Author byline as per print journal: Jon SB de Vlieger, PhD; Professor Stefan Mühlebach, PhD; Vinod P Shah, PhD; Scott E McNeil, PhD; Professor Gerrit Borchard, PharmD, PhD; Vera Weinstein, PhD; Beat Flühmann, PhD; Sesha Neervannan, PhD; Professor Daan JA Crommelin, PhD
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Abstract: |
Submitted: 16 September 2015; Revised: 15 October 2015; Accepted: 19 October 2015; Published online first: 2 November 2015
The concept of non-biological complex drug (NBCD) products has been presented and discussed on several occasions in the GaBI Journal [1–4]. The growing interest in this topic in academic, industrial and regulatory circles led to the establishment of an Editorial Section on Non-Biological Complex Drugs in both the GaBI Journal and GaBI Online starting in the third quarter of 2015.
In 2011, the first publication on NBCDs appeared [5] as a result of a workshop held in Leiden, The Netherlands, in 2009. For the first time this class of drug products was identified and recognized. These products are more complex than small, low molecular drugs and as complex or even more complex than biologicals; sharing many of the characteristics of the latter category but not being derived from living sources. As a consequence, the authors argued that for the equivalence testing of NBCD follow-on products a regu latory pathway should be developed that was similar to the pathways developed by the European Medicines Agency (EMA) and later the US Food and Drug Administration (FDA) for approving biosimilars. This proposal was backed up by evidence provided by a (still growing) number of published studies on NBCD follow-on versions that were authorized using a ‘standard’ but inadequate generic assessment protocol.
A working group hosted by the Dutch Top Institute (TI) Pharma in Leiden was set up to raise awareness of the challenges NBCD products present worldwide, to stimulate the publication of scientific reports and discussions and to provide a rigorous, sciencebased, regulatory policy for NBCD products [6]. These efforts led to a number of publications and a book exclusively dedicated to the NBCD concept and its regulation. These publications provide a definition for NBCD products, discuss different classes of NBCDs, propose an overarching regulatory philosophy for evaluating NBCD follow-on versions and, finally, outline what issues are still unresolved [7–9].
This paper to the GaBI Journal further explains:
A definition of NBCD products that was published earlier by the NBCD working group reads: ‘A Non-Biological 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 can’t be isolated and fully quantitated, characterized and/or described by stateof-the-art (physico)chemical analytical means and where the clinical meaning of the observed differences is not known. The composition, quality and in vivo performance of NBCDs are highly dependent on manufacturing processes of both the active ingredient as well as in most cases the formulation’ [7].
Present product ‘families’ and beyond
At present the following NBCD product groups or ‘families’ have been identified and discussed in the literature: liposomes, polymeric micelles, glatiramoids, iron-carbohydrate complexes, albuminanticancer drug nanoparticles and nanocrystals. The rapidly growing group of nanomedicines will add many NBCDs to this list [9–10]. Interestingly, there are also medicinal products such as the low molecular weight heparins (LMWHs) showing similar complexity but falling under different regulatory policies, i.e. by EMA LMWHs are seen as biologicals and by FDA as non-biologicals.
Over the last few years a number of studies on these NBCD product families have been published. This list is growing and expanding beyond only parenteral drugs. Recently, the present science base, including the: (1) chemistry and structure; (2) manufacturing; (3) (physico)chemical characterization; (4) pharmacology; and (5) regulatory status, of these product groups was reviewed in a book [9]. The availability of these data in the public domain should contribute to sciencebased discussions and could serve as a model to be followed for consideration of other NBCD product families. In addition, questions regarding interchangeability and substitutability of NBCD follow-on versions have important implications for the handling of such medicinal products by healthcare professionals. Requests are being made by these healthcare professionals for education on the topic of NBCDs and for further, tailor-made, reliable information for patients.
Other candidate NBCD product families that are waiting to be identified include emulsions (parenteral or ocular), dry powder inhalers and oral bioactive polymers such as complex phosphate binders.
The regulatory landscape
In earlier publications in GaBI Online the differences between the characteristics of small, low molecular weight molecules and biologicals were listed, see Table 1 [11]. If the items in the ‘biological drugs’ column (in italics) that relate to the biological source of the product and immunogenicity are removed, what remains demonstrates that there is a striking resemblance between the characteristics of biologicals and NBCD products.
Because of this similarity in product characteristics, the NBCD Working Group has proposed on several occasions that regulators should follow the same regulatory pathway for NBCD follow-on products as for biosimilars. This proposal is schematically shown in Figure 1 where ‘Totality of evidence’ is the key phrase when assessing therapeutic equivalence of NBCD innovator and follow-on products.
