The European framework for intellectual property rights for biological medicines

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Author byline as per print journal: Josette Sciberras, MBA, MA Bioethics, BPharm (Hons); Raymond Zammit, SThD; Patricia Vella Bonanno, PhD

Introduction: The Pharmaceutical Strategy for Europe (2020) proposes actions related to intellectual property (IP) rights as a means of ensuring patients’ access to medicines. This review aims to describe and discuss the European IP framework and its impact on accessibility of biological medicines and makes some recommendations.
Methods: A non-systematic literature review on IP for biological medicines was conducted. Data on authorizations and patent and exclusivity expiry dates of biological medicines obtained from the European Medicines Agency’s (EMA) website and literature was analysed quantitatively and qualitatively.
Results: The analysis showed that as at end July 2021, 1,238 medicines were authorized in Europe, of which 332 (26.8%) were biological medicines. There were only 55 biosimilars for 17 unique biologicals. There is an increasing trend in biological authorizations but significant delays in submission of applications for marketing authorization of biosimilars, with no significant differences in the time for assessment for marketing authorization between originator biologicals and biosimilars. For some of the more recent biosimilars, applications for authorization were submitted prior to patent and exclusivity expiry. COVID vaccines confirmed the impact of knowledge transfer on accessibility, especially when linked to joint procurement.
Discussion: IP protects originator products and impacts the development of biosimilars. Strategies to improve competition in the EU biological market are discussed. Pricing policies alone do not increase biosimilar uptake since patients are switched to second generation products. Evergreening strategies might be abusing the IP framework, and together with trade secrets and disproportionate prices compared to R & D and manufacturing costs lead to an imbalance between market access and innovation.
Conclusion: The European Pharmaceutical Strategy should focus on IP initiatives that support earlier authorization of biosimilars of new biologicals. Recommendations include knowledge sharing, simplification of the regulatory framework and transparency of prices and R & D costs.

Submitted: 21 April 2021; Revised: 4 September 2021; Accepted: 8 September 2021; Published online first: 20 September 2021

Introduction

The EU biological medicines market
It is estimated that 25% of all new medicines developed are biologicals [1]. In 2018, the global biological market was worth approximately US$276 billion with 10 blockbuster drugs being biologicals, which increased from 3 such drugs in 2003 [2]. Table 1 shows the net sales of the top selling biologicals as reported by Pharmaceutical Technology [3]. In September 2019, monoclonal antibodies (mAbs) featured in the top 10-selling blockbuster prescription medicines globally by revenue, with adalimumab (Humira®) being the number one with US$19.9 billion sales and accounting for 7% of all global sales on the market despite the launch of biosimilars [3].

Table 1

The prices of biological medicines range in the thousands of Euros, making them unaffordable to some patients and some healthcare systems [4]. Innovation is considered to be the major driver of healthcare costs [5]. Biological medicines are the key drivers for the increase in pharmaceutical expenditure for the treatment of cancers, autoimmune disorders and diabetes [6]. These chronic diseases are responsible for the economic burden of disease or the ‘cost-of-illness’ both through direct costs (the cost of medicines) and indirect costs (the cost as a consequence of the disease) [7]. The problem of affordability for low-income countries and financial sustainability of healthcare systems, even in high-income countries, are a priority on the agenda of policymakers [6].

The European Commission acknowledges that health systems and patients have difficulty bearing the cost of medicines. In November 2020, it proposed a Pharmaceutical Strategy with one of the aims to ensure access to affordable medicines for patients whilst supporting competitiveness, innovation and sustainability of the EU’s pharmaceutical industry and the development of high quality, safe and effective medicines [8]. At its June 2021 meeting, the Council of the European Union approved the proposal for the revision of the regulatory framework for intellectual property mechanisms and the pharmaceutical legislation related to market competition to improve access to biosimilars so as to increase competition whilst protecting innovation [9].

Scope
The EU defines a biological medicinal product as ‘a product, the active substance of which is a biological substance. A biological substance is a substance that is produced by or extracted from a biological source and that needs for its characterization and the determination of its quality a combination of physicochemical and biological testing, together with the production process and its control’ [10]. For the purpose of this paper the following shall be considered as biological medicinal products: immunological medicinal products, medicinal products derived from human blood and human plasma, advanced therapy medicinal products, vaccines, allergens, gene therapy and biotechnology-derived products (recombinant medicinal products).

Aim and objectives
The aim of this study is to describe and discuss the EU intellectual property (IP) framework and its impact on access to biological medicines in order to improve their accessibility to patients. The first objective of this study is to discuss the IP system applicable to biological medicines in Europe. The ­second objective is to identify their impact on access to biological medicines through a quantitative and qualitative evaluation of biological authorizations by the European Medicine Authority (EMA) (1995 to July 2021). The third objective is to provide recommendations for improvement in order to increase access to biological medicines.

Methodology

A non-systematic literature review was performed through Google search on the following keywords: intellectual property rights, patent, R & D, biological medicines, pricing of medicines in Europe and accessibility. The list of medicines authorized until 31 July 2021 was retrieved from the EMA website which was last accessed on 1 August 2021 [11]. The authorized medicines were grouped as biological or non-biological based on the EMA definition [10] and the biosimilars were identified from the data downloaded. Data on first time authorizations was retrieved. This allowed the authors to measure the time between authorization of the biosimilar and that of its reference product. Further analysis was performed to identify the monoclonal antibodies authorized in Europe. The date of entry into force of biosimilar guidelines and product specific guidelines were retrieved from the EMA website. The patent and exclusivity expiry dates for originator biologicals for which a biosimilar is available were identified. A sub-analysis was performed on all biologicals authorized between 2006 and July 2021 with the aim to identify any differences in time for assessment for marketing authorization by EMA between originator and biosimilars.

Results

Review of the EU intellectual property protection framework for biological medicines
The European IP framework for biological medicines covers trade secrets, patents and European incentives to the pharmaceutical industry, including Supplementary and Protection ­Certificate, data, and market exclusivity, among others.

Trade secrets
It is claimed that trade secrets for biologicals contribute to the high cost of US$100–US$200 million for bringing a biosimilar to the market when compared to that of US$1–US$5 million for a generic medicine [12]. In the EU, trade secrets (referring to undisclosed know-how and business information) are protected at both European and national levels. EU Regulation 2309/93 provides protection against commercialization of trade secrets contained in applications for medicinal products [13]. On a global level, IP rights are regulated by the World Trade Organization (WTO) for its member countries through the setting up of Trade-Related Aspects of Intellectual Property Rights (TRIPS) Agreement, to which the European Community (EC) is also a party. Directive (EU) 2016/943 on trade secrets in Europe, which came into force in June 2016, is aimed at achieving harmonization for protecting and defending trade secrets across the EU [14]. Companies resort to trade secrets over and above patents so as to protect certain IP rights perpetually [15]. Data information resulting from research, clinical trial data and manufacturing processes of biologicals, proprietary biological databases and cell-lines are examples of data considered to be trade secrets [15]. In order to create a copy of the original biological, the originator cell line would be necessary for the competitive applicants [16]. This creates a ‘knowledge gap’ between the originator company and the competitive applicant [16]. The ‘knowledge gap’ could be closed or eliminated through disclosure of information. Dzintars Gotham (2018) proposed that prior to ­patent expiry, the originator company provides access to cell line and detailed description of the manufacturing process, termed as cell line access (CLA), where the product produced is referred to as a CLA biological [12]. A similar proposal was made by Knowledge Ecology International and Price & Rai (2017) who had proposed incentives to encourage disclosure of company secrets related to the manufacturing processes [12]. Gotham proposed the depositing of a living vial of the cell line to the regulatory authority on regulatory approval [12]. Lisa Diependaele and colleagues recommended some form of compensation to originator companies granting CLA through remuneration in terms of a contractual agreement with the competitor [17]. Yaniv Heled, however, claimed that developers should have access to whatever knowledge and material of the originator that was needed to create a copy at the expiration of the data exclusivity period. Heled argued that sample depositing and sharing requirements have already been incorporated in the US patent as well as Food and Drug law [16]. Though EU law already allows for sample depositing of cell lines, for example, for advanced therapeutic medicinal products and for patenting, this is not yet the case with respect to all biologicals. If an identical cell line and manufacturing process are used, the differences in the quality, efficacy and safety profile between the CLA biological and the originator are considered as minor and phase III comparability clinical studies may not be required by the regulatory authorities. In vitro analytical results would suffice to demonstrate clinical equivalence of the CLA biological [16]. The originator company would still benefit from IP rights enjoyed as per legislation, but other companies would market the CLA biological immediately on expiry of the exclusivity protection, resulting in greater price reductions.

Patent system
Patent law dates back to the Age of Enlightenment and is aimed at rewarding the inventor for disclosing one’s invention to make it freely available for the benefit of society [18]. Patents were originally introduced in biotechnology by farmers over a hundred years ago [19]. They may cover ‘the active ingredient, formulations, methods of medical treatment, method of manufacturing and chemical intermediaries’ [20].

In Europe, prior to 1994, patents were regulated at national level. Since then, they are regulated by the European Patent Office (EPO) which mandates that medicinal products be covered “by patent protection for a minimum of twenty years from the filing date of a patent application for any pharmaceutical product or process that fulfils the criteria of novelty, inventiveness, and usefulness” [21]. As from the year 2000, an inventor in the EU may choose to apply for a national patent or with the EPO, in which case the inventor should indicate the Contracting State this would apply to within the EU [20]. From a patent period of 20 years, generally 12–13 years are required for a new active substance to finally reach the market, with only eight years of patent protection remaining, which is not considered sufficient to obtain a return on investment [22].

Originator companies aim to retain monopoly status by setting high barriers to entry for competitors in order to recoup investment costs, regain the R & D costs and cover the high risk of ­failure [20]. The EC legislator argued that “without effective means of enforcing intellectual property rights, innovation and creativity are discouraged and investment diminished” [20].

The exorbitant prices of the blockbusters, especially mAbs, are presenting accessibility problems also in developed countries, such that European Governments considered using the 2001 Doha Declaration through the use of the compulsory licencing for biologicals [23]. WTO members declared that TRIPS “should be implemented in a manner supportive of WTO members’ right to protect public health and, in particular to promote access to medicines for all,” with the aim of protecting the health of populations in developing countries [21]. The compulsory licence “allows a patent to be used without the consent of the patent holder for a reasonable royalty payment” [24]. Governments could use compulsory licence allowing production or importation or procurement of generic or biosimilar medicines where the price of the originator medicine is considered to be unaffordable [24]. For medicinal products which are authorized through the EU centralized procedure, the EU data exclusivity directive (known as the ‘8+2+1’ regime) supersedes a compulsory licence, even if such licence was issued [24]. The European Parliament called on the Commission and Member States to make use of flexibilities under the WTO TRIPS agreement such as compulsory licensing and parallel importation and to coordinate and clarify their use where necessary [25]. The process is a complex one and these flexibilities are legally challenging.

European IP incentives for the pharmaceutical industry
European IP incentives were introduced with the aim of protecting innovation to newer therapies, whilst keeping a balance to provide accessibility through more affordable generic or biosimilar medicines [26]. The various regulatory mechanisms include: the Supplementary Protection Certificate (SPC), data and ­market exclusivity, Paediatric Use Marketing Authorisation (PUMA) and marketing exclusivity for orphan drugs. The relationship between the various mechanisms is illustrated in Figure 1 [27]. This figure refers to “global marketing authorisation” which contains the initial authorization and all variations, extensions, additional strengths, pharmaceutical forms and administration routes for a specific active substance authorized within the EU [27]. It does not cover further medical indications of the same active substance, which would generate a new period of data exclusivity and market protection [27].

Figure 1

Supplementary Protection Certificate (SPC)
As per Regulation (EC) 469/2009 [28], at the end of the patent life, a maximum five-year extension may be granted to a ­patent right. The Supplementary Protection Certificate (SPC) may be extended by a further six months, referred to as a Paediatric Extension (PE) if studies (referred to as the Paediatric Investigation Plan (PIP)) are performed to support paediatric indications, so as to ensure that children also benefit from innovative therapy. Multiple SPCs exist for the same product across Europe as SPCs are granted by the national patent office. Different interpretations of the regulation by national patent offices and courts resulted in inconsistencies across Member States which led to a ruling by the Court of Justice by the European Union (CJEU) that concluded that there was the risk that the SPC mechanism was being used to extend patent protection that goes against the spirit of the same regulation which should consider primarily the interest of public health [29]. A 2019 waiver of the SPC allowed EU-based generic and biosimilar companies to manufacture SPC-protected medicines but only for export to non-EU countries where protection of the SPC expired or is non-existent or for stockpiling during the final 6 months of an SPC before entry into the EU market [29]. It was therefore argued that the changes made to the SPC manufacturing waiver do not address the issue of affordability and accessibility of medicines in Europe [4].

Data and market exclusivity
Referred to as the ‘8+2+1’ regime, this harmonizes the EU period of protection of data for innovative products, starting at the point of ‘global marketing authorization’. As shown in Figure 1, this regime provides eight years of data protection, during which the data of the reference product cannot be used by other manufacturing companies to obtain marketing approval for the generic product. An additional two years of market ­exclusivity are granted during which ­regulatory authorities cannot grant a marketing authorization to the generic product. An additional one year is granted for new therapeutic indications, such that an originator product may benefit from a maximum of 11 years data exclusivity [30]. An investigation that was commissioned by the government of The Netherlands to evaluate the cumulative costs of the supplementary protections to the Dutch healthcare system for three drugs could not confirm that innovation was improved through the ‘8+2+1’ regime, and subsequently called for further investigation [25].

Paediatric-Use Marketing Authorisation regulation (PUMA)
An additional data exclusivity of 8 years and market exclusivity of 10 years from the date of marketing authorization may be granted for those medicinal products authorized exclusively for children, and which are not protected by an SPC or SPC qualifying patent. Its aim is to drive innovation in medicines for children, especially in oncology and neonatology, which is still lacking behind.

Marketing exclusivity for orphan drugs
Supplementary marketing exclusivity for orphan medicines is granted at the point of marketing authorization for each specific indication. This is aimed to protect innovation of medicines intended for rare diseases or where the medicine is unlikely to generate sufficient profit due to very high R & D costs. As illustrated in Figure 1, on granting of a marketing authorization for a specific indication, an orphan medicine may benefit from up to an additional ten years of market exclusivity. A further eight years of market exclusivity are granted at the point of the market authorization of the second indication, with the possibility of another two years for a paediatric indication. Research tends to be focused on the development of ‘blockbuster’ drugs which render a high return on investment, resulting in the disproportionate allocation of resources on some diseases at the expense of leaving others untreated [31]. The European Parliament recommended reviewing the prioritization system of unmet medical needs and the definition of orphan drug designation by revising the rare disease register, whilst calling on the Commission to revise the requirements of public funded research in this regard [25].

Analysis of the impact of the EU IP framework for ­biological medicines
Impact on authorizations of biologicals in Europe
An analysis of medicines authorized by EMA showed that as of 31 July 2021, 1,238 medicines are authorized, 332 (26.8%) of which are biological products for 277 biological active substances, see Table 2. Figure 2 shows an increasing trend in authorizations of biologicals in Europe since 1995, starting from an average of six per year for the period (1995–2001) to an average of 28 per year for the period (2016–July 2021), which peaked to 41 in 2018, 13 of which were biosimilars. Figure 3 shows an increase in authorization of monoclonal antibodies in recent years. Table 2 shows that there are 55 biosimilars (excluding products marketed under different brand name) authorized for only 17 of biological active substances, see Table 3. Figure 2 shows that notwithstanding the 2004/27 Directive, there were few biosimilars approved between 2006 and 2016 (a period of 10 years), and though quite a number of biosimilars were approved in 2017 and 2018, the numbers decreased in the following years.

Table 2
Table 3

Figure 2
Figure 3

The results in Table 3 show that there is a significant delay in the submission of applications for marketing authorization of biosimilar products compared to first date of authorization of originator biological (11.9 to 19.74 years), with the exception of somatropin. Table 3 shows that for six newer biologicals, the biosimilar application for authorization was submitted prior to the expiry of patent and exclusivity of the originator biological.

The results of the sub-analysis on the data between 2006 and July 2021 show that a total of 254 biologicals were authorized during this period, of which 199 were originator biologicals. The mean time for assessment of marketing authorization was 1.19 years; maximum 4.60 years and minimum 0.05 years. A total of 55 biosimilars were authorized during the same period with a mean time for authorization of 1.20 years; maximum 2.06 years and minimum 0.55 years. The above shows that the difference in time for assessment for marketing authorization between originator biologicals and biosimilars is insignificant.

Impact on prices of biologicals on the European market
The pharmaceutical industry plays a critical role in the global economy to produce innovative medicines through R & D [8]. The expenditure on R & D in Europe in 2017 reached 35.2 billion which nearly doubled since the year 2000 [26]. The European Federation of Pharmaceutical Industries and Associations (EFPIA) defends the high prices of biologicals attributing them to the high R & D costs, estimated in 2016 at 1,926 million (US$2,558 million dollars) [22]. Tuominen (2011) observed that originator companies still invest heavily in marketing and retain huge profits [20]. As per estimates by Gotham, the costs of manufacturing for the active ingredient (AI) of blockbuster drugs are “0.001%–6% of the current ­lowest prices in the US and 0.004%–14% of prices in the UK” [12]. Manufacturing companies invest only 15% of the profits in R & D whilst one- to two-thirds of R & D costs are covered through public funding, for example through Horizon 2020 and Innovative Medicines Initiative [4]. The EC confirmed that part of the research is publicly funded or funded through research facilities (universities and specialized laboratories of research) [26]. The Corporate European Observatory reported that monopolies are resulting in excessive prices of innovative biologicals which are disproportionate to the research and development costs, resulting in accessibility problems [4]. For example, the price for Humira® (the originator for adalimumab) in the US increased by 18% annually from 2012 to 2016 and also in later years as a result of monopoly [32].

The pharmaceutical industry further employs various strategies, termed as ‘evergreening’ to extend patent protection with the aim to retain monopoly [20]. These include patent ‘thickets’ or ‘clusters’, where the originator pharmaceutical company files in numerous patents for the same molecule, which may vary from a broad patent to more specific patents; secondary patents or follow-on patents, where the innovator company files for an application for improvement to the medicine, e.g. different formulation or a different salt, just before expiry of the patent so as to extend the product’s life cycle, presenting delays in competition, patent settlements or pay-for-delay, where an agreement is reached between the patent owner and alleged infringer to disrupt free competition [20]; withdrawal of the marketing authorization of the originator product and its replacement by a new formulation, such that generic companies cannot apply for an abridged marketing authorization [26]; downgrading the generic name, where the generic brands are given a bad name, influencing healthcare professionals against switching to generics or biosimilars [26]; mergers between originator and biosimilar companies, so as to achieve control over which product to place on the market preventing biosimilars from entering the market [26]; offering bonuses and other incentives to healthcare professionals to favour their products [4]; and collusion between competitors for price fixing, which involves hidden agreements between competitors for products within the same therapeutic class [4].

These strategies are indicative of a lack of transparency. Agreements or cartels between associations are prohibited by the Treaty on Functioning of the European Union (TFEU) as they may disrupt free competition within the internal market (Article 101), and may lead to abuses related to the dominant position on the market (Article 102) [4]. Regulation (EC) No 1/2003 empowers the EU Commission and National Competent Authorities to investigate any arrangements that do not observe the Treaty [33]. Due to different interpretations, in March 2017 the European Parliament called on the CJEU “to clarify, in accordance with Article 102 TFEU, what constitutes an abuse of a dominant position by charging high prices” which is not resolved yet [25]. The European Commission also called for more transparency in costs of R & D (including those obtained from public funding), costs for marketing, and monitoring and investigating patent settlements (pay-for-delay), and enforcement of EU competition legislation [25].

As per Article 168 (7) of the TFEU, Member States are free to set prices and policies for reimbursement of prescription medicines according to their economy through government [34]. National authorities may decide which treatments may be reimbursed under their social security system according to political and other priorities. For new medicines to be reimbursed, national authorities require marketing authorization holders to submit the price and usually there is negotiation. However, the set prices and negotiations are not linked to any prior public funding supporting the research phase.

Impact on the accessibility of the COVID-19 vaccine
The 2020 COVID-19 pandemic presented a global public health emergency which necessitated international cooperation to combat the SARS-CoV-2 virus. This required fast R & D of the COVID-19 vaccine candidates through vaccine technologies ranging from viral vector-based, protein-based, mRNA and lipid nanoparticle technologies [35].

The fast development of COVID-19 vaccines was possible as knowledge was transferred by scientists which allowed multiple companies and research companies to develop and bring to the market a number of COVID-19 vaccines within a year. Gaviria and Kilic (2021) claim that the COVID-19 vaccine technology is protected by a ‘web of intellectual property’, effecting equitable access and fair allocation [35]. The various technologies, namely, mRNA technology, lipid nanoparticle technology and delivery systems technology, are all covered by IP rights owned by large companies, which create legal barriers to the development of these vaccines by other manufacturing companies [35].

In October 2020, India and South Africa submitted an initial proposal for a temporary waiver of patents for COVID-19 vaccine to increase production to meet the global demand and thus provide access to the vaccine to all citizens in all countries. By April 2021, this was supported by 60 WTO members. In May 2021, the US Biden Administration supported these calls to drop intellectual protection for COVID-19 vaccines due to the global health crisis.

Pharmaceutical companies strongly objected to this proposal as they claimed that this would create a precedent and threaten future innovations [36]. Some European leaders and the UK Prime Minister opposed the patent waiver proposal, stating that transfer of knowledge to generic manufacturing companies is not sufficient as these companies lack the expertise in biological technology and workforce to build vaccine plants and would not guarantee the production of the vaccine [36].

Nevertheless, the EU Parliament in June 2021 voted in favour of the resolution that supports waiving the patent for COVID-19 vaccine, with some amendments. In June 2021, the WTO TRIPS Council agreed to move to the next stage of text-based negotiations of the India and South African proposal. Consensus needs to be achieved on the draft by the WTO General Council and a decision on the waiver is expected to be reached by December 2021 [37].

In parallel, in 2020, the EU set its COVID-19 strategy which included a joint procurement scheme to deliver vaccines across its 27 Member States and simplify the price negotiation processes with pharmaceutical companies once they reached authorization. This ensured timely, equitable, and affordable access to COVID-19 vaccines that meet quality, safety and efficacy EU standards for all European citizens [38].

Discussion

The biologicals market in the EU
Following marketing authorization, a medicinal product is launched on the market and follows the cycle through ­market growth, maturity and decline. Companies cannot produce generics for biologicals due to their nature. The EU introduced the biosimilar regulatory pathway for biologicals to achieve competition through biosimilars. The production of biosimilars involves reverse engineering and setting up a new cell line and manufacturing process. Companies are required to present phase III clinical trials data to EMA in order to provide assurance regarding clinical similarity to the originator [5]. The complexity of biosimilar development presents delays for them to reach the market, such that originator biological products do not face the ‘patent cliff’ as for chemically synthesised products [39].

The biosimilar regulations came into force in October 2005 through Directive 2004/27 [40]. Table 3 also shows the dates of coming into force of more specific biosimilar guidelines. One notes that only a few originator biologicals have biosimilars. Table 3 shows that only 17 active substances have authorized biosimilars, out of a total of 277 authorized biological active substances shown in Table 2. This means that only 6.14% of biological active substances have biosimilars. IQVIA (formerly Quintiles and IMS Health, Inc) claimed that only five biologicals dominated the loss of exclusivity over the period 2013–2018 [41]. This was confirmed in the data from Figure 2. The limited number of biosimilars could be attributed to the fact that it may be difficult to apply the biosimilar approach to biological medicinal products, ‘which by their nature are more difficult to characterize, such as biological substances arising from extraction from biological sources and/or those for which little clinical and regulatory experience has been gained’ [42]. One may of course argue that the delay in bringing biosimilars to the ­market was a result of the fact that biosimilars could not be placed on the market before October 2005, for it was then that the legal basis for a biosimilar framework became possible through Directive 2004/27. However, Druedahl et al. (2020) report that lack of clarity in biosimilar approval requirements was identified as one of the regulatory barriers to biosimilar manufacturing companies, even despite the product specific guidelines developed by EMA [43]. Biosimilar manufacturing companies generally resort to seeking scientific advice from the regulators at various stages of the development process at an additional financial cost. The same authors report ambiguity with regards to the need for clinical trials for biosimilar development and generally, the decision is taken on a case-by-case basis. Biosimilar companies are also required to use novel study techniques as part of the development [43]. This implies that biosimilar companies face intellectual property challenges throughout the product development process, which could hinder the submission of applications for biosimilars [44]. Druedahl et al. (2020) reported that in 2017 EMA tried to address this issue through a pilot project on setting up a stepwise biosimilar development plan, which does not replace the need for biosimilar manufacturing companies to seek advice from EMA [43]. Scientific advice is sought prior to submission of the biosimilar application to EMA for authorization which is not reflected in the time for authorization by EMA including stop clocks. A further analysis of the date of submission of biosimilar applications in relation to patent expiry for the same biological as shown in Table 3 points to the fact that IP rights were also a major contributing factor until 2014. Since 2015 biosimilar companies started submitting application for biosimilars prior to patent expiry.

Intellectual property is affecting several aspects in the development process also for biosimilars. There could be other factors, for example, the fact that biologicals are quite sensitive to environmental and manufacturing conditions which are usually kept as trade secrets by the originator company. Moreover, novel studies required by the regulator may also be protected by intellectual property. Thus, although the EC attempted to bring competition by setting up the biosimilar regulatory framework, the EC’s IP rights regulations continue to favour and protect the originator manufacturers.

It is projected that in the next 4–5 years a high number of products with valid protection status will lose exclusivity rights. These mainly represent smaller patient populations. Programmed cell death protein 1 (PD-1) inhibitors, which are forecasted to impact a large patient population, will also lose intellectual protection [41]. It is yet to be seen whether companies will find it feasible to develop biosimilars to these products.

