AMSA Convention 2016 Logo

On the Trail of Rare Disease

Investigators and advocates hunt for collaboration and smart funding

The New Physician November 2007
Patients coping with a chronic condition their doctors may never have seen before can feel isolated and discouraged about the future. Similar is the frustration of that disease’s larger community—the few researchers and physicians fixated on finding treatments and cures for some of the rarest of human disorders.

The National Institutes of Health (NIH) and other federal agencies classify a disease or disorder as “rare” if it affects fewer than 200,000 Americans directly. But having a rare disease isn’t uncommon at all: NIH estimates that 25 million Americans have some type
of rare disorder: Hamman-Rich syndrome, Sandhoff disease or one of thousands more known but highly exceptional medical conditions.

Piece of the pie

A late-1980s survey by NIH of its own rare disease research efforts found that 15 percent to 18 percent of the overall research budget went toward the study of rare diseases. Stephen Groft, who heads the NIH’s Office of Rare Diseases (ORD), thinks that percentage is still about the same.

“It’s a fair amount of research,” he notes. “The problem is, with over 7,000 diseases, many times you don’t have a lot of research projects going on with any particular rare disease, and that’s why it is important to generate that interest in rare disease [generally] within the research community.”

Disease research funding is a complex system that is not always equitable or proportionate. The system is influenced by advocacy groups pushing for their piece of the pie or taking the funding fight into their own hands. But it’s increasingly clear that rare disease research is dependent on partnerships between government, industry and philanthropic groups—as well as among research centers themselves.

In fact, the ORD fills gaps between other NIH institutes, focusing on activities that benefit all of them in the collective pursuit of rare cures. This includes coordinating and administrating the relatively new Rare Diseases Clinical Research Network (RDCRN), mandated by Congress in 2002.

Lost in translation

Industry—mostly pharmaceutical researchers and manufacturers, but also device and equipment makers—is paying for most of the medical research in the United States. It spends nearly $65 billion a year—though critics note that pharmaceutical R&D budgets often include money spent on marketing—bringing new drugs to market or
doing basic research to find a starting point for cures, according to estimates put together by Research!America, a collection of research institutions and interested parties.

Though by far the biggest game in town, private industry is joined by many branches of the federal government in medical research funding. Aside from well-known agencies like the NIH, the Agency for Healthcare Research and Quality and the Centers for Disease Control and Prevention, there are some other interesting players: NASA and the departments of Defense and Agriculture, for example. But NIH is the health research destination for the biggest portion of the tax dollar, and for better or worse, the institutes also have the corner on the basic science market.

“The federal government is the biggest supporter of basic scientific research,” explains Bill Leinweber, Research!America’s executive vice president. “Industry supports basic research, clinical research and translational research. The government does all of those as well, but the biggest piece of the pie in the government is for basic research.” Meanwhile, private industry excels at translating that basic research into clinical applications.

“It was NIH, for example, that discovered the growth factors in blood cells, and it was the industry that went forward and developed erythropoietin into a new biologic,” notes Abbey Meyers, president of the National Organization for Rare Disorders (NORD), an umbrella for disease-specific patient advocacy groups.

But translational research is currently the weak spot in studying rare disease. Funding has been hard to come by due to NIH’s focus on basic research, and industry has been the main player in translation, Meyers says. The NIH is responding to criticism by focusing more on translational research of its own, but more is needed.

Most of the NIH’s budget goes into extramural research done at medical schools and universities, as opposed to intramural research done at NIH headquarters in Bethesda, Maryland. The extramural research system is highly dependent on researchers applying for NIH grants, and the level of their interest in particular diseases can sway the mix of research. For lack of interested researchers, disease Z may go uninvestigated, while disease Y’s titillation of physician scientists may draw disproportionate funding.

Patients need interested physicians to step up and apply for funding to translate basic research pertinent to the patient’s rare condition. “If you are studying a rare bone disease, for example, you are learning about all of the basic research discoveries that have to do with bone,” Meyers posits. “In your mind, you say, ‘How can I apply this to the patients that I am seeing?’” And that’s where the responsibility for moving basic research onto the wards lies.

The evolution of advocacy

The most significant dynamic in the history of rare disease research has been the rise of vocal patient advocates. From often-humble beginnings, many groups develop a knack for building attention for their disease, either through legislation or their own fund-raising efforts.

It’s tempting for those considering the funding of research to look at the money NIH and others spend on researching a disease, and divide that dollar amount by the number of patients affected. This may seem like a great way to compare the relative value of disease study. But Meyers explains that it’s a lot more complex.

“You really can’t analyze it, and NIH knows that,” she says. “And that’s why they cannot report to the public and to Congress and say, ‘We’re spending this amount of dollars on this disease.’ Because so much of the basic research dollar can be applied to each one of those diseases.”

When there was a sudden push for funding HIV/AIDS research, for example, a fair amount of the NIH’s research budget went into studying the basics of the immune system. Though that money was technically spent on the study of AIDS, the knowledge was broadly applicable, benefiting the study of other autoimmune disorders under the purview of the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

“You have to understand, a lot of these [rare disease] groups start with members of a family where somebody got sick, and they start on somebody’s kitchen table,” Meyers says. “It takes them a long time to get that organization up and going, and become advanced enough to understand the importance of advocacy in Washington.”

But once they do, their influence can be significant, although, Meyers says, it hasn’t always been helpful. In pushing Congress to earmark certain NIH funds for particular diseases, those funds become unavailable to other institutes—even if funds go unused because there aren’t enough researchers interested in taking a piece of the pie for that particular disease.