Neither FDA nor EMA uses special NBCD regulatory schemes. These agencies use existing pathways for the introduction of innovative and follow-on NBCD products. FDA uses the 505(b)(1)/505(b)(2) and 505(j) pathways for innovator products and follow-on versions, respectively. However, both FDA and EMA are paying increasing attention to regulatory issues related to NBCD families [12–13].
Generally speaking, there are two clearly distinct regulatory documents for these NBCD product families. On the one hand, FDA and/or EMA published ‘draft guidance’ and/or ‘reflection papers’ on new products such as liposomes [14], polymeric micelles [15], and surface coatings [16]. On the other hand, both agencies issued documents on the development of follow-on versions of NBCD products such as EMA documents on iron-based nano-colloidal products [17–19] and on existing products [20], and FDA on iron complexes [21], ciclosporin emulsions [22] and on liposome follow-on products [23–24]. Interestingly, FDA has awarded funding to characterize and clinically compare originator and follow-on versions after approving these products [25–26]. It is clear that the present arsenal of regulatory documents from these agencies will be expanded in the years to come. Hopefully, it is not too late to reach global agreement through the World Health Organization (WHO) or perhaps the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) initiatives. On the pharmacopoeial side, interest is growing in dealing with NBCD families. For example, a European Directorate for the Quality of Medicines and HealthCare (EDQM) working group is developing a monograph on ‘iron sucrose concentrated solution’ as an example for non-biological complexes and the United States Pharmacopeia (USP) is currently evaluating similar actions [27]. The British Pharmacopoeia (BP) has published a new monograph on iron sucrose injections, which is basically in line with the USP existing monograph.
One interesting feature of the European legal landscape is that certain NBCD product families are not approved through the centralized procedure (EMA). Instead, approval follows either the purely national procedures or the mutual recognition procedure under the aegis of national competent authorities. This is true for iron sucrose products and for oral bioactive polymer phosphate binders [28]. Considering the complexity of these products and the problems encountered in certain countries with generic versions of NBCD products (see below), approval thro ugh the centralized procedure and the CHMP team would be preferred.
For all NBCD product families where follow-on versions are on the market, a growing number of studies have become available in the public domain demonstrating examples of follow-on products that were approved by (national) competent authorities that differed structurally and/or in clinical practice from the originator products [9]. Often these differences were clinically relevant. Examples include publications by Rottembourg et al. [29]; Martin-Malo et al. [30]; Stein et al. [31]; Lee et al. [32] and Agüera et al. [33] for iron sucrose similars; and Weinstein et al. [34] and Towfic et al. [35] for glatiramer acetate follow-on products. These (clinical) examples raise questions to the regulatory science community in the countries mentioned in these publications about how appropriate the current systems are in ensuring equivalence in NBCD product quality, efficacy and safety. Is the current approach rigorous enough?
These examples provide lessons that should be communicated throughout the scientific community as well as to medical/pharmaceutical practitioners. More over, in the years to come, study of these examples can also help competent authorities to establish appropriate, science-based approval procedures for these complex drug products.
Expanding: The number of NBCD product families will continue to grow. It is time to pay attention to these (new) families and discuss their specific characteristics and their implications for the regulatory process at an early stage. Much information is often already available but there is a need to go through the archives and analyse these data so that scientific deficiencies are brought to the forefront.
Outstanding issues: for a list of outstanding issues concerning NBCD products one can refer to the list drawn up for biologicals. For example, labelling, comparability and attribute drift, NBCD-questionables (cf. bio-questionables [36]), extrapolation [37], interchangeability, substitution, and last but not least: a single global approach (WHO in the lead?) [38].
Facts please: For a fact-based debate on NBCD products we need to stimulate publications in the public domain. This will strengthen the science base for decisionmaking. Transparency of the regulatory process is another essential element for such a discussion. We hope that all parties (academic, industry and regulatory) involved in this debate will continue, and even step up their efforts to provide this science base.
Goal: We feel that the GaBI Journal and the GaBI Online platform offer excellent opportunities to stimulate awareness around the critical issues related to both new, innovative NBCD products and the introduction of follow-on versions. The growing science base for NBCD product legislation, e.g. in Europe and the US, and hopefully in other countries in the future, needs a non-biased publication outlet. With the GaBI publication platform we have the ambition to become the central and preferred publication hotspot for this complex topic.