Strategies to improve competition in the EU biological market
The Organisation for Economic Co-operation and Development (OECD) claimed that healthcare systems stand to benefit from competition of referenced (off-patent) biologicals and biosimilars [45]. IQVIA, reported that in 2020 biosimilar medicines reached €8.4 billion which represents 9% of the total biologicals market in the EU with a growth of 60% year-on-year [41]. The potential cost savings from biosimilars are projected to be US$54 billion over 10 years [46]. Nonetheless, pricing policies alone are not sufficient to increase biosimilar uptake [6]. Though price reductions of 50%–70% have been reported by IMS Health (2016) with some biosimilars, there is a poor correlation between the biosimilar market share and price reduction due to patients being switched to second-generation products, for example with erythropoietin (EPO) and granulocyte colony-stimulating factors (G-CSF), biosimilars [47] and insulins [41]. Focusing on biosimilar uptake alone is not a suitable solution [41]. It is therefore essential to bring biosimilars of the new biologicals earlier to the market to achieve sustainable competition, which would reduce market prices and thus improve access to biologicals. Thus, while the delay in authorization of biosimilars shown in Table 3 might be partly due to the lack of a biosimilar framework before October 2005, it remains imperative to remove as many barriers from the IP framework as possible to bring biosimilars to the market as early as possible, before second generation products are produced. The high prices of biologicals for smaller patient populations would also need to be addressed.

Recommendations for improvement of the EU IP framework
Knowledge sharing
The literature has shown that knowledge sharing which took place for the COVID-19 vaccines provided tangible advantages in terms of access to COVID-19 vaccines. This was essential to meet the global public health crisis brought about by the COVID-19 pandemic. It also presented advantages to the pharmaceutical industry which could not cope as the demand was too large for any one company to achieve on its own. Moreover, the novel therapeutics, especially the mRNA technology, reached the market quickly, without the need of high-level phase III clinical trials. It has also promoted the novel technology for future development of biologicals. Knowledge sharing should therefore be considered for biologicals where accessibility to essential treatment is considered to be a critical issue.

As seen in the literature, knowledge sharing may also be implemented by providing CLA to other manufacturers. Patency and exclusivity rights would still be retained by the originator company, which may benefit from remuneration from the CLA biological company for granting access to its CLA. This proposal would require further analysis from the legal and regulatory perspectives.

Patents and exclusivity protection incentives
Some authors report that there does not appear to be a link between the data and market exclusivity protections with innovation [22]. The SPC framework in Europe is also considered to be complex and there is the risk that the SPC mechanism is being used as an ‘evergreening’ strategy.

The regulations governing the EU IP framework thus need to be revised to reduce the complexity and bureaucracy of its framework which is leading to abuse of the incentive system.

The ‘evergreening’ strategies are also responsible for extending patent validity. They need to be addressed through revisiting patent law, vis-à-vis what makes a product innovative and what makes it covered by a patent as a new product, so as to eliminate patent thickets and patent extension systems. The European Commission should also revise the legislation of the ‘Sunset Clause’ which allows market withdrawals. There should also be transparency on public disclosure of relationships between pharmaceutical industry and patient groups, institutions and healthcare professionals so as to ensure independent decision taking.

Moreover, as the IQVIA report [41] points out, biosimilars are only sustainable if their sales are sufficient to attain a return on investment. This is of course very important in the case of biologicals which target diseases relevant for small patient populations (orphan drugs). The designation of orphan drug status needs to be restricted to rare diseases only coupled by a revision of the prioritization of unmet clinical needs.

Excessive pricing for biologicals
The prices of biologicals depend on a number of factors, including demand-side factors which are not related to intellectual property rights. However, as evidenced in the literature [8], IP protection rights are a major contributing factor to monopoly, resulting in high prices of biologicals. The prices of biologicals are also disproportionate compared to the cost of development [4]. The question of public funding of research leading to private patents and private profits seems to escape scrutiny. One way of addressing excessive prices is through transparency.

Transparency of information on R & D costs and prices
The Commission has called for transparency in costs of R & D, including costs obtained from public funding. Sharing of data on prices of medicines by different Member States would be beneficial to governments towards fair pricing, i.e. the right balance between affordability and innovation. In May 2019, WHO launched the World Health Assembly Resolution 72.8 on Transparency [48]. In July 2021, WHO published a report on ‘mechanisms for improving transparency of markets for medicines, vaccines and health products’ which provides policy recommendations to Member States when negotiating prices for medicinal products [49]. These include implementing legislation on pricing transparency, using caution when entering in confidentiality agreements with manufacturers, implementing price regulation, monitoring and reporting, among others. In practice, the progress on the uptake of measures related to transparency seems to be quite slow and difficult and requires more commitment from European Member States. Literature has shown that joint procurement at EU level representing 27 Member States provides higher bargaining power to EU Member States in price negotiations with the pharmaceutical industry which could be utilized to achieve timely, equitable, and affordable access to biologicals [38].

Conclusion

The analysis confirmed a low percentage of biosimilar authorizations in Europe. It was also confirmed that there were significant delays in biosimilar authorizations, which were not related to the assessment of the marketing authorization process but were mainly attributed to the complexity in the development process and IP protection of the originator biological active substance, trade secrets for cell line and manufacturing processes, and the novel studies required in the biosimilar development process. The evidence in the literature points out that prescribers are moving to the new biologicals and thus price reductions are not necessarily being achieved with biosimilars. Focusing on the uptake of biosimilars is not considered sufficient to increase access to biologicals. The evidence from the literature confirms that the pharmaceutical industry benefits from the monopoly status of originator biologicals resulting from the various IP systems that protect innovation. This results in excessive prices of biologicals whereby the actual costs of the products are disproportionate to investment costs on R & D. Sharing of knowledge, for example, through CLA was identified as a possible solution, which could provide significant results, but requires further analysis. The definition of what constitutes an orphan drug appears to be too broad and should be re-defined whilst the prioritization of unmet clinical needs to be revised. The EU regulatory incentives require revision so as to provide protection to innovation without impacting accessibility. The ‘evergreening’ strategies employed by pharmaceutical industry further extend the monopoly status. Incidents of potential abuse need to be investigated in a timely manner by ongoing monitoring and application of proportionate punitive action by the responsible competent authorities. In addition, a transparent pricing system capturing R & D costs and public funding of research should be introduced so as to achieve fair pricing with the aim to improve market access. The central EU joint procurement mechanism should be considered for biologicals as it provides negotiation power to the EU Member States.

This study confirms that the EU Pharmaceutical Strategy should prioritize the revision of the current EU IP system in order to achieve its aim of ensuring timely, equitable, and affordable access of biological medicines to all EU citizens. Unless changes to the EU IP system are implemented, the current status quo will not be addressed.

For patients

Once the patent of biological medicines expires, similar biological medicines, termed as biosimilars, can enter the market. Biosimilar medicines have similar effectiveness as the originator medicine but are 50%-70% cheaper. In view of the high prices of biological medicines, biosimilar medicines allow patients to access safe, effective and high-quality biological medicines at reduced prices of the branded originator medicines. The ­patent system is intended to allow originator companies to protect innovation as the industry would have invested heavily in R & D and manufacturing. Thus, the manufacturing company can recoup its investment costs and is also encouraged to continue to perform research for new medicines, to secure development of new medicines to treat diseases which so far are untreatable. The European Union also introduced other mechanisms to lengthen the patent protection period, such as supplementary protection certificate and data or marketing exclusivity. However, manufacturing companies started using strategies to further extend the patent period which exploit the legal framework such as ‘evergreening’ which mainly involves multiple ­patent systems. The patent and other protection systems can stifle competition and create a monopoly thus contributing to the high prices of biological medicines. This is resulting in problems for patients to access biological medicines, for treatment of diabetes, cancer and other diseases. This review shows that the EU regulations for patent protection may not be supporting innovation to the expected levels and originator companies may be abusing of this system to extend monopoly status and keep their prices high. This review recommends improvements for mitigation of the negative effects from patents, such as sharing of knowledge between originator and other companies, a less complex regulatory framework for patenting in Europe and also transparent prices and costs related to the R & D and manufacturing costs and public funding. These aim to bring biosimilars to the market earlier thus improving accessibility of biological medicines to patients.

Funding sources

None.

Competing interests: None.
Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

Josette Sciberras, MBA, MA Bioethics, BPharm (Hons)
Raymond Zammit, SThD
Patricia Vella Bonanno, PhD

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Author for correspondence: Josette Sciberras, MBA, MA Bioethics, BPharm (Hons), Room 204, Department of Moral Theology, Faculty of Theology, Humanities A Building, University of Malta, Msida MSD 2080, Malta

Disclosure of Conflict of Interest Statement is available upon request.

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A critical review of substitution policy for biosimilars in Canada

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Author byline as per print journal: Professor Philip J Schneider1, MS, FASHP, FASPEN, FFIP; Michael S Reilly2, Esq

Canada has approved a total of 36 biosimilars. While the approval of biosimilars is regulated at the national level, decisions about biosimilar substitution are made at the provincial level. Four Canadian provinces, representing around 50% of the population in Canada, have now implemented policies requiring non-medical switching of biosimilars – switching from a patient from an originator biological to a biosimilar primarily for economic reasons. In this article, we compare biosimilar substitution policies in Canada to policies in Europe and the US, finding an enhanced focus on clinical and marketplace factors in these regions. We also find evidence that in some cases non-medical switching may pose a risk to patients and suggest that Canada could learn from more mature markets, such as those in Europe, where switching policies better consider patient needs, preserve physician choice and promote market competition.

Submitted: 29 May 2021; Revised: 22 July 2021; Accepted: 26 July 2021; Published online first: 30 July 2021

Introduction

The rising cost of health care is a matter of global concern. Drug pricing has been a growing part of the discussion about this issue and the high cost of new biologicals medicines has contributed to the concern. While these therapies have been medical breakthroughs, access to them because of cost has been a concern, as has the potential for bankrupting the funding for health care. Health authorities and payers are scrambling to find solutions to this dilemma.

Biosimilars – copies of biological drugs that are similar but not identical to the product on which they are based – have proliferated significantly over the past decade as the patents for several biologicals have expired. Biosimilars have been developed across a variety of therapeutic areas globally, including oncology and inflammatory diseases. The rationale for creating biosimilars is to promote competition among manufacturers to lower prices, thereby increasing access to expensive biological medicines. A competitive marketplace typically produces price competition in general, and for biological medicine this is no exception. The unexpected challenge has been realizing the potential savings.

There has been the temptation to apply the lessons learned from the creation of generic versions of simple molecules to biological medicines and biosimilars. This is understandable because of the substantial saving resulting from price competition, price reductions, and the ability to freely substitute a much less expensive generic version is dispensed when a more expensive brand name product is prescribed. This model is not possible for biologicals because while highly similar, biosimilars are not identical to the reference product with which they compete. This has prompted many studies of the comparability of biosimilars to their reference product, including switching studies where patients are switched from the reference product to a biosimilar. These studies have confirmed the similarity of biosimilars to reference products but may have been inconclusive about important clinical differences that may affect patients being treated. As a result, there have been a variety of different regulatory and policy approaches to the use of biosimilars around the world.

Regulatory and policy approaches to the use of biosimilars are usually developed with the goal of reducing drug costs by stimulating their use. These approaches should, but do not always have a goal in assuring the effectiveness and safety when biosimilars are used in the clinical setting. Other considerations include maintaining an environment for future innovation, sustaining a competitive market, and assuring a reliable supply chain. Good regulations and policies consider all these factors.

As of 30 April 2021, Canada has approved 36 biosimilars, and another 13 are under review [1]. While this is on par with the Food and Drug Administration’s (FDA) approval of 30 biosimilars [2] and the European Medicines Agency’s (EMA) approval of 73 biosimilars (13 of which are not considered biosimilars in the US) [3], Canada’s recent implementation of policies requiring a non-medical switch to biosimilar medicines in British Columbia, Alberta, New Brunswick, and Quebec stands in contrast to biosimilar substitution practices in the US and Europe and does not consider some of the factors used in other countries to foster the effective and safe use of biosimilars as ways to control rising healthcare costs are considered.

Overview of biosimilars in Canada

Health Canada originally issued their regulatory guidelines for biosimilars, Information and Submission Requirements for Biosimilar Biologic Drugs, in 2010 [4]. Since then, 36 biosimilars based on 13 reference products have been approved, see Table 1. To improve the efficiency of the regulatory review of drugs and devices and to support timely access to biological products, Health Canada issued a Regulatory Review of Drugs and Devices initiative (also known as ‘R2D2’) in 2017 [5]. A key objective of R2D2 was to work with local health partners, including health technology assessment organizations, to reduce the time between Health Canada approvals and reimbursement recommendations.

Table 1

While the approval of biosimilars is regulated at the national level by Health Canada, decisions about biosimilar substitution are made at the provincial level. Policies requiring the switching of a patient’s medicine from an originator biological to a biosimilar primarily for economic reasons is referred to as ‘non-medical switching’ and have been avoided by Canadian ­payers until recently. Newer initiatives to realize potential savings opportunities offered by biosimilars have reflected a shift in the perspective of provincial payers, and four of Canada’s provinces, that are inhabited by approximately 50% of the country’s population, have begun implementation of biosimilar switching programmes, see Table 2. Other provinces are expected to consider similar biosimilar initiatives soon.

Table 2

In May 2019, British Columbia announced that it would forcibly switch more than 20,000 of its arthritis, psoriasis and diabetes patients from their originator biological medicines to the government’s choice of preferred biosimilar products. In September of the same year, it was announced that an additional 1,700 patients with inflammatory bowel disease would be switched [6,7]. The province of Alberta announced plans to switch at least 26,000 patients, including those being treated with infliximab for ulcerative colitis and Crohn’s disease, from biological therapies (etanercept, infliximab, insulin glargine, filgrastim, pegfilgrastim) to biosimilars by the summer of 2020 [8]. The COVID-19 pandemic has delayed the implementation of these programmes. The recent implementation of forced non-medical switching policies by Canadian payers represents a departure are different from biosimilar substitution practices in the US and Europe in that they focus on economics, not clinical or marketplace factors.

Policies in established biosimilars markets

In the US, pharmacy-level substitution of a biosimilar for an originator biological without physician consent is only permitted for biosimilars that have been designa­­ted ‘interchangeable’ by FDA. To receive an interchangeable designation, the product must meet additional re­­quirements beyond being biosimilar, which translates to more clinical development – including switching studies. The rationale for this policy is based on the acknowledgement that biosimilars are similar but not identical to the reference product and to protect patients, additional evaluation of comparability is needed. Prior to 26 July 2021, no biosimilars in the US had been approved as interchangeable, therefore, non-medical switching has not existed in the US§.

In contrast, EMA does not have recommendations on interchangeability but the decision-making authority on substitution policies rests with the individual EU Member States. While automatic substitution is prohibited in most European countries, a few financially constrained countries in Central and Eastern Europe, e.g. Estonia, Latvia, Poland and Serbia, allow pharmacy-level substitution [9]. Particularly in Bulgaria, Poland and Serbia, tendering procedures are applied for purchasing biologicals and dictate which product a patient will receive. However, the prescription of switching to a biosimilar medicine in Europe most commonly occurs under the supervision of a physician in consultation with the patient. These policies are based on the responsibility and accountability of the physician for the care of their patient, while acknowledging the need to consider cost when making treatment decisions.

Successful biosimilar markets in the EU and US have demonstrated that forced medical switching is unnecessary to achieve high uptake of biosimilars and the associated savings. While the global biologicals market is dominated by the US, which has a share above 50%, Europe is the leader in biosimilar approval and commercialization [10]. The EU was the first to establish a regulatory framework in 2004 and has the largest biosimilar market in the world, representing ~60% of the global biosimilar market [10]. Biosimilars have attained market shares as high as 91% for older products (before the approval of the first monoclonal antibody biosimilar in 2013) and as high as 43% for newer products (approved post-2013) in some European markets. The success of the European biosimilar markets reveals three common principles: physician choice, not mandating automatic substitution, and promotion of competition [11-13]. This fosters a robust and sustainable biosimilar market with multiple suppliers in any given product class. Tenders are designed to include value-based criteria in addition to price and award multiple contracts not single-winner tenders to ensure continuity of supply and healthy competition [12]. Experience in the EU suggest that competition not regulation results in cost savings without compromising patient care [13].

Internal concerns about Canadian biosimilars policy

The introduction of major reimbursement policy changes by Canadian payers that is intended to increase the use of biosimilars, has been criticized by various groups in Canada. Physicians, medical societies and patients themselves have argued that non-medical switching will adversely affect patient care. Furthermore, these policies conflict with principles believed to be the foundation for a sustainable biosimilars market.

At the behest of Quebec’s Ministry of Health and Social Services, the Institut National d’Excellence en Santé et Services Sociaux (INESSS) conducted a state-of-knowledge report about the risks associated with non-medical switching and the interchangeability of biologicals [14]. The systematic review on which this report is based indicated that the available scientific data are insufficient to support the safety of switching between originator biological and biosimilar, particularly in inflammatory bowel diseases and oncology, and that larger studies are needed to address the uncertainty associated with switching between biologicals in these indications. Furthermore, the report indicated that non-medical switching is generally not supported by clinicians due to the potential destabilization of complex patients, along with many other patient-related concerns. While clinicians in Quebec support the use of biosimilars in patients who have not used the corresponding reference product, they believe that switching to a biosimilar should be carried out under medical supervision. A survey of Canadian prescribers of biologicals conducted by the Alliance for Safe Biologic Medicines indicated that 83% of physicians across 13 therapeutic specialties considered it ‘very important’ or ‘critical’ that the prescribing physician decide the most suitable biological for their patients [15]. Most prescribers were not comfortable with a third-party switching a patient’s medicine for non-medical reasons.

In a joint statement from the Canadian Association of Gastroenterology and Crohn’s and Colitis Canada, non-medical switching was not recommended for patients who are stable on biological treatment [16]. Further, gastroenterologists across Canada do not support automatic substitution of any kind but supported starting treatment-naïve patients on biosimilar products if they had active disease and the price differential between the originator biological and the biosimilar is significant. The Gastrointestinal Society stated that reimbursement policies must recognize and respect the physician’s right to prescribe based on clinical evidence and a patient’s right to choose the therapy that is best for them [17].

The Biosimilars Working Group of Canada, a key collaboration of diverse non-profit organizations, registered health charities, and healthcare advocacy coalitions dedicated to ensuring good outcomes for patients, stated that the cost-driven objective of the forced-switch policy is worrisome as it fails to put physician wisdom, patient choice, appropriateness of care, accessibility, and affordability at the forefront of health policy [18]. When Canadian researchers surveyed patients with gastrointestinal diseases and their caregivers to determine their views on the use of biological and biosimilar drugs, 95% of those surveyed believed it was important that decisions regarding choice of medication be determined solely by the treating physician in collaboration with the patient [19].

The burden on healthcare systems is clear according to the Gastrointestinal Society’s report on the impact of British Columbia and Alberta’s non-medical switching policies. Patients reported experiencing delays with biosimilar doses, with some reporting shortages in availability, inadequate education on biosimilars, as well as the physical and mental toll they experienced in navigating their new treatment pathways [20].

It can be concluded that many Canadian physicians feel that non-medical switching of biological products poses a risk to patients [14-17]. As prescribers of biosimilar medicines, these physicians feel that it is critical for them to retain the right to make treatment decisions that best benefit their patients, see Table 3. While the opinions of these Canadian physicians are at odds with the forced non-medical switching policies of Canadian drug plans in British Columbia, Alberta, New Brunswick and Quebec, they are aligned with the views of experienced prescribers from the US and Europe [11,14].

Table 3

Discussion

Health policy decisions in Canada affecting the clinical use of biosimilars focuses primarily on economic factors and a strategy to reduce rising healthcare costs. While this is a laudable aim, it does not consider other factors that are important when making regulatory decisions. Factors that must be considered include the effectiveness and safety of therapy, the supply chain, and sustaining a healthy market for innovation and price competition. Mandatory switching for non-medical reasons does not consider that not all patients respond the same way to medications and that this can increase the financial burden on healthcare systems. In a recent systematic literature review conducted to evaluate the economic impact of non-medical switching, Liu et al. [20] identified 17 studies that reported an overall increase in real-world costs associated with non-medical switching. Higher rates of surgery (11%) increased steroid use (13%) and biosimilar dose escalations (6% to 35.4%) were cited as some of the reasons for the cost increases. Most studies evaluating the economic impact of non-medical switching consider only drug costs; however, a comprehensive evaluation should incorporate all elements of healthcare service needs [21].

For example, Alberta’s switching policy resulted in many unintended consequences, the health and financial impacts of which the province has said it needs to investigate [22]:

In Alberta, patients were switched from infliximab, etanercept, pegfilgrastim, and filgrastim originator biologics. They were also switched from insulin glargine originators, although in the United States there are no official biosimilars for these products yet.

Alberta ran into some problems. For example, some pharmacies began stocking only preferred biosimilars, which meant that patients and their providers could not choose. Alberta has attempted to remedy this problem.

The government has succeeded in switching over 60% of patients from reference infliximab to biosimilar infliximab, but there has been opposition. In addition, more than 15% of patients moved to a different biologic and roughly 15% dropped or terminated their government coverage, [Alberta Health Assistant Deputy Minister, Chad Mitchell] said. The government is attempting to find out the reasons for these coverage departures and treatment changes.

For the originator insulin glargine product Lantus, more than 40% of patients moved to a different biologic after switching was initiated, and 15% of beneficiaries dropped or terminated their coverage. Mitchell said 10% to 20% of beneficiaries in other biosimilar categories terminated coverage. More investigation is needed to understand the significance of these trends, he said.

Non-medical switching to biosimilar products may also have a negative impact on patient safety in cases where administration devices for self-administered biosimilars differ from the reference product [22,23]. Without proper guidance from a healthcare provider, biosimilar products available in different presentations compared to their reference products could lead to inappropriate use by patients or caregivers – again highlighting the need for physician responsibility in treatment decisions.

While the European biosimilars market has been credited with higher uptake compared to the US market, rates of uptake differ from country to country in Europe and can vary significantly by product class. A report by KPMG commissioned by Medicines for Europe to analyse the procurement of medicines in hospitals in eight European countries highlighted the variability in biosimilar sales against originator in these different Member States [24]. An average of hospital biosimilar volume in March 2019 showed that Denmark achieved 63% overall biosimilar volume, with the UK coming in second at 45%. Germany had 40% biosimilar volume, France had 34%, and Belgium tied with Switzerland for last place among the countries studied at 14%. In a recent assessment of the impact of biosimilar competition in Europe, 16 European countries were reported to have achieved > 90% biosimilar utilization for filgrastim and pegfilgrastim in 2018, while utilization in Ireland was just 27%. Among anti-tumour necrosis factor biosimilars (adalimumab, etanercept and infliximab), Norway and Denmark had 81% and 96% biosimilar uptake, respectively, while every other country’s utilization was less than 50% [25]. Variations in adoption rates among individual European countries as well as across therapeutic areas are influenced by government involvement, reimbursement structures and tender procurement policies.

In the US, biosimilars have gained significant share in the majority of therapeutic areas in which they have been introduced, ranging on average from 20% to 25% within the first year of launch, with some projected to reach greater than 50% within the first two years [26,27]. As expected, first-to-market biosimilars tend to capture a greater portion of the segment compared to later entrants. Filgrastim biosimilars have been on the market the longest at five years and have achieved a 72% share, while bevacizumab and trastuzumab biosimilars have approximately 40% share. Rituximab and infliximab have had the most limited adoption, with approximately 20% market share [25].

Conclusion

Canada desires a robust biosimilar market share like that observed in Europe. While there may be short-term savings from non-medical switching, a long-term consequence of this policy may be decreased competition resulting from fewer products launches and a negative impact on patient safety. Potential drug shortage issues may develop in the absence of multiple suppliers of biologicals in each product class. There would also likely be undermining the confidence of both physicians and patients in biosimilars that creates an additional barrier to biosimilar uptake.

The successful uptake of biosimilars in Europe was not accomplished by limiting the choice of biological or forced non-medical switching, but through preserving choice for physicians and patients and by promoting competition among all products approved by regulatory authorities. To foster its success in creating a sustainable biosimilars market, Canadian payers can learn from the lessons learned in more mature markets and implement evidence-based transition policies that consider patients’ needs primary.

Funding sources

This paper is funded by the Alliance for Safe Biologic Medicines (ASBM).

The ASBM is an organization composed of diverse healthcare groups and individuals – from patients to physicians, innovative medical biotechnology companies and others – who are working together to ensure patient safety is at the forefront of the biosimilars policy discussion.

The activities of ASBM are funded by its member partners who contribute to ASBM’s activities. Visit www.SafeBiologics.org for more information.

Competing interests: Professor Philip J Schneider is a member of the International Advisory Board of Alliance for Safe Biologic Medicines (ASBM) since 2012 without compensation. From September 2014, Emeritus Professor Schneider has been the Chair of the International Advisory Board of ASBM and is paid a small stipend for that role. Mr Michael S Reilly, Esq is the Executive Director and employed by Alliance for Safe Biologic Medicines. Mr Reilly served in the US Department of Health and Human Services from 2002 to 2008.

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

§On 26 July 2021, the US FDA approved its first interchangeable biosimilar, the insulin glargine product Semglee. To be designated interchangeable, a biosimilar must provide additional data to FDA demonstrating that a patient switched repeatedly between the biosimilar and the originator product can expect the same clinical result without additional risks, compared to a patient who remained on the originator product. As of April 2021, all US states permit interchangeable biosimilars to be substituted at the pharmacy level without prior physician authorization.

