Getting the ODD: The Art of Orphan Subsetting

Why is the term ‘orphan subsetting‘ important for you to understand, and how does it affect your Orphan Drug Designation (ODD) application? This important consideration can make the difference in whether your ODD is approved. Let’s break it down.

ODD is granted for a particular drug, biologic, or diagnostic in a specific indication. In ODD applications, the Agency refers to all of these as “drugs”, even the biologics and diagnostics. When the proposed intent to treat population (ITT) is part of a larger indication, a persuasive argument needs to be made that the drug can only be effective in the specific population you’ve calculated the prevalence of. Let’s take breast cancer patients as an example. If your drug is only intended to treat a certain type of breast cancer patient, and you’re positing that the number of those patients currently in the US is less than 200K (a main requirement for ODD), a justification for the exclusion of the rest of the breast cancer patients in the US needs to be included in the application for ODD.


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Subsetting is the art of defining a certain patient population as the ONLY patients who could ever benefit from the proposed drug. This is very different from the ITT population, and completely separate from the patient population your review division grants you permission to conduct clinical trials in. Your review division considers safety and medical need – they look at a risk/benefit ratio. The Office of Orphan Drug Products (OOPD), which grants ODD, does not. They are solely concerned with whether your drug could possibly be effective in the larger non-rare disease population. Going back to the breast cancer example, we would need to explain why the proper population calculation for ODD is smaller than the SEER more than 3,577,264 women in the US with breast cancer.

There are only 3 types of arguments the OOPD will accept for subsetting:

  1. The mechanism of action of the drug makes it ineffective in any other patient population
  2. The toxicity profile of the drug confines its suitability to patients with extremely high medical need
  3. Prior clinical experience demonstrates this drug doesn’t work in specific populations

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The first point, mechanism of action, could be used to explain why certain breast cancer patients would not benefit from this drug. For instance, if the drug were a gene therapy targeting a specific rare genetic mutation, and it couldn’t actually impact patients without that rare mutation, a solid case could be made for a subset.

Another solid case for subsetting is based on toxicity. This is almost exclusively seen in cancer therapies, since cancer drugs can be quite toxic. Returning to breast cancer, an argument might be made that a particular drug should not be used in early stage patients, since resection can be curative and treatment with highly toxic drugs can have extreme side effects that last a lifetime.


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Lastly, and most rarely, if there is clinical data demonstrating a drug has zero efficacy in a particular patient population, that would lay the groundwork for a valid subsetting argument. For example, if there is data demonstrating a particular drug doesn’t elicit any response in breast cancer patients with HER2 mutations, that could be sufficient for a subsetting argument. However, it is prudent to get ODD long before entering the clinic, so this is usually not the preferred pathway. Further, proving a negative (the drug will NEVER work in this patient population) can be challenging, so the supporting data would need to be robust.

Hopefully, this will help your team understand the difference between how the FDA review divisions view the ITT and how the OOPD views a subsetting argument. If you have any questions, please contact us for a free regulatory consultation!

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