EU Product Registration Ep.2
Do we actually need clinical trials of bioequivalents to also register a product in Europe as a generic, as we would do in other states?
In the case of parenteral solutions, which are drugs administered directly into the bloodstream, bioequivalence requirements can be waived. This is because it can be assumed that 100% of the drug is injected directly into the body. However, for other dosage forms, the demonstration of bioequivalence is necessary. This is because the way these drugs are taken and administered into the body must be defined, ensuring that an adequate amount of the drug reaches the target organ or organs. Regarding bioequivalence trials conducted outside the EU, it is a common issue that arises. However, it is possible for EU authorities to accept and approve such trials provided that the generic formulation was compared to the European reference product, and that the trial complies with good clinical practices. This can be found within the ICH guidelines.
What are the requirements for the reference product in terms of formulation and development registration in Europe and the United States?
The European legal definition of a reference product pertains to a medicine that has been authorized based on a comprehensive dossier, containing preclinical and clinical data that support the product’s quality, safety, and efficacy in its therapeutic indication. Additionally, for a product to be qualified as a reference product, the exclusivity period protecting innovative drugs must have expired. This means that any medicine meeting these criteria can serve as a reference product once its exclusivity period has lapsed.
When comparing this to the US framework, we observe a clear distinction. In the US, the reference product is defined more explicitly. The US FDA publishes the Orange Book, which lists all the reference products and reference standards to be used during development and bioequivalence studies. Unfortunately, Europe does not have a comparable framework or an equivalent to the Orange Book. This means that any generic company or developer in Europe must independently check the availability of a European reference product, review the legal basis and dossier, and verify if the exclusivity period has expired.
Furthermore, it is crucial for the reference product to be on the market. This is not only necessary for procuring it for comparative studies, but also for cases where bioequivalence studies can be waived. If the reference product is not available on the market, there is a risk that the competent authority may not accept it, as they consider a reference product’s efficacy and safety profile to be under control if it has been on the market for years.