Authors

Professor Philip J Schneider1, MS, FASHP, FASPEN, FFIP Michael S Reilly2, Esq, Executive Director

1College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA
2Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA

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Author for correspondence: Michael S Reilly, Esq, Executive Director, Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA

Disclosure of Conflict of Interest Statement is available upon request.

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Microbiological, scientific and regulatory perspectives of hand sanitizers

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Author byline as per print journal: Adjunct Associate Professor Sia Chong Hock, BSc (Pharm), MSc; Tan Ying Ting, BSc Pharm (Hons); Associate Professor Chan Lai Wah, BSc Pharm (Hons), PhD

Hand sanitizers are rub-on formulations for the purpose of inactivating microorganisms on the hands. With the recent COVID-19 pandemic, a surge in the manufacturing, sale and use of hand sanitizers is observed. However, the effectiveness and safety of hand sanitizers are not well understood by the public; thus, hand sanitizer usage may not confer adequate protection and may pose safety threats. Globally, the emergence of safety threats and inappropriate manufacturer claims also suggest that regulatory frameworks are insufficient in ensuring optimal effectiveness and safety standards for hand sanitizers. This paper presents an overview of the activity of antimicrobials as active ingredients in hand sanitizers and the principles of test methods to evaluate the effectiveness of hand sanitizers. Different antimicrobials confer different activities, rendering some more useful than others. There are also no specific compendial test for efficacy of hand sanitizers and the choice of test method is left to the discretion of manufacturers. It has also been reported that a significant number of hand sanitizers were improperly labelled or had inappropriate claims. Implementing a tighter regulatory framework, developing pharmacists’ knowledge and capabilities, raising consumer awareness and debunking common myths are some possible solutions to address the problems encountered.

Submitted: 17 March 2021;Revised: 13 May 2021; Accepted: 15 May 2021; Published online first: 28 May 2021

Introduction

Globally, millions of people suffer from healthcare-associated infections (HCAIs) each year [1]. HCAIs occur in patients while receiving care for another medical condition [2] and one identified cause is poor hand hygiene [3]. Recently, the emergence of Coronavirus Disease 2019 (COVID-19) poses an unprecedented challenge to healthcare globally. In light of persistent HCAIs and this public emergency, strategies to mitigate infectious spread are crucial.

According to the World Health Organization (WHO), the most crucial measure towards mitigating the spread of harmful microbes is practicing proper hand hygiene [4]. Following COVID-19, the Center for Disease Control (CDC) recommends the use of alcohol-based hand sanitizers as a substitute to handwashing with soap and water [5, 6]. Consequently, the sale, supply and use of hand sanitizers have skyrocketed. Hand sanitizers are rub-on formulations [7] categorized as alcohol-based (ABHS) or non-alcohol-based (NABHS). ABHS contain alcohol and components, such as water and humectants [8]. The alcohols commonly used include ethanol (ethyl alcohol) and isopropyl alcohol [9]. NABHS, also known as “alcohol-free hand rub”, commonly contain benzalkonium chloride, chlorhexidine gluconate, hydrogen peroxide or iodine [9]. Hand sanitizers may be liquids, gels or foams used to inactivate or suppress the growth of microorganisms found on hands [8].

Many manufacturers claim that their products kill 99.9% of microbes effectively. Such claims have become common practice [10] and have misrepresented the effectiveness of hand sanitizers because the percentage of kill claimed is specific to the microorganisms used in the test method. Currently, the US Food and Drug Administration (FDA) allows manufacturers to produce hand sanitizers without formal approval [11]. This may encourage the rise of ineffective hand sanitizers by unethical manufacturers. In fact, the lack of tighter regulatory controls has compromised safety, as evident in recent cases of methanol poisoning due to the use of methanol-contaminated hand sanitizers [12]. More regulatory oversight is warranted to ensure safety checks and balances are in place to avoid safety threats.

With the perceived ‘shotage of supply’ of hand sanitizers amid the COVID-19 pandemic, consumers have become less discerning. They may also hold misconceptions regarding hand sanitizers which hinder them from receiving the desired protection. The misconceptions have resulted in safety issues for consumers. In this regard, there is a need to debunk these myths, raise consumer awareness and promote consumer education.

Studies have investigated the efficacy of using hand sanitizers vis-a-vis handwashing with soap and water [13, 14]. Some studies have also compared the efficacies of different hand sanitizer brands [15-18]. As there is no specific compendial test for efficacy of hand sanitizers, various methods have been used and the results obtained may not be comparable or may not provide useful information. There is also a lack of studies to investigate the multitude of factors that can affect the efficacy of hand sanitizers and to debunk the misconceptions regarding their activity and safety. To date, there is no reported survey on the quality, safety and efficacy of commercial hand sanitizers available to consumers.

This paper aims to highlight useful antimicrobial compounds and provide a better understanding of the different test methods. It also aims to debunk myths and identify factors that affect the activity and safety of hand sanitizers, and consequently, propose solutions to educate consumers. Last, but not least, a regulatory framework for control of hand sanitizers, is proposed.

The microbiology of bacteria, fungi and viruses

To evaluate the effectiveness of hand sanitizers, it is necessary to understand the nature of microorganisms, which are targets of hand sanitizers. Microorganisms are tiny living things not visible to the naked eye unless they proliferate to form a mass. Scientifically, bacteria and fungi are considered microorganisms, but viruses are not because viruses exist in sub-micron size and are non-living outside of a host [19]. However, manufacturers of hand sanitizers have often claimed that their products kill 99.9% of microorganisms [10, 20] which is perceived to include viruses. Moreover, common efficacy tests employed consist of methods developed for bacteria and fungi, suggesting that viruses are not covered.

Bacteria are prokaryotes with each cell consisting of a double-stranded DNA (dsDNA), plasmids and ribosomes in the cytoplasm surrounded by a plasma membrane, see Figure 1a, [21, 24]. Most bacteria have a cell wall made up of a continuous peptidoglycan. Gram-positive bacteria have a thicker peptidoglycan than Gram-negative bacteria. Some bacteria also possess flagella which enable bacterial motility, and fimbriae and capsule which enable attachment to surfaces. The capsule also provides additional protection to the cell. Some bacteria may produce spores which are highly resistant to chemicals.

Figure 1

Fungi consist of yeast and mould. Unlike bacteria, fungi are eukaryotic. Their cells consist of nucleus, mitochondrion, Golgi apparatus and vacuole, which are membrane-bound, in a cytoplasm surrounded by a plasma membrane and cell wall, see Figure 1b [22]. The cell wall of fungi is typically composed of mannoproteins, chitins and glucans [25]. Fungi produce spores that are less resistant than bacterial spores.

Viruses are obligate parasites consisting of genetic material, either DNA or RNA, enclosed within a capsid composed of protein, see Figure 1c [23, 26]. Structurally, viruses are described as enveloped when their capsid is enclosed by an outer lipoprotein envelope, or non-enveloped. The envelope consists of peplomers for attachment to the host organism. Some pathogenic viruses include, for example, those belonging to the families Adenoviridae, Coronaviridae and Herpesviridae [26]. The coronavirus is part of the Coronaviridae family.

It can be clearly seen that bacteria, fungi and viruses possess characteristic structures that may differ in chemical composition. Therefore, depending on their mechanisms of action, some compounds are effective only against certain microorganisms.

Antimicrobial compounds and their applications in hand sanitizers
The antimicrobial compounds are classified based on their chemical composition, see Table 1. They may show one or more mechanisms of action against one or more types of microorganisms.

Table 1

Ethanol and isopropyl alcohols are ABHS recommended by WHO. Some studies have shown that alcohols are sporicidal [9,28] or sporostatic [29]. Other studies have shown that alcohols lack activity against fungi [30, 31] including two common fungal species found in indoor air, namely Aspergillus fumigatus and Penicillium chrysogenum [30]. With conflicting findings, the effectiveness of alcohols on fungi cannot be ascertained, but their activities on bacteria and viruses are conclusive.

Quaternary ammonium compounds (QAC) are usually dissolved in an aqueous medium to produce NABHS, which are non-volatile. A commonly used QAC, benzalkonium chloride, is regarded as one of the safest and most efficacious synthetic biocides [28]. It is thought to interfere with the plasma membrane of microorganisms, thereby inducing leakage of its cellular contents [28]. Another example of a QAC that was widely employed is benzethonium chloride. It was, however, banned from use in hand sanitizers by FDA in 2019 due to insufficient efficacy data. Although it has not been found to cause harm, its use in hand sanitizers may mislead consumers on its effectiveness and result in false protection [39].

Biguanides are also employed in NABHS. The most notable example is chlorhexidine gluconate (CG) which is commonly used in hospitals. CG is highly bactericidal against Gram-positive bacteria, microbiocidal against enveloped viruses and has some weak activity against Gram-negative bacteria and fungi [9, 34]. Several studies demonstrated its rapid kill of two commonly found bacteria, namely Escherichia coli (E.coli) and Staphylococcus aureus (S.aureus) [36, 40-42]. However, CG lacks sporicidal activity and is ineffective against spore-forming bacteria. CG was reported to cause damage to the plasma membrane of yeast cells, leading to the leakage of intracellular components and cell death [36, 43-46].

Chlorine and iodine are examples of halogens used for antisepsis. Chlorine is more commonly used to disinfect water. Iodine, commonly available as povidone-iodine, is more often used for skin disinfection before and after surgery. Both halogens have broad activity against bacteria and viruses. Some studies on chlorine have postulated activity against spores [36, 47-49]. Povidone-iodine, which is used at 5%–10% in formulations for skin application, inactivates but does not kill spore-forming bacteria [9]. At 2%, povidone-iodine is effective against E. coli but a higher concentration of 7.5%–10% is needed against non-enveloped viruses [50].

Chloroxylenol is used in antimicrobial hand soaps and surgical hand scrubs. Chloroxylenol exerts strong activity against bacteria and enveloped viruses, with the exception of Pseudomonas aeruginosa (P. aeruginosa) [9, 51-53]. However, chloroxylenol is not used in hand sanitizers despite its strong efficacy and safety for cosmetic use because studies have concluded that chloroxylenol has less immediate efficacy and less residual activity compared to CG and povidone-iodine [8, 51, 53-56].

Triclosan is an example of a bisphenol with strong bactericidal activity against Gram-positive bacteria and mycobacteria. In the past, triclosan was used in hand sanitizer formulations. However, in 2019, it was banned under the FDA Consumer Antiseptic Rub Proposed Rule [57], after studies highlighted toxicities of triclosan, such as decreased thyroid hormone levels [58] and breast cancer with long-term use [59, 60]. In fact, a study also found that the effectiveness of triclosan products was similar to plain soap [61]. Therefore, the risks from triclosan use outweigh its benefits, limiting its application in hand sanitizer formulations.

Hydrogen peroxide is a peroxygen which damages cell lipids, proteins and DNA of microorganisms [9, 36]. Although it damages these structures, it exhibits little antimicrobial effectiveness when used alone; hence, it is often combined with other active ingredients such as alcohol [8]. Today, possible damage to fibroblasts and risk of bleeding limits its use [62]. FDA recommends the use of ABHS or BKC-containing NABHS in the COVID-19 pandemic, while Centers of Disease Control and Prevention (CDC) recommends the use of ABHS [63]. However, studies have shown that CG and povidone-iodine are also useful against the coronavirus [9]. At a concentration of 0.12%, CG is postulated to demonstrate antiviral activity against the coronavirus [9, 64]. Nasal povidone-iodine has also been shown to prevent perioperative spread of COVID-19, though the efficacy of povidone-iodine in hand sanitizers has yet to be proven [9, 65].

Test methods used to evaluate efficacy/effectiveness of hand sanitizers
There are no compendial methods (pharmacopeial standards) for evaluating the efficacy of hand sanitizers and the choice of method is left to the discretion of manufacturers. Standards such as the European Standards (EN) and the American Society for Testing and Materials (ASTM) standards are more commonly employed. Within these standards, there are different methods for hand sanitizers including EN1500, EN1040, ASTM-E1174 and ASTM-E2755, see Table 2.

Table 2

EN1500, ASTM-E1174 and ASTM-E2755 are in vivo tests while EN1040 is an in vitro test. In vivo tests are preferred as they are more realistic. The microbial load, which will have an impact on the outcome, is not always clearly stated. The exposure time to the test hand sanitizer is currently not standardized. It is 30 seconds for the in vivo tests but 5 minutes for the in vitro test. EN1500 has a control to exclude confounding factors but ASTM-E1174 and ASTM-E2755 do not include any control. The acceptance criteria are different, with EN1040 being the most stringent. The test organisms used are also not similar, with some organisms known to be more susceptible than others. ASTM-E1174 is recommended in the FDA Tentative Final Monograph 2016 revised version [8] and is more widely used in the US and Canada [67]. Nevertheless, the choice of test method lies with the discretion of the manufacturer of the hand sanitizer.

It can be clearly seen that the test methods apply only to bacteria. Additional tests should be performed to encompass a wider range of ‘microorganisms’ to support the claim of being effective against 99.9% of microorganisms. The ASTM-E1838 is a finger pad method for viruses [73]. In contrast, the ASTM-E2613 is a finger pad method for fungi [74] while the ASTM-E2011 is a whole hand method for viruses [75]. In principle, manufacturers should consider these additional tests to substantiate the efficacy of their hand sanitizers beyond solely bacteria.

Factors affecting the effectiveness and safety of hand sanitizers

To derive solutions to tackle the effectiveness and safety of hand sanitizers, factor affecting these issues need to be investigated.

The contact time of a hand sanitizer is a particularly important determinant of its effectiveness. Contact time refers to the duration of exposure of microorganisms to the antimicrobial compound. For a particular concentration of antimicrobial compound, the percentage of surviving microorganisms is dependent on the contact time. However, contact time required varies across microorganisms. A study showed that a 15 second contact time for 85% w/w ethanol effectively killed Gram-positive and Gram-negative bacteria as indicated by a 5-log-reduction in bacterial count [76, 77]. Another study demonstrated that 70% ethanol, isopropanol and other ABHS inactivated the coronavirus in 30 seconds [78]. Conversely, 0.2% BKC required at least 10 minutes of contact time to inactivate the coronavirus [78]. Due to its excessively long contact time, BKC is not useful as a hand sanitizer formulation.

Hand sanitizers can be formulated in different forms, such as liquids, gels and foams. Studies have shown that the mode of delivery affects the drying time of hand sanitizers but not their effectiveness [79, 80]. While gels take longer to dry than liquids, they are equally effective against test organisms [79, 81]. The active ingredient and its concentrations play a larger role in determining effectiveness. The spectra of activity of antimicrobial compounds used in hand sanitizers have been discussed in Section 3. FDA recommends a concentration of 60%–95% w/w ethanol or 70%–85% w/w isopropanol in ABHS [50, 82-84]. QACs, such as BKC are effective against enveloped viruses at concentrations of 0.05%–0.1% [50]. However, this finding is specific to certain enveloped viruses that do not include the coronavirus.

Different hand sanitizer formulations containing the same antimicrobial compound have been reported to exhibit different effectiveness [8, 9, 27]. In the formulation of hand sanitizers, ingredients used should be compatible and do not interfere with the action of the antimicrobial compound. Coupled with appropriate contact times and proper usage, hand sanitizers can deliver protection for consumers.

Importantly, safety issues may occur when manufacturers do not provide appropriate information to alert consumers. This is more commonly seen in ABHS than NABHS. Globally, cautionary labels relating to flammability and inadvertent ingestion of alcohol are not mandatory. In the absence of such labels, consumers are unknowingly exposed to safety threats. For example, leaving ABHS near open flames may ignite a fire in the hand sanitizer. ABHS should be rubbed to complete dryness to prevent alcohol on hands from triggering a fire. Labels should warn consumers of the dangers and precautions to be taken.

Lastly, with the rise in use of hand sanitizers, manufacturers who advocate for environmental protection have initiated campaigns to recycle containers [85]. However, the use of recycled containers can pose contamination and quality issues if it is inadequately controlled. A report by Health Canada warned consumers against using food and beverage containers for hand sanitizers [86]. Coupled with inadequate cautionary labels, consumers especially young children may inadvertently ingest the hand sanitizer, resulting in acute toxicity. The ingestion of BKC could lead to vomiting, respiratory distress [87], kidney damage [88] and fatality [87, 88]. As for alcohol, ingestion could result in central nervous system depression and respiratory distress and fatality [89]. In fact, during this COVID-19 pandemic, US poison control centers have received a 79% increase in calls relating to accidental hand sanitizer ingestion compared to March 2019 [63]. In Spain, the number of hand sanitizer intoxications during COVID-19 is 10-times of that reported in 2019, and children accounted for two-thirds of these cases [89]. These figures highlight the need for tighter safety controls.

FDA policy for testing of alcohol and USP limits for methanol
In response to emerging cases of methanol poisoning, FDA has issued a guidance document on Policy for Testing of Alcohol and Isopropyl Alcohol for Methanol [90]. Due to the toxicity of methanol, FDA has formally requested for a test on methanol limits in the United States Pharmacopeia (USP) monograph for alcohol (ethanol) and isopropyl alcohol [90]. An impurity level of methanol below 630 ppm is mandated by FDA [90]. For both ethanol and isopropyl alcohol, FDA recommends the test method described in the USP monograph for alcohol. Given the risks to consumers (including death) associated with methanol substitution, FDA strongly recommends the test for methanol be conducted in a laboratory that has been previously inspected by FDA and found in compliance with current good manufacturing practice (cGMP). Any ethanol or isopropyl alcohol that contains more than 630 ppm methanol is not consistent with this latest Policy for Testing of Alcohol and Isopropyl Alcohol for Methanol and may be considered as evidence of substitution and/or contamination. Hand sanitizers containing methanol-contaminated ethanol or isopropyl alcohol are subject to adulteration charges under the Food, Drug and Cosmetic Act. Such contaminated alcoholic materials should be destroyed, and the manufacturer should contact FDA regarding the contaminated materials and their sources [90].

To prevent accidental ingestion of methanol containing alcohols by children, FDA recommends the inclusion of denaturants into hand sanitizers or the use of denatured alcohol, which confer an unpleasant taste to deter inadvertent ingestion [63, 90]. The alcohol is denatured either by the alcohol producer or at the point of production of the finished hand sanitizer product by the manufacturer. In addition to methanol poisoning due to accidental oral ingestion of hand sanitizers by children, harmful effects of methanol may also come from other routes of administration. When hand sanitizers adulterated with methanol are applied on the skin, absorption through the skin is rapid and this can cause toxicity in the same way as methanol ingestion via the oral route. Therefore, both denaturing of alcohol and laboratory test to limit the amount of methanol are necessary to mitigate the toxic effects of methanol via both the oral and transdermal routes [90].

Common myths about hand sanitizers
According to WHO and CDC, there are a number of myths perceived by consumers in relation to hand sanitizers. Debunking these myths is important to promote effective and safe use of hand sanitizers.

Myth 1: All hand sanitizers effective against bacteria can also inactivate viruses
As discussed in Section 3, there is a wide variety of hand sanitizers in the market containing different active ingredients, which confer different spectra of activity. For example, QAC has high activity against bacteria but limited against viruses. In this COVID-19 pandemic, FDA, CDC, WHO and Australia Therapeutic Goods Administration (TGA) have published consumer advisories on hand sanitizers and advocated the use of ABHS as they are known to be effective against viruses [63, 91, 92]. While some postulate the potential of BKC to provide effective protection against the coronavirus, TGA and FDA have stated that QAC-based hand sanitizers including BKC, which are NABHS, lack activity against the coronavirus [63]. Hence, in the COVID-19 pandemic, ABHS is the mainstay.

Myth 2: Higher alcohol content in hand sanitizers equates with greater effectiveness against microorganisms
Many consumers assume that a higher alcohol content in hand sanitizers offers greater protection against microorganisms. Notably, FDA recommends the use of an ABHS with a concentration of 60%–95% w/w ethanol or 70%–85% w/w isopropanol as they have the greatest antimicrobial activity [93]. Beyond the upper limit of alcohol concentration, the rate of kill decreases tremendously [93]. This may be attributed to the higher alcohol content which evaporates more rapidly, hence remaining on hands for a shorter time period. The contact time between the hand sanitizer and microorganisms on the hand is decreased, reducing the hand sanitizer activity. To obtain the same extent of kill, contact time needs to be increased through continuous reapplication of the hand sanitizer. This is inconvenient and is not practised in reality. Additionally, a 100% alcohol concentration or ‘absolute-alcohol’ is completely ineffective in inactivating or killing microorganisms, as water is crucial for alcohol activity [93]. Water is a catalyst in denaturing proteins which make up important components of the microbial cell and virus. It also assists alcohol to penetrate the cell wall, cause protein coagulation and kill the bacterial cell [93].

Myth 3: Hand sanitizers are more effective than handwashing with soap and water
The CDC recommends the public to use hand sanitizers only when soap and water are not accessible [5, 6]. Proper handwashing with soap and water is more effective. However, the portability of hand sanitizers is advantageous with regard to availability and convenience of use. Although hand sanitizers do not kill all microorganisms, they still confer some protection. In fact, studies have shown that hand sanitizer usage reduced transmission of diseases at home and in school [94-96]. Therefore, the use of hand sanitizers is undoubtedly better than leaving hands contaminated with microorganisms. There are recommendations and training courses on good hand hygiene practices, and how viral outbreaks may be managed through handwashing [97-100].

Although handwashing with soap and water is more effective, the CDC and WHO recommend ABHS as the preferred choice for healthcare personnel, when hands are not visibly soiled [8]. Performing hand hygiene using ABHS confers several advantages over soap and water in a healthcare setting. Firstly, ABHS contains alcohol which can kill common vegetative bacteria found on human skin [27]. ABHS has a more persistent activity; hence it slows down the proliferation of microorganisms on hands. Hand sanitizers containing alcohols are also more efficient for healthcare providers working in a bustling environment and having to perform hand hygiene routines repeatedly throughout the day. ABHS provide greater convenience and can be placed directly in wards, dispensing counters and consultation clinics [101-104]; thus, immediate hand hygiene can be performed without causing work disruption.

Myth 4: Hand sanitizers can ‘sterilize’ hands
Hand sanitizers do not kill all microorganisms. Microorganisms such as Clostridium difficile and Cryptosporidium produce spores that are not destroyed by hand sanitizers [6]. Neither handwashing with soap and water nor hand sanitizers can ‘sterilize’ hands. When exposed to body fluids and dirty facilities during an infectious outbreak, one should perform handwashing with soap and water to prevent the transmission of diseases [101-103]. When consumers perform activities such as eating food with bare hands, the CDC recommends handwashing with soap and water as hand sanitizers may cause health hazards when ingested. It has been reported that the norovirus, a group of viruses that are a common cause of food poisoning and gastroenteritis, which is transmitted via close conversations and sharing food, is not killed by the use of hand sanitizers. Upon ingestion, the norovirus can proliferate, leading to the norovirus infection [100]. Moreover, mucus from coughing and sneezing forms a protective barrier, blocking the action of hand sanitizers against viruses. These viruses may be ingested together with food and cause infections. For food store workers, the use of ABHS to disinfect hands is not advised as their hands are often contaminated with fatty or protein-rich food [101-103] which reduce effectiveness of the alcohol against pathogens. Therefore, before the preparation of meals, the use of soap and water for handwashing is recommended.

Myth 5: All hand sanitizers are approved by regulatory authorities (RAs) and are therefore safe and effective
According to the FDA, hand sanitizers are not subject to pre-market approval. Therefore, labels of hand sanitizers which claim FDA approval are fake and misleading. This is also the case for other RAs such as the UK Medicines and Healthcare products Regulatory Agency (MHRA), the European Medicines Agency (EMA) and the Singapore Health Sciences Authority (HSA). Hand sanitizers currently have relatively free entry into the consumer market as many RAs do not mandate pre-market registration. Nevertheless, RAs such as TGA allows hand sanitizers which make claims against specific microorganisms to be labelled ‘AUST R’ if they have been evaluated and approved by TGA [91]. Although there are policies and guidelines published by RAs relating to compounding of ABHS and limits of methanol, this should not be interpreted that the ABHS offered for sale, have been approved by the RAs [105-108].

Myth 6: Prolonged use of hand sanitizers can cause bacterial resistance
Several researchers have postulated that prolonged exposure of hand sanitizers to microbes can drive mutations and bacterial resistance [109-113]. However, FDA is of the view that the risk of development of bacterial resistance from the use of hand sanitizers is low due to the rapid speed of action and mechanism of action of ABHS [114]. For example, ABHS can exert bactericidal effect within 15 seconds [76, 77] by coagulating or precipitating the proteins in bacteria [27]. The rapidness and the way hand sanitizers act on bacteria do not potentiate resistance. In addition, the volatility of alcohol denies bacteria of an environment for prolonged exposure and the opportunity to adapt themselves to the ABHS. Thus, prolonged use of ABHS is unlikely to cause bacterial resistance.

A lack of regulatory framework
The forensic classification of hand sanitizers varies across national jurisdictions. For example, countries such as the US, Australia and Singapore, have classified hand sanitizers as over-the-counter (OTC) drugs, therapeutic goods and medicinal products, respectively. In general, hand sanitizers are perceived to be of lower risks in comparison to other prescribed health products. Therefore, hand sanitizers have not been subjected to the same extent of pre-market regulatory approval and licensing requirements as for prescription medicines and other classes of therapeutic products. Generally, there is still a lack of regulatory framework for hand sanitizers internationally. Labelling of expiry dates should be mandatory as it indicates the duration when active ingredients remain stable and effective. Manufacturers can determine this time period using the test methods described (Section 4). Since alcohols confer antimicrobial activity, the loss of alcohol content indicates a reduction in antimicrobial activity and protection. Due to the COVID-19 pandemic, consumers have stockpiled on hand sanitizers. The absence of expiry dates may create misconceptions that hand sanitizers are effective for an indefinite period of time and can be used beyond their shelf-life.

