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From our perspective: Encouraging drug development for rare diseases

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Jonathan Goldsmith, M.D., FACP, Associate Director for Rare Diseases in the Office of New Drugs, discusses the challenges in drug development for rare diseases and the steps FDA and others are taking to help address these issues.Jonathan Goldsmith, M.D., FACP

Rare diseases defined

As you might expect, a rare disease affects a limited number of people, specifically less than 200,000 people in the United States. But, it’s important to note that the term “rare” disease can be deceptive. There are approximately 7,000 different rare diseases, collectively affecting as many as 30 million people or about 10 percent of the U.S. population. So, while the number of patients with any given rare disease may be small, the cumulative impact on public health is large.

Rare diseases are seen across a wide array of therapeutic areas, including certain types of cancer, urea cycle disorders, and other genetic disorders, such as Gaucher’s disease. Rare diseases are chronic, debilitating conditions that are often inherited and frequently lead to early mortality. These facts are especially troubling when you consider that about half of those affected by rare diseases are children, and many of the diseases lack effective treatments.

Orphan drug designation

Historically, it has been more attractive for industry to develop drugs for large patient populations in order to recoup their clinical development investments and be financially viable. This trend toward drug development for more prevalent diseases seems to be changing, no doubt due in large part to 1983’s Orphan Drug Act.

Congress passed the Orphan Drug Act to spur development of “orphan drugs,” a term derived from the time when rare diseases were said to be forgotten or “orphaned” by the drug development industry. The act introduced financial incentives for orphan drug development including 7 years of market exclusivity for an approved orphan product, waiver of a prescription drug user fee, and other tax benefits.

When a company submits their request for an orphan-drug designation, FDA’s Office of Orphan Products Development determines if the product meets the criteria for an orphan drug ̶ namely that the disease prevalence is less than 200,000 people and there is a medically plausible basis for expecting the drug to be effective in the rare disease. I’d like to take a step back to point out that granting an orphan designation does not change FDA’s requirements for approval. An orphan drug must still demonstrate safety and effectiveness through adequate and well-controlled studies.

Challenges in orphan drug development

While any development program can experience challenges in demonstrating safety and effectiveness, the biggest challenge to orphan drug development by far is the small size of rare disease populations. Patients with these progressive, serious, life-limiting and life-threatening diseases are often geographically dispersed, which can make it difficult to find enough patients able to reach clinical trial sites. Additionally, it can be difficult for medical practitioners to develop expertise in conditions that are seen so rarely. This often results in a consolidation of expertise at a single or few locations that may be challenging for some patients to reach.

Small patient populations may also restrict clinical study design and the possibility of study replication. Large, placebo-controlled, randomized trials or repetition of even small trials are not always feasible in small populations. Regulatory flexibility in terms of the evidence required for drug approval, the acceptability of clinical outcomes that serve as trial end points, and innovative statistical design is often used for orphan drug evaluation and approval. 

Another challenge in orphan drug development is that the natural history of rare diseases is often poorly or incompletely understood. A natural history study is a valuable tool in learning how the disease progresses over time. Frankly, I think natural history studies are the backbone of drug development for rare diseases. With the information generated from these studies, more targeted clinical trials can be designed and clinically meaningful endpoints can be established to facilitate the development of potential new treatments.

An additional, perhaps over-looked challenge to orphan drug development is the lack of support groups for many rare diseases. Support groups can be instrumental for patients and families by providing knowledge about the disease, guidance and resources. Support groups can help to advocate for research funding and to identify interested patients that may be appropriate for new and ongoing clinical trials. These groups can also support patient-focused drug development efforts by voicing patient and family concerns and perceptions of disease.

Increasing awareness - Rare Disease Day

In 2008, the European Organization of Rare Disorders launched Rare Disease Day to increase public awareness and promote advocacy for rare diseases. The United States joined the movement in 2009 and now 80 countries participate in this event held annually on the last day of February. As 2016 is a leap year, Rare Disease Day falls on February 29th, the rarest day of all.

Patients and their families, policy-makers, health care providers, pharmaceutical representatives, legislators, regulators and researchers are among those who participate in Rare Disease Day. FDA’s Office of Orphan Products Development and CDER’s Rare Diseases Program each present programmatic updates and contribute posters describing the previous year’s accomplishments at the annual NIH-led event. Over the years, this event has become a major force in stimulating global recognition of the importance of the impact of rare diseases on patients and families.

The 2016 Rare Disease Day theme is the “Patient Voice.” The theme stresses the essential role of the patient in shaping our understanding of the disease, potential or existing treatments, and the realities of patients, families, and caregivers who confront rare diseases.

As a result of Rare Disease Day, we have seen an increased recognition of rare diseases from industry and the public. I’m very pleased to note that 21 of the 45 new molecular entity approvals in 2015 at CDER were treatments for rare diseases.

FDA supports orphan drug developers

To help address increasing interest in the orphan drug development space, The Rare Diseases Program at CDER offers annual staff training on rare diseases and issues guidance documents to assist drug developers. In August 2015, FDA issued a draft guidance that discusses issues most commonly encountered in rare disease drug development. We appreciate the input received from many stakeholders and are now reviewing their comments. I think this draft guidance is just the beginning. Moving forward, there will most certainly be a need for additional guidances, and we look forward to working with stakeholders to develop them.

We also recognize the importance of the patient voice in drug development. FDA has hosted a series of patient-focused drug development meetings on various therapeutic areas. Nearly half of the meetings have been focused on rare diseases. These meetings give FDA an important opportunity to hear directly from patients, patient advocates, and caretakers. We learn more about the symptoms that matter most to patients, the impact the disease has on their daily lives, and their experiences with available treatments. This input can help shape FDA’s decisions and oversight both during drug development and review.

Additionally, I am encouraged by the increased interest FDA’s reviewers have shown in learning more about rare diseases. We also now have a Rare Disease Council consisting of representatives from several centers throughout the agency that meets to discuss, coordinate, and collaborate on rare disease issues.

Working together for new therapies to treat rare diseases

In the Rare Diseases Program, our top priority is to support people affected by rare diseases by accelerating, supporting and facilitating the process of getting orphan drug products to market. As we move forward toward our goal of increased access to quality drug treatments for patients with rare diseases, it is of utmost importance that we continue to collaborate with industry and other stakeholders. Our shared hope is to maintain momentum spurred by the Orphan Drug Act and Rare Disease Day to foster effective collaborations and stimulate development of ground-breaking orphan drugs.

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Dr. Goldsmith started his career with FDA in 2005 in the Center for Biologics Evaluation and Research as Deputy Director of the Office of Blood Research and Review. From 2008 to 2014, he was a Deputy Branch Chief of the Division of Blood Diseases and Resources at the National Heart, Lung, and Blood Institute/NIH. In 2014, he returned to FDA, joining the Center for Drug Evaluation and Research as Associate Director of the Rare Diseases Program in the Office of New Drugs. Dr. Goldsmith earned his medical degree from New York University School of Medicine, received post-graduate training in Internal Medicine at Vanderbilt University Hospitals, and completed specialty training in Hematology and Blood Coagulation at the University of North Carolina. Prior to his federal service, he had an extensive career in academia as a tenured professor, in regulated industry where he focused on clinical drug development, and with orphan disease foundations.

 

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