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The Rapidly Expanding World of Rare Diseases

November 4, 2015 | Kathryn Tworkoski, PhD, Clinical Research Scientist | Regulatory Affairs, Drug Development Consulting

When you think about drug development, you probably assume that pharmaceutical companies are most likely to invest in therapies that can be used by a large percentage of the population to treat common diseases. Yet recent years have witnessed an explosion in the development of so-called “orphan” drugs that treat rare diseases.

In 2013, 33% of the New Molecular Entities (NMEs) approved by the Center for Drug Evaluation and Research were orphan drugs and in 2014, 41% of NMEs were orphan drugs. All of which begs the question: what’s driving this interest in orphan drug development?

Rare Diseases

Image courtesy of jk1991

Although an individual rare disease affects fewer than 200,000 people in the US, there are roughly 7,000 rare diseases that impact over 25 million Americans.

Congress first incentivized drug development for the treatment of rare diseases with the 1983 Orphan Drug Act (ODA), which provided tax credits and federal grants to companies developing orphan drugs. Importantly, the ODA also made orphan drugs eligible for 7 years of marketing exclusivity once approved.

Since enactment of the ODA, interest in orphan drug research (and associated funding) has steadily increased. In fact, in 2015 the FDA’s Orphan Products Grant Program received 92 grant applications and awarded 18 new grants totaling over $19 million in research dollars!

Expanding Incentives for Orphan Drugs

Since 1983, Congress has added several incentives for rare disease research. One recent example (see our previous post) is the pediatric rare disease priority review voucher (PRV) program. This program, which was initiated in 2012, rewards the approval of a drug to treat a rare pediatric disease with a voucher that a company can use to shorten the FDA review period of a future drug program.

New Congressional proposals introduced in September 2015 would expand these PRV programs to include “wildcard exclusivity,” which would offer a 1‑year extension on patent exclusivity to companies with a successful drug intended for neonates.


New (Draft) Guidance on Rare Diseases

In August 2015, the FDA released a draft guidance meant to provide insight that will help companies successfully develop orphan drugs.

The image on the right depicts the six main concepts that the FDA highlighted as being important considerations in orphan drug development.

Although the guidance offers plenty of food for thought, the FDA also acknowledged that there is great variability between rare diseases and states that “scientific judgement” will have to be employed for “individual drug development programs.”

Such statements touch on the difficulties presented by rare diseases. In fact, at multiple points in the guidance, the FDA alluded to the challenges inherent in orphan drug development. In my mind, these challenges can be subdivided into 3 categories (see image below).

challengeThreshold for Proof

Since there aren’t many patients available for a rare disease clinical trial, orphan drug trials frequently have a lower number of subjects than conventional trials, and safety and efficacy endpoints are typically adjusted.

In September 2015, the National Organization for Rare Disorders (NORD) asked the FDA to acknowledge that “special flexibility” is needed for the review and marketing of rare diseases. Although the FDA did not change the official guidance, they listed examples of the considerations given to rare diseases and implied that the “special flexibility” requested by NORD is already (unofficially) in place.

Clinical Trial Design

Image courtesy of Master Isolated
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The small pool of potential subjects for a rare disease clinical trial means that it can be difficult to run more than one clinical trial for a particular rare disease at any given time and raises some concerns over which trials can and should be conducted.

Additionally, clinical trials frequently use eligibility criteria to weed out subjects who may have contraindications or who may not respond well to the drug. But when a patient has no means to treat their serious rare disease, is it appropriate to deny them a potential treatment based on eligibility criteria?

Patient and Advocate Input

Image courtesy of Start Miles

Clinical trials are traditionally designed to minimize the risk to potential subjects, but since rare diseases are frequently life‑threatening, some patients/advocates argue that they’re willing to accept greater potential risk.

Furthermore, since roughly 50% of patients with rare diseases are children, there are concerns surrounding the ability of a patient to provide fully informed consent for any investigational treatment.

Such issues have prompted a push for greater patient/advocate involvement in the development of orphan drugs. Advocacy groups raise money for research, petition the FDA and pharmaceutical companies for input, and attempt to shape FDA regulations.

One example of advocate success comes from the Parent Project Muscular Dystrophy (PPMD) group, which submitted a June 2014 draft guidance to the FDA for the development of drugs to treat Duchenne Muscular Dystrophy.

Subsequently, the FDA released an official June 2015 draft guidance that was influenced by PPMD’s draft guidance. This official guidance marked the first time that an FDA guidance was preceded by a patient/advocacy group’s suggested guidance.

What’s Ahead?

In the future, it will be exciting to see how orphan drugs evolve and how patients and advocates interact with the FDA and pharmaceutical companies to promote regulatory and drug development for rare diseases. Interest in rare diseases has been steadily increasing, and it is unlikely to fade in the near future. In fact, a new bipartisan bill was introduced in September 2015 to further incentivize the development of orphan drugs.

For those who are interested in entering the world of orphan drugs, IMPACT has experience with rare disease programs including Duchenne Muscular Dystrophy, cystic fibrosis, acute lymphoblastic leukemia, dermatomyositis, and Waldenström’s macroglobulinemia, among others. Go ahead and contact us: we’re always happy to help!

Category: Regulatory Affairs, Drug Development Consulting
Keywords: Rare disease, orphan drug, FDA guidance

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