Safety issues have surfaced due to insufficient controls. With the exception of Health Canada, a product license or registration is not required by other RAs. Ingredients that make up hand sanitizers need not be manufactured in accordance with GMP, yet the hand sanitizers can still be placed on the market. As a result, consumers may be exposed to contaminated, adulterated and harmful products. This is evident in cases of methanol poisoning where numerous ABHS were reported to have caused blurred vision and seizures to consumers during post-market surveillance [109]. In retrospect, if more regulatory controls had been placed on manufacturers, such problems may be avoided. The COVID-19 pandemic has caught many off-guard, causing the demand for hand sanitizers to surge. Regulators may postpone the need for tighter regulations in lieu of concerns over shortage and access. However, post-COVID-19, regulators should look into tightening controls to ensure quality safety and efficacy of hand sanitizers, beyond just assuring supply and access. Regulations could come in the form of regular inspection of manufacturers to assure GMP compliance and ascertain validity and sufficiency of test method documents. These costs will be borne by the manufacturers and passed on to consumers. Hence, the rise in regulatory and compliance costs may create socio-political problems and have to be properly managed.

Proposed solutions

Tightening the regulatory framework
Table 3 introduces a stricter regulatory framework. A listing or certification is recommended for the product to be manufactured and placed in the market. Product licensing or registration is not always feasible as it can severely increase regulatory costs. Therefore, the proposed idea balances the current lack of regulatory oversight versus over-regulation and increasing compliance costs. Moreover, to safeguard consumers, sale in bulk volumes/packs should be prohibited, hand sanitizers should not be enclosed in bottles resembling food packaging and cautionary labels should be mandatory. Regulations should also include the need to perform the efficacy tests (Section 4) and to seek approval by RAs to ensure effectiveness of hand sanitizers. Additionally, it is important to prevent consumer misinformation by restricting advertisements to company websites, prohibiting unfounded claims and labelling of a blanket claim on killing 99.9% of microorganisms.

Table 3

The proposed framework may encounter difficulty for international harmonization. Similar to other health products, such as therapeutics, quasi-medicinal products and medical devices, differences in regulations exist across RAs. Furthermore, a tighter framework adds regulatory burden and redirects resources away from more important domains, such as other higher-risk medicinal products.

Training pharmacists on hand sanitizer vigilance
Hand sanitizers may be sold in pharmacies or other retail outlets. In comparison to supermarkets and other general retail outlets, pharmacies are managed under the personal supervision of licensed pharmacists. Hence, pharmacies have been perceived to be ethical retail outlets which offer for sale and supply health products, including hand sanitizers, that are reliable. Pharmacies should restrict themselves only to the sale of reliable and accurately labelled hand sanitizers to safeguard consumer health. Pharmacists can be trained to possess adequate knowledge on the regulations of antiseptics. This could be performed through the provision of regulatory and international guidelines. The knowledge could be used to identify inappropriately sold hand sanitizers and pharmacists should be given the autonomy to request for removal of the product from the store. In fact, pharmacists should better educate and address consumers’ queries on hand sanitizer effectiveness.

Public Education
Apart from regulation, conscious efforts should be placed on educating the public. Consumers hold misconceptions about hand sanitizers and safety issues have occurred due to the lack of knowledge in this field. Therefore, public education is necessary in collaboration with relevant stakeholders [99, 100]. Public education can focus on general hand hygiene, including the myths and benefits of hand sanitizers and the harms of using disinfectant-grade antimicrobial agents interchangeably with antiseptic-grade skin formulations. Additionally, collaborations with pharmacies can be explored. For example, the placement of posters next to sales counters of hand sanitizers can provide a second line of defense to combat consumers’ misinformation. Some content could include sharing on the WHO 6 Steps of ‘How to hand-rub’ technique to promote effective use and storage advice to reiterate safety precautions. Collaboration with stakeholders facilitates the education of a wider target group due to the extensivity of outreach. Collaborative education also reduces the burden on regulators.

Conclusion

The multifaceted challenges of safety, effectiveness will grow and hence, regulatory control will continue to evolve with the progression of COVID-19 pandemic. This paper has shown that hand sanitizers are assets to hand hygiene, especially during the COVID-19 pandemic, provided they are used properly. Therefore, educating the public on hand sanitizers, including misleading claims and proper use, is crucial. ABHS remain the mainstay as recommended by WHO and other international organizations and should be more tightly regulated due to safety concerns. Future developments can consider the feasibility of international harmonization of regulations and explore other standards for testing efficacy that may be more representative of all microorganisms. A tripartite relationship among consumers, regulators and manufacturers should be established for the ultimate benefit of everyone.

Competing interests: None.

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

Authors

Adjunct Associate Professor Sia Chong Hock, BSc Pharm, MSc
Tan Ying Ting, BSc Pharm (Hons)
Associate Professor Chan Lai Wah, BSc Pharm (Hons), PhD

Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543

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Author for correspondence: Adjunct Associate Professor Sia Chong Hock, BSc (Pharm), MSc, Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543

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The EU regulatory network and emerging trends – a review of quality, safety and clinical development programmes

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Author byline as per print journal:
Marta Zuccarelli1, PharmD; Benjamin Micallef1, PharmD; Mark Cilia1, PharmD; Anthony Serracino-Inglott1,2, PharmD; John-Joseph Borg1,3, PhD

Introduction/Study Objectives: The development of biosimilars is challenging due to the complexity of the active substances as well as the strict regulatory requirements to show similarity with a reference medicinal product. This review aims to describe the regulatory experience of approving biosimilars in the European Union (EU) within the EU framework, identify emerging trends in the EU regulatory pathway when approving biosimilars and discuss where the EU biosimilar framework is heading.
Methods: Marketing authorisation applications (MAAs) submitted up to 2019 were retrieved from the public domain. The European public assessment report database was searched for approved biosimilars and clinical development programmes of biosimilars belonging to the same class were reviewed. In order to observe if biosimilars released onto the market increased safety concerns, we compared disproportionate adverse event reports pre- and post-licensure.
Results: Up to December 2019, 90 MAAs were submitted and 53 biosimilars were approved for 14 different biologicals. Total number of clinical trials (both phase I and III) steadily goes up driven by an increase number of approvals in later years, while the average number of both phase I and III trials decreased over time with some with Pegfilgrastim biosimilars being approved without conducting any phase III clinical trials. No new safety concerns were identified from the analysis of disproportionate adverse event reports.
Discussion: Clinical development programmes of biosimilars and the requirements set for biosimilars approval are changing over time. Biosimilars approved seem to be as well tolerated as the reference products when approved based on stringent regulatory requirements.
Conclusion: Regulation of biosimilars is progressing as more knowledge is gained.
Keywords: Biosimilars, clinical development programmes, EMA, EPARs, regulatory, safety

Submitted: 3 December 2020; Revised: 11 February 2021;Accepted: 15 February 2021; Published online first: 1 March 2021

Introduction/Study Objectives

The regulatory framework in the EU
According to the European Union (EU) law, a similar biological medicinal product or ‘biosimilar’ is a biological medicinal product which is similar, but not identical, to a reference biological medicinal product [1]. Biosimilar products in the EU would have demonstrated similarity to the reference medicinal product in terms of physicochemical characteristics as well as safety and efficacy through a comprehensive comparability exercise [2].

It is important to note that different regions worldwide have varying definitions of biosimilar products or equivalent terms, see Table 1, and have different requirements surrounding biosimilar clinical interchangeability, switching and substitution [3].

Table 1

In order to understand the complexities of the EU regulatory framework surrounding the approval of biosimilars, it is important to clarify that the approval of a biosimilar in the EU is based on an ‘abridged’ marketing authorisation application (MAA), where similar biological products do not require full scientific data as for new biological applications [4]. In principle, biosimilars can be developed for any well characterized biological product [5] which is produced by biotechnological methods, however, biosimilars are unlikely to be produced for vaccines, allergens, blood or plasma-derived products and gene/cell therapy products.

In the EU, the regulatory framework on biosimilars is built on guidelines, with the European Medicines Agency (EMA) issuing the first guideline on similar biological medicinal products in 2005 [5]. This overarching guideline provided complementary directions to the legal basis set out by the Directive 2001/83/EC in 2004 [1]. Since 2005, an additional two overarching guidelines dealing with non-clinical and clinical issues and on quality were also published [6]. Furthermore, product-specific guidelines ­laying down scientific recommendations for the development of biosimilars were issued for similar biological medicinal products containing monoclonal antibodies, recombinant follicle stimulation hormone, recombinant interferon beta, recombinant erythropoietin, low-molecular-weight heparins (LMWHs), recombinant interferon-alfa, recombinant granulocyte colony stimulating-factor (G-CSF), somatropin and recombinant human insulin [7], see Figure 1.

Figure 1

As a consequence of the regulatory framework set up in the EU since 2005, there has been a steady increase in the number of biosimilar medicinal products during the last 20 years, with successful use in treating and managing many chronic, debilitating and life-threatening diseases, such as autoimmune diseases and various forms of cancer [8].

Biosimilarity is proven through the use of a stepwise approach, first in quality, then in the non-clinical setting [using comparability exercises in pharmacokinetics (PK) and pharmacodynamics (PD) both in vitro and in vivo and then clinically [9].

In this study we aimed to describe and discuss the regulatory experience of approving biosimilars in the EU (from 2005–2019), through qualitative and quantitative evaluations. In addition, we discuss how the EU regulatory network has fared and what are the noteworthy emerging trends in biosimilar development as identified through a review of quality, safety and clinical development programmes. The results of this review are of interest to both developers and regulators and may help in understanding the changing landscape of biosimilar regulation.

Methods

Review of clinical development programmes
The number of MAAs for biosimilar medicinal products submitted for regulatory review up to December 2019 was retrieved from the EMA website [10]. The applications submitted for biosimilars were grouped as MAAs currently under review and MAAs which reached the post-authorization phase. The latter group was further subdivided in line with the opinion given to each biosimilar (either positive or negative) and MAAs which were withdrawn. Biosimilar medicinal products which received a positive opinion and maintained a valid authorization were further analysed. To detect emerging trends, a comparison of clinical development programmes of biosimilar products with comparable clinical development was carried out.

Using the EMA database of European public assessment reports (EPARs), biological originators and the number of biosimilars for each originator were retrieved. The EPARs of biosimilar medicinal products with a valid marketing authorization (up to December 2019) were used as the main source of information [11-58].

Information on clinical development programmes of each biosimilar were compared with the approved guidelines [7] to detect any notable considerations and consequent justification. The extrapolation of indication was analysed for applicable biosimilar me­­dicinal products.

It should be noted that not all biosimilar medicinal products analysed were different products. Some companies conducted one clinical development programme for the biosimilar and then marketed the same product under different names. Biosimilar products having the exact same clinical development programme, but different trade names are indicated with a slash, e.g. Inflectra®/Remsima®, in the results section.

Safety
Since the safety of biosimilar medicinal products could be of a ‘potential’ concern, static reporting odds ratio (ROR) reports [at the System Organ Class (SOC) level] concerning each biosimilar medicinal product were retrieved from the EudraVigilance data analysis system (EVDAS). SOCs ‘product issues’ and ‘social circumstances’ were excluded a priori because they were not considered relevant for the purpose of this review. To detect any new disproportionate reporting that may have arisen in the post-marketing phase, adverse event data were captured separately for the period before the authorization date of the first biosimilar reaching the market and period after authorization (up to a cut-off date 25 June 2020). Adverse event data from the two periods was then compared.

The expectedness of new disproportionate reporting identified from period after the first biosimilar authorization was evaluated in line with the summary of medicinal product characteristics (SmPCs) of the reference product. For each new disproportionate SOC reaction, the following SmPC sections were evaluated; 4.4 – Special warnings and precautions for use, 4.6 – Fertility, pregnancy and lactation, and 4.8 – Undesirable effects.

For SOCs which were deemed unexpected, i.e. not listed in the above-mentioned sections of the SmPCs, another static ROR evaluation was performed to identify which preferred terms (PTs) were disproportionately reported within each SOC. PTs which were disproportionately reported were evaluated for expectedness in line with the SmPC of the reference product (as described previously). Disproportionate PTs which were unexpected were then compared to EMA’s designated medical event (DME) list [59]. The PT, ‘fetus malformation’ was also considered (in addition to DMEs) as a serious adverse event of interest for the analysis we carried out. Disproportionate PTs which were unexpected, and which were also DMEs were further assessed by performing a causality assessment using the French imputability method [60] to confirm or confute potential signals of disproportionate reporting.

Results

The experience gained reviewing biosimilar marketing authorisation applications
Since 2004, EMA has gained significant experience in the scientific evaluation of biosimilar applications and revision of the regulatory scientific guidelines for the European markets was observed, see Figure 1.

Up to December 2019, 90 MAAs had been submitted to EMA for review. Figure 2 shows the authorization status of each MAA as well as applications under review. Fifty-three biosimilar products held valid marketing authorization in Europe as of December 2019. These 53 biosimilars resulted from 35 unique development programmes and were based on 14 different reference biologicals (adalimumab, bevacizumab, enoxaparin sodium, epoetin, etanercept, filgrastim, follitropin alfa, infliximab, insulin, pegfilgrastim, rituximab, somatropin, teriparatide, trastuzumab).

Figure 2

Biosimilar guidelines: evolution in EU – totality of evidence founded on quality data
In Europe, guidelines were issued for biosimilars to help applicants prepare MAAs. The first guidelines for similar biological medicinal products was published in October 2005. Since 2005, an additional two overarching guidelines (one on non-clinical/clinical issues and one on quality), eight product-specific guidelines and one reflection paper were published, see Figure 1. The reflection paper will be addressed as a product-specific guideline throughout this review. The first product-specific guideline was published in 2006 to discuss non-clinical and clinical studies recommended during the development of insulin’s biosimilars. Following the first guidelines on insulin, product-specific guidelines on somatropin, recombinant G-CSF, epoetin, interferon alfa (IFN-α), LMWH, monoclonal antibodies (mAbs), interferon beta (IFN-β) and recombinant follicle-stimulating hormone (follitropin) were published between 2006 and 2012. Six out of nine product-specific guidelines (insulin, somatropin, G-CSF, epoetin, LMWH, follitropin) were revised between 2015 and 2019, see Figure 1. It was observed that for certain biosimilar classes, revision of guidelines was related to more experience and knowledge gained by regulators over time. For example, the first guidelines on G-CSF emphasized the performance of ‘at least one repeat dose toxicity study in a relevant species’ and the performance of ‘confirmatory clinical trials to compare efficacy and safety of the biosimilar and reference’. In the revised draft of the guidelines for G-CSF, in vivo studies are no longer recommended, and confirmatory efficacy clinical trials are not deemed necessary as ‘pivotal evidence for similar efficacy will be derived from the similarity demonstrated in physicochemical, fu­­­­-­nc­­­­­­­­­­­­­tional, pharmacokinetic and ph­­ar­­-macodynamic comparisons’ [61-62]. Another example of guideline revision is the LMWH guideline. In the first issue of the LMWH guidelines, in vivo PD studies were always deemed necessary, but in the revised guidelines, in vivo PD studies are not required as part of the comparable studies unless physicochemical and biological comparability has not been already demonstrated. According to the revised LMWH guidelines, toxicological studies are only required in specific cases, while in the first issue of the same guideline, at least one repeated dose toxicity study in one relevant species was requested. In addition, according to the revised LMWH guidelines, clinical efficacy studies are not required any longer as efficacy data will be ‘derived from the similarity demonstrated in physicochemical, functional and pharmacodynamic comparisons’ [63-64].

The biosimilar guidelines are not meant to be prescriptive step-by-step guides on how to design a clinical study programme to obtain approvals for biosimilars but rather these guidelines contain scientific recommendations to facilitate development of biosimilars through comparability programmes with a reference medicinal product. The biosimilar comparability exercise is pivotal to understanding the degree of similarity between test and reference products and is crucial in the benefit-risk assessment of biosimilar products. Initially, biosimilar guidelines could have been considered as conservative when ­laying down clinical requirements required by a manufacturer to prove biosimilarity. Where, for example, in the case of epoetins: two clinical studies are required in titration and maintenance phase with additional emphasis on animal data to be provided before licensure. Also, the number of patients, number of studies and duration of studies are three important parameters that should be taken into consideration whilst designing a clinical development programme as these para­meters determine the success and efficiency of a clinical developmental programme. Notwithstanding these considerations, it is interesting to note that revised product-specific guidelines have re-considered the regulatory requirements on clinical data and in general, have shifted to rely more on extrapolation with usage of PD markers for clinical endpoints as a surrogate for efficacy and additional supportive evidence from relevant non-clinical in vivo studies. The strategy behind this shift is to have an increased reliance on the detailed and comprehensive quality data required in the marketing authorization dossier. This shift in regulatory requirements is based on the regulatory experience obtained to date approving biosimilars by EU regulators. In order to better understand the experience we have to date in approving biosimilars, we reviewed the clinical development programmes of 11 biosimilar active substances (adalimumab, bevacizumab, epoetin, etanercept, filgrastim, follitropin alfa, infliximab, insulin glargine, pegfilgrastim, rituximab, trastuzumab) to identify any emerging common trends between classes as described in their EPARs. A comparison was also made between biosimilars clinical development programmes of the same class.

Clinical development programmes of biosimilars
Clinical development programmes of 48 out of the 53 currently authorized biosimilar medicinal products were compared. Enoxaparin sodium, insulin lispro and somatropin were not included because only one biosimilar medicinal product was developed or maintained a valid authorization at the time of review, therefore a comparison could not be performed. Teriparatide was not included in the comparison exercise since the two biosimilars authorized were based on the same development programme and were then sold under different brand names.

When considering the 48 biosimilar medicinal products compared, it was observed that, in general, total number of clinical trials (both phase I and phase III) across all biosimilars increased over time, see Figure 3a. This is not unexpected since the total number of biosimilar approvals increased over time, with the number of approvals peaking in 2018 when 16 biosimilars were approved based on 14 clinical development programmes, see Table 2. The number of studies leading to approval changed over time. In 2007, the average ­number of phase I clinical trials was 3.5 and the average number of phase III clinical trials was 3. In 2019, the average number of phase I clinical trials was 1.67 and the average number of phase III clinical trials was 1, see Figure 3b, with certain biosimilars of pegfilgrastim, such as Pelmeg®/Pegfilgrastim Mundipharma® and Udenyca®, not having carried out any phase III clinical trials.

Figure 3a

Figure 3b

Enrolled subjects
The total number of subjects enrolled in clinical trials (phase I and phase III combined) across all biosimilars compared was observed to have generally increased through time although a high variability in the number of enrolled subjects per development programme was noted. We also evaluated the number of subjects enrolled in phase I and phase III clinical trials (not combined), see Figure 4a. Figure 4a shows an increased total number of subjects enrolled in phase I and phase III clinical trials through time although the increased number of biosimilar medicinal products authorized in more recent years should be considered. For this reason, we evaluated the average ­number of subjects enrolled in clinical trials as shown in Figure 4b. From Figure 4b, it can be appreciated that the average number of subjects enrolled in phase I clinical trials was mostly stable. In phase III clinical trials, it can be observed that the average number of subjects enrolled steadily increased between 2010 and 2017 and decreased from 2017 to 2019.

Healthy volunteers were enrolled for phase I clinical trials for all biosimilars clinical development programmes, except for insulin glargine biosimilars (where both healthy volunteers and patients with type 1 diabetes mellitus were enrolled), infliximab biosimilars (where only patients with rheumatoid arthritis (RA) were enrolled and in the case of Inflectra®/Remsima® in addition to RA patients, patients with ankylosing spondylitis were also enrolled) and rituximab biosimilars (where only patients with RA and diffuse large B-cell lymphomas were enrolled).

Figure 4a

Figure 4b

Table 2

Table 2

Table 2

Table 2

Table 2

Primary endpoints to support pivotal data
Demonstration of pharmacokinetic (PK) equivalence between the test product and reference product is deemed necessary for the approval of a biosimilar. PK was observed to be mainly studied in phase I clinical trials on healthy volunteers since a cohort of healthy volunteers is considered to be a more heterogeneous population. Supportive PK data are derived from phase III clinical trials. During the clinical development programmes of insulin glargine biosimilars, infliximab biosimilars and rituximab biosimilars, PK studies were conducted on patients where, AUCinf, AUClast and Cmax with an acceptance level of between 0.8 and 1.25 with 90% confidence interval (CI) were the primary PK endpoints used to evaluate bioequivalence between test product and reference product, see Table 2.

There have been examples where therapeutic equivalence was demonstrated despite PK study results not falling within the pre-specified acceptance level. During the development of adalimumab biosimilars Hyrimoz®/Hefiya®/Halimatoz®, a second phase I PK clinical trial (study GP17-104) was deemed necessary after two out of three primary PK endpoints (AUCinf and AUC0last) were above pre-specified acceptance level in the first phase I PK clinical trial (study GP17-101) carried out. In the second PK study, the study design was adapted, and the primary endpoints were reduced to two (with AUCinf, Cmax and AUClast not calculated). The results obtained from the second PK study were within the pre-specified acceptance level of 0.8–1.25 with 90% CI. In this case, PK was further investigated in a phase III clinical trial (study GP17-301) before biosimilarity between the test product and the reference product could be definitively confirmed [13-15].

It is observed that, in some cases, the acceptance level of PK parameters was changed in post-hoc analysis and such an approach was considered acceptable when considering the justification provided. For epoetin zeta biosimilars, the primary endpoints were evaluated with 90% CI and the acceptance level for Cmax was widened by the applicant to 0.7%–1.43% in the post-hoc analysis. In the EPAR, it is explained that the applicant ‘referred to the Scientific Advice given by CHMP in April 2004 that stated that the concept of “comparability” cannot use bioequivalence but that similar PK profiles of SB309 and the reference product would strengthen the choice of reference in the clinical trials. The advice concluded that for this purpose descriptive statistics will suffice’ [23, 24].

PD studies to evaluate clinical comparability between test product and reference product are recommended by the guidelines, however, for active substances adalimumab, bevacizumab, epoetin, etanercept, infliximab and trastuzumab, no established PD surrogate markers were available at the time when the studies were conducted. Due to lack of accepted PD markers there were cases in which no PD studies were carried out. Clinical comparative PD studies were not conducted for any of the adalimumab biosimilars as no specific and accepted PD markers to predict efficacy exists. For all adalimumab biosimilars except for Hulio®, the EPAR states that only in vitro PD studies were carried out during the development of the products. For Hulio®, the mechanism of action (MOA) is described, but no PD studies are mentioned [16].

PD surrogate markers were explored by applicants for certain products. For example, during the clinical development programme of epoetin alfa biosimilars (epoetin alfa hexal®/Abseamed®/Binocrit®), PD studies were conducted as part of PK studies with PD markers set by the applicant [20-22]. However, during the clinical development programmes of epoetin zeta biosimilars, no studies were conducted to define the PD profile.

During the clinical development programme of Erelzi®, PD was indirectly evaluated in a phase III clinical trial. The PD marker serum high-sensitivity C-reactive protein (hs-CRP) was measured, showing a similarity between Enbrel® and Erelzi®. However, in the EPAR it is stated that data on serum hs-CRP should be considered as supportive since this is not a specific biomarker [26]. It is interesting to notice that there are no specific biomarkers available for tumour necrosis factor-alpha (TNF-α) inhibitor and that clinical comparability can be demonstrated also by clinical evidence other than PD surrogate [65, 66].

Another example for which no PD markers are accepted surrogates is represented by infliximab biosimilars although the applicant explored CRP for Inflectra®/Remsima® and Zessly®. In the Zessly®’s EPAR it is stated that ‘CRP is a marker of disease activity but does not have a clear relationship to therapeutic effect’ [39]. By comparing CRP differences between the reference products and the test product, similarity was evaluated. For well-known active substances, such as filgrastim, more stringent PD criteria were required by regulators, as observed for both Filgrastim Hexal® and Zarzio®, where the PD bioequivalence criteria (80% to 125%) at 95% CI was not accepted as an acceptance criterion for PD studies, as stricter acceptance criteria were expected (+/- 10%). The rationale for a stricter acceptance criterion is explained in the EPAR as follows, ‘The predefined equivalence boundaries were derived by the applicant from published data on the effect observed for Neupogen compared to placebo. It was assumed that the smallest clinically relevant difference in PD response between the test and reference product was 15% of the effect observed for Neupogen® compared to placebo in the published study. Decreasing this margin to 10%, which approximately corresponds to half the increase in the area under the effect curve (AUEC) between the 2.5 µg/kg and 5 µg/kg doses, would result in more acceptable equivalence intervals; indeed, the 95% CI for ANC AUEC and Emax in study EP06-103 would still fall within these tighter equivalence boundaries’ [29, 30].

Data also show that for highly characterized active substances, such as in the case of pegfilgrastim biosimilars Udenyca®, Pelmeg® and Pegfilgrastim Mundipharma®, no phase III clinical trials were required, see Table 2.

Extrapolation of indication
According to the CHMP, safety and efficacy data can be extrapolated from studies of a biosimilar for a different indication than the one studied during a clinical trial. Extrapolation of safety and efficacy data is based on physicochemical, functional, non-clinical and clinical data available showing similarity between the biosimilar and the reference product. A dedicated section on extra­polation of data is present in eight out of nine product-specific guidelines (insulin, somatropin, G-CSF, epoetin, IFN-α, LMWH, mAbs, IFN- β and recombinant follicle-stimulating hormone).

During the review of the clinical development programmes, it has been observed that extrapolation of data has been a ­common approach when approving biosimilars that usually have the same therapeutic indications as the originator in spite of the fact that the biosimilar may not have been studied in any indication or has been studied in only one indication.

