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By Jon S. B. de Vlieger, Vinod P. Shah, and Daan J. A. Crommelin

Jon S. B. de VliegerVinod ShahDaan J.A. CrommelinFive years have passed since the discussion was initiated about the regulatory processes around follow-on versions of nonbiological complex drugs (NBCDs) including many nanomedicine products such as iron-carbohydrate complexes, glatiramoids, polymeric micelles, and liposomes. While guidance for developing generic versions of small molecule drugs is well-established, and progress has been made for biologics, guidelines for follow-on versions of NBCDs are lagging behind. With NBCDs being more complex than small molecules and often exceeding the structural complexity of biologics, the answer to the question how to regulate NBCDs proved complex.

A first requirement for alignment of regulatory rules and actions is global consensus on terminology. Following discussion sessions that engaged experts from industry, academia, and regulatory bodies, we proposed a standardized terminology in The AAPS Journal in 2014. NBCDs were defined as medicinal products, not being a biological medicine, where the active substance is not a homomolecular structure but consists of different (closely related) structures that cannot be isolated and fully quantitated, characterized, and described by physicochemical analytical means.

The fact that NBCDs and their follow-ons by definition cannot be fully characterized indicates that the generics approach for small molecule drugs cannot be applied to NBCDs, as this approach relies heavily on well-characterized molecular structures and a fully detailed composition. The regulatory challenge is further complicated as minute variation in the manufacturing process can substantially change the composition and structure, thus influencing surface and morphology of an NBCD, which often shows nanoparticular properties, and thereby affecting its biodistribution. The potential changes in the composition of the NBCDs become particularly important when the active moiety is unknown as it might have a significant and unpredictable impact on safety and therapeutic performance of the drug product. Therefore, comparative studies in appropriate biological settings are needed to guide regulatory decisions for approval of a follow-on version and to ensure that interchangeability of such an NBCD follow-on product with the innovator’s product is appropriate.

allimagesscreenshotIn this respect, it is worthwhile to consider how much of the biosimilar approach would be applicable to the NBCD class of drugs. Biosimilars are biological products authorized by an abbreviated regulatory pathway. Authorization requires similarity to a licensed biological product in physicochemical characteristics, in vitro and in vivo studies, and clinical data showing similarity in efficacy, safety, and immunogenicity. The idea to use the biosimilar approach as a guiding principle for the introduction of follow-on products of NBCDs makes sense and is receiving increasing support from the scientific community.

In conclusion, the discussion on how to regulate NBCDs has led to an established terminology and greater awareness of the challenges faced. The new book in the AAPS Advances in Pharmaceutical Sciences series, Non-Biological Complex Drugs: The Science and the Regulatory Landscape, gives a comprehensive overview of the state of affairs. The review highlights the different families of NBCDs, closely related complex drugs such as low molecular weight heparins, the available analytical toolbox, and outstanding challenges with NBCD characterization to ensure their safe clinical use.

Jon S. B. de Vlieger, Ph.D., obtained his doctoral degree in bioanalytical chemistry from the VU University in Amsterdam. He is involved in the strategy department of the Dutch Top Institute Pharma, a not-for-profit organization catalyzing the development of medicines by establishing partnerships and actively managing research programs.
Vinod P. Shah, Ph.D., is a pharmaceutical consultant. He retired as a senior research scientist from FDA after 30 years of service in 2005. He was the scientific secretary for FIP from 2003 to 2011 and is a steering committee member of NBCD.
Daan J. A. Crommelin, Ph.D., is emeritus professor at the department of pharmaceutics at Utrecht University and publishes extensively in the field of advanced drug delivery and pharmaceutical biotechnology. He was the scientific director of the Dutch Top Institute Pharma, a public private partnership.