The regulatory body for approval of medicines in the European Union (EU) is the European Medicines Agency (EMA). The agency is responsible for the scientific evaluation of medicines developed by pharmaceutical companies for use in the EU and this also includes non-biological complex drugs (NBCDs).
Although the definition of NBCD is not officially recognized and there is no corresponding term in EU pharmaceutical legislation or scientific guidance, the authors argue that NBCDs are covered by the existing EU legislation. The legal basis for submission, as detailed in Directive 2001/83/EC, includes stand-alone, generic, hybrid, biosimilar, well-established use, fixed combination and informed consent applications. All of these, according to authors Ehmann and Pita, can be used for NBCDs depending on the product [1].
Ehmann and Pita believe that follow-on NBCDs will fall under one of the following legal bases:
- Generic, if the follow-on medicinal product has the same qualitative and quantitative composition in active substance(s) and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies.
- Hybrid, where the bioequivalence cannot be demonstrated through bioavailability studies or in case of changes in the active substance(s), therapeutic indications, strength, pharmaceutical form or route of administration, vis-à-vis the reference medicinal product, the results of the appropriate preclinical tests or clinical trials shall be provided.
Follow-on NCBDs have been authorized via the generics regulatory pathway (national route/decentralized procedure). However, EMA tends to refer to biosimilars regulations when considering follow-on NBCDs. The major difference is the fact that follow-on NBCDs may receive marketing approval through the decentralized route, unlike biosimilars, which must follow the centralized procedure [2].
The view of a number of experts from the Steering Committee of the NBCD Working Group of Lygature, however, is that ‘the approval process of follow-on versions of NBCD products should follow (being mandatory and not optional) the centralized procedure where the combined competence of the large network of EMA experts is directly available, as is the case for biosimilars’. This opinion is based on the outcome of clinical studies of follow-on versions of nanomedicines authorized following national procedures that ‘clearly showed differences in clinical performance between the innovator and follow-on products’ [3].
Such results are perhaps not surprising when we consider that NBCDs are made of structures that cannot be isolated and fully quantitated, characterized, and/or described by analytical means, to which it is unknown which therapeutic elements might impact therapeutic performance and with clinical performance highly dependent on the production process.
Conflict of interest
The authors of the research paper [1] declared that the views expressed are those of the authors and should not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency.
The authors of the research paper [3] declared that the views expressed are those of the authors and should not be understood or quoted as being made on behalf of or reflecting the position of the individual organizations or the NBCD Working Group as a whole.
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References
1. Ehmann F, Pita R. The EU is ready for non-biological complex medicinal products. Generics and Biosimilars Initiative Journal (GaBI Journal). 2016;5(1):30-5. doi:10.5639/gabij.2016.0501.008
2. GaBI Online - Generics and Biosimilars Initiative. EU guidelines for biosimilars [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2017 Apr 7]. Available from: www.gabionline.net/Guidelines/EU-guidelines-for-biosimilars
3. de Vlieger JSB, Borchard G, Shah,VP, Flühmann B, Neervannan S, Mühlebach S. Is the EU ready for non-biological complex drug products? Generics and Biosimilars Initiative Journal (GaBI Journal). 2016;5(3):101-2. doi:10.5639/gabij.2016.0503.026
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