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Rare Disease Research Gets Boost
Tracy Hampton, PhD
WHILE SCIENTISTS WHO STUDY conditions such as cancer, heart disease, or stroke can present alarming statistics to highlight a need for funding for their research, those who study rare diseases can find it hard to compete for research dollars. But rare does not mean unimportant, according to the National Institutes of Health (NIH), which announced it will devote $71 million to launch the first clinical studies of its Rare Diseases Clinical Research Network. More than 20 studies are expected to open in the next few months at about 50 sites in the United States and other countries.
Coordinated primarily by the Office of Rare Diseases and the National Center for Research Resources at the NIH, the network will consist of a central data and technology coordinating center and 10 research consortia charged with investigating a variety of the approximately 6000 rare diseases identified to date. The program has the potential to improve diagnosis and treatment of numerous rare disorders and to provide researchers with a better understanding of the diseases’ characteristics and progression.
Rare diseases, defined as diseases or conditions affecting fewer than 200 000 individuals each in the United States, affect an estimated 25 million Americans. The 10 research consortia will study a range of diseases including Angelman, Rett, and Prader-Willi syndromes; myelodysplastic syndrome and other bone marrow failure conditions; lymphangioleiomyomatosis and other rare lung diseases;
Source: Rare Diseases Clinical Research Network (http://rarediseasesnetwork.epi.usf.edu/study-overview.htm).
Accessed May 30, 2006.
Longitudinal Study of Urea Cycle Disorders
Rett Syndrome Natural History Study
Episodic Ataxia Syndrome: Genotype-Phenotype Correlation
and Longitudinal Study
Nondystrophic Myotonias: Genotype-Phenotype Correlation
and Longitudinal Study
Screening Protocol and Longitudinal Study of Bone Marrow
Failure Syndromes and Cytopenias
Phase 1/2 Trial of Sirolimus (Rapamune) and Cyclosporine in
Patients With Refractory Aplastic Anemia
Phase 1 Study of Revlimid in Combination with Azacitidine
in Patients With Advanced Myelodysplastic Syndrome
Longitudinal Protocol for Giant Cell Arteritis
Longitudinal Protocol for Takayasu’s Arteritis
Longitudinal Protocol for Polyarteritis Nodosa
Longitudinal Protocol for Wegener’s Granulomatosis and
Microscopic Polyangiitis
Longitudinal Protocol for Churg-Strauss Syndrome
Rare Genetic Disorders of the Airways: Cross-sectional
Comparison of Clinical Features, and Development of Novel
Screening and Genetic Tests
Urea Cycle Disorders
Consortium
Angelman Syndrome Natural History Study
Angelman, Rett, and Prader-
Willi Syndromes Consortium
Consortium for Clinical
Investigation of Neurological
Channelopathies
Bone Marrow Failure
Disease Consortium
Vasculitis Clinical Research
Consortium
Genetic Diseases of
Mucociliary Clearance
Consortium
Rare Diseases Consortium Studies Currently Recruiting Participants
The Rare Diseases Clinical Research Network is enrolling patients in more than a dozen studies on certain rare disorders. Trials for other rare conditions are expected to begin in the near future. episodic ataxia, Andersen-Tawil syndrome, and nondystrophic myotonias; several vasculitides; urea cycle disorders; antiphospholipid syndrome and other rare thrombotic diseases; rare pediatric liver diseases; and rare genetic steroid defects.
A LOW PROFILE
Research on rare diseases has often had a low profile and has not received considerable attention or financial support. “Funding through usual channels is far more difficult for rare diseases because there is a lesser pool of experts, there is less knowledge about them, and the research tends to be more difficult,” said Jaroslaw Maciejewski, MD, PhD, of the Taussig Cancer Center at the Cleveland Clinic.
But physicians who treat individuals with rare or “orphan” diseases note that helping patients is rewarding regardless of how infrequent their diseases may be. “In fact the orphan diseases are called this because they were underappreciated,” said Maciejewski, an investigator in the network who is studying bone marrow failure syndromes, diseases such as aplastic anemia, advanced myelodysplastic syndrome, and certain preleukemia syndromes that are characterized by a drastic decline in the marrow’s ability to produce mature blood cells. “If you add up all of these relatively rare conditions together, a significant proportion of the population would be affected,” he said.
The network’s NIH funding came after President George W. Bush signed 2 bills into law in 2002 that increased funding for both the NIH’s and the Food and Drug Administration’s research programs on rare diseases. The Rare Diseases Act (HR 4013) and the Rare Diseases Orphan Product Development Act (HR 4014) have allowed the agencies to provide greater numbers of new research grants to investigators and have helped establish a link between basic and translational research on rare diseases.
