The Federal Food, Drug, and Cosmetic Act defines an orphan drug as one with efficacy against a disease affecting fewer than 200,000 people in the United States or one that scientists and economists at the FDA determine will not be profitable for 7 years after FDA approval.1 Axiomatically, therefore, a rare disease is one that affects fewer than 200,000 people in the United States. More than 5000 different types may exist, ranging from Aarskog syndrome to Zellweger syndrome. Over 20 million Americans may be affected by them.

A sad example of someone with a rare disease is Mattie Stepanek, the young poet and poster boy for the Jerry Lewis Telethon. Along with his 3 siblings, he died from a type of muscular dystrophy called dysautonomic mitochondrial myopathy. His mother also was recently diagnosed with the adult-onset version of the disease.

A rare disease database, with reports on >1150 diseases compiled by the National Organization for Rare Disorders (NORD), is available on its Web site, NORD also supplies information on >2000 patient organizations or support groups that help patients with rare diseases.

If the rare disease is caused by a single- gene disorder, an excellent resource for information is provided by the National Institutes of Health (NIH). Online Mendelian Inheritance in Man ( provides detailed clinical reviews for 14,184 single-gene disorders, together with the latest genetic research.2 According to the NIH, ~1000 genetic tests are now available for a variety of diseases and conditions, and the number of tests is still growing. Most of these tests are used for newborns or for families with a strong history of a disease.

It has been estimated that 80% of rare diseases are genetic in origin, and an increased understanding of genetics has led to a growing awareness that studying rare diseases often contributes to knowledge of more common ones.3 This article will discuss information about which pharmacists should be aware, including (1) the causes and effects of rare diseases; (2) the Orphan Drug Act and how drugs to treat rare diseases are approved, even though the usual standards of scientific evidence often are underpowered; and (3) ongoing research studies on rare diseases.

Causes and Effects

As mentioned above, recent research confirms that most rare diseases are genetic in origin. They are ultimately traceable to pairs of genes. These genes, which are the functional units of DNA, are strung by the hundreds or thousands along the 23 pairs of chromosomes in the nucleus of each cell in the body. Altogether they make up the genome, or complete code of inheritance. Each gene codes for a particular trait, the result of the underlying proteins that produce the trait.

Occasionally, a variation can occur in the making of a gene. If the error is in a particularly critical location and produces a destructive change in body chemistry, the fetus will die early in the gestation process. If the genetic alteration represents only a small deviation, however, it may survive to be passed on to the next generation as a new trait or as a genetic disease.4

The Orphan Drug Act

Rep Henry Waxman (D, Calif) was primarily responsible for the enactment of the Orphan Drug Act. Early in 1982, he introduced a bill offering incentives to entice drug companies to increase their research on rare diseases. At the hearings held to discuss the bill, several hundred victims of rare disorders along with their respective support groups offered support.

Less than 1 year later, on January 4, 1983, President Ronald Reagan signed the bill into law. Incentives for pharmaceutical companies included substantial tax breaks and rights to market resulting drugs exclusively for 7 years. Congress also mandated that funds be available to academic researchers and pharmaceutical firms to conduct research into rare diseases under the FDA Orphan Drug Grant Program. Additionally, a marketing application for a prescription drug product that has been designated as a drug for a rare disease or condition is not subject to a prescription drug user fee unless the application includes an indication for other than a rare disease or condition.

In the intervening years since the law was passed, 282 orphan drugs and biological products, providing treatment for more than 14 million patients, have come to market. In the 8 to 10 years before 1982, only 10 treatments for rare diseases had been approved by the agency and brought to market.1

Because of the limited number of patients diagnosed with a rare disease and the inability to recruit sufficient patients, the current method for clinical trials (hypothesis testing) cannot detect or exclude clinically worthwhile differences between treatments with standard levels of statistical confidence. Clinicians must rely on observational studies, historical controls, anecdotal information, limited clinical experience, and the perception of biological plausibility.5 The problem has been partially solved by changing the level of statistical certainty and employing the Bayesian approach. This method enumerates the probabilities of effects of different sizes, and the trial is analyzed as data accumulate.6

Small patient populations have thus far not presented a major problem in the approval process. For example, the clinical trial for bovine pegademase (Adegen) used in the treatment of severe immunodeficiency syndrome of the adenosine deaminase type involved just 8 patients, and only 14 people had the disease at that time. A historical control was used in the trial, and the drug proved 100% effective.1

Ongoing Research

A number of rare disease studies currently are enrolling patients. Studies include argininosuccinate lyase deficiency, Rett syndrome, polyarteritis nodosa, Wegener's granulomatosis, Churg-Strauss syndrome, heparin-induced thrombocytopenia, Angelman's syndrome, Andersen-Tawil syndrome, myelodysplastic syndromes, and large granular lymphocyte leukemia. Other studies that will begin later include trials for rare lung diseases, thrombotic defects, and urea cycle disorders. A complete list can be found on the Rare Diseases Clinical Research Network Web site.7 Other information regarding orphan drug designations and approvals is available on the FDA's Web site.8

Mr. Sherman is president of Sherman Consulting Services Inc.

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