Jon SB de Vlieger, PhD
Dutch Top Institute Pharma, PO Box 142, NL-2300 AC Leiden, The Netherlands
Professor Stefan Mühlebach, PhD
Vifor Pharma Ltd, 61 Flughofstrasse, PO Box, CH-8152 Glattbrugg, Switzerland; Department of Pharmaceutical Sciences, Pharmacenter, University of Basel, 50 Klingelbergstrasse, CH-4056 Basel, Switzerland
Vinod P Shah, PhD
NBCD Steering Committee member, Pharmaceutical Consultant, 11309 Dunleith Place, North Potomac, MD 20878, USA
Scott E McNeil, PhD
Director, Nanotechnology Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc, PO Box B, Frederick, MD 21702-1201, USA
Professor Gerrit Borchard, PharmD, PhD
Professor, Biopharmaceutical Sciences, School of Pharmaceutical Sciences, University of Geneva, University of Lausanne 30, Quai Ernest-Ansermet, CH-1211 Geneva 4, Switzerland
Vera Weinstein, PhD
Teva Pharmaceutical Industries Ltd, Discovery and Product Development, Global Research and Development, Netanya, Israel
Beat Flühmann, PhD
Vifor Fresenius Medical Care Renal Pharma Ltd, 37 Rechenstrasse, PO Box, CH-9001 St Gallen, Switzerland
Sesha Neervannan, PhD
Senior Vice President, Pharmaceutical Development Brands R & D, Allergan Plc, RD2-3A, 2525 Dupont Drive, Irvine, CA 92612, USA
Emeritus Professor Daan JA Crommelin, PhD
Department of Pharmaceutical Sciences, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands
Competing interest: All authors are members of the steering committee of the Non-Biological Complex Drug (NBCD) Working Group, hosted at the Dutch Top Institute Pharma (TI Pharma), Leiden, The Netherlands (http://www.tipharma.com/NBCD).
Provenance and peer review: Not commissioned; externally peer reviewed.
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Author for correspondence: Jon SB de Vlieger, PhD; Dutch Top Institute Pharma, PO Box 142, NL-2300 AC Leiden, The Netherlands |
Disclosure of Conflict of Interest Statement is available upon request.
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Source URL: https://gabi-journal.net/non-biological-complex-drugs-nbcds-and-their-follow-on-versions-time-for-an-editorial-section.html
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
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Introduction: Besides biologicals, a new class of complex drugs – non-biological complex drugs (NBCDs), e.g. liposomes, iron carbohydrate products and glatiramoids – has emerged. Originator NBCD products have been approved by established regulatory rules. However, their follow-on products comprise a challenge to the regulators, manufacturers, physicians and pharmacists. |
Submitted: 12 August 2013; Revised: 24 September 2013; Accepted: 27 September 2013; Published online first: 11 October 2013
The progress in pharmaceutical sciences and manufacturing techniques together with more targeted and better-tolerated pharmaceutical formulations gave rise to a new class of medicinal products with complex macromolecular (nanoparticulate) structures, the so-called non-biological complex drugs (NBCDs) [1, 2]. Amongst others, NBCDs comprise liposomes, iron carbohydrate products and glatiramoids. The complexity of these synthetic NBCDs may even exceed that of biologicals. Originator NBCDs have received regulatory approval based on proven quality, efficacy and safety and have been established for many years. Some NBCDs have already been introduced before the growing awareness about the specific issues related to the production and characterization of nanostructures. Accordingly, regulatory approval of NBCD follow-on products is subject to a lively discussion about the requirements to prove therapeutic equivalence and being eligible as substitute for the reference product.
The Non-Biological Complex Drugs Working Group at Dutch Top Institute Pharma, a public–private partnership in The Netherlands, is a network of scientific and clinical experts from academia, industry, regulatory bodies, and knowledge institutes to discuss specific aspects of the development and evaluation of NBCDs and give its expert opinion. This paper briefly summarizes the key discussion points of a closed workshop at the FIP (International Pharmaceutical Federation) Centennial Congress in 2012, organized by the FIP Board of Pharmaceutical Sciences, in order to assist the understanding of the regulatory challenges associated with NBCD follow-on products such as the definition of science-based policies for interchange and substitution. The closed workshop on invitation only was followed by an open discussion symposium the following day at the FIP Centennial Congress about the proposed terminology and a planned paper on points to consider for regulation [3, 4].
NBCD are defined as a medicinal product of non-biological origin with an active substance that is not a homo-molecular structure, but consists of different closely related and mostly nanoparticulate structures. Accordingly, there is not a single substance that can be isolated, quantitated and fully characterized or described by state-of-the-art physicochemical analytical means [4]. Changes in the composition and morphology of an NBCD can substantially influence the quality, biological properties and therapeutic profile of the medicinal product and result from minute variations in the manufacturing process [1, 2, 5]. However, not all structural changes and mechanisms that affect the therapeutic profile are fully understood. Notably, the complexity of NBCD prevents establishing full proof of pharmaceutical equivalence by state-of-the-art analytical means, which comprises one of the two pillars in the evaluation of a generic medicinal product, see Figure 1.
