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Impact of first-to-market product on orphan designation status for subsequent products in the EU4

22 January 2025

Background and Objectives

In Europe, orphan designation status plays a vital role in encouraging the development of treatments for rare diseases.

This special status grants valuable incentives—most notably, a 10-year market exclusivity period—designed to attract innovation and investment in life-saving therapies for rare conditions. But to receive this designation, a treatment must meet three essential criteria:

  • The medicine must address a life-threatening or chronically debilitating disease.
  • The prevalence of the disease in the EU (European Union) must not exceed 5 in 10,000 people, or the medicine must be unlikely to generate sufficient returns to justify its development.
  • There must be no satisfactory methods of diagnosis, prevention, or treatment for the condition—or, if such methods exist, the new medicine must demonstrate a “significant benefit” to patients. This is typically assessed by measuring its clinical advantage or its major contribution to patient care1.

When it’s time to apply for marketing authorization, sponsors must reapply to maintain this orphan designation status. This step ensures that the product still meets the orphan criteria before the Committee for Human Medicinal Products (CHMP) of the European Medicines Agency (EMA) grants market approval.

At this stage, if there’s already an authorized treatment available, sponsors must prove that their product offers a significant benefit over existing therapies. Importantly, the data required for maintaining orphan status at this point are more comprehensive than those for the initial designation2. If similar treatments exist, an evaluation of “orphan similarity” may also be necessary1.

While this framework encourages first-of-its-kind treatments, it can inadvertently create obstacles for subsequent medicines aiming for orphan designation in the same indication.

The presence of a first-to-market orphan product—particularly one that has achieved meaningful outcomes in the indication—can complicate the pathway for second- and third-to-market products. Factors such as the timing of approval and the need to demonstrate significant benefit over existing options can impact the success of subsequent orphan designations.

In this research, we explore how first-to-market orphan products influence the orphan designation status of follow-up treatments within the same orphan indication. 

Methods

Through targeted secondary research, we identified a sample of second- and third-to-market products that were initially granted orphan designation by the EMA7,8.

This sample—comprising Uplizna, Zilbrysq, Lytgobi, and Amvuttra—allowed us to illustrate the various factors impacting the assessment of significant benefit and the timeline of the orphan designation process.

By integrating secondary research insights with consulting expertise, we highlighted the unique challenges these therapies face within the regulatory landscape, shedding light on the key drivers of orphan designation outcomes across the EU

Results

The findings showed that Uplizna failed to maintain its orphan designation3, while Zilbrysq and Lytgobi’s sponsors withdrew their applications at the market authorization stage4,5

As there is already a product available on the market for each indication the three products targets, a significant benefit is needed to maintain orphan status. The findings showed that all three products failed to demonstrate significant benefit due to methodological uncertainties and inconclusive data. This meant a clinically relevant advantage or major contribution to patient care over the first-to-market product was not proven, which is a key criterion for orphan designation.

Amvuttra, a third-to-market orphan product, successfully demonstrated significant benefit using protocol assistance against its first- and second-to-market products within the same indication6.

Table 1: Summary of data on second- and third-to-market treatments for orphan conditions that resulted in either the removal or maintenance of orphan designation status, depending on their ability to meet the orphan designation criteria.

Table 2: Summary of significant benefit assessment of second- and third-to-market treatments for orphan conditions in relation to clinically relevant advantage and major contribution to patient care

Discussion and conclusion:

For rare disease therapies, orphan drug designation can be a crucial step in securing market access in key EU markets like Germany and France. However, for second- and third-to-market treatments, maintaining this status requires strategic consideration of factors like demonstrating “significant benefit” and the timing of approval

Protocol assistance, provided by the EMA, is highly recommended to support clinical development2. For instance, Amvuttra benefited from this guidance to maintain its orphan designation by effectively demonstrating its advantage over alternative treatments. This support can be instrumental in helping therapies meet the stringent requirements for orphan status, paving the way for better patient access to innovative options.

References:

Abbreviations: 

AChR-Ab – acetylcholine receptor antibody, CHMP- Committee for Human Medicinal Products, COMP- Committee for Orphan Medicinal Products, EC- European Commission, EMA- European Medicines Agency, gMG – Generalized Myasthenia Gravis, NMOSD – Neuromyelitis Optica Spectrum Disorder, SOC- standard of care, TTR- transthyretin

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