Fixed combination: application under Article 10b for a combined product
A fixed combination application under Article 10b of Directive 2001/83/EC covers a product combining known active substances not used together before.
Article 10b of Directive 2001/83/EC deals with medicinal products containing active substances that are each used in authorised products but have not previously been used in combination for therapeutic purposes. The applicant must provide new pre-clinical tests or clinical trials on the combination itself, but need not supply the scientific references for each individual substance. The result is a full application in the sense of Article 8(3), supported by the known profile of the components and by data on the combination.
EMA's guideline on the clinical development of fixed combination medicinal products sets the central question: does each substance contribute to the claimed effect, and is the combination better than the components alone on efficacy, safety or adherence? Factorial studies, or comparisons with the components at the same doses, are the usual answer. The guideline distinguishes a combination that adds a substance to an inadequate first-line therapy, a combination for the substitution of concurrent monotherapy, and a combination that lowers the dose of each substance. Each needs a different evidence base.
A fixed combination is a new global marketing authorisation, not part of the authorisation of either component, so it starts its own data exclusivity and market protection periods. Generics of the combination can later be filed under Article 10(1) against the combination as the reference product. Applicants can use the centralised, decentralised or national routes depending on the substances and the markets. EMA's guideline also expects a justification for the chosen dose ratio and a discussion of the pharmacokinetic interaction between the components, usually supported by a dedicated interaction or bioavailability study.
What goes wrong: filing a combination as a line extension of one component, which the authority will refuse because a change of active substance composition is a new application; assuming literature on the separate substances replaces a contribution-of-components study; a posology that does not match the approved doses of the single components without justification; and product information that copies the component SmPCs instead of describing the combination. Some applicants also confuse Article 10b with a co-packaged kit, which is assessed on the basis of the component products and is not a fixed combination.
Used in
Before planning studies, check the evidence a fixed combination application must contain in Workbench, with every answer cited to EMA guidance.
Related terms
- GMA: global marketing authorisationThe global marketing authorisation (GMA) groups an initial authorisation with its later strengths, forms and extensions, so exclusivity runs once for all.
- Hybrid application: abridged application under Article 10(3)A hybrid application under Article 10(3) of Directive 2001/83/EC relies partly on a reference product's data and partly on new bridging studies.
- Line extension: extension application to an existing authorisationA line extension (in EU terms, an extension application) adds a new strength, pharmaceutical form or route of administration to an authorised product.
- Data exclusivity: regulatory data protectionData exclusivity is the eight years after a reference product's first EU authorisation in which generics cannot rely on its preclinical and clinical data.
- Scientific advice: EMA or national guidance on development before submissionScientific advice is formal guidance from EMA or a national authority on the studies and data a developer should generate before applying for an MA.
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