If a drug gets a marketing authorization in Europe with orphan designation (meaning that it is approved for rare diseases), it will get a market exclusivity for 10 years (meaning that no "similar" drugs for the same indication cannot enter into the market). Please see this document for more details:
Therefore, the European Medical Agency, which is responsible for marketing authorization of medical products, requires the applicant of a new drug to submit a "similarity report", which compare the new drug with existing drugs in terms of molecular structure, mechanism of action, and indication. For more details, see Section 2.1 of this document:
While the molecular structure similarity comparison is required for drug approval, molecular similarity is a very subjective concept, and no standard way to evaluate it.
For this reason, some papers have analyzed molecular similarity among approved drugs using several 2-D similarity methods:
However, these studies evaluated molecular similarity using 2-D similarity methods, and if 3-D similarity methods are used, we will have some different insights on similarity assessment for EMA's orphan designations.
This study will take the following steps:
- Get all approved orphan drugs from the European Medicines Agency
- Retrieve all known drugs from a public database (e.g., PubChem, DrugBank)
- Generate 3-D conformers for the drugs in (1) and (2)
- Compute 3-D similarity scores between the drugs, using the 3-D conformers generated in (3) and several 3-D similarity methods.
- Compute 2-D similarity scores between the drugs, using commonly used 2-D fingerprint methods.
- Identify drug-drug pairs with a low 2-D score but with a high 3-D score (meaning that the two drugs are similar in 3-D but not in 2-D).
- Identify drug-drug pairs with a high 2-D score but with a low 3-D score [that is, opposite to (6)].
- Discuss the difference between 2-D and 3-D similarity in recognizing molecular similarity.
- Discuss potential impacts of using 3-D similarity methods for EMA's similarity assessment for marketing authorization.
- Discuss how EMA's and FDA's regulations are different in terms of orphan drug marketing approval.
This project is quite straightforward, but would take more time than other projects, because 3-D similarity comparison takes longer than 2-D similarity comparison.