In contrast to the mainly direct and systemic drug-target interaction of small molecules with defined receptors in a concentration-dependent manner, most NBCDs comprise nanoparticles from which the active ingredient has to be released or formed and then transported to certain biological compartments where the intended activity should be performed. Even a slightly different release or formation rate of the active ingredient, e.g. due to differences in higher order structure of the precursor molecules, can negatively affect the safety and efficacy profile of an NBCD or its follow-on product. For example, in products for intravenous iron therapy such as iron carbohydrate nanoparticles, the highly reactive iron is bound in a polynuclear core, which in turn is stabilized by a carbohydrate shell. After intravenous administration, this complex is first phagocytized by monocytes where the iron is released and transiently stored before it is bound to transferrin and transported to the target tissue where it exerts its action, e.g. incorporation into newly synthesized erythrocytes in the bone marrow; or is stored in an accessible compartment for later physiological use [6, 7]. Hence, the biological activity of an NBCD is not necessarily correlated to its serum pharmacokinetics (central compartment), the generics pathway’s second pillar to show bioequivalence.
In the case of glatiramoids, products that comprise a complex mixture of polypeptides for the treatment of relapsing-remitting multiple sclerosis, even no pharmacokinetic profile and no validated biomarker for efficacy are available. However, although the originator, Copaxone®, and a follow-on product are similar in many physiochemical properties, e.g. size distribution, molar ratio of amino acids; sensitive chemical and biological analyses demonstrated differences between those products, e.g. gene expression patterns of glatiramoid-primed murine splenocytes [8].
In contrast to follow-on compounds of biologicals that are evaluated according to distinct biosimilar guidelines (originally established in the EU), some NBCD follow-on products are classified as generics although the two prerequisites for the generics approach cannot be fulfilled. As outlined above, the inability to fully characterize an NBCD prevents proof of pharmaceutical equivalence or clinically meaningful differences between a follow-on NBCD and its reference product. Moreover, bioequivalence assessment in healthy volunteers does not necessarily reflect the biological fate of and therapeutic response to an NBCD as outlined by the example of the iron sucrose complex below. Notably, this lack in proof of therapeutic equivalence and potential differences in tolerability or safety of NBCD follow-on products can easily become a concern since these products are often used as chronic treatment and in patients with already poor health states, e.g. iron carbohydrate products for haemodialysis patients, liposomal formulations of cytotoxic agents for cancer patients and glatiramoids for multiple sclerosis patients [1, 9, 10]. In such patients, even slight but clinically meaningful differences between the products may interfere with clinical success and thus the feasibility for interchange with the innovator’s product.
The potential clinical consequences of the above-mentioned differences could be illustrated by comparative clinical and non-clinical studies of a well-established NBCD (iron sucrose, Venofer®) and different follow-on preparations (iron sucrose similars, ISS). One study evaluated the effects of switching iron treatment from the iron sucrose originator to an ISS in 75 consecutive stable, haemodialysis-dependent chronic kidney disease patients who underwent at least 60 dialysis sessions before and after the switch at a French dialysis centre [11]. After the switch to an ISS, haemoglobin levels decreased rapidly and anaemia medication had to be increased to return to targeted haemoglobin levels after quite a lengthy re-adjustment period. In addition to this apparent lack of therapeutic equivalence of an ISS, other ISS were associated with an increased risk of adverse events (658 patients at a South Korean centre who had been treated with the iron sucrose originator or an ISS) [12], even if the originator iron sucrose has been well tolerated before (three case reports in Germany) [13]. Furthermore, non-clinical studies showed not only differences between ISS and the originator product [14] but also among different ISS [15], particularly with respect to off-target iron disposition from ISS and induction of oxidative stress and inflammation.
In many countries generics approval of follow-on products allows automatic substitution at the pharmacy level. Since the International Nonproprietary Names of the innovator’s and follow-on products are the same, clinicians, caregivers and patients are often not aware of the change in medication. In contrast to the substitutability and interchangeability of fully characterized small molecule generics with well-established therapeutic equivalence, approval for substitution or interchange of NBCD products should only be granted on the basis of appropriate non-clinical and/or clinical comparisons. Together with the comparability of physicochemical quality this would allow to exclude clinically meaningful differences between the NBCD follow-on products and the reference product [1, 2]. Lacking information in case of insufficient response or intolerance can lead to unnecessary diagnostic tests and use of potentially more invasive and more expensive treatment options [8, 10]. Overall, drug product replacement that is guided by acquisition cost only may increase other costs and not be cost-effective from the patient’s and payer’s perspective.
