CRED ERP 25

4. Bibliographic/well-established use/combination products

10a Well-established use – bibliographic; definition of well-established use: • This applies to an active substance that has been used within the Union for at least 10 years with recognised efficacy and an acceptable level of safety • Well established for a particular therapeutic purpose • No new “efficacy /safety ” studies permitted: It is not possible to submit proprietary data which is used in-part to demonstrate efficacy and/or safety in the target population. The spirit of WEU is that the application/benefit/risk ratio is based on published scientific literature. The only proprietary data permissible (other than Module 3) are those data which demonstrate a bridge between the Applicant’s product and the product referenced in the literature if necessary. • Criteria for consideration: o Time in regular use, extent of use and geographical basis and pharmacovigilance monitoring o Extent and coherence of scientific literature Well-established use applications require the submission of: • Full Module 1, 2 and 3 with literature forming the basis for Modules 4 and 5 • If an entirely new therapeutic use is included in the application, then this would be considered to fall under Art. 8(3) • The need for some type of bridging data cannot be excluded. 10b New fixed combination products If the application relates to a fixed dose combination of two previously authorised substances then the following will need to be taken into consideration: • You will need to provide the results of pre-clinical and clinical tests on the new combination (but not for the individual original substances) • A key principle of the acquis is that there must be a marketing authorisation for each medicinal product that is put on the EU market • The combination will have a new period of exclusivity as unique product • All modules need to be addressed in relation to the combination • Where data on the actual combination is missing it may be possible to justify this by reference to individual substances, however, this is not always successful. Further reading: (in particular guidelines on pre-clinical and clinical aspects): • Pre-clinical CHMP/EMEA/CHMP/SWP/258498/2005 https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-non-clinical-development- fixed-combinations-medicinal-products_en.pdf • Clinical CHMP/EWP/240/95 Rev. 1 and new draft guideline EMA/CHMP/281825/2015 https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-development fixed-combination-medicinal-products-revision-2_en.pdf • Quality guideline for medicinal products when used with a medical device CHMP/QWP/BWP/259165/2019 https://www.ema.europa.eu/en/documents/scientific guideline/guideline-quality-documentation-medicinal-products-when-used-medical-device-first version_en.pdf 10c informed consent In the case of a so-called “informed consent” application, the Applicant has express permission to directly refer to the full dossier of the originator:

• New applicant should have access to the full data and all modules in order to be able to fulfil