expertise to develop treatments for small patient groups. Despite the urgent health need for these medicines, they came to be known as "orphans" because companies were not interested in "adopting" them.

This changed in 1983 when Congress passed the Orphan Drug Act (ODA). The ODA created financial incentives for drug and biologics manufacturers, including tax credits for costs of clinical research, government grant funding, assistance for clinical research, and a seven-year period of exclusive marketing given to the first sponsor of an orphan-designated product who obtains market approval from the Food and Drug Administration for the same indication. At the same time, federal programs at the FDA and the NIH began encouraging product development, as well as clinical research for products targeting rare diseases.

Since 1983, the ODA has resulted in the development of nearly 250 orphan drugs, which now are available to treat a potential patient population of more than 12 million Americans. In contrast, the decade prior to 1983 saw fewer than 10 such products developed without government assistance. As a result, treatments are available to people with rare diseases who once had no hope for survival.

In April 2003, for example, the FDA approved the very first treatment for Fabry's disease, a serious metabolic genetic disorder that affects 1 in 40,000 American men. Fabrazyme (agalsidase beta) was approved under an accelerated or early approval policy that allows faster approval of therapies that treat serious or life-threatening illnesses. Accelerated approval can be granted when favorable results in early studies indicate outcomes that are likely to predict long-term clinical benefit.

Fabrazyme, given intravenously, is a version of the human form of a natural enzyme produced by recombinant DNA technology. This replacement of the missing enzyme reduces a particular type of lipid (fat) accumulation in many types of cells, including blood vessels in the kidneys and other organs. It is believed likely that this reduction of fat deposits will prevent the development of life-threatening organ damage and have a positive health effect.

"A key part of our accelerated approval process involves further study of the new treatment after approval to confirm clinical benefit," says Jesse Goodman, M.D., M.P.H., director of the FDA's Center for Biologics Evaluation and Research. "In this case, FDA has worked closely with the product developer to make sure that, despite the relatively small number of patients with this disease, all reasonable steps will be pursued to make sure that we learn more about the product's clinical benefits and long-term safety once it is on the market."

Despite the success of the ODA, however, rare disease advocacy groups argue that the plight of people with orphan diseases deserves even more attention.

The FDA's Role

"A lot of people are affected," says Marlene E. Haffner, M.D., M.P.H., director of the FDA's Office of Orphan Products Development (OOPD). "That makes it a major public health impact, and in time, we're going to see even more rare diseases requiring treatment."

Because of the FDA's desire to find ways to bring orphan drugs to the marketplace, the agency established the OOPD in 1982. Its mission is to identify orphan drugs and biological products and to promote development of those that demonstrate promise for the diagnosis and treatment of rare diseases. The OOPD does this by working with the medical and research communities, professional organizations, academia, and the pharmaceutical industry, as well as rare disease groups.

Each orphan product designation request must stand on its own merit. People need to know that the approval of an orphan designation request does not change the standard regulatory requirements or the process for obtaining marketing approval. That means the product must go through the new drug approval process like any other drug. The safety of a product, and its effectiveness, also must be established through adequate and well-controlled studies.

In addition, the OOPD administers a grants program that funds clinical studies for the development of orphan products. The goal of the program is to encourage clinical development of products for use in rare diseases or conditions. The products studied can be drugs, biologics, medical devices, or medical foods.

Medical devices are not eligible for orphan designation. However, in 1996, the FDA took a major step intended to make it easier and less costly for manufacturers to bring to market medical devices for orphan diseases. The Humanitarian Device Exemption (HDE) provisions of the Safe Medical Devices Act of 1990 allow a medical device to be approved as long as manufacturers show it is safe and has probable benefit to patients with an extremely rare condition. These regulations allow approval without costly clinical studies to establish effectiveness.

To qualify for HDE approval, the device must be intended for use in the treatment or diagnosis of a disease or condition affecting fewer than 4,000 individuals per year in the United States. Humanitarian use device designation is granted to sponsors developing a medical device that targets rare disease treatment.

Since October 1996, the OOPD has designated 51 humanitarian use devices, and 32 of these devices were given HDEs.

"The success of the ODA," Haffner says, "has also inspired the implementation of orphan legislation outside the United States to address the treatment needs of patients worldwide who have rare diseases." Subsequent legislation has taken the study of rare diseases to even greater heights.

Support for Research

Congress passed the "Rare Diseases Act of 2002," establishing a role for the ORD at the NIH in encouraging orphan disease research. The ORD provides information on rare diseases, diagnosis, and treatment. The office links investigators with research subjects and patients, identifies rare diseases where research is lagging or lacking, identifies rare disease research opportunities, and supports research in those areas.

The Rare Diseases Act authorized the expansion of national research in developing diagnostic tools and treatments for patients with rare diseases. In addition, Congress approved funding for several regional Centers of Excellence on rare diseases. The ORD makes grants to public or private nonprofit organizations to cover the cost of basic operating expenses for clinical research at these centers. These grants support training in and demonstration of diagnostic, prevention, control, and treatment methods for rare diseases.

The ORD responds to public inquiries about rare diseases, supports national and international scientific workshops, and maintains the ORD Web site and interactive rare diseases list. The workshops benefit the rare diseases community through promoting research, patient care, and disease awareness.

Patient Support Groups

Rare diseases affect so few people that information about them may be difficult to find, making the situation more traumatic and stressful. Before Congress enacted the ODA, families coping with a rare disease usually struggled alone. Support could only be found through telephone calls to other families suffering with similar diseases, and only if the names were provided by doctors.

Support groups such as the National Organization for Rare Disorders (NORD) have worked aggressively in the last 20 years to draw attention to people with rare diseases, especially the lack of treatment options. Paramount in NORD's ongoing cause are efforts to promote legislation, such as the ODA, that encourages further research and continuing development of products that are necessary--and often life saving--and to provide easier access to such treatments.

While only 1 in about 15,500 people get ALD, two of Paula Brazeal's sons died from it in the 1970s. Eager for more information, Brazeal and her husband Ron were among the founders of the ULF--a voluntary health organization dedicated to providing patients who have these diseases, and their families, with specific information.

"Twenty-five years ago support groups provided hand-holding for the emotionally needy," says Brazeal. "Today, we provide education, advocacy, a link between patients and clinical trials, and doctor referrals.

"And we serve as a communication network for families in matching up people geographically with similar diseases."

Equally important to being informed, Brazeal says, is being realistic: "Health care professionals should not sugar coat your disease. They need to be brutally honest with you so that you can level with other family members, especially kids." She adds, "There's more fear of the unknown, than when you're informed and prepared."

The role of the support group is evolving, says Brazeal. "I think the recent trends at FDA and NIH in encouraging scientists to become involved with patient support groups has brought research even further." Having had first-hand experience with the devastating effects of a rare disease, Brazeal adds, "We remember what it was like when there was no one at the other end of the phone line."

Rare Diseases and Approved Orphan Products

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