At the NBCD workshop in the course of the FIP Centennial Congress 2012, experts from academia, industry, regulatory bodies and knowledge institutes agreed that there is a need for a globally harmonized approach to authorize NBCD follow-on products. This approach should be linked to an accepted common terminology [4]. Also the requirements for an abbreviated procedure showing comparability between different types of NBCD follow-on products and feasible reference products should be clear. In order to approve an NBCD follow-on product that will be interchangeable with the innovator’s product, relevant and comparative clinical and/or non-clinical trials should be performed. Aims of these studies will be an appropriate characterization of the NBCD with up-to-date analytical techniques and to identify the extent of similarity with the originator product. Clinical trials should be sufficiently powered, conducted in patients rather than healthy volunteers to cover for disease-associated changes in pharmacokinetics (PK) and pharmacodynamics (PD). Furthermore, trials should include suitable biological tests to evaluate the similarity of PK, PD and safety/tolerability in populations with similar aetiology of the disease as for the aimed indication. For these means also surrogate efficacy and safety markers may be used. Based on the degree of similarity that could be confirmed by the results of such trials and markers, approval of an NBCD follow-on product can be gradually extended to allow for interchange or even automatic substitution in newly diagnosed patients or those on existing chronic treatment. Such a stepwise similarity approach towards totality of evidence can help manufacturers of follow-on products in the development of safe and effective products and to make a realistic prediction of development costs and timelines.
Furthermore, the expert panel indicated that post-approval pharmacovigilance for NBCD and follow-on products should be based on specific brand names as already proposed earlier [16]. An information exchange among treating healthcare professionals and eventually the patient is mandatory to allow for appropriate treatment and drug product traceability in the individual patient.
An increasing number of NBCDs including nanomedicines become target for development and introduction of follow-on products. Recent clinical data with NBCD follow-on products (iron sucrose) that were approved like small molecule generics revealed significant differences in efficacy and tolerability compared to the originator product. Accordingly, regulators are prompted to establish a global regulatory framework that considers the structural complexity and specific biological properties of NBCD and provides clear guidance for the development and documentation of safe and effective follow-on products. The experts from academia, industry, regulatory bodies and knowledge institutes at the FIP 2012 workshop suggest a stepwise similarity approach that includes appropriate clinical and/or non-clinical studies that evaluate markers of PK, PD (if applicable) and safety/efficacy in relevant patient populations. As long as proof of therapeutic equivalence and similar safety profiles by appropriate studies is missing, interchange and automatic substitution between NBCDs and their follow-on products should be discouraged. Overall, a critical review of the current and emerging regulation of NBCDs and NBCD follow-on products encourage further multidisciplinary research and consensus discussions among all stakeholders to develop guidance towards the definition of an NBCD and the development of NBCD follow-on products [3].
Medical writing support was provided by Mr Walter Fürst, SFL Regulatory Affairs and Scientific Communication, Switzerland, and funded by Vifor Pharma Ltd.
Disclosure of financial and competing interests: This manuscript was written within the framework of the Non-Biological Complex Drugs Working Group, hosted at Dutch Top Institute Pharma. The NBCD Working Group is currently supported by Sanofi, Teva Pharmaceutical Industries Ltd and Vifor Pharma International Inc. Professor Stefan Mühlebach is an employee of Vifor Pharma Ltd, Dr Vera Weinstein is an employee of Teva Pharmaceutical Industries, and Dr Beat Flühmann is an employee of Vifor Fresenius Medical Care Renal Pharma.
Provenance and peer review: Not commissioned; externally peer reviewed.
Professor Stefan Mühlebach1,2, PhD
Professor Arnold Vulto3, PharmD, PhD
Jon SB de Vlieger4, PhD
Vera Weinstein1,5, PhD
Beat Flühmann1,6, PhD
Vinod P Shah1, PhD
1Steering Committee member, NBCD Working Group, TI Pharma, Leiden, The Netherlands
2Vifor Pharma Ltd, Glattbrugg, Switzerland
3Erasmus University Medical Center, Hospital Pharmacy, Rotterdam, The Netherlands
4TI Pharma, PO Box 142, NL-2300 AC Leiden, The Netherlands
5Teva Pharmaceutical Industries, Petach Tikva, Israel
6Vifor Fresenius Medical Care Renal Pharma, St Gallen, Switzerland
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Author for correspondence: Professor Stefan Mühlebach, PhD, Vifor Pharma Ltd, CH-8152 Glattbrugg, Switzerland |
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