Non-biological Complex Drugs Research Articles

The authorization of non-biological complex drugs (NBCDs) follow-on versions: specific regulatory and interchangeability rules ahead?

Author byline as per print journal: Professor Stefan Mühlebach, PhD, Professor Arnold Vulto, PharmD, PhD, Jon SB de Vlieger, PhD, Vera Weinstein, PhD, Beat Flühmann, PhD, Vinod P Shah, PhD Introduction: Besides biologicals, a new class of complex drugs – non-biological complex drugs (NBCDs), e.g. liposomes, iron

Workshop on the challenges in substitution of nonbiological complex drugs

Over recent years, nonbiological complex drugs (NBCDs) such as iron carbohydrate complexes for i.v. use, heterogeneous polypeptide mixtures as immunomodulators, and liposomes have been approved by established regulatory rules.[1][1] However, approval and handling of follow-on products comprise an

How to Regulate Nonbiological Complex Drugs (NBCD) and Their Follow-on Versions: Points to Consider

The aim of this critical review is to reach a global consensus regarding the introduction of follow-on versions of nonbiological complex drugs (NBCD). A nonbiological complex drug is a medicinal product, not being a biological medicine, where the active substance is not a homo-molecular structure, but consists of different (closely related and often nanoparticulate) structures that cannot be isolated and fully quantitated, characterized and/or described by state of the art physicochemical analytical means and where the clinical meaning of the differences is not known. The composition, quality and in vivo performance of NBCD are highly dependent on manufacturing processes of both the active ingredient as well as in most cases the formulation. The challenges posed by the development of follow-on versions of NBCD are illustrated in this paper by discussing the 'families' of liposomes, iron-carbohydrate ('iron-sugar') drugs and glatiramoids. It is proposed that the same principles for the marketing authorization of copies of NBCD as for biosimilars be used: the need for animal and/or clinical data and the need to show similarity in quality, safety and efficacy. The regulatory approach of NBCD will have to take into consideration the specific characteristics of the drugs, their formulation and manufacturing process and the resulting critical attributes to achieve their desired quality, safety and efficacy. As with the biosimilars, for the NBCD product, family-specific methods should be evaluated and applied where scientifically proven, including sophisticated quality methods, pharmacodynamic markers and animal models. Concerning substitution and interchangeability of NBCD, it is also advisable to take biosimilars as an example, i.e. (1) substitution without the involvement of a healthcare professional should be discouraged to ensure traceability of the treatment of individual patients, (2) keep an individual patient on a specific treatment if the patient is doing well and only switch if unavoidable and (3) monitor the safety and efficacy of the new product if switching occurs.

Different Pharmaceutical Products Need Similar Terminology

In the last decade, discussions on the development of the regulatory framework of generic versions of complex drugs such as biologicals and non-biological complex drugs have attracted broad attention. The terminology used is far from harmonized and can lead to multiple interpretations of legal texts, reflection papers, and guidance documents regarding market introduction as well as reimbursement. This article describes the meaning of relevant terms in different global regions (Europe, USA, WHO) and offers a proposal for a globally accepted terminology regarding (non-) biological complex drugs.

Structural characterization of iron oxide/hydroxide nanoparticles in nine different parenteral drugs for the treatment of iron deficiency anaemia by electron diffraction (ED) and X-ray powder diffraction (XRPD)

Drug products containing iron oxide and hydroxide nanoparticles (INPs) are important for the treatment of iron deficiency anaemia. Pharmaceuticals prepared by the complexation of different kinds of INPs and carbohydrates have different physicochemical and biopharmaceutic characteristics. The increasing number of parenteral non-biological complex drugs (NBCD) containing iron requires physicochemical methods for characterization and enabling of cross comparisons. In this context the structure and the level of crystallinity of the iron phases may be connected to the in vitro and in vivo dissolution rates, which etiologically determine the therapeutic and toxic effects.X-ray powder diffraction (XRPD) and electron diffraction (ED) methods were used in order to investigate the nine different parenteral iron formulations Ferumoxytol (Feraheme®), sodium ferric gluconate sucrose (Ferrlecit®), iron sucrose (Venofer®), low molecular weight iron dextran (CosmoFer®), low molecular weight iron dextran (Infed®), high molecular weight iron dextran (Ironate®), high molecular weight iron dextran (Dexferrum®), iron carboxymaltose (Ferinject®) and iron isomaltoside 1000 (Monofer®).The iron phase in CosmoFer®, Ferinject®, Monofer®, Infed®, Ironate® and Dexferrum® was identified as Akaganéite/Akaganéite-like (β-FeOOH), with low amounts of chloride. By combining results of both methods the iron oxide in Feraheme® was identified as Magnetite (Fe3O4) with spinel-like structure. Ferrlecit® and Venofer® were difficult to analyze due to the low degree of crystallinity, but the iron phase seems to fit Lepidocrocite/Lepidocrocite-like (γ-FeOOH) or an amorphous kind of structure. The structural information on the type of iron oxide or hydroxide together with the particle size allows predicting the stability of the different complexes including their labile iron content. The combination of ED and XRPD methods is a very helpful approach especially for structural analysis of nanoscopic or low crystalline materials.

