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Introduction


Non-biological complex drugs: an introduction


This article provides a definition for non-biological complex drugs (NBCDs), discusses different classes of NBCDs, proposes a regulatory philosophy for follow- on versions, and outlines the relationship between NBCDs and nanomedicines


Jacques Rottembourg MD MPH Department of Nephrology, Groupe Hospitalier Pitié-Salpêtrière, Paris, France


The concept of non-biological complex drugs (NBCDs) was introduced as the result of a workshop held in Leiden, The Netherlands, in 2009.1


For


the first time, this class of drug products was identified and recognised: NBCDs are more complex than small, low-molecular drugs, and as complex as, or even more complex, than biologicals, sharing many of the characteristics of the latter category but not being derived from living sources.2,3 More recently, the NBCD concept has been extended to nanomedicines, which are highly complex drugs, and are the result of difficult to control manufacturing processes.4,5


There is much evidence that for the equivalence testing of NBCD follow-on products, a regulatory pathway should be developed, similar to the pathways developed for biosimilars by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). Numerous publications, studies, and workshops demonstrated that authorisation of NBCD follow-on versions is inappropriate through the standard generic protocol.6–8


This article


provides a definition for NBCDs products, discusses different classes of NBCDs, proposes a regulatory philosophy for NBCD follow-on versions, and outlines the relationship between NBCDs and nanomedicines.


Definition and characterisation A NBCD is defined as a medicinal product, not being a biological medicine, where the active substance is not a homo-molecular structure, but consists of different (closely related) structures that cannot fully quantitated, characterised and/or described by (physico) chemical analytical tools. The composition and quality of NBCD are dependent on the manufacturing process and controls.


When the patent of a classical small molecule drug expires, generics may be marketed if their therapeutic equivalence to the original drug has been established.9,10


Conventional


generics for an orally administered drug are considered to be therapeutically equivalent to a reference once pharmaceutical equivalence (that is,


identical active substances) and bioequivalence (that is, comparable pharmacokinetics essentially on healthy volunteers) have been established in a crossover study and do not require formal clinical efficacy and safety studies. The therapeutic equivalence then allows the therapeutical interchangeability.11


The acceptance


intervals to show that bioequivalence for the logarithm transformed area under the curve (AUC) and Cmax ratios lie within an acceptance range of 0.80–1.25 for the 90% confidence intervals. In some cases, the acceptance interval needs to be tightened, and in other cases, a wider acceptance may be suitable.


The classical generic approach based on showing pharmaceutical equivalence and bioequivalence has been the basis


www.hospitalpharmacyeurope.com 3


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