Guidelines To Write and Submit an Orphan Drug Application For A Rare Disease

While working on our orphan drug application for Cyclodextrin for the treatment of Niemann Pick Type C disease, I searched the Internet looking for examples of an actual orphan drug application that was filed with the U.S. Food and Drug Administration.

Not surprisingly, I could not find any ‘real applications’ that could be used as a reference or starting point. Since most applications are filed by Pharma or BioTech companies, the applications are typically kept confidential.

Here is a PDF document of the actual orphan drug application we filed with the FDA a few weeks ago (it takes a minute to download as the PDF is large). I hope that the posting of our completed application will benefit someone else who is going through the application process and is not sure where to start.

Dr. Timothy Cote stressed at the FDA Orphan Drug Workshop at Keck Graduate Institute that too many companies over complicate the process and file volumes of data when it’s not really necessary. Making a request for orphan drug designation is a  simple process and the application can be 10 or so pages with backup material.

Things To Consider Before Filing Orphan Drug Application

Here are some key things I learned at the FDA Workshop on how to file for a request for orphan designation (RFD):

• In 2009, 250 requests for orphan drug designation were filed with the FDA, and 160 received it.  According to the FDA, roughly 60-70% of applications result in granting of orphan status
• Denials were generally as a result of not meeting rare disease prevalence requirements (ie. trying to submit for something that is not a rare disease or a subset of a larger disease)
• Here is what you will need to be prepared to answer in your filing:
  • What is the disease and is the disease rare (less than 200,000 prevalence)?
  • Will your drug treat this rare disease?
  • Can you demonstrate that there is “promise” that the drug will be effective in treating the rare disease. According to the FDA, “promise” is liberally interpreted to include:
    • Data from clinical trials OR
    • Data from case studies/reports OR
    • Data from animal models OR (rarely)
    • Data from in vitro experiments
    • Theories are NOT accepted

• Expect roughly 60 days to get a decision once you make a filing
• A negative decision can always be overturned.  The record remains forever open according to Dr. Cote
• If you receive a designation, you need to file an annual report each year to give an update on your progress. You can now file a single annual report with the FDA and EMA.  If we receive a designation for Cyclodextrin, I will write a separate blog on other requirements we will need to fulfill

Suggested Reference Materials

Here is some suggested reference materials that the FDA uses to guide people who call the FDA with questions on creating requests for orphan designations (RFD).

• Code of Federal Regulation 21 CFR 316
• 21 CFR 316 Jan 1991 Preamble to proposed legislation – This document provides the Agency’s thinking about Orphan drug development regulation
• Orphan Drug Act
• Do a Designation Notes (word document)
• Rare Disease Prevalence data
• Tips for submitting a Request for Designation (RDF)
• How to apply for Designation as an Orphan Product – For Industry
• European Medicines Agency documents

Dr. Cote told the group that the FDA’s Office of Orphan Products Development is there to help people with the process. I have had many dealings now with the staff at the FDA and they have been extremely helpful.