What to look forward to in GaBI Journal, 2013, Issue 2

The first of two Letters to the Editor is from Ms Gaspani and Ms Milani expressing their concerns about the lack of clear regulatory guidelines for approval of liposomal generic formulations. Liposomal products are only one and perhaps some of the best-characterized example of non-biological complex drugs (NBCDs).

Innovative Approaches for Demonstration of Bioequivalence: the US FDA Perspective

In this article, the authors will briefly introduce the general concepts and background of bioavailability and bioequivalence (BE), discuss the conventional method for BE demonstration, and present case examples where novel approaches have been adopted by the US FDA for BE demonstration. Here, 'novel approaches' include unconventional BE studies, as well as statistical criteria for comparison. More specifically, biowaivers, methods to demonstrate BE for highly variable drugs and drug products, and narrow therapeutic index drugs, partial AUCs as additional metrics for some modified-release drug products, methods to demonstrate BE for locally acting gastrointestinal, dermatological, nasal and inhalation products, and non-biological complex drug products, and future perspectives in the field of BE assessment will be discussed. Methods adopted by other agencies, such as European Medicines Agency and Health Canada will be compared with the FDA approaches when appropriate.

GRP-124 Non-Biological Complex Drugs and Their Regulatory Approach – of Concern For Hospital Pharmacists and Medicines Management?

BackgroundIntended copies of originator medicinal products (MPs) are categorised as generics or biosimilars (complex large molecular biological MPs) with distinct regulatory pathways for marketing authorization. In recent years, a new...

Scientific considerations for complex drugs in light of established and emerging regulatory guidance

On March 9, 2012, the New York Academy of Sciences brought together experts representing a variety of perspectives--including academic, industrial, regulatory, as well as those from physicians and consumers--to discuss considerations for the non-biological complex drug (NBCD) regulatory approval pathway, given the emerging regulatory guidelines for biosimilars (follow-on biological complex drugs). Some of the organizers of the conference expressed their belief that NBCDs share a number of characteristic features with biologicals: the structure cannot be fully defined by the available (physicochemical) analytical tests, and quality assurance is based on in-depth knowledge, consistency, and control of the production process. However, their view on NBCDs was not universally accepted among the experts who participated in the conference. Plenary sessions addressed the most recent regulatory developments, experimental design, interchangeability, and immunogenicity issues for follow-on versions of complex drugs from the perspective of key audiences, including industry, regulatory agencies, physicians, and consumers. This report summarizes these various perspectives on NBCDs and the scientific and regulatory considerations associated with complex drug categories.

Nanoparticle iron medicinal products – Requirements for approval of intended copies of non-biological complex drugs (NBCD) and the importance of clinical comparative studies

Currently, most countries apply the standard generic approach for the approval of intended copies of originator nanoparticle iron medicinal products, requiring only demonstration of bioequivalence to a reference medicinal product by bioavailability studies. However, growing evidence suggests that this regulatory approach is not appropriate. Clinical and non-clinical studies have shown that intended copy preparations of nanoparticle iron medicinal products can differ substantially from the originator product in their efficacy and potentially in their safety profile. An adapted regulatory pathway (separate from the standard generic approach) with defined data requirements is needed for approval of intended copies of iron medicinal products. Here, we discuss the difficulties involved in assessing therapeutic equivalence of nanoparticle iron medicinal products and suggest key concepts of a regulatory approach. Standardized non-clinical comparative studies are necessary but, as demonstrated in the reported clinical data, they may not be sufficient to demonstrate a comparable efficacy and safety profile. Validated, prospective, comparative clinical studies might be needed, in addition to non-clinical studies, in order to enable appropriate assessment of therapeutic equivalence. Furthermore, including brand names in addition to the International Non-proprietary Names (INNs) in safety reports could enable effective safety monitoring of intended copies and originator products.