For example, biosimilars of infliximab have the same indications as the infliximab originator Remicade® even though biosimilars of infliximab have only been tested in patients with RA (and in the case of Inflectra®/Remsima® also in ankylosis spondylitis), while originator Remicade® was tested in patients with rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosis spondylitis and psoriatic arthritis. To allow for extrapolation of data from the clinical development programme of Remicade®, the biosimilarity of Inflectra®/Remsima® was demonstrated through a comparability exercise as is detailed in the product-specific guidelines. Based on the robust comparisons of the physicochemical and in vitro and ex vivo biological analyses, and together with clinical data demonstrating pharmacokinetic and therapeutic equivalence in rheumatology conditions, Inflectra®/Remsima® was considered biosimilar to the reference product Remicade and extrapolation to all other indications of Remicade was considered appropriate [36, 37]. The choice of using patients with RA during the development of Inflectra®/Remsima® to prove clinical efficacy is due to the more sensitive endpoints used in RA compared to endpoints used in Crohn’s disease and ulcerative colitis.

Extrapolation of indication does not always require comparability of efficacy data. In the case of clinical development programmes of Udenyca® and Pelmeg®/Pegfilgrastim Mundipharma® no phase III clinical trials on affected patient populations were carried out. Only clinical trials on healthy volunteers were submitted and therefore no comparability efficacy data were generated. Extrapolation of the indication was performed based on PK/PD similarity data, immunogenicity and safety. The absolute neutrophil count (ANC), a well-established PD marker, was used to established PD comparability. This is in line with the EMA biosimilar guidelines on recombinant granulocyte-colony stimulating factor (EMEA/CHMP/BMWP/31329/2005), according to which extrapolation of indication can be done if PD similarity with the reference product is demonstrated on healthy volunteers using ANC as a marker [61, 62].

In certain cases, the extrapolation of indication is restricted to certain specific indications. In the application of Silapo®/Retacrit®, the indication ‘reduction of allogeneic blood transfusions in adult non-iron deficient patients prior to major elective orthopaedic surgery’ was not granted because of lack of safety and efficacy data for the subcutaneous (SC) route of administration. The EPARs of Epoetin Alfa Hexal®/Abseamed®/Binocrit® state that ‘the claimed indications initially included also reduction of allogeneic blood transfusions in adult non-iron deficient patients prior to major elective orthopaedic surgery. However, during the CHMP scientific assessment it became evident that ‘efficacy and safety of Epoetin zeta have not been demonstrated for the SC route of administration in immunocompetent patients’ as well as ‘The benefit-risk ratio is not considered positive for the major orthopaedic surgery indication because immunogenicity of SC administered SB309 has not been assessed in immunocompetent individuals’ [20-22].

Extrapolation of safety and efficacy data is addressed by regulators in a specific section within the EPAR. For example, in the EPAR of Biograstim® (approved in 2008; biosimilar of Neupogen® (filgrastim)), information on extrapolation of safety and efficacy data is reported in the EPAR section ‘Overall conclusions, risk/benefit assessment and recommendation’ within the ‘Risk-benefit assessment’ subsection. The extrapolation of data was accepted with uncertainties and the outstanding issue was then tackled post-authorization in the products’ life cycle as an issue within the risk management plan. In the EPAR of Accofil®, a biosimilar containing filgrastim approved in 2014, extrapolation is discussed in the benefit-risk balance section, in the ‘Uncertainty in the knowledge about the beneficial effects’ subsection. In the EPARs of Biograstim® and Accofil®, uncertainties on biosimilarity are addressed differently. In the EPAR of Biograstim®, the mobilisation of peripheral blood progenitor cells is the only area of uncertainty and was due to the lack of complete understanding of the MOA. The case of Biograstim® indicates that there are uncertainties on extrapolation which are tackled in the risk management plan (RMP). In the EPAR of Accofil!®, the totality of quality, non-clinical and clinical data are considered when proving biosimilarity [67].

Safety concerns
In Malta, the Medicines Authority receives feedback from clinicians during annual stakeholder meetings. According to Maltese clinicians, concerns on the safety of biosimilars is one of the barriers to the uptake of biosimilars. For this reason, we investigated this perceived notion by checking for emerging safety concerns by comparing disproportionate adverse event reports pre- and post-biosimilar licensure. Sixteen biosimilar active substances authorized between 2007 and 2019 were evaluated and results are shown in Table 3.

Table 3

Medical Dictionary for Regulatory Activities (MedDRA) SOC reactions for the 16 biosimilars were retrieved. A total of 144 disproportionality reports (DRs) were observed, 18 of which were only present in the pre-approval phase (only with the originator), 42 of which were only present in the post-approval phase and 84 of which were present in both pre-approval and post-approval phases.

New reports of disproportionality (DR only present in the post-approval phase) were further analysed and out of 42 DRs, 33 were expected/listed while nine were not expected/not listed according to the originator product’s SmPCs. Since 33 DRs were expected/listed, the increase in the number of reports to the point of disproportionality could be explained by constant pharmacovigilance monitoring of biosimilars.

To verify if the safety specification of the biological is changing post-biosimilar licensure, the nine non-expected/non-listed DRs were further analysed. For each SOC DR, the corresponding PTs within the SOC MedDRA hierarchy were retrieved from EVDAS and matched with the EMA list of designated medical events (DMEs). Two potential ‘signals’ that were serious enough to warrant further investigation were identified. These were deafness for insulin lispro and foetal malformation for etanercept. Causality assessment of deafness for Insulin Lispro showed that out of 50 Individual Case Safety Reports (ICSRs), 48 were classified as uncertain, one was classified as unlikely, and one was classified as probable as per the French method. Causality assessment of foetal malformation for etanercept showed that all 226 ICSRs were uncertain (it is pointed out that during the case review, 225 out of 226 ICSRs were found to duplicates of the same case). From this analysis of post-marketing adverse event data, we did not observe any emerging safety concerns related to biosimilars. Since 2005, no new safety issue has arisen when biosimilars have been authorized in line with the EU framework.

Discussion

Since setting up a regulatory framework on biosimilars in 2005, more experience has been gained by the EU regulatory network in approving biosimilar medicinal products, as evidenced by the increased number of marketing authorizations granted over time. Guidelines on the development of specific biosimilars have been described as ‘living documents’ [68] since they are constantly revised and updated as needed.

During the review of EPARs it was observed that, in general, the product-specific guidelines were followed by applicants. There were some cases where some deviations from guidelines occurred, however, approval was still granted since the overall application still showed biosimilarity.

Applicants often sought to engage with the regulators during the product development to obtain scientific advice concerning different quality, non-clinical and clinical aspects of the biosimilar’s development. This is reflected in the number of scientific advice requests which were logged on adapting clinical and chemistry development programmes for biosimilars in one region to meet the EU requirements, see Figure 5. In addition to this, in 2017 the EMA started a pilot project on tailored scientific advice to support companies in carrying out appropriate studies on biosimilars [69].

Figure 5

The review of clinical development programmes of ­biosimilars currently marketed within the EU showed that the average ­number of phase I clinical trials was generally higher than the number of phase III clinical trials, except for biosimilars approved in 2016 in which the average number of phase I and phase III clinical trials were the same. It was also observed that, in general, the average number of both phase I and phase III clinical trials decreased in the reviewed period (2007–2019). It was also observed that certain clinical development programmes consisted of only phase I clinical trials without phase III studies. Phase III clinical trials are usually carried out with the intent to support clinical equivalence between the biosimilar and originator following full quality data and phase I clinical trials. In the literature, some authors have argued that an informative and robust CMC package together with meaningful and well-planned phase I clinical trials may reduce the uncertainty on biosimilarity to such an extent that, in certain cases, additional large and expensive phase III clinical trials to confirm biosimilarity may not be needed [70, 71].

Generally, the total number of patients enrolled in phase I clinical trials is lower than the number of patients enrolled in phase III clinical trials, however, there have been cases where the number of patients enrolled in phase I trials was greater than the number of patients enrolled in phase III trials, see Table 2. As already said, some biosimilars were also approved when no phase III clinical trials were conducted, as in the cases of certain Pegfilgrastim biosimilars. However, it was also noted that approval in such cases was dependent on the adequate scientific justification of the absence of phase III studies and, in addition, the scientific advice being sought during the clinical development programme phase.

For phase I clinical trials, mainly healthy volunteers were enrolled. Exceptions to this common trend was observed in the clinical development plan (CDPs) of biosimilars of rituximab, insulin glargine and infliximab. In the clinical development programmes of bevacizumab, etanercept and trastuzumab, it was observed that only healthy male volunteers were enrolled. Under-representation of women in clinical trials is a well-known issue present when studying most medicinal products and is mainly related to the fact that women have childbearing potential and their exclusion from clinical trials is in an attempt to protect fetuses from unknown side effects [72, 73].

Extrapolation of indication was a common approach. Concerns on extrapolation of indication are present since biosimilars can be authorized with the same indications for which the biological originator is approved, without conducting clinical trials with the biosimilar on a specific disease state. Extrapolation for the other indications is permitted if it is properly justified. Regulatory agencies operate strict control when assessing supporting data provided by the applicant for extrapolation of indication [9]. However, extrapolation of an indication remains a challenge from a regulatory perspective, since demonstrating safety and efficacy of a biosimilar is challenging, due to their biological differences. Moreover, each product-specific guideline provides recommendations on studies to be carried out to potentially allow the extrapolation of indication. In certain cases, extrapolation was restricted to some indications as biosimilarity was not shown in all route of administrations. Although extrapolation was based on scientific ground, concerns related to safety of biosimilars are still present in clinical practice.

Results from the analysis of MedDRA SOC reactions showed that 58.3% of SOC reactions occurred in both the pre-approval phase (only with the originator) and in the post-approval phase (following approval of the first biosimilar medicinal product), suggesting a high degree of similarity in the safety profile of biological originators and their biosimilars. Also, from the analysis of PTs, it was observed that 78.6% of the reaction were expected and listed in biosimilar’s SmPCs, therefore are already known and labelled. Among the two non-expected adverse events, it was observed that the PT reactions which matched with the DME list, and hence deserve further analysis, (deafness for insulin lispro and foetal malformation for etanercept) were unlikely to be related to the use of the relevant biosimilar. Deafness has several aetiologies, including diabetes and patients’ ages [74]. In addition, data retrieved from EVDAS did not indicate any causality between the identified PTs and the use of etanercept and insulin glargine biosimilars.

Conclusions

Clinical development programmes of biosimilars and the approval requirements set up by regulatory agencies are changing over time. The EU regulatory framework focuses on CMC and biosimilarity. Therapeutic equivalence is arrived at through PK/PD endpoints, extrapolation, PD markers and PK reliance. This integrated way of proving biosimilarity, reduces the ­number of clinical trials needed to show biosimilarity and, over time, may lead to shorter clinical development programmes and faster access to medicinal products for patients. Scientific advice is a useful regulatory tool that allow applicants to discuss their development strategies with the regulator early during the development phase, which facilitates the development of safe and efficacious biosimilar medicinal products. Following the regulatory experience of approving biosimilar in the EU, guidelines are being updated to reflect new knowledge on biosimilars gained. Analysis of the spontaneous reports indicates that the above-mentioned framework results in robust quality, safety and efficacy of biosimilar medicinal products, as no increase in safety concerns is observed. These results show that the EU framework of biosimilar is moving in the right direction.

In conclusion, regulation of biosimilars is progressing as more knowledge is being gained and this is reflected in the application of the product-specific guidelines.

For patients

A biosimilar is a medicine which is similar, but not identical, to a reference biological medicine which is already being utilized in clinical practice. Similarity between a biosimilar and a reference biological medicine is demonstrated via physicochemical, clinical safety and clinical efficacy characteristics. In the EU, the regulatory framework for biosimilars is built on guidelines, with EMA issuing the first guideline on similar biological medicinal products in 2005. Since 2005, a total of 12 guidelines have been issued, nine of which were updated in line with new knowledge gained by regulators. Using these guidelines as a direction to be followed, 90 applications for various biosimilars have been submitted by applicants to EMA and 53 biosimilars are marketed in 2019 (biosimilars of adalimumab, bevacizumab, enoxaparin sodium, epoetin, etanercept, filgrastim, follitropin alfa, infliximab, insulin glargine, insulin lispro, pegfilgrastim, rituximab, somatropin, teriparatide, trastuzumab). The safety review carried out does not show emergence of any new adverse events following biosimilars reaching the market. The European framework supports the development and authorization of good quality, safe and efficacious biosimilar medicinal products.

Funding sources

None.

Competing interests: The authors declare no direct or indirect potential conflicts of interest.

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

Authors

Marta Zuccarelli1, PharmD
Benjamin Micallef1, PharmD
Mark Cilia1, PharmD
Professor Anthony Serracino-Inglott1,2, PharmD
Professor John-Joseph Borg1,3, PhD

1Malta Medicines Authority, Sir Temi Żammit Buildings, Malta Life Sciences Park, San Ġwann SĠN 3000, Malta
2Department of Pharmacy, Faculty of Medicine and Surgery, University of Malta, L-Università ta’ Malta Msida, MSD 2080, Malta
3School of Pharmacy, Department of Biology, University of Tor Vergata, Rome, Italy

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76. World Health Organization. Expert Committee on Biological Standardization – Sixtieth Report Annex 2 – Guidelines on evaluation of similar biotherapeutic products (SBPs). Geneva, Switzerland 2009 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.who.int/biologicals/publications/trs/areas/biological_therapeutics/TRS_977_Annex_2.pdf?ua=
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Author for correspondence: Professor John-Joseph Borg, Post-Licensing Directorate, Medicines Authority, Sir Temi .ammit Buildings, Malta Life Sciences Park, San .wann, S.N 3000, Malta

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Continuous manufacturing versus batch manufacturing: benefits, opportunities and challenges for manufacturers and regulators

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Author byline as per print journal:
Adjunct Associate Professor Sia Chong Hock, BSc (Pharm), MSc; Teh Kee Siang, BSc (Pharm)(Hon); Associate Professor Chan Lai Wah, BSc (Pharm)(Hon), PhD

Continuous manufacturing (CM) is the integration of a series of unit operations, processing materials continually to produce the final pharmaceutical product. In recent years, CM of pharmaceuticals has transformed from buzzword to reality, with at least eight currently approved drugs produced by CM. Propelled by various driving forces, manufacturers and regulators have recognized the benefits of CM and are awaiting the completion of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q13, a harmonized guideline on CM that would be implemented by ICH members.
Although significant progress is evident, the uptake of CM is still sluggish in the pharmaceutical industry due to many existing challenges that have hindered manufacturers from adopting this technology. The top two barriers that manufacturers currently face are regulatory uncertainties and high initial cost. These issues are crucial in unleashing the untapped potential of CM, which has significant implications on patients’ access to life-saving medicines, while mutually benefitting manufacturers and regulators.
Despite numerous studies, there have been few existing publications that review current regulatory guidelines, highlight the latest challenges extensively and propose recommendations that are applicable for all pharmaceuticals and biopharmaceuticals. Therefore, this critical review aims to present the recent progress and existing challenges to provide greater clarity for manufacturers on CM. This review also proposes vital recommendations and future perspectives. These include regulatory harmonization, managing financial risks, hybrid processes, capacity building, a culture of quality and Pharma 4.0. While regulators and the industry work towards creating a harmonized guideline on CM, manufacturers should focus on overcoming existing cost, technical and cultural challenges to facilitate the implementation of CM.

Submitted: 30 November 2020; Revised: 20 December 2020; Accepted: 21 December 2020; Published online first: 6 January 2021

Introduction

Continuous manufacturing (CM) is the integration of a series of unit operations, processing materials continually to produce the final pharmaceutical product. This CM technology started in the eighteenth century during the first Industrial Revolution and has since been adopted by many industries [1]. However, it is only in recent years that CM of pharmaceuticals has transformed from buzzword to reality.

To date, there has been no standardized definition of CM, and the terms ‘continuous manufacturing’, ‘continuous production’ and ‘continuous processing’ are often intermingled [2]. Nonetheless, these terms are not interchangeable as they have different nuances. As the name suggests, ‘continuous production’ refers to a production schedule operating continually for 24 hours, seven days a week [2]. On the other hand, ‘continuous processing’ refers to a single unit operation where raw materials are continuously being loaded, processed, and unloaded without interruption [2].

There are many interpretations of CM and its related terminologies. However, end-to-end CM according to the US Food and Drug Administration (FDA), refers to an approach where the drug substance and drug product process steps are fully integrated into a single continuous system [3]. On the other hand, the hybrid approach is a combination of batch and continuous processing steps [3]. The pharmaceutical industry is increasingly adopting hybrid systems as it combines the advantages of batch and continuous processes [4–6].

Although significant progress is evident, the uptake of CM in the pharmaceutical industry remains sluggish due to various challenges [5–8]. Moreover, a lack of harmonized regulatory guidelines on CM has resulted in uncertain regulatory expectations by different regulatory authorities (RAs) [8]. To overcome the regulatory challenges and to reconcile CM-related concepts, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is developing a new quality guideline, ICH Q13: Continuous Manufacturing of Drug Substances and Drug Products [9].

At present, multiple studies have elaborated on significant technical and regulatory challenges for the CM of specific dosage forms, while others have conducted economic analyses on CM [10–14]. For example, Lee et al. [10] reviewed the benefits of CM, emphasized prime quality considerations and proposed solutions to address them. Additionally, a recent review by Vanhoorne and Vervaet [11] presented an overview of the technical aspects of CM and discussed regulatory guidelines on CM, specifically for oral solid dosages (OSDs). Despite many studies, to date, there have been few publications that review existing regulatory guidelines, highlight the latest challenges or make recommendations that are applicable for all pharmaceutical and biopharmaceutical products.

As portrayed in Figure 1, the implementation of CM is attributed to many factors. Therefore, this review aims to identify the benefits and opportunities of CM, assess the current extent of implementation, review existing regulatory guidelines and comprehensively highlight the existing challenges. The review also includes recommendations to facilitate the implementation of CM. The general concepts discussed in this review apply to all pharmaceutical dosage forms and biopharmaceutical products.

Figure 1

Overview of continuous manufacturing

CM is a combined process consisting of a sequence of more than one unit operation, developed to process materials continually to produce the final product [3]. As shown in Figure 2, CM is the integration of individual continuous unit operations with process analytical technology (PAT) which monitors and controls the critical process parameters (CPPs), critical material attributes (CMAs) and critical quality attributes (CQAs) [10]. Furthermore, CM streamlines manufacturing processes by eliminating work-up unit operations [10]. As such, CM equipment is typically smaller and is located within a single facility [10]. Batch manufacturing (BM), on the other hand, involves discrete unit processes with off-line quality testing and storage before each step [10]. Moreover, BM involves shipping of intermediates from one facility to another.

Figure 2

QbD and PAT
CM can improve pharmaceutical manufacturing with an enhanced development approach of Quality by Design (QbD) and the use of PAT [3, 10, 11]. As depicted in Figure 3, a comprehensive QbD approach allows for continuous improvement through product and process understanding to ensure better product quality [11, 15–17].

PAT is necessary for highly automated processes and continuous processing, as it fulfils quality requirements, such as residence time distribution (RTD) [18–21]. RTD refers to the distribution of time that materials remain in a unit operation; thus, it is critical for material characterization [21]. PAT uses multiple data sources for real-time product quality monitoring and control to achieve an integrated QbD quality system [10, 22]. CQAs such as the percentage of active pharmaceutical ingredient (API), particle-size distribution, granule size, and many others can be monitored with PAT [23]. As PAT and QbD tools can also be used in BM, manufacturers would be able to gain a better understanding of these processes, thereby facilitating a smoother transition to CM [22].

Figure 3

Benefits of CM

As listed in Table 1, there are various benefits of CM, which have been recognized for more than a decade [24].

In contrast to BM, CM provides greater scale flexibility in terms of its ability to scale-up production without any hindrance [10, 34, 35]. As depicted in Figure 2, CM eliminates the need for off-line testing and storage, thereby reducing the number of manufacturing steps [24, 29, 36]. Therefore, CM is more efficient than BM, as it reduces the processing time from raw materials to finished drug products, potentially by several months.

Also, CM has a greater response capacity to supply chain disruptions and drug shortages [10, 30]. This benefit of CM is accentuated in pandemics such as COVID-19, where ramped-up production of vaccines is required [29, 37]. As a result, there could be vast implications on global health and recovery of economies. On the other hand, it is difficult to adjust the production schedule of BM to meet changing demands [31], as building a new BM line in response to crises takes several months [10].

Table 1

Benefits and opportunities for generics manufacturers
Realistically, generic manufacturers operate on low-profit margins and need to constantly take measures to keep drug prices low [38]. With increased processing speed and control from CM, it will lower the cost of production and grant tremendous cost advantages, especially with high-volume production [39]. Furthermore, as CMAs and CPPs are kept constant, there would be lower batch-to-batch variability [10]. Hence, CM allows generic manufacturers to match the narrow process variability of branded drugs [38]. Therefore, adopting CM is an opportunity for generics manufacturers to be prepared for new drug products from originator manufacturers [38]. At present, generics companies such as Dr Reddy’s Laboratories, Mylan Pharmaceuticals and Aurobindo are developing CM lines in India [4], while Lupin Pharmaceuticals is developing a continuous purification process for a biosimilar monoclonal antibody drug [40]. Therefore, CM is beneficial for both brand-name and generics manufacturers.

Driving forces of CM
The principal driving force for the implementation of CM is its potential to cut production costs, as manufacturers seek to maximize profits [14, 41]. Pharmaceutical companies are facing a threat to their earnings due to competition from generics and biosimilars manufacturers, increasing research and development costs, a forecasted low growth rate in developed economies, and greater demand for the affordability of drugs for patients [42]. As such, manufacturers are exploring the use of CM as it has proven to reduce operating expenses and capital expenditure [18].

Secondly, there is an increasing demand for speed to market for breakthrough therapies [14, 24, 31, 43]. CM can accelerate product development, delivering life-saving medicines to patients more quickly [31] without compromising product quality [11, 14, 24].

Thirdly, the pharmaceutical industry is transiting from large volume blockbuster drugs towards the production of personalized medicines [24]. This requires a shift from the current BM system towards CM, which is flexible in volume output and product variety [24, 31]. This feature is beneficial for the production of personalized medicines.

Lastly, environmental conservation will be a point of contention in the coming years, mounting greater external pressure on manufacturers. As CM supports greener processes and is proven to have reduced environmental footprint [11, 25, 28, 44, 45], the Pharmaceutical Roundtable recommends CM as the top priority in green engineering research [46]. These external trends, coupled with its compelling benefits, serve as fundamental driving forces for the adoption of CM.

Initiatives by international organizations to advance CM
Furthermore, there are various initiatives taken by international organizations to advance CM. In particular, the International Society for Pharmaceutical Engineering (ISPE) organized the 2020 ISPE Continuous Manufacturing Virtual Workshop, whilst the Massachusetts Institute of Technology (MIT) and the Continuous Manufacturing and Crystallisation Consortium (CMAC) organized the International Symposium on Continuous Manufacturing of Pharmaceuticals (ISCMP), which brought together various stakeholders and culminated in white papers on CM [47]. As listed in Table 2, there is an increasing number of global consortia collaborating to develop and share knowledge on advanced manufacturing technology [48]. Undeniably, these initiatives would accelerate the transition from BM to CM.

Table 2

Extent of implementation of CM

From the first approval of drug products manufactured by CM in 2015, there have been a total of at least eight drug products approved. However, all of the currently approved drugs are OSDs. Hence, further development of CM for API, biopharmaceuticals and other pharmaceutical dosage forms is imperative.

The approved drugs in Table 3 utilize separately produced APIs [52]. At present, while there is a development of end-to-end CM that integrates continuous API production with drug product processes, there are none that comply with the current good manufacturing practice (cGMP) standards as of yet [25, 56]. This owes to the fact that there are more technical challenges in continuous processes for drug substances compared to drug products [25, 52, 57, 58]. Continuous API manufacturing is more complicated due to longer residence time [25, 52], higher quantity and diversity of unit operations [25, 57, 58], and intractably greater complexity of distinguished key molecules [57]. !However, many organizations are developing continuous flow processes for APIs [44, 52, 58-64]. For example, the Novartis-MIT collaboration has demonstrated that there are opportunities for integration of API and drug product processes with their end-to-end CM of aliskiren hemifumarate tablets [25]. Hence, cGMP-compliant end-to-end CM would most likely be realized in the future.

Similar to the CM of APIs, there is currently no fully continuous bioprocessing facility [13]. As today’s continuous downstream unit operations are still in their nascent stage of development, hybrid systems are expected to be implemented before end-to-end systems [30]. Nonetheless, the development of continuous bioprocessing is also gaining momentum [58]. Therefore, drugs in various pharmaceutical dosage forms would likely be approved in the coming years as development of CM progresses.

Table 3

Existing regulatory guidelines on CM

Currently, there are three main regulatory guidelines on CM from ICH, FDA and ASTM International. As stated in Table 4, ICH Q13 and FDA guidance are still a work-in-progress. Other RAs and international organizations such as the World Health Organization (WHO), the Pharmaceutical Inspection Co-operation Scheme (PIC/S), and the Association of Southeast Asian Nations (ASEAN) do not have established guidelines on CM. As a result of this regulatory uncertainty, manufacturers would unlikely take the risk to implement CM as adopting new technology may lead to delays in regulatory approval, and consequently delays in delivering drug products to patients.

Nonetheless, the regulatory expectations for both BM and CM are essentially the same [3, 7]. Regardless of the mode of production, manufacturers are expected to have technically sound and risk-based processes to produce quality products [7]. For existing products manufactured by BM, filing for a post-approval change for the implementation of CM is a requirement by most RAs [3].

Notably, a key difference among the guidelines is that FDA draft guidance does not apply to biopharmaceuticals and APIs. Many stakeholders have expressed concern about these differences and expect FDA guidance to be aligned with ICH Q13 to ensure global harmonization [67]. Harmonization can be achieved through ICH Guidelines, since ICH is well-represented by regulatory and industry members [68].

While ICH guidelines are not mandated by law, ICH members are expected to implement ICH guidelines in Step 5 of ICH Procedure, as illustrated in Figure 4 [69]. Therefore, with the implementation of the harmonized ICH guidelines by RAs around the world, manufacturers will have greater clarity on the regulatory expectations of the various countries.

