From Alzheimer’s to Zebrafish: Eclectic Science and Regulatory Stories 48
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 US or one that US Food and
Drug Administration (FDA) scientists and economists determine will not be profitable for
at least seven years following FDA approval.1 Axiomatically, therefore, a rare disease is
one that affects fewer than 200,000 people in the US. There may be more than 5,000 differ-
ent orphan diseases, ranging from the Aarskog to the Zellweger syndrome. More than 20
million Americans may be affected by them. A sad example is Mattie Stepanek, the young
poet and poster boy for the Jerry Lewis telethon, who along with his three siblings died
from a muscular dystrophy called dysautonomic mitochondrial myopathy. His mother
has also recently been diagnosed with the adult-onset version.
A rare-disease database with reports on more than 1,150 diseases compiled by the
National Organization for Rare Disorders (NORD) is available on its website http://rare-
diseases.org. NORD also supplies information on more than 2,000 patient organizations
and 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. Online Mendelian Inheritance in Man (www.ncbi.nlm.nih.gov/omim)
provides detailed clinical reviews for 14,184 single-gene disorders, together with the latest
genetic research.2 According to NIH, there are about 1,000 genetic tests 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 specific disease.
It has been estimated that 80% of rare diseases are genetic in origin. 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 discusses information
of which regulatory professionals should be aware, including: causes and effects of rare
diseases the Orphan Drug Act and how drugs to treat rare diseases are approved, even
though the usual standards of scientific evidence are often underpowered and ongoing
research studies on rare diseases.
Causes and Effects
As mentioned above, recent research confirms that most rare diseases are genetic in origin,
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 those traits. 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. But if the genetic alteration
represents only a small deviation, 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
Congressman Henry Waxman (D, CA) was primarily responsible for 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 their support. Less than one year later, on 4 January 1983, President Ronald
Reagan signed the bill into law. Incentives were included to encourage pharmaceuti-
cal companies to begin research on drugs for rare diseases. They included substantial
tax breaks and seven years of exclusive marketing rights. 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 market-
ing application for a prescription drug product designated as a drug for a rare disease
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 US or one that US Food and
Drug Administration (FDA) scientists and economists determine will not be profitable for
at least seven years following FDA approval.1 Axiomatically, therefore, a rare disease is
one that affects fewer than 200,000 people in the US. There may be more than 5,000 differ-
ent orphan diseases, ranging from the Aarskog to the Zellweger syndrome. More than 20
million Americans may be affected by them. A sad example is Mattie Stepanek, the young
poet and poster boy for the Jerry Lewis telethon, who along with his three siblings died
from a muscular dystrophy called dysautonomic mitochondrial myopathy. His mother
has also recently been diagnosed with the adult-onset version.
A rare-disease database with reports on more than 1,150 diseases compiled by the
National Organization for Rare Disorders (NORD) is available on its website http://rare-
diseases.org. NORD also supplies information on more than 2,000 patient organizations
and 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. Online Mendelian Inheritance in Man (www.ncbi.nlm.nih.gov/omim)
provides detailed clinical reviews for 14,184 single-gene disorders, together with the latest
genetic research.2 According to NIH, there are about 1,000 genetic tests 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 specific disease.
It has been estimated that 80% of rare diseases are genetic in origin. 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 discusses information
of which regulatory professionals should be aware, including: causes and effects of rare
diseases the Orphan Drug Act and how drugs to treat rare diseases are approved, even
though the usual standards of scientific evidence are often underpowered and ongoing
research studies on rare diseases.
Causes and Effects
As mentioned above, recent research confirms that most rare diseases are genetic in origin,
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 those traits. 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. But if the genetic alteration
represents only a small deviation, 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
Congressman Henry Waxman (D, CA) was primarily responsible for 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 their support. Less than one year later, on 4 January 1983, President Ronald
Reagan signed the bill into law. Incentives were included to encourage pharmaceuti-
cal companies to begin research on drugs for rare diseases. They included substantial
tax breaks and seven years of exclusive marketing rights. 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 market-
ing application for a prescription drug product designated as a drug for a rare disease