Author byline as per print journal: Jon SB de Vlieger¹, PhD; Professor Daan JA Crommelin², PhD; Beat Flühmann³, PhD; Professor Imre Klebovich⁴, PharmD, PhD, DSc; Professor Stefan Mühlebach^3,5, PhD; Vinod P Shah⁶, PhD

Submitted: 28 August 2019; Revised: 9 September 2019; Accepted: 10 September 2019; Published online first: 23 September 2019

Introduction

The 3rd International Symposium on Scientific and Regulatory Advances in Biological and Non-Biological Complex Drugs: A to Z in Bioequivalence was organized in Budapest, Hungary on 12–14 November 2018 by the Department of Pharmaceutics of Semmelweis University with other Hungarian science organizations under the auspices of the International Pharmaceutical Federation (FIP), European Federation of Pharmaceutical Sciences (EUFEPS) and the NBCD Working Group hosted by Lygature [1]. The aim of the conference was to provide an update on the progress in the field by experts and to discuss recent developments in the regulatory status of nanomedicinal drug products in moderated panels with stakeholders. A widespread international group of experts from originator and generic drug companies, regulatory authorities, academia and contract research organizations participated in the meeting and discussion sessions. The conference introduced and discussed in detail the US Government Accountability Organization (GAO) report [2] on non-biological complex drugs (NBCDs) together with the US Food and Drug Administration (FDA) draft guidance on drug products containing nanomaterials [3] and the possibility of global harmonization of regulatory policies regarding NBCD products. This report highlights the main conclusions of the meeting and lists a number of topics that would benefit from further debate within the scientific and regulatory community.

Key questions

The meeting was structured to discuss the following key questions:
– What is equivalence and why does it need our attention?
– Will recent technology developments solve the challenges in determining Critical Quality Attributes (CQAs) of complex drug products?
– Can the successful biosimilar development approach inspire the development of nanosimilars?
– Is there a possibility for global harmonization of regulatory policies for NBCD products and other complex drug products?
In the sections below, we summarize the discussions held during the meeting, in an attempt to answer these key questions.

What is equivalence and why does it need our attention?
Generic drug manufacturers are generally seeking therapeutic equivalence (TE) designation for their drug, as this is a prerequisite for substitution and/or interchangeability with the reference drug product (Orange Book in the US [4). Therapeutic equivalence means that the product is pharmaceutically equivalent (PE) and bioequivalent (BE) to the brand-name product, i.e. PE + BE = TE. Drug products are considered pharmaceutically equivalent if they contain the same active ingredient(s) in the same dosage form, are taken via the same route of administration and are identical in dose. Bioequivalence can be demonstrated using pharmacokinetic, or pharmacodynamic approaches, comparative clinical trials or an in vitro bioequivalence method. Already for decades, these approaches are successfully applied to small molecule drug products for drug approval. Because of the complexity of biological and NBCD products, developers encounter challenges in applying the TE concept.

For follow-on versions of biological products (biosimilars), extensive comparative characterization and preclinical studies are required followed by a limited set of clinical studies to demonstrate safety and efficacy. This may demonstrate similarity but not ‘automatically’ therapeutic equivalence. This biosimilar approach has been introduced and regularly evaluated and updated by the European Medicines Agency (EMA) and is currently considered an established, science-based regulatory approach. FDA has introduced its biosimilar approach as well, which essentially follows the EMA principles.

Determination of TE, through PE and BE, of NBCD products, including nanomedicines, can be a significant challenge. The first discussion on this issue in Budapest in 2014 identified the problem and indicated that CQAs are key to determine TE [5]. The preferred regulatory pathways to establish TE for NBCDs was debated during a number of meetings, including at the New York Academy of Sciences in 2016 [6] and subsequently at the second conference in Budapest in 2016 [7]. Because of the difficulties involved in assessing equivalence with the originator NBCD products, concerns have been raised about safety and efficacy that might appear only after the follow-on versions are introduced on the market.

During the discussions, the topic of consistent terminology has also been raised. Earlier in 2014, a terminology paper was released by the NBCD Working Group [8]. Since then, several new items popped up and the most recent discussion on terminology has evolved around using the terms ‘generic’, ‘follow-on’ and ‘similar’. In a recent publication, Marden et al. make an important statement that terminology in the regulatory field should be used correctly and consistently [9]. As the word ‘generic’ implies therapeutic equivalence and substitutability, this report refers to follow-on products and similars for complex drug products that cannot be fully characterized by physicochemical characterization. The term complex generic is mainly used by FDA and EMA tends to use follow-on, and/or similar.

Will recent technology developments solve the challenges in determining Critical Quality Attributes of complex drug products?
Identification and a thorough (physicochemical) characterization of CQAs is an important step towards the development of a follow-on or similar complex drug product. According to ICH ‘a CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality’. In other words, a critical attribute is a property of which its variation will adversely impact the quality and the clinical profile of the product. At present, both EMA and FDA have adopted a stepwise approach in similarity determination of biosimilars. The development of a biosimilar product therefore requires a thorough comparative in vitro (physico-)chemical characterization of (critical) quality attributes of the test product with the reference product. These thorough analytical comparability studies are followed by non-clinical and clinical studies.

Acknowledging the present challenges to assess CQAs for NBCD products and their design space (DS) that would lead to PE, attention should be paid to further research on elucidating mechanisms of action and on the development and validation of relevant analytical techniques.

This is broadly recognized as, in the meeting, recent developments in state-of-the-art technologies were presented. More importantly, examples were presented how these technologies were applied in the process of characterizing complex drug products. Although the relevance of application of such advanced technologies is to be seen on a product-by-product basis, the progress in technology development for sure impacts the efficiency of characterization activities and brings CQA/DS information closer by.

