Q&A: What makes 'rare diseases' rare, and their treatment costly?

As a group, "rare diseases" are far from rare: About 6,500 of them affect a total of more than 25 million Americans. Because each disorder afflicts so few patients, however, they generally are hard to study and costly to treat.

Yet at a time when rising drug prices complicate nearly every area of medicine, rare-disease research holds important lessons for health care in general, says physician and geneticist Christopher P. Austin, director of the National Center for Advancing Translational Sciences at the National Institutes of Health.

He spoke recently with The Inquirer about rare-disease research and how advances in the translational science process can help get treatments to patients more quickly.

What are rare diseases?
The U.S. Orphan Drug Act, originally passed in 1983, defines a condition as rare if it affects fewer than 200,000 Americans. It was the best estimate of the threshold at which substantial economic incentives were felt to be required to get pharmaceutical companies interested in these disorders. The law provides a series of incentives to drug companies, such as longer market exclusivity and waiver of fees by the Food and Drug Administration.

Do rare diseases have anything in common?
They tend to be genetic, caused by a single gene with a big mutation - think cystic fibrosis or Huntington's disease - that affects multiple organs, unlike type 2 diabetes, which is probably hundreds of different genes. They also tend to be less affected by environmental issues. There are exceptions: Anthrax is a rare disease. And Ebola. Neither is genetic.

Why are rare diseases hard to diagnose and treat?
For anything, you need numbers. Simply finding enough patients with a specific rare disease to study can be difficult. Finding researchers with expertise in particular disorders also can be challenging. Rare-disease patients will tell us that they have traveled from doctor to doctor to doctor for two to three years before they get a diagnosis.

Are they studied differently?
Biomedical research is changing across the board. Medicine traditionally has been organized around organs and symptoms. Many diseases, like cancers, were named that way, too. But Mother Nature works with genes and biochemical pathways.

After the Human Genome Project, it became possible to define molecular causes. Because rare diseases tend to be caused by a single major genetic lesion, it was easier to make this transition from symptomatology to molecular than it was for more common diseases.

That sounds like precision medicine.
From my point of view, rare diseases are precision medicine. They are diagnosed not based on symptoms but on genetics and genomic lab tests.

How do you prevent new treatments from becoming unaffordable - not just for rare diseases but for everyone?
Targeted drugs are expensive. But the only way to decrease drug costs is to increase efficiency of the whole process by which a drug is made. It is a relentlessly empirical process, from protein in a lab to a cell to an animal to a human to a human in a clinical trial to a free-range human.

The likelihood of being successful with this trial-and-error clinical approach is vanishingly small. It takes 12 to 15 years, fails over 95 percent of the time, and typically costs between $1 billion and $10 billion.

Is there an alternative?
Answering that question is part of why our center was formed. One approach is studying diseases as a systemwide problem. Not what is making this disease different, but what is similar.

Overall, we're trying to take a scientific approach - to understand the general principles of the translational science process and then develop, demonstrate, and disseminate innovations.

The current trial-and-error approach is like building a bridge without understanding the principles of civil engineering. Rather than building a bridge and have it fall down, we're trying to understand the principles of a bridge.