Are you developing a new medicinal product for a rare disease and interested in applying for orphan drug designation (ODD) in the European Union (EU)?

The Orphan Regulation (Regulation EC 141/2000) was introduced in the EU to encourage sponsors to develop and market medicinal products for the diagnosis, prevention or treatment of rare diseases (the so-called “orphan” drugs) by means of regulatory, financial and commercial incentives, with market exclusivity as of the most appealing incentives. An ODD may also bring indirect benefits such as increased product and company visibility to investors. However, strategic and timely planning is necessary to successfully obtain the designation and its associated incentives.

An ODD application can be submitted at any stage of the product development before the marketing authorisation application. A good understanding of the qualifying criteria and a critical evaluation of the feasibility of an ODD request for your product at a given time will help you to define the right timing for an ODD application within your overall development strategy.

This blog lists the main areas that you will need to address in your ODD application:

1. Clearly define the proposed condition and orphan indication

The EMA will first assess whether the condition for which the ODD is sought fits the definition of a rare disease, which requires that the condition affects no more than 5 in 10,000 people in the EU (prevalence criterion). In addition, the condition must be life-threatening, seriously or chronically debilitating and must be justified as a recognized distinct medical entity (typically a disease or syndrome) defined in terms of its specific pathophysiological, histopathological, and clinical characteristics. A subset of a non-rare condition could be only considered a valid condition if patients in that subset present distinct and unique evaluable characteristics linked to the condition which are essential for the medicinal product to carry out its action. Rare adverse effects of an authorized medicinal product or manifestations that can occur in the course of a disease will never be accepted by the EMA as valid conditions.

The proposed orphan indication should specify the therapeutic intent (i.e., treatment, prevention or diagnosis of the condition) and the target patient population. The orphan indication may comprise a broader population than the population defined by the proposed therapeutic indication. This broader population should be the basis for estimating prevalence.

2. Elaborate an up-to-date prevalence estimate

The fulfilment of the prevalence criterion defined above should be demonstrated by performing a comprehensive review of relevant and up-to-date epidemiological data available in publications and other reliable sources such as databases and registries. Data from as many EU countries as possible should be gathered. The methodology used for the calculation, as well as the result and conclusions, should be described and justified.

3. Collect adequate and enough data to demonstrate medical plausibility

The intention to treat (or prevent or diagnose, as applicable) the condition with the medicinal product must be scientifically justified, supported by a description of the medicinal product and its mechanism of action and by all relevant available nonclinical and clinical data. If clinical data is not yet available, the EMA will accept nonclinical data provided that the in vitro and/or in vivo model used is recognized as relevant for the target orphan indication in humans and the endpoint chosen in the nonclinical studies is indicative of therapeutic effect on the condition in humans. Early-stage clinical data, even if preliminary, will increase the chances of success of the ODD request, provided that the study population and endpoints are relevant to the sought indication.

4. Explore the therapeutic landscape and demonstrate significant benefit over existing therapies

One of the key qualifying criteria for designation is that either there is no satisfactory treatment available or, if there is, the product for which ODD is sought is of significant benefit to those patients affected by the condition. In the former case, meeting the criterion is quite straightforward by making reference to scientific and medical literature and other relevant information sources which evidence that the condition is an unmet medical need as no satisfactory therapeutic methods are available. In the latter case, it must be justified why the new product offers a significant benefit over the existing options, which involves demonstrating the therapeutic advantage, improvement in efficacy, safety, or quality of life. Any claim for a “clinically relevant advantage” in efficacy or safety profile needs to be supported by nonclinical and, even better, by clinical data. If comparative data are not yet available, a critical review comparing existing therapeutic methods and the activity of the new product should be provided explaining why significant benefit can be assumed.

Supporting the notion of significant benefit is probably one of the most challenging aspects of an ODD application. Early discussions with EMA through Protocol Assistance can be of great value to get guidance on this particular and on the orphan drug development in general. It is also highly recommended to request a pre-submission discussion (virtual meeting) with EMA at least two months prior to the planned submission date of the ODD application, covering all areas of the application.

Conclusion

After carefully considering the above criteria, the availability of required data to adequately cover the areas mentioned above will define the appropriate timing to prepare a thorough, structured and well-documented ODD application. The completeness and quality of the application and its timely submission are crucial factors for a smooth evaluation and a positive outcome on the initial ODD application.

Need help? Rho is highly experienced in preparing ODD applications and supporting the whole designation procedure with EMA (and with FDA). Contact us for more information.

References

Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products.

Guideline on the format and content of applications for designation as orphan medicinal products and on the transfer of designations from one sponsor to another (2022/C 440/02).

Procedural advice for orphan medicinal product designation. Guidance for sponsors. EMA/420706/2018 Rev 14. 6 March 2024.

Beatriz Criado Bueno, MSc, Director, EU Regulatory Strategy, has more than 25 years of experience in regulatory affairs in the pharmaceutical, biotech and CRO industries where she has held a range of leadership positions in regulatory affairs. Ms. Criado is well versed in bringing products from development to market and in post-approval life cycle management regulatory activities. She has a solid background in biological and biotech-based products, and broad experience in a wide variety of therapeutic areas, including immunology, neuroscience, oncology, dermatology, rare diseases, and pediatric indications. Ms. Criado has significant experience preparing and filing regulatory submissions including more than 50 marketing applications across EEA countries and UK and multiple orphan designations and pediatric investigation plans. She has also coordinated more than 20 CTAs including complex clinical trials such as umbrella and platform designs, more than 10 Scientific Advice procedures (EMA and National) and a similar number of pre-submission meetings with EMA and National Regulatory Authorities.