Also, advocacy groups for diseases both common and rare have occasionally lobbied to create a new institute at NIH—a very costly endeavor, Meyers says. She explains that a significant portion of the funding to a new institute gets lost to administrative costs, and having yet another subdivision of science can confound those who are trying to apply for grant funding.

Nowadays, savvy patient advocacy groups lobby for language that compels NIH to hold symposiums on a disease or set progress goals for the next few years. In this way, their efforts don’t tie up money, but their cause doesn’t get left behind. The ORD has held weekend seminars for the executive and research directors of such patient
advocacy groups, familiarizing them with the way the institutes work, how the research funding process functions and where the groups themselves can fit in.

“They will be the main source of information about the clinical studies that are ongoing; they’ll be asked about the value of participating in clinical studies,” Groft says. “So we try to explain to them so they have a good understanding of research.”

There is another key role for advocacy groups in addition to providing voice, support and a knowledge base for patients: “The bottom line is, they have to be out there raising money to fund research. These support groups, they have to fund research to get the doctors interested in that disease so they’ll study it,” Meyers says. “And a lot of the organizations have realized that’s what they need to do.”

And there is an interested next generation of niche researchers among medical students. Aaron Viny, now in his fourth year at Case Western Reserve University’s five-year M.D. program, spent his research year as a Howard Hughes fellow. He worked on the genetic study of large granular lymphocyte (LGL) leukemia, one of several rare bone marrow failure syndromes studied in that lab. Through the additional funding for his fellowship, he was able to work with whole-genome array “snip chips”—massive collections of genetic data for comparison—looking for a complex causation for the disease.

“One of the hardest parts of studying a rare disease is that you have a small sample size inherently. It’s a rare disease. You don’t have a lot of cases. So your statistical power goes down,” he says. Other challenges include getting published, as major journals try to appeal to a broad audience of physicians. But the lab’s work led to identifying a cluster of genes that could put patients at risk of LGL leukemia, which mostly affects adults. “We’ll have to see how it pans out as we do some testing, but it’s certainly exciting thus far.”

Several patients in Viny’s program formed their own advocacy group and raised enough money to fund a postdoctoral fellowship to help out with the lab’s bone marrow failure research.

Fishing for industry funds

Common conditions like high cholesterol have proved a cash cow for pharmaceutical companies. Their efforts to develop and push popular drugs have led to further development in those areas—and controversy. But as the largest funder of translational research, their role is unavoidable.

“The reality is, as a profit-making sector, industry has shareholders to respond to,” says Research!America’s Leinweber, whose consortium includes industry partners. “That’s not a negative; that’s the reality of capitalism. And as such, the focus of their efforts is, in large part, on diseases and disabilities that impact large populations.”

Drugs that could be used for rare diseases were long considered by private industry as a dead end, and virtually ignored. However, in 1983, through lobbying efforts by NORD and other groups, Congress passed the Orphan Drug Act (ODA), providing incentives like tax credits, windows of exclusivity and application fee waivers to drug companies that continue with research that may lead only to a handful of customers, and help make those drugs available to those with rare disorders.

The ODA incentives are administered by the FDA’s Office of Orphan Products Development, which also has a small budget for providing grants to spur rare disease research.

To be designated as an orphan drug, the manufacturer must demonstrate that the treatment is for a condition affecting less than 200,000 people—or, if the drug will be administered to more than that number, that there is no reasonable expectation that the costs of drug development will be recovered. In essence, they have to show that the drug’s development flies in the face of a profit-making enterprise.

According to Meyers, the process works, and there are about 320 approved orphan drugs now on the market and another 1,400 in the research pipeline. “Some of the rarest diseases...for example, lysosomal storage diseases that each affect fewer than 5,000 patients in the United States [are being treated by] enzyme replacement therapies on the market now.”

After working to get ODA through Congress, NORD began monitoring the act’s implementation and lobbying for research funding at large. Drugs for rare diseases are very expensive, so NORD also helps patients afford their unusual medicines through payment assistance programs, Meyers explains. “It’s a long process from encouraging the research to encouraging the development of the treatment to making sure that the patients have access.”

In some ways, the pharmaceutical companies’ research programs offer a model for federal rare disease efforts, and that’s where the ORD’s new clinical research network, the RDCRN, fits in.

“We draw multiple research sites together in a way that we can conduct common protocols,” Groft explains. “Industry does this very successfully for their own studies, and I think that the realization is that, with the rare diseases, you have to do that even more.” The
lab in which Viny worked is part of one of the RDCRN’s nine consortia, and works with other labs at other institutions toward a common, if rare, goal.

Despite some challenges, the study of a rare disease offers opportunity, Viny notes. “Because so few people have looked at it, because there are so few cases, the potential to make a big discovery is that much greater, particularly when you have some of the new tools that are being focused more on common diseases.”

Groft agrees: “The individuals in training are looking for something different.… This is one of the benefits of the rare disease. You are able to pick a disease that no one has done a lot with in many respects.”

Viny, along with the director of the bone marrow failure lab, worked with a statistician to devise new ways of dealing with small sample sizes in their genomic studies. Viny presented their findings at an ORD-sponsored conference in September so other rare disease researchers would benefit.

That kind of exchange, between researchers working on different disorders and med students and mentors, is what Groft, ORD and the millions of Americans with an uncommon condition count on to keep rare disease research alive.

For now, Viny is back on the wards, but wants to make the study of immunologic and hematological disorders part of an academic career, a track that presents challenges of its own. “There is pressure to see more patients, and it’s harder and harder to get protected research time,” he says of teaching hospitals. “But if you’re studying a rare’s a better opportunity to have that kind of a career. And that’s what I'm looking for.”
Pete Thomson is a freelance writer in New York City.