It first started with the generics for small-molecule drugs, followed by the biosimilars for biologic drugs. With nanomedicines on the rise, a new class of non-biological complex drugs (NBCDs), which include nanosimilars, has emerged. Once again, drug regulators are faced with the challenge of defining a framework to ensure the safe introduction of the follow-on nano-therapeutics. Stefan Muhlebach, scientific director of Vifor Pharma Ltd, Glattbrugg, Switzerland, professor of pharmacology and hospital pharmacy, Basel University, Switzerland, and chairman of the NBCD Working Group in the Netherlands, explains why NBCDs cannot be assessed using the standard generic or biosimilar approaches.
PharmTech: How do you define NBCDs?
Muhlebach: NBCDs are complex macromolecular drug products from an elaborate synthetic manufacturing process. NBCDs contain non-homomolecular structures showing partly nanoparticular properties (nanosimilars). Examples include iron carbohydrates (such as iron sucrose), glatiramoids, and liposomal drugs.
PharmTech: Why are NBCDs considered different from generics and biosimilars?
Muhlebach: In contrast to generics, NBCDs cannot be fully characterized by physicochemical means, and the generic paradigm cannot be used for comparability testing. Biosimilars are also complex macromolecular drug products but they are biologics (i.e., manufactured by living organisms).
PharmTech: How do you determinecomparability of NBCD follow-on nanomedicines or nanosimilars?
Muhlebach: A multiple step approach is indicated but not yet established: physicochemical comparability, in-vivo non-clinical evaluation (animal model for biodistribution and drug tissue targeting) and clinical head-to-head analysis in patients for therapeutic
equivalence (substitution and interchange).
PharmTech: Can you describe the regulatory framework if there is one?
Muhlebach: There are guidance for industry documents from FDA and reflection papers by EMA, such as the bioequivalence assessment of different IV iron products (FDA) (1) and reflection papers on data requirements for follow-on liposomal and nanoparticular IV iron preparations (EMA) (2).
PharmTech: What type of studies do regulators such as FDA and EMA require?
Muhlebach: In addition to assessment/quantification of nanoparticles (e.g., sizing and morphology with up-to-date analytics), there are non-clinical (EMA) and clinical studies to evaluate pharmacokinetic-pharmacodynamic bioequivalence (such as which
compartment is most reliable for comparing) and data on therapeutic equivalence for substitution and interchange. There are still no defined regulatory documents at the moment.
PharmTech: What does the future hold for NBCDs and nanosimilars?
Muhlebach: The appearance/awareness of NBCDs showed that these are complex drugs that can no longer be dealt with using the generic approach of demonstrating pharmaceutical equivalence and bioequivalence in volunteers. For NBCDs, a similarity approach and the totality of evidence demonstrated will indicate how similar the reference and test product have to be for therapeutic equivalence and full drug product characterization. The challenge is to know what clinically meaningful differences exist between two products to exclude patient efficacy and safety concerns.
It is difficult to define an abbreviated procedure for market authorization for NBCDs. There is a major concern to what extent such products could or should not be interchanged and how they perform after market approval. Nanomedicines represent an attractive field of drug innovation to change drug targeting and the fate of the products in the body with even established drugs to improve efficacy and safety. There are established NBCDs that have been introduced and used safely for a long time even though their nano-character is not fully known. It is, therefore, not clear if the data required by regulators would motivate marketing authorization applicants to go for an independent full new chemical entity submission or for a reference similar approach where the data requirements are high with no guarantee for a successful regulatory submission.
1. FDA, Draft Guidance on Iron Sucrose, (Rockville, MD, recommended Mar 2012; revised Nov 2013).
2. EMA, “Guidelines and concept papers,” Press Release, Aug. 2, 2013.