Carima Andrady, Ph.D. - Senior Regulatory Specialist, Pharmalex
There are key eligibility criteria to consider when preparing an EU orphan drug designation (ODD) application (different to that of the US); one of which is justifying the “significant benefit” of ones’ product over existing products for an orphan condition. Demonstrating significant benefit contributes considerably in securing a successful ODD application if the correct approach is taken, as described in two recent publications by the EMA in collaboration with the Committee for Orphan Medicinal Products (COMP).1,2 The COMP is in charge of reviewing applications for orphan designation.
What Is “Significant Benefit” And Why Is It Important?
Three unique EU regulatory criteria must be fulfilled by all applications for ODD status, as follows:
- The medicine must treat, prevent, or diagnose a disease which is life-threatening or chronically debilitating
- The disease must not affect more than 5 in 10,000 people across the EU
- No satisfactory method of diagnosis, prevention or treatment exists, or if such a method already exists, the medicine must be of significant benefit to those affected by the condition
In 2020, there were 235 ODD applications submitted to the EMA; only 149 of these applications received ODD status. Of these ODDs, 64% were made based on the value of significant benefit.3
The need to demonstrate significant benefit is of particular importance. Aside from missing out on key orphan incentives set up by the EMA, on a global scale, an application with a lack of adequate comparative data may block new products from obtaining ODD status and therefore its access to patients, state the EMA/COMP.1
How Do I Justify Significant Benefit in Order to Make My ODD Application Have Every Chance Of Success?
Firstly, part of justifying the significant benefit of one’s product is identifying satisfactory methods that already exist. The EMA/COMP make a point about distinguishing the meaning of the word ’satisfactory’ and ‘efficacious’:
“The fact that a medicine is not curative or fully effective does not imply that it is not considered ‘satisfactory’ from a regulatory point of view as long as the benefit/risk balance is deemed positive”.1
That said, the EMA/COMP have identified what constitutes ‘satisfactory’ methods of treatment (prevention or diagnosis) as follows:
- Medicines/methods authorized for use in the EU, in one or all member states, and NOT a product that is used off-label or under hospital exemption (exceptional cases may be medicines supplied as ‘magistral formulas’).
- Medicines/methods used for a broader patient population than the targeted orphan condition, e.g., corticosteroids or anti-epileptics with broad labels.
- Non-pharmacological therapy (e.g., surgery, radiotherapy, diet etc.) recognized as per up-to-date treatment guidelines.
- Old, unused products as well as newly approved products. This becomes an issue particularly in orphan conditions where there are constantly new medicines and changing clinical practice, e.g., in oncology, many treatment options exist but their clinical use in practice is not often standardized, such as multiple myeloma.
- Where the orphan condition is a broad disease, medicines/ methods authorized for the treatment (or prevention or diagnosis) of symptoms rather than the disease. For example, anti-seizure medication is authorized for treatment of specific seizure types, and thus are approved for specific conditions where these various types of seizures occur.
Secondly, the COMP expects a comparative discussion, based on available data, to demonstrate clearly an advantage of the proposed product over existing methods, such as improved efficacy, improved safety or a major contribution to patient care. This is usually based on evidence from non-clinical or clinical data showing:
“effects on an aspect of the disease or patient population that is not covered by the label of the authorised medicines; improved effects on common aspects treated by the juxtaposed treatments; or by highlighting data showing add-on effects when the proposed product is added to the standard of care”, state the EMA/COMP.2
Most cases of significant benefit have been argued on the basis of improved efficacy.2 The COMP advise against there being sustainable arguments on the basis of improved safety, due to most products being in early developmental stages at the time of ODD application.
Similarly, the consideration for claims based on major contribution to patient care (such as improved quality of life data including a more convenient mode of administration or improved availability of the product) can only be considered assuming efficacy and safety aspects.
In the end, it is the applicant’s task to accurately capture as much up-to-date information as possible on the current standards of care across the EU (as a whole and/or individual member states if there are differences) and discuss comparatively highlighting clearly the significant benefits of the proposed product based on this data. The EMA have written formal guidance on the information required to support the assumption of significant benefit for an orphan designation (EMA/COMP/15893/2009 Final).
Summary
Significant benefit is a unique criterion in the EU Orphan Regulation framework when applying for ODD status. A successful application will demonstrate a clear justification of the benefit of a product over existing satisfactory methods, where these are present already for the orphan condition.
For certain orphan conditions, this can often be a challenging task to fulfil, not least because the specific meaning of “satisfactory methods”, particularly in the face of changing clinical practice and numerous treatment options.
References
- Sheean ME, Naumann-Winter F, Capovilla G, Kalland ME, Malikova E, Mariz S, Matusevicius D, Nistico R, Schwarzer-Daum B, Tsigkos S, Tzogani K, Larsson K, Magrelli A, Stoyanova-Beninska V. Defining Satisfactory Methods of Treatment in Rare Diseases When Evaluating Significant Benefit-The EU Regulator’s Perspective. Front Med (Lausanne). 2021 Aug 27;8:744625. doi: 10.3389/fmed.2021.744625. PMID: 34513895; PMCID: PMC8429787.https://www.ncbi.nlm. nih.gov/pmc/articles/PMC8429787/pdf/fmed-08-744625.pdf
- Tsigkos S, Mariz S, Sheean ME, Larsson K, Magrelli A, Stoyanova-Beninska V. Regulatory Standards in Orphan Medicinal Product Designation in the EU. Front Med (Lausanne). 2021 Jun 25;8:698534. doi: 10.3389/fmed.2021.698534. PMID: 34249982; PMCID: PMC8268149. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268149/pdf/fmed-08-698534.pdf
- MA. Orphan Medicines Figures 2000- 2020. https://www.ema.europa.eu/en/documents/ other/orphan-medicines-figures-2000-2020_en.pdf. Last updated 02/2021. Accessed 09/2021.
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