Can the successful biosimilar development approach inspire the development of nanosimilars?
In a report on an earlier meeting in the SRACD Conference series, the similarities between the complexity of biological and non-biological complex drug products and the implications for TE assessment [5] were pointed out. These discussions continued and the idea of applying the biosimilar paradigm to other complex drug products gained traction. Very concretely, following a publication by authors from EMA, a nanosimilar evaluation process was suggested using the ‘totality of evidence’ concept with a stepwise procedure [10]. This stepwise procedure includes physicochemical structural characterization, animal toxicity studies, in vivo comparative equivalence studies (PK/PD).

For example, in a series of reflection papers for intravenous iron-based nano-colloidal products EMA (proposes a stepwise procedure and ‘totality of evidence’ approach [11].

The success of a new drug modality concept is depending on more factors than appropriate regulatory frameworks alone. In the end, the adoption of new technology and its related products needs multi-stakeholder support. A major effort by different stakeholders was made to explain the scientific background of the biosimilar concept and clinical experience with these biosimilars to healthcare professionals [12]. The EMA brochure on biosimilars from 2017 is a good example of such an effort [13]. Stakeholders in the nanomedicine field should use this successful example of a policy to inform healthcare professionals about the specific challenges encountered with nanosimilars, now and in the future. A first step has already been made by Astier et al. by publishing a list of factors to consider when selecting a nanosimilar [14].

Is there a possibility for global harmonization of regulatory policies for NBCD products and other complex drug products?
The success of harmonization efforts can be judged when comparing the content of guidance documents and reflection papers by the regulatory authorities. A prominent example of guidance documents that could be harmonized are those concerning the approval of follow-on doxorubicin liposome formulations.

Liposomes are one of the most important classes of NBCD products that are used since years in patients. The complexities of liposomal drug products are recognized and dealt with in the FDA and EMA guidance reflection documents. Major efforts were undertaken through the Global Bioequivalence Harmonization Initiative, with participation of EMA and FDA, to align the approaches by the two regulators. It is important to differentiate between nice-to-know and need-to-know requirements. At present, and despite the harmonization exercise, FDA and EMA have taken different decisions on essentially the same follow-on formulation of Doxil®. Moreover, very recently, a case study was published describing the authorization of a generic version Copaxone® in Europe and the US. Whilst EMA requested a full clinical assessment programme, US FDA approved a follow-on version of Copaxone without any clinical data supporting therapeutic equivalence. The approval of these follow-on versions evaluated through different approaches by both agencies leaves open questions on the equivalence of these drug products [15].

In response to concerns raised by the scientific community, the US Government Accountability Office (GAO) was asked to assess FDA’s process of reviewing follow-on versions of NBCD products. In the conclusion and recommendations section, the GAO report underlined the scientific challenges involved when demonstrating equivalence between brand and generic NBCD products [2]. One of the main conclusions was that although all stakeholders agreed that demonstration of equivalence of follow-on NBCDs is scientifically challenging, no agreement could be found on how to move forward and whether the current legislation is sufficient. See Table 1 for a list of conclusions distilled from the full report.

Of note, shortly after the release of the GAO report, FDA issued a draft guidance for industry in December 2017 on ‘Drug products including biological products that contain nanomaterials’ [3]. The agency identified 11 key factors for the assessment of drug products containing nanomaterials. To discuss this draft guidance, an AAPS Guidance Forum workshop was held in September 2018 in Washington DC and the report of that workshop was published earlier in 2019 [16].

In Europe, the debate on whether similar versions of NBCD products should follow the centralized approval procedure are ongoing. A recent approval of an iron carbohydrate similar through the hybrid 10(3) pathway instead of earlier 10(1) generic drug approvals indicates that the field is moving. An overview of all NBCD products and their follow-on versions approved in Europe was recently published by Klein et al., presenting an interesting view on how these products were approved over the years and where the regulatory system may be improved [17].

Just before resigning from office, the former FDA Commissioner Scott Gottlieb voiced his opinion in support of an ICH approach in the area of complex generic drug products [18]. It is to be seen how this will develop, but the scientific and regulatory community should be ready to engage in discussions to increase coherence in the regulatory approach for this type of products.

Conclusion

The meeting successfully brought together experts from all relevant stakeholders, including regulatory authorities, academic institutes, generic and innovative pharmaceutical companies. Participants came from all over the world (five continents, 44 countries) and actively participated in the debates. It is important to note that compared to previous SRACD meetings, significant progress was made in formulating answers to the above four questions. Progress may have been made, but there was also a clear call for action to take the international discussions around alignment and harmonization to the next level.

Disclaimer

This paper may include opinions of the authors and not necessarily the opinions of their employers. Authors JdV, DC, BF, IK, SM, VS are members of the Non-biological Complex Drugs Working Group, hosted at Lygature, The Netherlands (www.lygature.org/NBCD).

The authors declare that there is no funding received to prepare this manuscript.

Competing interests: BF and SM are employees of Vifor Pharma Ltd, Glattbrugg, Switzerland.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

¹Foundation Lygature, 6 Jaarbeursplein, NL-3521 AL Utrecht, The Netherlands
²Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands
³Vifor Pharma Ltd, Glattbrugg, Switzerland
⁴Semmelweis University, Department of Pharmaceutics, Budapest, Hungary
⁵Department Pharmaceutical Sciences, Unit of Clinical Pharmacy and Epidemiology, University of Basel, Basel, Switzerland
⁶VPS Consulting LLC, North Potomac, MD, USA

References
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