Table 4
Figure 4

Challenges and opportunities in implementing CM

Although there is some progress, there is still considerable traction in the uptake of CM in the pharmaceutical industry. As listed in Table 5, there are various shortcomings of CM which may hinder manufacturers from adopting this technology.

Table 5

Regulatory challenges
In multiple studies, the authors concur that the top barrier for implementation of CM is the regulatory challenges stemming from a lack of a globally harmonized regulatory guideline on CM [11, 23, 29, 70, 71]. Harmonization is crucial; otherwise, manufacturers must obtain approval from different RAs to market their products in various countries [72]. Historically, RAs tended to suppress post-approval changes to drug products, inadvertently ingraining a fixed mindset of batch processes in manufacturers’ production philosophy [76]. Furthermore, fear of regulatory delays has hindered the adoption of CM by manufacturers [72].

Nonetheless, regulatory support for CM has grown in recent years. FDA, EMA and PMDA have established specialized teams to promote the adoption of CM. Established in 2014, FDA Emerging Technology Programme (ETP) aims to help manufacturers overcome implementation challenges [77, 78]. Furthermore, regulatory guidelines on key prerequisites of CM has been published to aid in the implementation. Guidelines include the definition of a ‘batch’ [3], process validation [3, 79], continuous process verification [80, 81], and PAT [19]. Also, with the implementation of ICH Q12 guideline in 2019 [82], unnecessary post-approval applications are reduced to promote manufacturing innovations [83]. Therefore, while regulatory uncertainty is currently the top barrier, it is plausible that ICH Q13 will address this challenge once the guideline is implemented.

High initial cost of investment
The development of continuous processes is costly, owing to the use of PAT and automation software [38]. The high initial cost is another crucial barrier for manufacturers in adopting CM [41], due to the difficulty in justifying the case for new equipment as existing batch equipment is still functional with established regulatory approval [49, 73]. Hence, investing in CM is not a priority for most manufacturers [49]. In particular, this is a significant barrier for generics manufacturers operating on low-profit margins [4, 84]. Unpredictable demand for generic drugs would further deter a generics manufacturer from investing in CM [85].

Despite the high initial capital investment required for CM equipment, manufacturers can expect to reap economic benefits, especially with high-volume production. In multiple studies, CM has proven to reduce the cost of production [6, 18, 25–28]. An analysis conducted by the Novartis-MIT Center for Continuous Manufacturing showed a significant reduction in labour cost, in-process inventory and energy consumption, resulting in more substantial cost savings [18].

Nonetheless, economic analyses for the CM of biopharmaceuticals show conflicting results. Studies conducted by Pollock et al. [86] and Klutz et al. [43] on continuous antibody production affirm that the hybrid approach is more economically favourable than end-to-end CM [43, 86]. However, Hammerschmidt et al. [87] contend that fully continuous processes allow for the most significant cost savings. The differences in findings are possibly due to the complexity of a myriad of factors in biopharmaceutical production [88]. Nevertheless, most economic analyses maintain that BM is the least economically favourable approach compared to CM [13, 43, 86, 87, 89]. Research has shown that the cost savings could outweigh the high initial cost of implementation [90]. Therefore, CM is an opportunity for manufacturers to generate long-term profits [91].

Quality, safety and technical considerations
Material traceability is a key quality concern as characterization of raw materials and intermediate properties are more complex in CM. It is difficult to define the start and end of each batch of product in CM processes [10, 70, 72, 92, 93]. This is exceptionally challenging in low-volume and low-dose drug products due to the high amount of excipients used [70]. To overcome this obstacle, RTD monitored by PAT is a potential solution to ensure material traceability by determining the time taken for the material to pass through each unit operation [70, 93–95].

Additionally, advanced process control strategies are critical for CM to assure process performance and product quality [80, 96]. According to ICH Q8(R2) and Q10 [80, 96], control strategies include material and product attributes, operating conditions, product specifications, and process control. ICH Q8(R2), Q9 and Q10 quality trio provide guidance on developing control strategies that incorporate QbD [80] and risk management [97]. As part of the control strategy, real-time process management segregates any non-conforming material, thereby ensuring the high quality of the drug product [73]. Also, start-up and shutdown can be minimized to reduce material loss and cost incurred [92].

Although CM is generally safer than BM in that there are fewer transition steps [15], still it presents critical safety considerations. Manufacturers need to prevent overfilling of material, over-pressurization of the system, and other potential hazards not found in BM [72]. In recent years, some publications have addressed these technical issues on CM [10, 73]. Moreover, many equipment manufacturers are collaborating with the pharmaceutical industry to overcome the technical challenges of CM. Therefore, technical challenges are not necessarily substantial barriers for manufacturers. As opined by Janet Woodcock, Director of FDA CDER, making the business case is a greater barrier than technical issues for biopharmaceuticals [29].

Equipment and technological challenges
There is currently a shortage of available CM equipment [14, 72]. Smaller manufacturers lacking such capabilities have to outsource their production to a limited number of contract manufacturing organizations (CMOs) with CM equipment [11, 49]. In this regard, manufacturers should also consider the risk of material cross-contamination and data security when engaging CMOs [98].

Apart from the lack of CM equipment, research on CM technology was initiated mainly by academic institutions and equipment manufacturers, without active involvement from the pharmaceutical industry [11]. Consequently, this led to late-stage adjustments to the equipment by pharmaceutical manufacturers, further delaying the adoption of CM [11]. The slow implementation by pharmaceutical manufacturers has decelerated the rate of innovation by equipment vendors [72, 99].

In addition, as asserted by several studies [33, 73], batch unit operations involve discrete equipment that can be easily rearranged to enable multiple manufacturing routes. However, discrete batch unit operations come at the expense of lower plant and equipment productivity [33]. While CM is currently less flexible in this aspect, ‘plug-and-play’ continuous equipment comprising distinct reconfigurable unit processes are being developed [23, 100].

Therefore, this challenge will presumably become a stumbling block of the past, as interest in CM is escalating amongst pharmaceutical manufacturers, spurring greater involvement in the innovation process. Biopharmaceutical manufacturers are also collaborating with equipment vendors to innovate new CM technologies for biopharmaceuticals [99].

Knowledge and skills gap
Highly skilled personnel are required to develop and implement CM technology in cGMP facilities [41]. As CM is still in its infancy in the pharmaceutical industry, there is a lack of personnel with the relevant skills and knowledge [41, 49, 57, 70, 72]. This is a hurdle for both manufacturers and regulators as continuous systems require statistically trained personnel to understand the data generated [72]. Although training has been conducted, addressing the knowledge gap would require greater multidisciplinary collaboration [41] and commitment from all relevant stakeholders [72].

Inevitably, the adoption of CM will also cause some manual jobs to become obsolete due primarily to automation [74]. However, since there is a need for highly skilled personnel, CM presents an opportunity to create new jobs in R & D and testing [74]. Additionally, reduction in labour intensity will also produce less human errors [4]. Therefore, there would be an increase in new job openings requiring highly competent workers.

Business, operational and cultural challenges
Optimally, CM should be implemented in the early phases of drug development [92] to eliminate regulatory requirements needed to prove equivalence to current batch processes [77]. Correspondingly for biopharmaceuticals, it is more effective to implement CM at the clinical stages rather than modifying existing batch processes [77]. This is because biopharmaceuticals are inherently more complex and highly process-dependent [77]. However, the steep learning curve for the CM of a new drug product may encumber a tight launch timeline [77]. Therefore, aligning the manufacturing innovation with a clinical trial timeline is an uphill task and may require structural changes within the organization [72].

Furthermore, regulatory uncertainty has led to a conservative culture in the industry, delaying the adoption of new technologies [57]. Hence, mindset and cultural changes are needed within the pharmaceutical industry to shift its production philosophy of BM [72, 73]. Additionally, new technologies need to have significant proven benefits before they are implemented widely in the pharmaceutical industry [72, 92]. Hence, it is paramount for international organizations to publish success stories of CM to build confidence amongst manufacturers [57].

Challenges for pharmaceutical and biopharmaceutical products
As presented in Table 3, all of the approved drugs manufactured by CM are OSDs. Tablets represent the majority of pharmaceutical dosage forms [73, 92], and there are existing technologies for the CM of OSD. Also, FDA draft guidance is tailored towards small-molecule OSD [3]. These factors enable manufacturers to implement CM for OSDs with greater ease. Nonetheless, a one-size-fits-all approach would not be feasible for all dosage forms. Off-the-shelf equipment made for small-molecule drug production is not applicable for biopharmaceuticals [13, 101, 102]. In light of the complexity of biopharmaceutical manufacturing processes and products, CM of biopharmaceuticals is more technically challenging than OSDs. Furthermore, in the manufacture of biological vaccines, there is a need to develop continuous processes for viral inactivation, ultrafiltration and diafiltration [103]. Therefore, more research and investments into biopharmaceutical CM are required to actualize it [90].

Nevertheless, there is promising progress in the development of CM for newer dosage forms. At present, PAT tools are available for formulations such as suspensions [104, 105], liquids [104, 106] and emulsions [104, 107]. Also, as reported by Worsham et al. [12], there are economical and quality benefits for the CM of liposomal drug products. Therefore, CM for various pharmaceutical dosage forms and biopharmaceuticals is gaining momentum and is expected to become more prevalent in the future.

Recommendations and future perspectives

Despite the challenges faced by manufacturers and regulators, progress towards the transition to CM is evident. In this section, key recommendations are proposed to facilitate the implementation of CM.

Regulatory harmonization
As emphasized throughout this review, regulatory harmonization is imperative to address the current regulatory uncertainty in the industry. Without harmonization, implementation will remain sluggish as regulators endeavour to understand new CM technologies [58]. This issue would be addressed in the upcoming ICH Q13, expected to be completed in 2022. With the ICH Q13, there would be harmonised expectations for dossier approval and lifecycle management [108]. Consistent regulatory assessment and oversight would likely speed up the adoption of CM [49, 65]. The benefits of harmonized regulations include process improvements, development of new manufacturing methods to produce new molecules, and ultimately improvement in the access of medicines to patients [65]. Currently, many of the major regulators are working on ICH Q13 as members of ICH. While ICH guidelines are not mandatory, it is still worthwhile for regulators that are not part of ICH to use the published guidelines as a reference to create their specific guidelines on CM. Assuredly, with global regulatory harmonization, implementation of CM would substantially increase, as manufacturers will have greater clarity on the regulatory requirements.

Management of financial risks
Industry-wide pre-competitive initiatives such as efforts by global consortia could be organized to de-risk investments [24]. Also, CM technology that is applicable for multiple products will reduce the investment risk [33]. It is also essential to conduct a comprehensive analysis on the functions, costs and benefits of new technology [33]. Currently, most economic analyses are performed on finished drug products, but not on APIs [57]. Hence, there is still a need to develop a business case for the CM of APIs [109, 110].

Sustained financial investments from the government will also alleviate the high initial cost [72]. Historically, tax and regulatory incentives have led to industry-wide advancements [49]. Tax incentives, namely in Ireland, Singapore, and Puerto Rico allowed pharmaceutical manufacturing hubs to thrive [49]. As CM would ultimately benefit patients with improved access to medicines [65], governments should provide tax incentives for CM [49]. Today, government support for CM technology is steadily increasing [58, 111].

In addition, regulators should consider granting regulatory incentives to manufacturers for implementing CM, to expedite the approval process and grant a patent exclusivity period for drugs manufactured via CM [49]. With these incentives, manufacturers would be motivated to adopt CM as they would have the opportunity to break even faster and make greater profits.

Hybrid processes
Implementing the full end-to-end continuum of CM might be a quantum leap for manufacturers given the myriad of challenges. To overcome this hurdle, manufacturers can employ hybrid approaches to implement CM in a stepwise and progressive manner [33]. By combining the advantages of batch and continuous processes [112], manufacturers can leverage on hybrid processes to generate revenue to offset the high initial cost [39], increase output [36], and gain experience with continuous unit processes. Hybrid approaches are also economically favourable in the production of antibodies [43, 86]. Through this approach, manufacturers can assess the benefits of continuous processes and progressively transition towards end-to-end CM, thereby reaping all the benefits of CM for both small-molecule drugs and biopharmaceuticals [13, 41].

Capacity building, collaboration and publication
Training programmes must be conducted to address the lack of skilled workers in CM technology [67, 75, 113]. Currently, there are training programmes organized by various organizations, including ISPE, C-SOPS and the United States Pharmacopoeia (USP). The pharmaceutical industry can also learn from other industries that have implemented CM and adapt the processes for their products [57, 73, 75]. Implementation of CM also requires cross-departmental collaboration and institutional partnerships [24]. Manufacturers should engage in constant communication with regulators and industry experts [7, 84]. Global conferences, such as ISCMP [47] and national initiatives such as the ‘Pharma Innovation Programme Singapore’ [63] are cornerstones for fostering collaboration to drive innovation forward.

In addition, the publication of success stories and challenges of CM would build confidence in the industry and establish best practice standards [57]. Training programmes and publications are equally indispensable to ensure that the industry is well-equipped with the knowledge and skills needed to implement CM [49, 70].

Culture of quality
For decades, the pharmaceutical industry has been utilizing BM, steadily instilling a narrow mindset and conservative culture within manufacturing organizations [37, 57]. In a published interview, Jayjock [114] asserts that shifting organization mindsets is the most challenging issue of adopting CM. In recent years, however, manufacturers are growing in receptivity towards CM, and are adopting pharmaceutical quality systems (PQS) which are crucial for CM [96]. Nonetheless, PQS has its limitations as quality outcomes are contingent on people making quality choices [115]. Hence, manufacturers need to embrace a culture of quality to produce quality products via CM [116]. Organizations can also adopt Kaizen or Lean Six Sigma principles to develop cross-functional continuous improvement of quality [115, 117].

Industry 4.0 and Pharma 4.0
At present, there is an astounding amount of data collected in the pharmaceutical industry that is underutilized [117], with data integrity still being a pressing issue [20]. These issues would likely be exacerbated in CM due to an increase in data collection from systems such as PAT [117].

Nonetheless, the pharmaceutical industry is progressing towards Industry 4.0 to overcome the challenges highlighted above. Pharma 4.0, modelled after Industry 4.0, is driven by technological advancements, such as big data, Artificial Intelligence (AI) and cloud-computing [20]. These technologies process, store and convert data into useful knowledge [22]. For instance, cloud computing [21] and deep neural networks (DNN) [118] can support the implementation of PAT in CM systems. With the support of guidelines [119] and pharmacopoeias [120] on computerized systems, uptake of these technologies has been rapid. Organizations are also working with regulators to integrate AI into CM to enable real-time release [121].

With time, Industry 4.0 would cause a paradigm shift in pharmaceutical manufacturing. As technology advances, machine learning and predictive analytics may even enable preventative maintenance without shutting down continuous processes [122]. Though CM aligns with Pharma 4.0 objectives [90], manufacturers should conduct more research in integrating new technologies into CM, as data security processes must be robust to prevent cyber threats [122]. Also, manufacturers are advised to start with minimal cGMP impact processes [117].

Conclusion

The pharmaceutical industry and regulators have recognized the benefits and opportunities of CM. Propelled by various driving forces, several manufacturers have successfully adopted this technology. Since the CM of pharmaceuticals is an emerging field, there are still significant challenges that need to be overcome. However, with the implementation of ICH Q13, regulators would have specific guidelines on CM, thereby eliminating the top barrier to implementation. Thereafter, the implementation of CM would substantially increase with regulatory harmonization. Nonetheless, due to the complexity of pharmaceutical processes and products, there is no one-size-fits-all solution. Therefore, it must be emphasized that while regulators work towards creating a harmonized guideline on CM, manufacturers should work on overcoming existing cost, technical, and cultural challenges.

Perhaps these challenges could be seen as opportunities for growth. Other industries have paved the way forward towards an optimistic future. Now it is time for the pharmaceutical industry to rise to the challenge, seize the opportunities and revolutionise pharmaceutical manufacturing with CM. Ultimately, the world would benefit from greater response capacities to drug shortages and pandemics, while contributing to environmental conservation. Closer to heart, individual patients’ lives would be improved with greater access to life-saving medicines.

Competing interests:
None.

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

Acronyms and abbreviation

Authors

Adjunct Associate Professor Sia Chong Hock, BSc (Pharm), MSc
Teh Kee Siang, BSc (Pharm)(Hon)
Associate Professor Chan Lai Wah, BSc (Pharm)(Hon), PhD
Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543

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Author for correspondence: Adjunct Associate Professor Sia Chong Hock, BSc (Pharm), MSc, Senior Consultant (Audit and Licensing) and Director (Quality Assurance), Health Products Regulation Group, Health Sciences Authority Singapore, 11 Biopolis Way, #11-01 Helios, Singapore 138667

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An overview of the current status of follow-on biologicals in Iran

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Author byline as per print journal: Farhang Rezaei, PharmD; Nassim Anjidani, PharmD

Background: The advent of follow-on biologicals in Iran and biosimilars worldwide have provided various treatment options for several severe and chronic diseases. The goal of the present study was to provide an overview of their current status in Iran.
Methods: A comprehensive search of clinical trial registry sites and other databases that publish scholarly articles, such as PubMed and Google scholar, enabled the current follow-on biologicals landscape in Iran to be mapped. In addition, the annual national wholesale data of pharmaceutical products published by the Iranian pharmaceutical regulatory were analysed. The share of biotechnological therapeutics in terms of the whole medicines market, was evaluated, along with the share of follow-on biologicals and the potential and actualized cost-saving associated with using them. Data were collected and analysed over the 2013–2018 time period.
Results: At the time of writing, 21 follow-on biologicals were available in Iran and these represent 17 different originator molecules. In 2018, approximately 13.5% of medicines spending in Iran was devoted to biotechnological therapeutics. Follow-on biologicals comprised approximately 47.2% of the biotechnological therapeutics’ total market value, up from 35.2% in 2013. The use of follow-on biologicals in Iran was associated with more than US$300 million cost-saving in 2018. A number of follow-on biological candidates, mostly monoclonal antibodies, are under development and will be subject to head-to-head clinical trials against originator products prior to regulatory approval and marketing.
Conclusion: Despite a significant rise in the use of follow-on biologicals in Iran, the proportional use of biotechnological therapeutics compared to the total medicines market has remained constant in recent years. Iranian healthcare authorities can improve patients’ access to life-saving biological medicines through promoting the use of follow-on biologicals instead of costly originators after making sure of the quality, efficacy and safety of the follow-on biologicals. The significant cost saving associated with using follow-on biologicals can also be utilized for other biotechnological medicines that are not currently in Iran’s drug list.

Submitted: 5 September 2020; Revised: 13 January 2021 ;Accepted: 13 January 2021; Published online first: 29 January 2021

Introduction

Since the development of human insulin via recombinant DNA technology in 1982, several medicinal biotechnological therapeutics have been marketed. These products have broadened the treatment armament for use against life-threatening and chronic diseases [1]. Due to costly manufacturing processes and the considerable investment in research and development required prior to their approval, these products are generally high priced. The mean daily cost of treatment with biotechnological therapeutics is estimated to be 22 times higher than conventional small-molecule medicines [2]. Therefore, despite biologicals’ well-known benefits, including providing more specific and life-saving treatments for a variety of diseases, their use will be restricted by ever-increasing healthcare costs. Healthcare authorities have been eager to find more affordable choices to facilitate patients’ access to these therapies. Follow-on biologicals are potentially less expensive options that can deliver the same benefits of originator biotechnological therapeutics.

According to the US Food and Drug Administration (FDA) definition, a biosimilar is a biological product that is highly similar to an already-approved biological with no clinically meaningful differences from the originator [3]. The European Medicines Agency (EMA) was the first regulatory agency to lay down a biosimilar approval framework in 2005 [4]. Following this, in 2006, somatropin became the first biosimilar molecule that was granted European Union (EU) marketing authorization. Since then, several biosimilar products have been launched in Europe. In 2013, an infliximab biosimilar was the first biosimilar monoclonal antibody that received EMA approval. Due to the complex macromolecular structure of biologicals and their manufacturing procedures’ sensitivity to small variations, approval frameworks outline the rigorous quality control and quality assurance measures required to ensure biosimilar and reference products’ comparability. In addition, they define when clinical studies are required to demonstrate that a biosimilar product is highly similar to the originator in terms of efficacy and safety [5].

Following the development of EMA’s biosimilar approval framework, the World Health Organization (WHO) and FDA established their own biosimilar authorization pathways [6, 7]. According to the guidelines published by EMA, FDA and WHO, several countries have established country-specific guidelines for biosimilar approval [8]. The Iranian pharmaceutical regulatory authority (Iran Food and Drug Administration, IFDA) developed its national biosimilar guidance based on WHO guidelines in 2010 [9].

The pharmaceutical industry in Iran began over 80 years ago [10]. In recent years, the commercial potential of producing follow-on biologicals and the favourable economic returns they offer, have encouraged several science-based companies to move towards producing biotechnological therapeutics. In 2000, Interferon alfa-2b was the first follow-on biological that was marketed in Iran. Since then, several other products have been developed and marketed in the country. This product, and other follow-on biologicals that were marketed before the issuance of IFDA biosimilar guidance in 2010, cannot be called biosimilars. This is because many of these follow-on products have not registered or published head-to-head clinical trials with the reference product and have not demonstrated that they are highly similar to their reference product, see Table 1.

Table 1

The present study had several goals: (1) To identify the follow-on biologicals in the Iranian market and summarize the available information regarding their market entry and related clinical trials; (2) To assess the share of biotechnological therapeutics in Iran’s pharmaceutical market and provide an overview of follow-on biologicals’ share in terms of the number of units sold (sales volume), total sales (sales value), and domestic production/imports; (3) To estimate the potential and actualized cost-saving associated with the use of follow-on biologicals; (4) To summarize information regarding follow-on biological candidates that might enter the market in the future.

Methods

Information from the Iranian Registry of Clinical Trials (IRCT), clinicaltrials.gov, and the International Clinical Trials Registry Platform (ICTRP) was used to identify related phase I and III clinical trials between 2013 and 2018. A PubMed and Google Scholar search was also conducted to find related scholarly articles. The descriptive search terms selected to retrieve data from online sources included the brand name, company name, generic name, biosimilar, clinical trial registration identifier, and Iran. The basic Boolean operator “AND” was used to combine the search terms in various ways in an effort to ­narrow down search results. Several articles were found using the snowball method by referring to article’s bibliography to pinpoint other relevant articles. In addition, information regarding marketing approval date, brand name and pipeline products of the companies were gathered through referring to reliable pharmaceutical, organizational and governmental sites, as well as via Google search in both English and Persian.

The information regarding pharmaceutical products sales was obtained from IFDA database. This database, which is updated annually, compiles information from all the pharmaceutical wholesale and distribution companies in Iran. The information includes the generic and brand name, dosage form, administration route, producer company, sales volume, and value. The proportion of healthcare spending on biotechnological therapeutics was calculated by dividing total sales of biotechnological products by the total sales of pharmaceutical products in Iran. By identifying the originators and follow-on biologicals for each molecule in the database, the total number of units sold (sales volume) and the total sales (sales value) of biotechnological products were obtained for follow-on biologicals and originators. Also, by determining the finished product producer, the share of domestic production and imported products was calculated in terms of sales volume and sales value. The compound annual growth rate (CAGR) was calculated ­during the 2013–2018 period. Since most biotechnological therapeutics were available in different potencies, the number of units sold was converted into a specific potency for each molecule (unified sales volume). The unit price was obtained by dividing the sales value by sales volume for each product. All the sales values and unit prices were converted into United States Dollar (USD), based on the average annual exchange rates provided in the customs administration of Iran (IRICA) website.

The actualized and potential cost savings associated with using follow-on biologicals were calculated using two scenarios. The actualized cost saving was determined by subtracting the total sales value of the molecule (originator and biosimilar/follow-on biological) from the product of multiplication of total sales volume of the molecule (originator and biosimilar/follow-on biological) in originator’s unit price. The potential cost saving that could be realized by using follow-on biologicals instead of originators was calculated by subtracting the product of the sales volume of originators in the unit price of the biosimilar/follow-on biological by year (if such an option was available that year) from the product of total sales volume (originator and biosimilar/follow-on biological) in the originator’s unit price.

The quantitative data were analysed using Microsoft Excel 2016 (Microsoft Corporation, USA).

Results

At the time of writing, 21 follow-on biologicals are produced and marketed in Iran, see Figure 1.

Figure 1

These products are related to 17 different reference products. Information regarding these follow-on biological products, including details of head-to-head studies with reference products, and their related publications, is summarized in Table 1.

The total biologicals market in Iran reached approximately US$745 million in 2018 (6-year CAGR = 21.51%). The proportion of healthcare spending on biologicals was 13.5% in 2018 (5-year CAGR = 1.38%).

In 2018, follow-on biologicals comprised approximately 47.2% of the total sales value of biotechnological therapeutics, up from 35.2% in 2013 (6-year CAGR = 28.6%). Despite demonstrating an upward trend (6-year CAGR = 16.64%), the proportional annual sales value of originators compared to the total sales value of biotechnological therapeutics decreased from 64.8% in 2013 to 52.8% in 2018, see Figure 2A. Conversely, in terms of the sales volume (number of units sold) the 6-year CAGR of follow-on biologicals (15.74%) was lower than the originators (43.49%). The proportional sales volume of follow-on biologicals in 2018 decreased to 34.6% from 60.7% in 2013. While originators proportional sales volume reached to 65.5% in 2018 up from 39.3% in 2013, see Figure 2B.

