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Clinical Trials for Rare Diseases: Small but Mighty…and Needed

Rare diseases are, well, rare. When it comes to research to find treatment and cures for them, that is a huge problem. Recruitment of enough suitable patients to obtain meaningful results is a major challenge. The patients are scattered throughout the country, or the world, and sometimes they are not even correctly diagnosed.

If gene therapy finally offers a cure for hemophilia B, an inherited blood condition that affects approximately 4,000 people in the United States, high on the list of people to thank are the fourteen participants in an NHLBI-funded clinical trial launched in 2009.

Photo of Dr. Andrew Davidoff
Andrew M Davidoff, M.D., chair of the Department of Surgery of St. Jude Children's Research Hospital. Courtesy of St. Jude Children's Research Hospital

Fourteen study participants.

That was the size of this pioneering clinical trial to test the safety of gene transfer in patients with the severe form of hemophilia B, a serious, chronic bleeding disorder that slows the blood clotting process. In severe cases, patients bleed excessively from small or minor cuts. Major injuries or any surgery pose immense risks. 

Hemophilia B is also a rare disease, which, in the United States, is a condition that affects fewer than 200,000 people. There are seven thousand rare diseases that, combined, affect an estimated 25 million Americans. Only a few hundred of these diseases have an approved treatment. 

In the face of the hurdles posed by rare diseases, standard research methodology and traditional clinical trial design fall short. This calls for adaptive design to allow modifications to the trial or statistical procedures after the initiation of the study, without undermining its validity or integrity. 

Andrew M Davidoff, M.D., chair of the Department of Surgery, and Ulrike Reiss, M.D., director of the Clinical Hematology Division, of the St. Jude Children's Research Hospital were the lead researchers of the hemophilia B clinical trial. Dr. Amit Nathwani, professor of the University College London Medical Sciences, was the lead investigator from his institution. For them, the biggest difficulty affecting recruitment of participants was fear.

“Fear from patients and doctors,” said Reiss. “Some physicians were really nervous about the study, and so were their patients. It was new and they were not sure of the prospects or the safety.”

The recruitment efforts included many direct conversations with patients and doctors. They also worked with the National Hemophilia Foundation in the US to educate potential participants and even received positive international interest, from the University College London which became a collaborator.

Photo of Dr. Ulrike Reiss
Ulrike Reiss, M.D., director of the Clinical Hematology Division, of the St. Jude Children's Research Hospital. Courtesy of St. Jude Children's Research Hospital.

Although their expenses were covered, the study required significant time and effort for the participants, who committed to years of follow up, to monitor their health and the long term effects of the therapy.

The researchers made accommodations to minimize the time participants had to be away from their families. For instance, initially they were admitting them overnight to the hospital, but then realized that outpatient management would work just as well. They also worked with local hospitals to do the screenings whenever possible.

“NHLBI is committed to conducting, funding and promoting clinical trials for rare diseases,” said Donna Dimichele, M.D., Deputy Director of the NHLBI Division of Blood Diseases and Resources. “This research contributes to alleviating the suffering of patients and their families, but also to the understanding of the mechanisms and causes of many other common conditions, and of their potential cures.”

“NHLBI is committed to promoting, facilitating and funding basic and translational research, as well as well-designed clinical trials for rare diseases,” said Donna Di Michele, M.D., Deputy Director of the NHLBI Division of Blood Diseases and Resources. “This research has tremendous potential to contribute to our understanding of the causes of rare diseases, which in turn leads to the discovery of effective treatment and cures to alleviate the suffering of patients and their families. Furthermore, rare diseases research often informs our understanding of the mechanisms, causes, and pathways to effective treatment for many other common conditions.”

The majority of these disorders are serious or life-threatening and chronic. Most of them are inherited, also known as genetic disorders.

“This hemophilia B study provided the first clear demonstration of the long-term safety and efficacy of gene therapy,” said Davidoff. “The results made a profound difference in the lives of study participants by dramatically reducing their risk of bleeding.”

To understand how meaningful the results of such a small trial could be, Davidoff says one just needs to look around at the planet now, as new genetic treatments are being tested and approved by the Food and Drug Administration.

“There was concern about gene therapy, about its safety and its promise. This small study has had a profound effect,” said Davidoff. “It also has allowed us to extrapolate to the understanding of other monogenetic disorders, those caused by a single gene, of the liver, for instance.”

Research into each rare disease helps to build the knowledge base, so that scientists are not starting from ground zero in the quest for treatments. Many of the methods and techniques developed could be generalized to other conditions.

Learn more

Hemophilia

Gene therapy helps patients with hemophilia B

The coming of age of gene therapy: A review of the past and path forward

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