Hybrid application: abridged application under Article 10(3)

Article 10(3) of Directive 2001/83/EC applies where a product does not meet the definition of a generic, where bioequivalence cannot be shown through bioavailability studies, or where the active substance, therapeutic indications, strength, pharmaceutical form or route of administration differ from the reference medicinal product. The applicant then provides the results of the appropriate pre-clinical tests or clinical trials that address those differences, while relying on the reference product's dossier for everything else. Typical hybrids are a new strength outside the approved range, an oral solution of a tablet, a prolonged-release version, a new route, a new indication for a known substance, or a product whose bioequivalence has to be shown with a clinical endpoint.

The route is often called a mixed or hybrid route because the dossier combines literature, the reference product's known profile and the applicant's own data. It follows the same timelines and exclusivity rules as a generic: the application can be filed after eight years of data exclusivity and the product can be marketed after the market protection period. Scientific advice is common, because the scope of the bridging studies is the main point of discussion with assessors. Where a bioequivalence study with a pharmacokinetic endpoint is not feasible, for example for locally acting products, EMA's product-specific guidance may accept pharmacodynamic or clinical endpoint studies or in vitro comparisons, and the application is then a hybrid even if the product is otherwise a copy.

In practice, hybrid applications are the usual home for value-added medicines and for reformulations by companies that do not hold the reference product. The product information generally follows the reference product's SmPC for the shared elements, with new sections for the differences, and the applicant must justify every deviation.

What goes wrong: bridging studies that are too small to support the new posology or indication; choosing hybrid when the change actually makes a new active substance, which needs a full application; relying on bibliographic data where the authority expects comparative studies; naming a reference product that is not authorised in the Member State and not qualifying as a European reference product; and underestimating the fee, which is higher than for a generic in several authorities.