Orphan Insights is a short series inspired by real conversations with emerging biotech companies developing therapies for rare and ultra-rare diseases. These discussions often begin with the same fundamental questions: When should we engage regulators? Which designations apply to our program? How soon can I get my designation, and how soon can I talk to the FDA about accelerating development (i.e., faster development plans)?
While there are no universal answers, there are inflection points, and asking the right questions, in the right context, and at the right time is often what separates a slow, costly path from a focused, time- and capital-efficient one.
In this first part, we offer insight into the Orphan Drug Designation (ODD) and provide clarity on the FDA and EMA frameworks.
Question 1: When is the right time, and how soon can I apply for orphan drug designation?
The "right" time to apply for ODD is multifaceted, differs between the FDA and EMA, and involves both a can and a should answer.
For both FDA and EMA orphan designations, you can apply at the preclinical stage (yes, this is true), and many successful orphan programs do. We also find it easier at this stage. When a relevant animal model of the rare disease exists, applying preclinically is often straightforward and less dependent on isolating a drug's treatment effect in humans, which can be challenging in earlier-stage trials.
For rare diseases where no animal model exists, ODD may still be achievable before clinical trials begin; however, success hinges on assembling a cohesive scientific rationale supported by mechanistic, translational, or in vitro data rather than animal efficacy.
The question of when you should apply depends largely on what you need the designation to achieve for your program – whether the designation is intended to support early financing, signaling regulatory momentum, or aligning early development strategy with regulatory input.
FDA ODD
Unlike the EMA ODD, the FDA orphan drug designation does not provide immediate regulatory incentives, nor does it automatically grant access to expedited regulatory pathways. Outside of the PREA regulatory exemption, the primary benefits of FDA ODD are realized later and are focused on supporting return on investment (e.g., PDUFA fee waiver, 7-year market exclusivity, and U.S. clinical tax credits).
That said, across the nearly 300 ODDs RareMoon has authored, submitted, and achieved, we consistently see that securing the designation as early as feasible can be done more efficiently and provides meaningful strategic value, particularly in investor engagement, signaling program focus and regulatory alignment, and in many cases, supporting early patient and advocacy awareness.
EMA ODD
The EMA ODD does offer earlier financial incentives, including significantly reduced or waived fees for Scientific Advice or Protocol Assistance. RareMoon's recommendation on when to pursue EMA ODD often differs from the FDA, and while there are still considerations related to investor attraction, this is more closely linked to your European development objectives, planned clinical trial footprint, and your regulatory engagement strategy in the EU.
Ultimately, the "right" time to apply for ODD hinges on program readiness, near-term development objectives, and what you need the designation to unlock (e.g., milestone payments). In most cases, particularly when a relevant animal model exists, we recommend applying at the preclinical stage, as doing so can strengthen early strategic positioning and provide added confidence in investor, partner, and advocacy conversations .
Question 2: Should we apply for ODD in the U.S. and the EU at the same time?
Not necessarily. Parallel submissions can be efficient, but the EU carries additional considerations. These considerations include differing criteria (see Question 3), Sponsorship, the public disclosure of information related to the drug , and internal resources required to support the application throughout the EMA submission process. Additionally, while there is no direct fee to submit an EMA ODD, the Agency may impose fees for withdrawn or rejected applications, which makes timing, preparedness, and experience especially important. If you are not familiar with these nuances, speak with an expert who can inform your decision and support you through the process.
Question 3: I already have an FDA ODD. Can I recycle the same information for my EMA ODD?
While certain components of your FDA ODD (disease background, product description, and scientific rationale) will be relevant, the EMA ODD is not a copy-and-paste exercise. The EMA applies different criteria and evaluates the designation under a different framework.
The key differences include:
- Disease Nomenclature and Definition
EMA may define or scope the condition differently from the FDA. Ensuring alignment on the disease nomenclature is critical, as EMA may not accept certain subgroup or phenotype-based orphan subsets.
- Prevalence Calculation
EMA requires prevalence to be demonstrated within the EU population , not the U.S. population, and based on a ratio (5/10,000) rather than an absolute number (200,000). The calculation must be based on the current EU population size , and the methodology and data sources must be acceptable to the EMA, per their recommendations.
- Significant Benefit Requirement
Unlike with FDA ODDs, EMA requires evidence, or a robust rationale, that your product offers a "significant benefit" compared to existing diagnostic, preventive, or therapeutic options. This requires a comparative argument, not just the demonstration of promise.
Because of these differences, a successful EMA ODD often requires reframing the narrative, rather than "recycling" the file.
Closing Remarks
RareMoon acknowledges that there are still many nuanced and program-specific questions we haven't touched yet in this initial set of questions. If there is a specific topic you would like us to address, please and we'll include it in an upcoming Orphan Insights Q&A.
If you would like to explore your specific program and determine the most strategic pathway forward, our team would be happy to talk.