Regulators Detail Challenges in Defining Orphan Conditions in EU
A new commentary by European regulators and members of the European Medicines Agency’s (EMA) Committee for Orphan Medicinal Products (COMP) in Nature Reviews Drug Discovery provides insights into drugmakers seeking orphan designation for their products for difficult to define conditions.Like the US, the EU offers certain incentives to promote the development of medicinal products to treat rare diseases, including 10 years market exclusivity for approved orphan indications.
However, regulators in the EU and US both have differing interpretations of what constitutes an orphan condition and recent advances in precision medicine are raising challenging questions for regulators in both regions.
“The definition of an acceptable orphan condition is the essential starting point for the assessment of any orphan designation application in the EU,” the authors write, noting that COMP looks at diseases in “broad terms, avoiding designations relating to artificial subsets of a particular condition.”
This is in part due to direction from the European Commission’s Orphan Notice, which states that “sub-setting a condition with the use of biomarkers will not be acceptable unless the sponsor provides solid evidence that the activity of the product should not be shown on the larger population.”
While the US Food and Drug Administration (FDA) has granted orphan designations for so-called tissue agnostic cancer treatments based on the presence of a specific biomarker, such as Ignyta’s entrectinib and Loxo Oncology’s larotrectinib in NTRK-fusion positive solid tumors, the authors point out that there have been “practically no recent examples of successful biomarker use for orphan designation in the EU.”
The authors attribute this to the fact that a sponsor would need to demonstrate both a “clinicopathological delineation” of the biomarker defined disease subset from the broader condition and prove that the product would not be effective in patients without the biomarker.
Indeed, COMP raised questions during its review of Loxo’s orphan designation application for larotrectinib to treat NTRK-fusion positive non-small-cell lung cancer (NSCLC) earlier this year, but granted orphan designation to the drug for the treatment of salivary gland cancer.
The authors also note that while symptoms of an underlying disease will most likely not qualify for orphan designation, a designation may be granted if sponsors can “support the designation with robust evidence demonstrating the pivotal role of the symptom in the condition and its clinical impact.”
Additionally, the authors say that COMP is unlikely to approve orphan designations for adverse reactions to authorized medical products or treatments, despite having granted such designations in the past for colchicine poisoning, methotrexate toxicity and other adverse drug reactions. However, the authors point out that COMP will still accept orphan designations for the treatment or prevention of environmental toxicities.
“Although applicants often compare the two types of intoxications by medicines and pollutants, they differ fundamentally in view of regulatory practice. While intoxication from medicines is warned against in regulatory documents, pollution with environmental toxins is unpredictable and the intoxication is often accidental,” the authors write.
For sponsors looking to better understand whether a condition is acceptable for orphan designation, the authors recommend reviewing COMP meeting minutes to see the committee’s rationale behind designation decisions.
The authors also say it is important to engage with EMA during the pre-submission phase and consult relevant guidance to tackle any uncertainty they have about their prospects for receiving orphan designation for a given indication.
Nature