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Key issues


NBCDs and follow-on compounds: the key issues


Regulatory and clinical challenges including issues of terminology, bioequivalence, immunogenicity, interchangeability and substitution are posed by non-biological complex drugs and their follow-on compounds


Christine Clark PhD PhD FRPharmS FCPP(Hon) Freelance Medical Writer, UK


Non-biological complex drugs (NBCDs) are large, complex molecules not of biological origin. They present regulatory and clinical challenges because they do not easily fit into the well- developed categories for either small molecules or biologics. So far, a number of NBCD-follow-on products have been authorised in Europe using the generic (small molecule) regulatory pathway rather than the centralised procedure. In the early days, it was not widely understood that considerable variations in efficacy and toxicity could result from apparently minor differences in complex structures. It was assumed that products would be readily interchangeable, much like conventional generic medicines. However, clinical reports began to emerge that showed clear differences between originator products and follow-on products. For example, an iron sucrose ‘similar’ (ISS) was automatically substituted for the originator product by a group of hospitals in Paris. A subsequent audit of dialysis patients, who routinely receive intravenous iron supplementation together with erythropoietin stimulating agents (ESAs), showed that haemoglobin was low and larger doses of ESAs were needed to bring haemoglobin up to acceptable levels.1


A growing number of publications showing clinical variations when NBCD- follow-on products are used has led to a more critical approach and the realisation that NBCD follow-on products need to follow a more rigorous authorisation


term, ‘NBCD-follow-on products’ is used. Pressing questions


Now that a number of NBCD-follow-on products has been authorised there are several pressing questions for clinicians and those responsible for purchasing medicines. These include: can bioequivalence be demonstrated; what are the risks of immunogenicity; when are products interchangeable; and when is substitution safe and reasonable?


NBCDs


procedure, similar to that used for biosimilars. At present, the terminology is still being developed to describe precisely NBCDs and their follow-on products. Clear criteria have been established to assess for the similarity of follow-on products of biologics and the term ‘biosimilar’ denotes that these have been met.2


However, there


are, as yet, no established regulatory criteria for NBCD-follow-on products, although both the European Medicines Agency (EMA) and the US Food and Drug Administration are addressing the topic actively. Some NBCD-follow-on products have been described as ‘similars’ (for example, iron sucrose similar) but a product that elicits a different clinical response – in terms of therapeutic effect or toxicity or both - cannot reasonably be described as ‘similar’; in this article the


NBCDs have been defined as products that satisfy the following criteria: 1. consists of a complex multitude of closely related structures; 2. the entire multitude is the active pharmaceutical ingredient; 3. the properties cannot be fully characterised by physicochemical analysis and;


4. the consistent, tightly controlled manufacturing process is fundamental to reproduce the product.


Examples of NBCDs include product families such as the glatiramoids, liposomes, and iron-carbohydrate complexes. Because of the complexity of originator products, the matter of dealing with NBCD-follow-on products is more challenging.


Bioequivalence Typically, with NBCDs no single substance can be isolated, quantitated or fully characterised.3


no clear relationship between plasma concentration and effect. Most NBCDs comprise nanoparticles from which the active ingredient is formed or released before being transported to the biological


www.hospitalpharmacyeurope.com


In addition, there is usually


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