Figure 2

As is the case for originator products, some follow-on biologicals used in Iran are imported from other countries. Figure 3 represents the proportional share of the domestic production or import of the biotechnological therapeutics in Iran, in terms of sales value, see Figure 3A and sales volume, see Figure 3B. In 2018, 42.5% of the follow-on biologicals in the Iranian pharmaceutical market were produced domestically, up from 27.8% in 2013 (6-year CAGR = 28.86%). The proportional sales value of the imported products decreased from 72.2% in 2013 to 57.5% in 2018, despite having a positive 6-year CAGR of 16.64%, see Figure 3A. The 6-year CAGR of domestic products (15.29%) was lower than that for imported products (40.56%) with respect to sales volume. The proportional sales volume of domestic products declined from 53.2% in 2013 to 29.7% in 2018. While the proportional sales volume of the imported products reached 70.3% in 2018, up from 39.3% in 2013, see Figure 3B.

Figure 3

From 2013 to 2018, IFDA priced the follow-on biologicals on average at 54.3±17.8% (mean ± standard deviation) of the originators’ price. during this time, the price of follow-on biologicals was 12%–78% lower than the originators.

The actualized cost saving associated with using follow-on biologicals has increased in recent years, with a 6-year CAGR of 8.91%, see Figure 4. The significant increase in cost saving in 2017 and 2018 has been mainly driven by an increase in the use of rituximab, adalimumab and trastuzumab follow-on biologicals. The potential cost-saving associated with using follow-on biologicals is also shown on Figure 4. The proportion of actualized cost saving to the potential cost saving was 82.68% on average. This means that it is possible to increase the uptake of follow-on biologicals and benefit from their associated cost savings.

Figure 4

As summarized in Table 2, several biosimilar candidates are under development in Iran. They may be granted marketing authorization in the future if they provide satisfactory comparative efficacy and safety results. These are biosimilar candidates for aflibercept, alteplase, cetuximab, denosumab, ocrelizumab, omalizumab, peginterferon beta-1a, pertuzumab, and tocilizumab. These biosimilar candidates are mostly monoclonal antibodies used to treat several life-threatening and debilitating conditions.

Table 2

Discussion

In the present study, the current status of follow-on biologicals in the Iranian market has been investigated by evaluating their ongoing and completed clinical trials. The article has highlighted that, as some products were approved as follow-on biologicals prior to the issuance of IFDA biosimilar guidance, they have not registered or published head-to-head clinical trials against the reference product. As biosimilars offer exciting therapeutic opportunities for healthcare authorities and patients in Iran in the future, all efforts should be made to ensure that true biosimilars are approved that are highly similar to reference products in terms of quality, efficacy and safety.

The annual national wholesale data on pharmaceutical products suggests that the use of biologicals in Iran has increased considerably in recent years in terms of both sales value and sales volume. However, there was only a slight increase in the proportional share of biotechnological therapeutics with respect to the total medicines market (from 12.7% in 2013 to 13.5% in 2018). According to the IQVIA reports, in 2018, biologicals represented 29.9% of the total medicines market in Europe with a CAGR of 1.93%. In the US, 42% of healthcare costs for medicines were devoted to biotechnological therapeutics (5-year CAGR = 8.78%) [23, 24]. Despite an increasing trend in the use of biological therapeutics in Iran, the proportion of healthcare expenditure on biotechnological therapeutics here is considerably lower than in Europe and the US, see Figure 5. The unwillingness of the Iranian healthcare authorities to add new molecules, specifically biotechnological therapeutics, to Iran’s national drug list may be a contributing factor to the comparatively low uptake of these products. This issue may stem from the greater cost associated with using biotechnological therapeutics and connected increase in healthcare burden. The importance of biotechnological therapeutics in the treatment of a wide range of severe and chronic diseases, together with escalating healthcare costs highlights the importance of using biosimilars as a lower-priced substitute for originator biologicals. The use of biosimilars can significantly reduce healthcare expenditure on biotechnological therapeutics. According to an evaluation by Mulchay et al. [25], it was projected that the emergence of biosimilars would reduce US healthcare spending by US$54 billion in 2026. The proportional difference in the use of biotechnological therapeutics in Iran compared to other regions might also be explained by various different pricing strategies adopted for biosimilars and follow-on biologicals. For example, in Europe, biosimilar developing companies have to price their products at least 30% lower than the originator [4]. According to a recent review of literature, the price difference between biosimilar developing companies and their originators ranges between 15%–30% [4]. While in Iran, from 2013 to 2018, follow-on biologicals’ price has been approximately 54.3% of originators.

Figure 5

In recent years, the share of follow-on biologicals produced domestically has increased considerably in terms of sales value. At the same time, the trend of the increase in sales volume was moderate compared to sales value. This might suggest that pharmaceutical and biotechnology companies in Iran have been more willing to invest in high-value, low-volume production. This tendency is also apparent in the biosimilar candidates in the companies’ pipelines. The majority of these products are monoclonal antibodies that usually have a high unit price.

The introduction of follow-on biologicals has offered significant cost saving for the Iranian healthcare system as actualized cost saving through follow-on biologicals use reached over US$300 million in 2018. These savings were influenced by the rate of ­follow-on biologicals use and the difference in unit price between follow-on biologicals and originators. Rituximab, adalimumab and trastuzumab were the main drivers of the ­significant cost saving in 2017 and 2018. This figure is likely to increase in the upcoming years due to the market entry of other biosimilars/follow-on biologicals currently under development.

The pharmaceutical landscape of Iran has changed significantly in the past 20 years. In recent years, some biopharmaceutical companies in Iran (CinnaGen and AryoGen) have endeavoured to move towards regulated markets, such as Europe. As a preliminary step, they have acquired EU-good manufacturing practice (GMP), the certificate of GMP, that has been published on EMA’s database [6, 7]. In 2017, CinnaGen initiated pharmacokinetics (PK) and pharmacodynamics (PD) studies of its interferon beta-1a biosimilar (CinnoVex®) in Finland [8]. As such, it seems that by the development of high-quality biosimilars bolstered by satisfactory non-clinical and clinical studies, Iranian pharmaceutical companies can expand their presence in regulated and semi-regulated markets.

Conclusion

Although biotechnological therapeutics have offered life-saving therapies to many critical diseases, their proportional uptake in Iran has remained constant in recent years. It seems that healthcare authorities can improve patients’ access to these medicines through promoting the use of biosimilars/follow-on biologicals instead of costly originators once their quality, safety, and efficacy have been ensured. The significant cost saving associated with using biosimilars/follow-on biologicals can be allocated to helping new biotechnological medicines to be included in Iran’s drug list.

Competing interests: Farhang Rezaei and Nassim Anjidani work in the medical department of Orchid Pharmed company which is in collaboration with AryoGen Pharmed and CinnaGen companies with respect to conducting clinical trials.

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

Authors

Farhang Rezaei, PharmD
Nassim Anjidani, PharmD

Medical Department, Orchid Pharmed Company, No 42. Attar Streeet, North Kurdistan Highway, 1994766411 Tehran, Iran

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14. Norouzi Javidan A, Shahbazian H, Emami A, Yekaninejad MS, Emami-Razavi H, Farhadkhani M, et al. Safety and efficacy of PDpoetin for management of anemia in patients with end stage renal disease on maintenance hemodialysis: results from a phase IV clinical trial. Hematol Rep. 2014;6(3):5195.
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21. Tabatabaei-Malazy O, Norani M, Heshmat R, Qorbani M, Vosoogh A, Afrashteh B, et al. Efficacy and safety of the biosimilar recombinant human parathyroid hormone Cinnopar® in postmenopausal osteoporotic women: a randomized double-blind clinical trial. Iran J Public Health. 2018;47(9):1336-44.
22. Farahani MF, Maghzi P, Aryan NJ, Payandemehr B, Soni M, Azhdarzadeh M. A randomized, double-blind, parallel pharmacokinetic study comparing the trastuzumab biosimilar candidate, AryoTrust®, and reference trastuzumab in healthy subjects. Expert Opin Investig Drugs. 2020;29(12):1443-50.
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Author for correspondence: Farhang Rezaei, PharmD, Medical Department, Orchid Pharmed Company, No. 42, Attar Street, Attar Square, North Kurdistan Highway, 1994766411 Tehran, Iran

Disclosure of Conflict of Interest Statement is available upon request.

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Pharmaceutical Data Integrity: issues, challenges and proposed solutions for manufacturers and inspectors

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Author byline as per print journal: Adjunct Associate Professor Sia Chong Hock1, BSc (Pharm), MSc; Vernon Tay1, BSc (Pharm) (Hons); Vimal Sachdeva2, MSc; Associate Professor Chan Lai Wah1, BSc (Pharm) (Hons), PhD

Abstract:
Data Integrity, which is data deemed Attributable, Legible, Contemporaneous, Original, Accurate, Complete, Consistent, Enduring, and Available (ALCOA-plus), has been the focus of the pharmaceutical industry in recent years. With the growing use of computerized systems and rising prevalence of outsourcing manufacturing processes, ensuring data integrity is becoming more challenging in an increasingly complex pharmaceutical manufacturing industry. To address this issue, multiple legislation and guidance documents such as ‘Data Integrity and Compliance with CGMP Guidance for Industry’ from the US Food and Drug Administration (FDA), ‘GxP’ Data Integrity Guidance and Definitions from the UK Medicines & Healthcare products Regulatory Agency (MHRA), and ‘Guidance on Good Data and Record Management Practices’ from the World Health Organization (WHO), have been published in recent years. However, with rising data integrity issues observed by FDA, WHO, MHRA and other pharmaceutical inspectors even after these guidance documents have been published, their overall effectiveness is yet to be determined.
This paper compares and evaluates the legislation and guidance currently in existence; and discusses some of the potential challenges pharmaceutical manufacturers face in maintaining data integrity with such legislation and guidance in place. It appears that these legislation and guidance are insufficient in maintaining data integrity in the industry when used alone. Last, but not least, this paper also reviews other solutions, such as the need for a company culture of integrity, a good database management system, education and training, robust quality agreements between contract givers and acceptors, and performance of effective audits and inspections, to aid in maintaining data integrity in the manufacturing industry. These proposed solutions, if successfully implemented, can address the issues associated with data integrity, and raise the standard of pharmaceutical and biopharmaceutical manufacturing worldwide.

Introduction

Data Integrity (DI) in the pharmaceutical manufacturing industry is the state where data are Attributable, Legible, Contemporane­ous, Original, Accurate, Complete, Consistent, Enduring, and Available (ALCOA+) [1–3], as outlined in Table 1. Data altered such that it no longer fulfils these criteria is considered as falsi­fied, regardless of it being due to human error or generated deliberately [2, 4].

Current legislation, good manufacturing practice (GMP) stan­dards and guidance on data management and governance published by organizations such as the US Food and Drug Administration (FDA) [6–8] and World Health Organiza­tion (WHO) [1] aim to guide the industry in ensuring DI is not compromised. These include the ‘Data Integrity and Compli­ance with cGMP Guidance for Industry’ from FDA [9], ‘GxP Data Integrity Guidance and Definitions’ from the UK Medicines and Healthcare products Regulatory Agency (MHRA) [10], and ‘Guidance on Good Data and Record Management Practices’ from WHO [1], which were published in recent years. Inspectors from various organizations inspect the pharmaceuti­cal manufacturing companies to assure compliance to such leg­islation, standards and guidance, where appropriate [3, 11, 12]. If violations of regulatory significance are observed, warning let­ters containing the key violations to be rectified would be sent to the companies [13]. However, with the number of FDA warn­ing letters issued citing DI violations quintupling from 2014 to 2017 [14], and large pharmaceutical companies getting cited for falsifying data in quality control results and other manufacturing processes, the effectiveness of such legislation and guidance to maintain DI remains yet to be seen [15, 16].

Table 1

With an increasing use of computerized systems in the pharmaceutical industry [17, 18], and current regulation of physical data being more well-defined than regulation of electronic data [19], it is uncertain if the legislation and guidance are still able to maintain DI as more electronic data are generated. Furthermore, the outsourcing of pharmaceutical manufacturing activities to improve productivity and business efficiency continues unabatedly [20]. A lack of synergy and good data management between companies increases the difficulty in standardizing protocols and procedures to assure DI [21], regardless of the legislation and guidance in place [22]. Additionally, protocols which help maintain DI in parent companies may not be adopted by their subsidiary companies [23]. Failure to prevent DI violations could lead to substandard medicinal products being released into the market, thus causing harm and possibly death to patients [24, 25] and, in the case of vaccines and biosimilars, loss of public confidence.

Hence, this paper strives to assess the prevalence and trends of recent DI violations, identify reasons why companies commit DI violations, evaluate the effectiveness of current legislation, guidance and challenges, and finally, explore solutions which can promote DI in the pharmaceutical and biopharmaceutical manufacturing industry. A systematic, scientific and comprehensive literature review, covering the websites of regulatory authorities, scientific journals, pharmaceutical fora and newsletters, national and international legislation, GMP and other good practices and guidance documents relating to DI, was conducted. Challenges and issues relating to DI were identified, and solutions to address them were proposed for the benefit of the manufacturers, inspectors and the global pharmaceutical and bio­pharmaceutical community in general.

Current trends

As reported by the Unger Consulting Incorporation [14], the prevalence of FDA warning letters that cited DI violations has been increasing exponentially, see Figure 1. This may be due to pharmaceutical inspectors proactively searching for DI violations [26], inspectors who are now better trained to detect DI issues, more companies taking risks in violating DI for various reasons, or ignorance and carelessness of operators [27]. It is not easy to analyse the root causes of DI violations as the increasing prevalence of DI issues and efforts to manage them appear to be a recent development [28].

Also, from Tables 2(a) and 2(b), it is noted that most of the DI violations cited pertain to manual, automatic, mechanical and electronic equipment, which includes ‘failure to calibrate and maintain written records’ and ‘failure to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in production and control records, laboratory records or other records’ [31]. The next few most cited DI violations pertain to quality control of the pharmaceutical product. The leading countries being issued DI associated warning letters include China and India [14], see Table 3, where parent pharmaceutical manufacturers in Europe and the US have been known to translocate their manufacturing plants to these countries to reduce production costs [20, 23]. It is also important to emphasize that DI violations are also routinely cited by FDA during inspections of domestic manufacturers as well.

Reasons for Data Integrity violations (inadvertent and intentional)

Pharmaceutical companies are often under pressure to improve their key performance indicators (KPIs), especially during economic downturns. Hence, data are known to be falsified to decrease the rejection of manufactured batches, with some companies deleting non-compliant records [32–36], or even churning out records without legitimately performing relevant tests to expedite regulatory approval [28, 34]. Furthermore, the lack of sup­port from senior management, due to insufficient involvement and resources, can aggravate the situation. Also, some employees may fear retrenchment due to unachieved KPIs [37, 38]. Thus, they may release the product without following internal protocols requiring them to seek approvals from authorized personnel [33], or alter records if given access to the database [35, 39]. Occasionally, and in particular, for systems involving manual transfer of data to the company database using hybrid computerized systems, transcription errors can occur, leading to inaccurate data records [40].

Figure 1

Table 2a b

An example of a hybrid approach is where laboratory analysts use computerized instrument systems that create original electronic records and then print a summary of the results. Where hybrid approaches are used, appropriate controls for electronic docu­ments, such as templates, forms and master documents, that may be printed, should be available. However, during on-site inspections of the laboratory systems, it has been discovered that data were being falsified on an industrial scale, using a variety of means, such as copy and paste, manipulation of weights, and unauthorized manual integration of chromatograms. The root cause is often a chromatographic data ­system (CDS) whose audit trail had been deliberately turned off, and therefore, cannot track who had falsified what data, and when [41].

Assuring and promoting Data Integrity via legislation and guidance documents

Legislation
In this article, regulations from the FDA and the European Union (EU) EudraLex, are discussed and compared. As DI in pharmaceutical manufacturing is strongly associated with GMP, it is important to understand the GMP regulatory framework and its impact on DI. The GMP legislative framework from FDA comprise the 21 CFR 210, 211, 212, 600, and 820, while those from EU comprise Commission Directive 2003/94/EC and its regulatory statute EudraLex Volume 4 [42]. 21 CFR 210 provides a very generic regulation on the safety, identity, strength, quality and purity of pharmaceutical products [7]. EU Commission Directive 2003/94/EC gives a general overview of GMP for the pharmaceutical manufacturing companies [43]. 21 CFR 211 and EudraLex Volume 4 are similar, regulating the required documentation for personnel qualifications and training, equipment protocols, inspections and maintenance, labelling and distribution processes, and even protocols for recalls, and corrective and preventive actions (CAPA) [8, 43], with EudraLex Volume 4 dedicating Chapter 7 to contract requirements for outso­urced manufacturing activities [43], whereas such requirements are not explicitly stated in 21 CFR 211. 21 CFR 212 and 600 regulate specifically radiological [44] and biological pharmaceutical products [45], respectively. In general, they require more accurate and attributable information to be kept for a longer time to retrace and recall when issues pertaining to the manufacture of the product arise. 21 CFR 820 dictates requirements to ensure quality is maintained throughout the manufacturing process, specifying the documentations required to validate such processes [46]. Clearly, these legislations cover many aspects where proper documentation and DI should be enforced.

Table 3

There are also legislation specifically promoting DI in pharmaceutical manufacturing. For example, 21 CFR 11 specifically targets requirements for electronic documentation, stating that these electronic documentations are as significant as paper records, and in certain cases can be used in lieu of them [6]. It regulates computerized systems which have external personnel authorized to access and edit, and systems that are employed within the company. EU Falsified Medicines Directive regulates the labelling and distribution practices of drugs, namely ensuring that packaging cannot be tampered without being noticed, the identity of the contents in the packaging are accurate and attributable, and documentation that assures Internet sales of pharmaceutical products is validated by relevant authorities [47]. The Drug Data Management Standard of China, as translated by the China Working Group of Rx-360, provides regulations to promote DI [48]. It regulates documentation of various processes such as training of personnel, validation of computerized systems and data management, and CAPA when DI violations are found. One section specifically provides examples on how DI would be maintained using ALCOA+ as a guide. In Article 7, it specifically promotes whistleblowing as part of the culture for pharmaceutical manufacturing companies as well [48].

Guidance documents
As legislation tend to be generic to facilitate applica­tion to a wide variety of pharmaceutical companies, guidance documents have been published to clarify legislative requirements [49]. In general, guidance documents encourage voluntary compliance and can be adapted to suit the company’s culture and manufacturing processes. Guidance documents published to promote GMP include the WHO Guidance on Good Data and Record Management Practices (WHO Technical Report Series 996, Annex 5) [1], FDA Data Integrity and Compliance with CGMP Guidance for Industry, MHRA GxP Data Integrity Guidance and Definitions, the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) Guide to Good Manufacturing Practice for Medicinal Products [50], PIC/S Guide to Good Manufacturing Practice for Active Pharmaceutical Ingredients [51], the latter is equivalent to the International Council on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q7 – Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients [52]. The WHO Guidance on Data and Record Management Practices also promotes a company culture of integrity and provides links to relevant legislation and guidance documents [1]. The PIC/S Guide to GMP for Active Pharmaceutical Ingredients has been established for many years already and it addresses the same issues as ICH Q7 [53, 54].

There are also guidance that clarify specific portions of the GMP, including PIC/S Good Practices for Computerized Systems in Regulated GxP Environment [55], FDA Standardization of Data and Documentation Practices for Product Tracing Guidance for Industry [56], FDA Contract Manufacturing Arrangements for Drugs: Quality Agreements – Guidance for Industry [57], and ICH Q9 – Quality Risk Management [58]. These documents provide in-depth guidance to the various aspects of GMP, with due consideration for the respective country’s regu­lation. However, as mentioned earlier in this paper, there are some guidance that specifically focus on DI. These include the PIC/S Good Practices for Data Management and Integrity in Regulated GMP/GDP Environment [59], FDA Data Integrity and Compliance with cGMP Guidance for Industry [9], and MHRA ‘GxP’ Data Integrity Guidance and Definitions [60], all recently published due to increasing attention on DI [3]. Generally, these guidance documents discuss audit requirements, personnel responsibility in promoting DI, and validation of computerized systems and other GMP processes. The WHO, PIC/S and FDA further provide clarification on CAPA to be taken when DI violations are found [9, 59], with PIC/S providing added clarification on outsourced processes and promotion of quality culture [59]. Some guidance documents also help companies to understand the legal requirements. For example, the Orange Guide [61] compiles relevant legislation and guidance notes for manufacturers planning to enter the UK pharmaceutical market, increasing the ease for manufacturers to understand the regulations by providing relevant guidance and binding legislation.

Overall, the legislation and guidance documents appear to be comprehensive in assuring and promoting DI. However, they are unable to prevent DI violations alone. Most DI issues only surface during on-site audits [18] or from whistleblowing [15], and by then, non-compliant pharmaceutical products would have already been distributed, with potentially substandard products having been consumed by patients. Hence, legislation and guidance must be supplemented with other approaches to promote and assure DI at a higher level.

Proposed solutions to better promote and assure Data Integrity

Culture of integrity

A study was conducted by the Parenteral Drug Association (PDA) to assess the effectiveness of its published DI guidance document. Although more than 90% found this guidance helpful in promoting DI, some remarked that a culture of integrity is required to truly attain DI [62], Incentives, including recognition for companies if no DI issues have been found for a consecutive number of years, could be introduced to encourage companies to follow the guidance.

As mentioned in some legislation and guidance documents, a culture of integrity is required in a company to make regulations work [62]. Setting a culture of integrity is important so that management would treat DI seri­ously [3, 63], and employees would then feel obligated to do the same [64]. According to a study by Yang, Sun and Eppler, for any strategy to be implemented successfully, the formulation needs to be of a certain standard, and inter- and intra-department relationships should be cordial [62]. Middle management is noted to be the main drivers for implementation [62], and close collaboration with the top management increases its effectiveness [62]. However, if management ignores the DI issues, implementation would be hindered [65]. Open and supportive communication between employees and management aid in effective strategy implementation [62, 66]. Providing internal whistleblowing opportunities to flag any DI issues will further promote a company’s culture of integrity [67, 68]. This method is adopted by FDA, where under the Dodd-Frank Wall Street and False Claims Act, monetary rewards are used to promote whistleblowing behaviour [67].

Having a culture of integrity within the company will reduce DI issues, and ultimately bring about a positive perception of the company’s pharmaceutical products [63]. However, for a large company, it is difficult to start a culture of integrity if this culture was absent in the first place, as the implementation of such a culture requires some time before the effects are fully felt [65]. Furthermore, old habits may cause top management to resist adopting such a culture unless specific incentives are provided [65]. Therefore, some regulations should be in place to start this culture of integrity within the company [64].

Database management systems

Another proposed solution to promote DI is by having good and effective database management. A database management system (DBMS) stores data [69] and presents them in an understandable format when accessed [112]. With data becoming larger in volume and variety in the pharmaceutical manufacturing industry [70], user-friendly and efficient DBMS are in high demand [71]. With validated DBMS, manufacturers and regulators would be better able to focus on other DI-related issues.

This paper also evaluates some of these DBMS, and their effectiveness in promoting DI below. Specifically, the advantages and complications of three major categories of DBMS are ­compared, see Figure 2.

Figure 2

Table 4

Relational and non-relational database management system
Relational database management systems store data in either a two-dimensional table or a three-dimensional ‘object’ [72, 77]. Non-relational database management system on the other hand does not have a specified structure of storing data. Further elaboration is provided in Tables 4, 5 and 6.

With a wide variety of DBMSchoices currently in the ­market, adopting one that keeps data ALCOA+ throughout its lifespan would minimize the cost required to maintain it manually [95].

Blockchain technology
Blockchain is hypothesized as the next pharmaceutical manufacturing DBMS innovation [96, 97]. It is a decentralized record of digital events, with validation by the participants occurring before it is recorded [98], making manipulation of previously verified transactions including data entry or movement very hard, and cannot be deleted [99]. Blockchain has three main ways to ensure data security. Firstly, it has a hash function, which identifies blocks, and calculation of hashes involves the previous block’s hash [100]. Secondly, it has a peer-to-peer network to verify before it is added to the current blockchain as a legitimate block [97], removing the need for an authorized person for approval of transaction [98]. Once a block is added, it is added to all the copies of the verified blockchain across the entire network [101], hence remaining in the system indefinitely. Thirdly, as only pre-approved participants can participate in adding new blocks, the identity of the node adding the block would be documented [102], which ensures data attributability.

Furthermore, by using blockchain-utilizing smart contracts, DI can be enforced [103], using blockchain technology to ensure all components of the contract are met before transactions such as approvals occur [103, 104]. This can also be employed for auditing as well, where, if certain values deviate from the acceptable range, they would be flagged up for inspection [100]. Companies such as BlockVerify [103] and One Network Enterprises [96] have started to employ blockchain to maintain DI in the pharmaceutical market. Blockchain has also been applied in promoting DI in the distribution of pharmaceutical products through modium.io AG [105], making use of an array of sensors to ensure erroneous data would not be entered into the system in the first place [103]. In the future, blockchain could even be used to supplement guidance ­documents [106, 107].

Table 5

Table 6

However, handling large volumes of information and simultaneous transactions is slow with current blockchain technology [108], and with more data being generated in pharmaceutical manufacturing companies, this translates to lower efficiency of maintaining DI for large data stores. Furthermore, the difficulty in comprehending and using the code gives the developer the power to maintain DI [109], rendering both authorities and companies incapable of maintaining DBMS DI themselves. Additionally, having a private blockchain requires data encryption [109] to protect data from unauthorized access [107, 110].

In general, having a good DBMS promotes DI as it streamlines audits. Guidance in the form of questions are available to help companies find the best DBMS options available for them [75]. Furthermore, it is common to use multiple databases for different functions [90]. However, relying on DBMS alone will not prevent all DI issues. Firstly, DBMS is unable to ensure data entered was ALCOA-plus, and audits are required to ascertain that [111]. Secondly, unvalidated or outdated systems require upgrading, and migration of data while updating may cause errors to be carried forward unknowingly, especially for large volume of data [95, 112], leading to an inaccurate database. Therefore, DBMS alone cannot prevent all DI issues. Continually upgrading DBMS by periodically reviewing documentation and procedures which influence the quality of pharmaceutical products manufactured against established standards would aid in promoting DI in the future as well [113–116]. However, audits take resources to perform, and smaller companies might not be able to perform frequent and comprehensive self-audits. Nonetheless, having such audits would ensure that the DBMS employed by the company are current and efficient, ultimately promoting DI [95, 114].

