Bibliographic application (well-established use)

A bibliographic application makes it possible to obtain a marketing authorisation by replacing the results of preclinical tests and clinical trials with published scientific literature, where the active substance has been in well-established medicinal use. It is provided for by Directive 2001/83/EC, which requires the substance to have been used in the Union for at least ten years, with recognised efficacy and an acceptable level of safety. It is a free-standing route, distinct from the generic authorisation regime, since it does not rely on any reference medicinal product.

Conditions of well-established use

The ten-year period runs from the first systematic and documented use of the substance as a medicinal product in the Union. Annex I to the Directive specifies the factors to be taken into account, including the duration of use, the quantitative extent of use, the degree of scientific interest shown in the published literature and the coherence of scientific assessments. The literature must cover the indication claimed and be of sufficient quality to demonstrate efficacy and safety, failing which additional studies are required. The route is open to chemical medicinal products and to herbal medicinal products, the latter also having a simplified traditional-use registration regime.

Bibliographic applications and data protection

The published data on which the application relies belong to no applicant, and a competitor may rely on the same literature to apply for its own authorisation. The Directive does, however, provide for a non-cumulative year of data exclusivity where a new indication is applied for in respect of a well-established substance, provided that significant preclinical or clinical studies have been carried out to support it. This protection is distinct from the additional year of protection for a new indication granted to the holder of a medicinal product that is still protected.

Practical and litigation issues

Bibliographic applications most often concern older substances whose basic patents have expired. The litigation risk then shifts to patents covering a formulation, a dosage or a second medical use, which the applicant must identify before targeting an indication. Whether the use is well established may also be contested, particularly where the application appears designed to circumvent the data protection of a medicinal product authorised on the basis of full trials.

Key points

A bibliographic application substitutes published literature for trials where the substance has been used in the Union for at least ten years with recognised efficacy and acceptable safety. It requires no reference medicinal product, and the literature on which it relies remains available to competitors. It suits older substances, but leaves secondary patents in place. Before filing, the robustness of the literature for the intended indication should be checked, together with the absence of any formulation or indication patent still in force.

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This glossary entry is general in scope and does not constitute legal advice.

Dhenne Avocats acts in pharmaceutical patent disputes and on the medicines regulatory questions that accompany them, from the marketing authorisation to the supplementary protection certificate.

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