Jonathan Kay, MD


July 16, 2014

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Orphan Drugs for Rare Diseases

Hello. I am Dr. Jonathan Kay, Professor of Medicine and Director of Clinical Research in the Division of Rheumatology at UMass Memorial Medical Center and the University of Massachusetts Medical School, both in Worcester, Massachusetts.

Welcome to Medscape. I'm here in Paris, where I have been attending the European League Against Rheumatism (EULAR) Annual Scientific Meeting, and I am going to talk about one of the presentations at this meeting.

I was invited to give a presentation about orphan drugs in the rheumatologic diseases. This is a subject about which I was relatively unfamiliar before I was asked to speak. I thought that an orphan drug was a drug that had lost all of its parent's compounds. However, upon researching this subject, I learned that orphan drugs are drugs developed to treat rare diseases. The reason for this is that the pharmaceutical industry has little incentive to develop drugs for diseases that affect relatively few patients, because there is little chance of recovering the cost of developing and marketing these products.

"Rare disease" is a regulatory definition. In the United States, the US Food and Drug Administration (FDA) defines a rare disease as a condition affecting fewer than 200,000 people. The European Commission defines a rare disease as being one that affects fewer than 5 in 10,000 individuals or fewer than 250,000 people in the European Union. There are between 5000 and 8000 rare diseases that affect between 6%-8% of the population. This translates to 27-36 million people in the European Union and 25-30 million people in the United States. Most rare diseases affect fewer than 1 in 100,000 people, and nearly all are of genetic origin.

Incentivizing Orphan Drug Development

The rationale for the Orphan Drug Act, which was passed in the United States by the US Congress in 1983, and the Orphan Regulation, which was passed by the European Commission in 2000, are that adequate drugs have not been developed for many rare diseases and conditions. Because very few individuals are affected by rare diseases or conditions, pharmaceutical companies that develops an orphan drug may expect small sales revenue relative to the cost of developing the drug and a possible financial loss from marketing such a drug for a rare disease. The expectation that promising orphan drugs would not be developed unless changes were made in applicable US federal laws or European regulations to reduce the cost of developing these drugs and to provide financial incentives to develop them led to the passage of these laws.

The incentives for orphan drug development are similar between the United States and the European Union (EU). In both cases, the drug regulatory agency -- the FDA and the European Medicines Agency (EMA) -- provide free advice to assist companies to develop protocols to optimize the development of orphan drugs for rare diseases. In the United States, there is a 7-year period of exclusivity granted after an orphan drug is approved. In Europe, that period of exclusivity is 10 years, with an additional 2 years of extension if pediatric studies are conducted. In both cases, fees are waived.

In the United States, the prescription drug user fee is waived. In the EU, the fees for protocol assistance or for preauthorization inspections are waived completely, and the fee for marketing authorization is reduced by 50%. In the United States, tax credits are provided for the costs of clinical research to companies developing orphan drugs. In the EU, there is access to a centralized procedure for marketing authorization. In the United States, several million dollars of federal grant funding are allotted each year to help defray the costs of qualified clinical testing expenses for orphan drugs. In the EU, member states have programs, some of which include grant funding, to help in the development of orphan drugs.

The Growing List of Orphan Drugs

The orphan drug designation is a legal procedure that allows a medicinal substance with a therapeutic potential for a rare disease to be designated before its first administration in humans, or during its clinical development. The exact indication is defined at the time the drug is authorized for marketing. In the United States, the FDA has designated more than 3000 products as orphan drugs since the Orphan Drug Act was passed in 1983, and 455 orphan drugs have been approved for rare diseases. Since 2000, the EMA has designated more than 1000 drugs as orphan medicinal products and has authorized 103 orphan drugs for rare diseases.

Most orphan drugs that have been developed have been for oncologic indications; the next largest group is for genetic disorders. As of 2011, however, 18 drugs were in development for autoimmune disorders. Between 2000 and 2010, 4% of the orphan drugs approved by the EMA were for immunologic indications. Between 2006 and 2011 in the United States, 8% of orphan drugs approvals were for rheumatologic conditions.

The rheumatologic diseases that are considered orphan diseases include juvenile idiopathic arthritis, for which several drugs are approved because this condition affects fewer than 200,000 individuals. Another is periodic fever syndrome, including cryopyrin-associated periodic syndrome, which includes familial cold autoinflammatory syndrome and Muckle-Wells syndrome, familial Mediterranean fever, and neonatal onset multisystem inflammatory disease; these have also received approval for orphan drugs. Finally, in vasculitis, antineutrophil cytoplasmic antibody-associated vasculitis has recently received approval for rituximab to be used in this condition, and Paget disease of bone has had approval for human calcitonin.

In the EU, rilonacept and canakinumab have been approved for patients with cryopyrin-associated periodic syndromes. The orphan drug regulation allows designation of a medication as an orphan drug to receive the potential benefits to encourage its development for use in a rare disease. However, once designated as an orphan drug, the drug goes through the same study and approval process that any medication would undergo -- with phase 1, phase 2, and pivotal phase 3 trials, and then regulatory approval looking for effectiveness, safety, and other attributes that would warrant its authorization by the regulatory agency.

Orphan drug designation allows for regulatory and economic incentives for manufacturers to develop treatments for rare disease. An increasing number drugs have been given orphan drug designation, both in the EU and in the United States. This process allows the unmet need for the treatment of patients with less prevalent rheumatologic diseases to be addressed. Patient organizations can take part in this process by encouraging patients with these rare diseases to volunteer for clinical trials to help develop treatments that will benefit others with those conditions in the future.

I hope that this summary of orphan drugs has been as interesting to you as it has to me during the time that I have been investigating this subject. I look forward to seeing you again on Medscape. Thank you very much.


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