Efforts by the nonprofit National Organization for Rare Diseases, in Washington, DC, were instrumental in getting these bills passed, although work remains to keep rare disease research moving forward, particularly within the pharmaceutical industry. While the Rare Diseases Orphan Product Development Act provides a 50% tax credit, 7 years of market exclusivity, and a waiver of some of the fees involved in new drug applications for companies that develop drugs for use in human clinical trials of rare diseases, making a profit on orphan drugs can still be difficult.
“It’s a business risk to develop products for extremely small patient populations,” said Diane Dorman, the National Organization for Rare Diseases’ vice president for public policy. “Therefore it is important to ensure that the incentives remain and are strong,” she added.
NEW INDICATIONS
While convincing companies to design new drugs for rare diseases may be difficult, asking them to provide currently available drugs for new indications to be studied through the Rare Diseases Clinical Research Network is less of a challenge. Robert Griggs, MD, of the Department of Neurology at the University of Rochester, in New York, is testing such drugs for the treatment of a group of diseases called channelopathies, conditions caused by abnormal cell channels that regulate the levels of chemicals such as sodium, calcium, and potassium. Patients with these diseases can experience periods of paralysis or muscle spasms that can eventually lead to persistent muscle weakness.
Griggs is using the NIH funds to investigate
treatments for periodic paralysis, episodic ataxia, and nondystrophic myotonias. “We’re excited that there are a number of treatments that deserve study for these conditions,” he said. ”By putting together the network and bringing together teams of people, we’re going to be able to bring those treatments into the clinic over the next several years.”
Initiated in 2003, the NIH’s Rare Diseases Clinical Research Network has spent the last 3 years establishing protocols and coordinating investigators. “With so many of the rare disorders, the patients are scattered throughout the country, and you need multiple research sites to gain sufficient numbers of patients,” said Stephen Groft, PharmD, director of NIH’s Office of Rare Diseases. Now that numerous sites have been recruited and the collaborations set in place, the first trials are ready to launch.
Investigators have all attended protocol and training programs at a data and technology coordinating center created at the University of South Florida, in Tampa. “What we’re trying to do there is foster collaboration in the designing of the clinical protocols, data management, and analysis,” said Groft. Data generated from the different sites will be collected at the data and technology coordinating center. “With data from multiple sites, we can follow a number of patients and start to see what parameters or what biomarkers we should look at a little more carefully,” said Groft. By getting a better picture of diseases and their progression in this way, researchers may be able to improve diagnosis and treatment.
CLUES TO COMMON DISEASES?
Another rationale for the endeavor is that it may help shed light on more common diseases and health in general.
For example, the rare disease aplastic anemia “has been extremely instructive in terms of our understanding of how bone marrow works, where blood is being made, and what stem cells are all about,” said Maciejewski. He added that studies on treatments for aplastic anemia also led to the development of bone marrow transplantation.
Other rare diseases have had similar research and clinical value. In addition, rare diseases that involve gene defects can offer insights into normal biological processes and how they go awry in disease states. For example, a gene defect that causes Bloom syndrome— an autosomal recessive disorder characterized by short stature, sensitivity to sunlight, reduced fertility, and increased incidence of cancer—has been found to encode a protein that plays an important role in DNA repair. Similarly, research on the premature aging syndrome progeria may lead to insights on aging.
RECRUITING PATIENTS
The Rare Diseases Clinical Research Network is also expected to help researchers recruit patients for clinical trials for rare diseases, an endeavor that is considerably more challenging than enrolling participants for trials involving common diseases. Patient advocacy groups are playing a significant role in finding participants for the various studies conducted by network researchers.
The NIH established a Coalition of Patient Advocacy Groups as part of the network’s steering committee, not only to help recruit patients but also to help ensure patient safety. “This has never happened before, where the funding body has made as a part of the research process a requirement for interacting with the advocacy groups to ensure good patient-centered research,” said Patrick Cochran, PhD, chair of the Coalition of Patient Advocacy Groups and founder and president of the nonprofit Periodic Paralysis Association, in Loma Linda, Calif.
The investigators in the network see patient advocacy groups as a much needed aid to their efforts. “They’ve helped enormously to facilitate information from patients to us and from us to patients,” said Griggs. The researchers also hope that clinicians in the community will aid in recruiting patients. “Physicians can help patients understand that there are clinical studies that are ongoing or that may be planned that perhaps they can look into,” said Groft. If travel is an issue, a charitable organization called Angel Flight (http://www.angelflightamerica.org/) arranges free flights for patients and their families to medical sites.
The extra effort necessary to ensure sound clinical trials for rare diseases is just now starting to pay off as the studies in the Rare Diseases Clinical Research Network get under way. “You do have to make special provisions to get patients into studies and to get the investigators mobilized to effect a common protocol,” said Groft. “In the long run, it should be a good example of how research can be done.”
A list of the studies and the investigators and institutions involved in the NIH Rare Diseases Clinical Research Network can be found at http://www.ncrr.nih.gov/clinical/rdcrn_studylist .asp. Information on the progress of the studies and how patients can enroll is available at http://www.rarediseasesnetwork.org.
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