Fundamental Concept: Know Your Audience!

The FDA Office of Orphan Products Development (OOPD), the EMA Committee for Orphan Medicinal Products (COMP), and your FDA review division are unique entities with individual characteristics. Care should be taken to ensure any submissions are written with your particular audience in mind.

Requests for Fast Track, Breakthrough Therapy, and RMAT designations are generally submitted to your FDA review division. Each of these designations has its own particular criteria, but essentially you will be demonstrating to the agency that your therapy is likely to improve patient outcomes over the current standard of care. This is the time to leverage your in-house clinical experts who know what is happening in the field: i.e., what drugs are given to your target patient population, what endpoints are commonly used to measure success (median survival, 6-minute walk test, etc.), and how your data stacks up against existing therapies.

Additionally, you’ll want to tap in to regulatory expertise from a company who regularly submits special designation requests. Your clinical and regulatory experts should work together to present the data in the most convincing way. The regulatory specialists should make sure the submission is focused on the criteria for acceptance, and the clinical experts should provide insights into which data is most likely to meet those criteria. Successful submissions tend to be a product of collaboration between the regulatory team and the clinical team.

The EMA COMP grants Orphan Drug Designation for the EU. Like your FDA review division, this body is filled with experts who are likely to have a basic understanding of the indication you’re intending to treat or prevent. Some of the people who review EMA ODD applications may even have clinical experience with the rare disease.

While the published guidelines for EMA ODD state non-clinical evidence is sufficient, in my experience, they almost always require safety and efficacy data in at least a few human subjects. Again, your in-house clinical experts should work closely with your regulatory experts to pro-actively give the COMP everything they are likely to require (so as to avoid a long list of issues [LOI] letter), and to address any LOI in as succinct and efficient a manner as possible.

In contrast to both the EMA COMP and the FDA review divisions, the OOPD is composed of educated, intelligent people who are not likely to have a specialty tied to your indication. They may be PhDs, PharmDs, MDs, or hold a similar degree. When evaluating ODDs, this office focuses primarily on whether the indication – as they determine it to be, not necessarily what you file for – currently has a prevalence less than 200K people in the US. This is known as point prevalence in epidemiology, although in some cases annual incidence is a more appropriate epidemiological parameter. OOPD will also determine whether your data demonstrates that your therapy has the potential to treat/prevent the indication. While the efficacy bar here is extremely low compared to EMA COMP or FDA review divisions, this office is much more sensitive to models used, and baseline data to determine if the studies presented represent the rare disease. Except in rare cases, data should only be from in vivo models of the disease. Further, data from similar drugs is not accepted.

So, if you are seeking FDA ODD, remember that OOPD is quite picky about the exact therapy being used in an animal model of the disease, but they do not require more than preliminary nonclinical evidence of efficacy. In contrast, the EMA COMP is filled with experts who may be familiar with your indication, and they usually require clinical data (in at least a few patients) demonstrating efficacy of the new therapy, as well as complete safety data, before granting ODD. The FDA review divisions are also packed with experts familiar with your therapeutic area, and before they grant Fast Track, Breakthrough Therapy, or RMAT designations, they will want to see detailed efficacy data to support an improvement in patient outcomes. Always keep in mind who the audience is, and tailor your submissions appropriately!

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