February 28 is the 12th Annual Rare Disease Day. This year’s theme is “bridging health and social care,” and will bring together the rare disease community in various cities across the world, highlighting the need for better medical, social, and support services to lessen the burden that rare diseases have on the daily lives of patients, their families, and caregivers. The day also highlights the need for continued research and development in rare and neglected diseases.

There are more than 7,000 known rare disorders that collectively affect nearly 30 million people in the United States. While there have been many advances in research in recent years (including some significant FDA approvals and some key pivotal trials with breakthrough gene therapies), the vast majority of rare diseases still have no treatments available and many of these diseases are not fully understood. Many of the treatments that are approved address symptoms of rare diseases but are not curative. Although the lack of treatments for most rare diseases may be partly due to the unique challenges that researchers face in developing new therapies to treat rare diseases, there is not a lack of clinical trials for rare diseases. According to Pharmaceutical Research and Manufacturers of America, there are about 600 therapies currently in development for rare diseases.

One of the major reasons for the significant amount of rare disease research is due to the Orphan Drug Act of 1983. This federal law was enacted to encourage research into rare diseases and possible cures. The Orphan Drug Act classifies a rare disease according to prevalence: any disease or condition that affects fewer than 200,000 people in the United States.

Almost universally, orphan drug legislation is considered to be successful. Prior to the legislative act, there were few drugs specifically developed to treat rare diseases. However, since passage of the Orphan Drug Act in the U.S. in 1983, 2,755 agents have received an orphan drug designation in the United States, with 425 orphan drug approvals.

Although this very successful Federal law is largely responsible for increasing research in rare diseases, there remains many challenges for developing new and effective therapies for individuals with rare diseases including small patient populations, limited understanding of rare diseases, and difficulties creating effective trial designs.

Small patient populations. It is frequently cited that more than 80% of clinical studies are delayed due to problems with recruitment, and only 4% of Americans have ever participated in a clinical trial study. With rare diseases, it is even more challenging to fill a clinical trial given the small number of patients who may have a rare disease. For example, researchers have to find the right patients and clinicians, raise awareness of relevant studies, and minimize the burden for patients and their families to participate. Patients, for example, may have a limited number of trial sites where they can participate. Traveling to the trial sites for appointments and laboratory tests can also be difficult for patients and their families. Such challenges can be compounded by the fact that many rare diseases are degenerative and can progress rapidly. Also, about 50% of patients with rare diseases are children, which also presents special challenges in planning and executing a clinical trial. Finally, if treatments are available for a particular rare disease, those with the disease and their clinicians may be reluctant to participate in a new clinical trial—even if the currently available treatment(s) does not completely cure the disease or address all its symptoms—unless the investigational agent had a clear advantage over current treatment. As one expert we spoke to for this needs assessment acknowledged, “In a condition where you could live relatively normally with treatment, it can be difficult to recruit patients.”

Limited understanding of rare diseases. In many cases, there is limited prior clinical research that can be used to support clinical trial design and planning for potential treatments of rare diseases. Because the population is small, information about the disease, its natural course and the impact of symptoms on patient health and quality of life are limited.  Also, rare diseases are usually poorly understood, which means that patients may be misdiagnosed or diagnosed too late for meaningful data to be collected on the progression of their disease.

Difficulties creating effective trial designs. Limited understanding of rare diseases requires researchers involved in finding treatments for rare diseases to spend a lot more time and effort thinking about appropriate trial designs—and to be more flexible in their designs—than researchers developing treatments for more common conditions.In many cases clear endpoints and outcome assessment tools are lacking. Also, researchers must deal with the ethical issue of using placebo or control drugs. While the use of controls strengthens trial design by addressing concerns surrounding clinical variability, and placebo-controlled trials are considered the gold standard when it comes to collecting meaningful clinical data, in rare diseases using a placebo or control drug raises significant ethical issues. The team caring for those with rare diseases frequently has limited, if any, treatment options to offer these patients outside of a clinical trial. Given that many of these patients have potentially shortened lifespans, it is unreasonable to give some patients in the trial a new drug that could help save or significantly impact their lives and give others a placebo. Researchers, therefore, must be sensitive to the needs and expectations of desperate patients and their families and, as a result, often find that they cannot justify conducting placebo-controlled clinical trials.

When caring for an individual with a rare disease who has exhausted standard treatments or for whom there are no treatments available, it is important for the care team to recognize that there are still options. Two important possibilities are clinical trials and expanded access (EA) programs to experimental products.

Clinical trials are an important way for patients to have access to emerging, cutting-edge treatments for rare conditions. However, clinicians and patients may not know where to begin to find an appropriate clinical trial for a rare disease. In addition, a number of barriers exist for both patients (e.g., matching trial participation criteria, travel) as well as the healthcare team (e.g., limited time, extra work, competing time demands and resources, extra paperwork, lack of staff and training). The healthcare team, therefore, needs education about how to find appropriate trials for their patients with rare diseases, and how to overcome these patient and team barriers.

February 28 will be a day to reflect on rare diseases and for the community to spread it’s accomplishments. CheckRare will be attending many of the gatherings in New York, Washington, DC, and Cambridge. We hope to see you out there.

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