Education and training
It is important for employees to undergo DI education and training for them to understand the importance of maintaining DI and the consequences if not maintained [117, 118]. More detailed sessions should be conducted for employees with access to ­modify processes, systems and records, further explaining their responsibilities [114, 118]. Training sessions could also standardize the procedures, terminology and concepts within the company, reducing DI violations due to miscommunication [114]. Currently, DI courses from external service providers such as ECA Academy [119] and Reading Scientific Services Ltd (RSSL) [120] exist.

However, training can be costly, especially to smaller companies. To mitigate part of the cost, a representative could be trained, before training their fellow colleagues, causing a multiplying effect. Furthermore, manufacturers may form associations together, getting group discounts from DI training providers [120]. To ensure knowledge retention of the training provided, constant refreshers are needed, be it refresher courses or incentivize maintaining DI with company culture, otherwise, such knowledge might be forgotten if infrequently used [121].

Robust quality agreements
With an increase in outsourcing of pharmaceutical manufacturing processes, quality agreements, which are written contracts between companies to ensure responsibilities and expectations for both parties are agreed upon [122], must be rigorously prepared, mutually agreed and signed. However, this process can be time-consuming as reaching a consensus can be challenging. Some guides, such as one from Rx-360 [123], help expedite this process. By having a concise understanding of expectations, the contract giver would hence be able to assure that practices which promote DI would be performed by the contract acceptor, while the contract acceptor understands what is expected of them [124].

Collaboration between countries
Each country has its own set of legislation. Although the legislation of different countries generally overlaps [125, 126], individual countries may not accept specific documents that originate from another country, exacerbating DI issues. Hence, collaborative use of legislation and mutual recognition schemes can help to promote DI [127, 128], with the added benefit of efficient international transactions as DI criteria would have been fulfilled prior to application for regulatory or other transaction approvals.

Effective and efficient audits and audit trail review
Audits are defined as validation checks conducted on manufacturing protocols and systems that assure quality in the processes, products, and computerized systems at the manufacturing site [129]. This includes both internal audits self-conducted by the manufacturer in accordance with Chapter 9 of the PIC/S GMP Guide [130], and external audits conducted by regulatory auditors including FDA and MHRA. As audits are limited in duration, meaningful and efficient audits should be conducted [124]. In general, processes or data that do not affect product safety and compliance, including data on accounting and finances [131], need not be audited. The audit can be streamlined by tagging relevant items to allow the auditor to quickly sieve them out for scrutiny [132, 133]. Audit trails may be divided into two different types: Data Audit Trail (DAT), which covers the raw data recorded, and System Audit Trails (SAT), which covers the systems in place to maintain DI during documentation.

When auditing DAT, critical quality attributes (CQA) and audit trail elements must be defined before conducting the audit. CQAs are the characteristics or properties that can harm patients if not properly controlled [117]. These attributes are to be defined by the company, referring to current legislation and guidance such as ICH Q8(R2) Part 2 [134]. Audit trail elements are the items which affect CQAs and are to be audited [132]. Other items need not be audited as frequently nor meticulously [131]. When auditing SAT, assuming the current system is validated, auditing for possible indicators of DI breaches can substitute an audit of the raw SAT data [131]. These indicators include multiple login attempts and read and write errors [135]. With the recent focus of audits being more SAT-oriented, coupled with more robust systems that can detect errors in DAT [131], falsification of data points prior to documentation may not be detected. As such, both DAT and SAT must be audited in tandem to achieve a more comprehensive audit outcome.

Finally, it must be emphasized that a reliance on periodic audits from the regulator is grossly inadequate to address DI issues. On the other hand, overly frequent internal audits may inefficiently use the company’s manpower. For SAT, an approach based on the risks and implications of DI breaches and the Good Automated Manufacturing Practices (GAMP 5) Software Category [131], as tabulated in Table 7, is recommended.

Table 7

Computerized systems validation
Pharmaceutical and biopharmaceutical manufacturers should validate their computerized systems such that they are fit for their intended purpose, and to ensure that adequate controls are in place to facilitate tracking and detection of deleted or altered data. The use of hybrid (paper and computerized) systems should be discouraged. However, where legacy systems are awaiting replacement, mitigating controls should be put in place. In such cases, original records generated during the course of GxP activities must be complete and must be maintained throughout the records retention period in a manner that allows the full reconstruction of the GxP activities. Replacement of hybrid systems should be a priority [41].

Conclusion

With increasingly complex pharmaceutical manufacturing processes, maintaining DI might become more challenging, and relying merely on legislation and guidance to maintain DI might be insufficient. Some possible solutions to tackle this challenge include having a company culture of integrity, having a good DBMS, education and training, forming effective quality agreements, collaborations between countries, and performing efficient audits. Together with existing legislation and guidance, these measures can help manage DI issues in the pharmaceutical manufacturing industry, improve the standard of pharmaceutical manufacturing worldwide, and ultimately, produce safe and quality medicinal products for patients internationally.

Competing interests: None.

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

Authors

Adjunct Associate Professor Sia Chong Hock1, BSc (Pharm), MSc
Vernon Tay1, BSc (Pharm) (Hons)
Vimal Sachdeva2, MSc
Associate Professor Chan Lai Wah1, BSc (Pharm) (Hons), PhD

1Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543
2Technical Officer (Senior Inspector), World Health Organization, Prequalification Team, Regulation of Medicines and Other Heath Technologies (RHT), Essential Medicines and Health Products (EMP), Health Systems and Innovation, 20 Avenue Appia, CH-1211 Geneva 27, Switzerland

Acronyms and abbreviation

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Author for correspondence: Adjunct Associate Professor Sia Chong Hock, BSc (Pharm), MSc, Senior Consultant (Audit and Licensing) and Director (Quality Assurance), Health Products Regulation Group, Health Sciences Authority Singapore, 11 Biopolis Way, #11-01 Helios, Singapore 138667

Disclosure of Conflict of Interest Statement is available upon request.

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Global challenges in the manufacture, regulation and international harmonization of GMP and quality standards for biopharmaceuticals

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Author byline as per print journal: Adjunct Associate Professor Sia Chong Hock, BSc (Pharm), MSc; Associate Professor Sia Ming Kian, BSc (Pharm) (Hons); Chan Lai Wah, BSc (Pharm) (Hons), PhD

Abstract:
Biopharmaceuticals belong to a class of medicinal products whose active pharmaceutical ingredient (API) is manufactured using living systems such as microbial and mammalian cells. With the patent expiry of the originator biopharmaceuticals, a surge in the production of biopharmaceuticals in the form of biosimilars is to be expected. However, biopharmaceuticals are inherently more complex than conventional chemical-based pharmaceuticals, hence requiring a more complicated manufacturing process. This paper provides a brief overview of the biopharmaceutical manufacturing processes and reveals that most biopharmaceuticals share similar processes and considerations. The complex nature of biopharmaceuticals presents various manufacturing challenges such as the inherent variation in quality and demand for extensive process and product understanding. Furthermore, downstream processing bottleneck also presents another manufacturing challenge. A brief comparison of the good manufacturing practice (GMP) standards of various regulatory authorities (RAs) and international organizations (IOs) reveals that the standards are largely similar and appropriate in addressing the manufacturing challenges. This review is one of the few covering the biopharmaceutical industry and the regulatory framework of the Association of South East Asian Nations (ASEAN). However, GMP alone does not address regulatory challenges such as evaluation of biosimilarity, differing outlook on interchangeability and a growing occurrence of data integrity lapses. Solutions such as the implementation of Industry 4.0, improved harmonization of regulatory efforts and creating a culture of quality within the organization may help to address the forgoing challenges.

Submitted: 6 May 2020; Revised: 26 May 2020; Accepted: 26 May 2020; Published online first: 8 June 2020

Introduction

Biopharmaceuticals belong to a class of medicinal products whose active pharmaceutical ingredient (API) is manufactured using living systems such as microbial, mammalian, insect, plant or animal cells. According to the Pharmaceutical Inspection Co-operation Scheme (PIC/S), a medicinal product is defined as any medicine or similar product intended for human use, which is subject to control under health legislation [1]. The API in the medicinal product is responsible for furnishing a pharmacological or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of the disease, or alteration of the structure or function of the body [2].

Depending on the regulatory authorities (RAs), biopharmaceuticals may be termed as ‘biologics’, ‘biological medicines’ or ‘biotherapeutics’ [3–5]. Biotechnological methods such as ex vivo expansion [6–8], recombinant deoxyribonucleic acid (rDNA) or hybridoma technologies are typically employed to produce biopharmaceuticals. Examples of biopharmaceuticals are vaccines, insulins, monoclonal antibodies (mAbs) and other therapeutic proteins [9]. Cell-based, tissue-based or gene-based therapeutic products, also known as advanced therapy medicinal products (ATMPs) in the European Union (EU), are also considered biopharmaceuticals [10]. Biosimilars, also termed ‘subsequent-entry biologics’ and ‘similar biotherapeutic products’, are biopharmaceuticals which are highly similar in terms of safety, efficacy and quality with the innovator biopharmaceutical [11]. Such similarities are demonstrated using comparability studies with the reference product, which is the innovator biopharmaceutical that has received market authorization by the relevant RAs [12].

Frost & Sullivan has estimated that US$16.83 billion worth of biopharmaceuticals in the global market would lose their patent from 2015 to 2025. The global biosimilar market is expected to grow at a compound annual growth rate of 31.5% and reach US$66.33 billion during the same period [13]. Given the highly promising outlook of the biopharmaceutical market, manufacturers are motivated to invest in the manufacturing of biopharmaceuticals. However, there are major differences between biopharmaceuticals and the conventional chemical-based pharmaceuticals which may necessitate the use of different types of manufacturing facilities and standards.

Biopharmaceuticals consist of API molecules with a highly complex structure and very high molecular mass [14], ranging from thousands to hundred thousands of Daltons. In comparison, conventional chemical-based pharmaceuticals consist of API molecules that are significantly smaller, and possess a much simpler molecular structure, see Figure 1. As such, the characterization of biopharmaceuticals may require different analytical tools and methods such as post-translational modification characterization for recombinant therapeutic proteins [15], viral ­vector sequence analysis for gene-based therapeutic products [16] and reverse transcriptase polymerase chain reaction (RT-PCR) for stem cell therapies [17].

Figure 1

Biopharmaceuticals commonly exist as injectables [19]. This is because of the large molecular weight which hinders penetration of the molecule through the intestinal epithelium, thereby reducing systemic absorption [20]. In addition, most biopharmaceuticals are highly susceptible to degradation by the extreme pH conditions in the alimentary canal [21]. Thus, injectables remain the only viable option as they allow the molecules to bypass these obstacles. In comparison, chemical-based pharmaceuticals exist in a variety of dosage forms such as tablets, injections, nasal sprays and topical products.

Unlike conventional pharmaceuticals whose quality can be consistently assured, there exists an inherent variability in the quality of biopharmaceuticals which is largely due to their sensitivity to various conditions such as temperature, pH and mechanical stress [22]. Exposure to these factors can easily affect the quality, safety and efficacy of the end product. Therefore, monitoring these conditions is crucial to ensure that these conditions vary within appropriate specified limits. Clearly, significant challenges are encountered in the manufacture of biopharmaceuticals, and it is vital to adopt relevant GMP guidelines. According to the PIC/S, GMP ensures that ‘products are consistently produced and controlled to the quality standards appropriate for their intended use and as required by the marketing authorisation or product specification’ [23]. This perspective is also shared by the various RAs and World Health Organization (WHO) [24–26].

The increasingly globalised nature of commerce allows manufacturers to outsource activities such as procurement of raw materials overseas, where different regulatory requirements may exist. Thus, there is a need to ensure that the GMP guidelines adopted by the RAs and international organizations (IOs) are harmonized and robust. A robust set of GMP guidelines helps to safeguard public health by assuring the quality, safety and efficacy of the biopharmaceuticals [26]. To date, review on the biopharmaceutical regulatory framework has been done on western countries, such as Canada and the US, as well as some Asian countries, such as Japan and Korea [27, 28]. However, few studies have been done on the regulatory framework for biopharmaceuticals in the ­Association of South East Asian Nations (ASEAN), with the exception of Singapore and Malaysia [27, 29].

ASEAN provides numerous incentives to biopharmaceutical manufacturers. The low manufacturing cost in some ASEAN Member States (AMS) enables greater cost-savings in the manufacture of biosimilars [30]. In addition, ASEAN is experiencing a general epidemiological shift from communicable to non-communicable chronic diseases [31], and biopharmaceuticals play an increasing role in managing the latter. With a combined population of 600 million, the ASEAN market will provide a sizeable patient population that attracts the importation and manufacturing of biopharmaceuticals in the region [32]. Thus, there is a need to ensure that the GMP guidelines adopted are adequate in assuring the quality of biopharmaceuticals.

Therefore, the aims of this project are firstly, to understand the challenges in the manufacture of biopharmaceuticals, excluding those derived from transgenic plants and animals due to their relatively inefficient commercial scalability [33, 34]. Secondly, this project aims to analyse the GMP standards of various RAs and IOs and determine if the regulatory frameworks adopted are suitable in addressing the challenges of biopharmaceuticals. Lastly, biopharmaceuticals also present unique regulatory challenges which will be discussed in later sections. Where necessary, solutions will be proposed to promote greater harmonization of GMP standards, with the ultimate goal of improving patient safety through better regulatory capacity.

Manufacture of biopharmaceuticals – an overview

Figure 2 shows the general processes involved in biopharmaceutical manufacturing. The processes involved are generally similar and are divided into two main stages – upstream and ­downstream processing. The upstream processes are briefly described in 2.1 to 2.3 while the downstream processes and ­formulation are described in 2.4 and 2.5, respectively. For all processes, controls on process variability and contamination should be highly ­prioritized and their risk mitigated with appropriate strategies [35].

Figure 2

Procurement and testing of biological starting materials
Starting materials used in the production of biopharmaceuticals include culture media, buffers and expression systems such as microbial or mammalian cells, and exclude packaging materials [36, 37]. The source, origin and suitability of starting materials should be clearly defined [1]. Western blotting, capillary electrophoresis and high-performance liquid chromatography (HPLC) are common analytical tools employed to assess the identity and purity of starting materials [38]. In addition, adequate controls, such as qualification of supplier through audits, screening for adventitious agents and viral reduction strategies should be in place to assure end product safety [39]. Where the starting materials are of human or animal origin, appropriate documentation on characteristics, such as general donor health status and age [40], should be demonstrated and meet relevant national legislation [1]. This requirement is especially relevant to ATMPs such as Chimeric Antigen Receptor (CAR) T cells, where the T cells are isolated from donors via apheresis [41].

Generation and characterization of cell banks/seed lots
The development of cell banks and seed lots begin with the construction of the vector and recombinant gene. Bacterial plasmids and cells are common choices for vector construction, and bacterial gene is manipulated using enzymes such as nucleases to insert the recombinant gene. Gene delivery into the host cells is achieved via transfection with replication-defective viruses, physical or chemical means. The choice of host cells is dependent on the type of biopharmaceuticals. In general, Chinese hamster ovary (CHO) cells dominate the manufacturing of mAbs [42], microbial cells such as Escherichia coli (E. coli) are commonly applied for simpler recombinant proteins that do not require post-translational modifications [43] and human embryonic kidney 293 (HEK-293) cells are commonly used to generate viral vectors [44]. The appropriate cell lines or seed lots are selected to establish the master bank of cell lines or seed lots. Extensive characterization of the master bank is crucial as it will be used to generate the working cells or seed lots. Titre amount, growth robustness, phenotypic and genetic stability are key considerations when selecting the master bank [45]. Cryopreservation is an essential strategy for prolonged storage of cell banks and seed lots [46].

Cell culturing
This process is responsible for producing the API. It is either done in a fed-batch or continuous manner, with fed-batch being more widely employed [47]. For tissue-based ATMPs, additional considerations should be given to the scaffolds where the cells will be seeded on. These scaffolds should not be immunogenic, and because they are derived from animal or human sources, measures to prevent contamination and disease transmission are crucial [48]. In fed-batch, the culture is expanded via sequential scaling up using bioreactors of increasing volumes, up to the maximum cell density. The cell culture is terminated before the death phase and the culture medium is harvested.

In comparison, continuous cell culture begins with the scaling up of cell culture to an optimum cell density. The culture medium is continuously harvested while fresh medium is added at the same rate to maintain the cell density, which should theoretically produce API of more consistent quality [49]. Continuous cell culture typically has a smaller footprint requirement than fed-batch cell culture due to the smaller bioreactors used [50]. However, it is generally more complex and costly to operate and to validate continuous fermentation [51, 52].

Isolation, concentration and purification of API
Downstream processing is commonly done batchwise [53] and entails the recovery, intermediate purification and polishing (RIPP) stages. The general guidelines governing the design of downstream processing are outlined in Table 1 [54].

Table 1

During the recovery stage, the API is separated from the harvested culture medium and subsequently concentrated. The localization of API is a crucial influence of the purification stage. For intracellular API, which is typically produced by microbial cells, cell lysis is essential for releasing the API. As such, further purification from cellular debris is necessary. In comparison, API produced by mammalian cells is typically secreted extracellularly, hence direct purification can be employed. Besides removal of impurities, viral inactivation or removal are generally necessary [55]. However, the latter is not appropriate for gene therapy API as it can damage the viral vectors [56]. Any remaining impurities are removed in the polishing stage. Table 2 lists the common methods used in each stage [57]. Where procedures that reduce bioburden cannot be applied, aseptic methods should be used [58].

Table 2

Formulation and filling
At the final stage, the API is combined with excipients such as buffers, salts and preservatives to prevent product degradation or contamination [59]. In addition, biopharmaceuticals are commonly formulated as freeze-dried powders, if immediate use is not required, due to their limited stability in liquid form [60]. Furthermore, considerations must be given to the packaging materials used. In general, the packaging material should not interact with the API in a manner that jeopardises the quality, such as leaching of materials into the product or structural alteration due to adsorption of API onto the packaging material [61].

Challenges concerning manufacture of biopharmaceuticals

Extensive process and product understanding required
As the quality of biopharmaceuticals is influenced by the processing steps [62], the latter must be designed such that the critical quality attributes (CQAs) of biopharmaceuticals remain within specifications [63]. CQAs are ‘analytical measures’ associated with the quality, safety and efficacy of a biopharmaceutical, such as absence of contaminants [64]. Inappropriate processing steps can adversely impact the quality. For instance, most recombinant glycoproteins except mAbs are prone to aggregation and dimerization in prolonged residence time hence fed-batch fermentation is inappropriate for these proteins [65]. In addition, any changes to the processes or formulation must be validated to assure that these changes do not significantly jeopardise product quality. This is exemplified by the infamous pure red cell aplasia (PRCA) incident associated with Eprex® (epoetin alfa), where the insufficiently validated formulation changes are associated with a surge in PRCA incidence amongst Eprex®-treated patients [66]. Hence, an extensive knowledge on the CQAs of biopharmaceuticals, together with appropriate validation, is crucial in assuring product quality.

Inherent variability of host cells
The inherent variability of the host cells can have unpredictable effects on the quality of biopharmaceuticals. This is exemplified by the widely employed CHO cells, whose genomic plasticity allows gene manipulation to produce the desired cell lines [67]. However, this has also contributed to cell line instability such as gene silencing [68]. In addition, the requirement for cell lines to produce high titre amount places considerable metabolic stress on the host cells, resulting in spontaneous recombinant gene deletion that may be difficult to predict [69, 70]. These factors will present obstacles in ensuring consistent product quality.

Downstream processing remains a key bottleneck
Downstream processing is commonly considered to be the key bottleneck of biopharmaceutical manufacturing, with chromatography being the most commonly cited [71]. Chromatographic separation is based on the degree of association between the individual components of the culture content and the stationary columns, and the separation efficiency can be modified by altering conditions such as ionic strength, pH and polarity. The designing of a chromatographic purification process has proven challenging owing to a lack of standardization arising from the myriad of chromatography modes and equipment to consider [72]. Thus, the designing process has traditionally taken a trial-and-error approach, which can be wasteful and time consuming [72].

Review of current GMP frameworks for biopharmaceuticals

Table 3 shows a comparison of GMP principles and guidance documents adopted by selected RAs and IOs. They are chosen because most of them are key players in regulatory harmonization or biopharmaceutical manufacturing [27, 29, 73]. In general, IOs and majority of the RAs adopt similar GMP principles. They emphasize on the implementation of quality risk management (QRM) principles: (1) risk evaluation should be scientifically sound and relevant to protection of patient; and (2) the amount of resources used for risk management should be proportional to the risk level [74]. QRM also facilitates better management of the manufacturing process by identifying and prioritizing the control on critical process parameters (CPPs) [75], as their variability can impact the CQAs and consequently the product quality [76]. Most guidelines acknowledge the inherent variability of biopharmaceutical quality and recommend using in-process controls and improving the robustness of manufacturing process to control the variability [1, 37, 77]. Table 3 also shows that most RAs and IOs adopt relatively similar GMP standards for API, suggesting a significant level of harmonization is already in place. However, there are major differences in the scope of the GMP standards. For instance, PIC/S provides guidance on all types of biopharmaceuticals within Annex 2 of its GMP guide, while the European Medicines Agency (EMA) provides recommendations for ATMPs in a dedicated guidance (Eudralex, Volume 4, Part IV) [78]. However, it is noted that PIC/S is currently drafting a dedicated GMP guide for ATMPs which may be implemented in the future [79]. In addition, PIC/S provides further guidance for selected types of biopharmaceuticals in Annex 2 Part B of its GMP guide [1] while WHO does not [37].

Table 3

Furthermore, the National Medical Products Administration (NMPA) of China has a GMP guideline for API that is not entirely relevant to biopharmaceutical APIs. This guideline provides recommendations on API produced by classical fermentation, which typically do not employ biotechnological processes and requires less stringent control on the manufacturing processes [80]. In addition, the APIs produced by classical fermentation, such as antibiotics, amino acids and vitamins, are generally of low molecular weights [77]. Instead, GMP pertaining to biopharmaceuticals and their APIs are covered under the Chinese GMP Annex 3 only. NMPA, being a regulatory member of the International Council for Harmonisation (ICH), is expected to implement ICH Q7 guideline – GMP Guide for API [81]. Hence, NMPA’s GMP guideline on API is likely to be harmonized with international standards. However, since NMPA is not expected to implement ICH Q5 guideline – Quality of Biotechnological Products, it is difficult to ascertain whether NMPA’s GMP standards on finished biopharmaceuticals are harmonized with international standards.

The Central Drugs Standard Control Organisation (CDSCO) of India, for instance, does not explicitly mention about the inclusion of biopharmaceuticals within the scope of its GMP guideline (Schedule M) [82]. However, the provisions appear to be adequate for biopharmaceuticals and also suggest that CDSCO adopts similar GMP principles as the well-established RAs and IOs. There is an additional guideline document for biopharmaceuticals on the CDSCO website, but it was inaccessible at the time of writing this review. It is worth mentioning that both China and India are currently undergoing regulatory reforms and have expressed interest to join PIC/S [83]. There are also reports that Chinese and Indian manufacturers are improving their product quality to meet international standards [84, 85], signalling their strong commitment to GMP.

Within ASEAN, the biopharmaceutical industry is at a nascent stage. Vaccines are the main biopharmaceuticals manufactured due to the high prevalence of infectious diseases [86]. In addition, there have been reports of vaccine shortages in ASEAN which may necessitate prioritizing vaccines over other biopharmaceuticals [87]. The review of ASEAN GMP standards reveals that the majority of AMS adopt PIC/S GMP recommendations for biopharmaceuticals [88–91]. The lack of unified adoption can be attributed to the current exclusion of biopharmaceuticals from the scope of the ASEAN Mutual Recognition Arrangement (MRA) [92]. In addition, some AMS are emphasizing on generic pharmaceutical manufacturing [93, 94] and medical devices [95], which may also contribute to the lack of GMP guidelines for biopharmaceuticals. However, efforts have been made, such as the recent agreement on the ASEAN common technical requirements of biological products [96], to include biopharmaceuticals for harmonization in the future [97].

Overall, the differences in the scope of GMP standards observed is not surprising in view of the diversity of biopharmaceuticals being manufactured, and that GMP guidance is contextualised to the respective countries. It is however heartening to know that most RAs and IOs share similar GMP principles for regulating biopharmaceuticals. With concerted efforts, the outlook on harmonization is bright. Nonetheless, it must be emphasized that the adequacy of GMP and quality standards adopted by the various RAs and IOs, will ultimately depend on the extent of compliance by the biopharmaceutical manufacturers, and the robustness of enforcement of the standards by the RAs and IOs.

Challenges in the regulation of biopharmaceuticals

Resource-intensive evaluation of biosimilarity
The standard approach for approving generic conventional chemical-based pharmaceuticals, or generics, is not appropriate for biosimilars. For the approval of generics, manufacturers only need to demonstrate that the generics have identical molecular structure and is bioequivalent to the reference product [98]. However, the inherent variability of biopharmaceuticals makes it impossible for biosimilars to exactly replicate the reference product. Manufacturers may have to modify the manufacturing process based on the reference product with appropriate optimization such that the CQAs of biosimilars are highly similar to that of the reference product [99]. There will be differences, albeit slight, in the processing that can affect the end product of biological nature. Hence, a ‘totality-of-the-evidence’ approach is used to evaluate biosimilarity. This approach considers the entirety of the information submitted in the biosimilar application, such as data from analytical, preclinical, clinical studies and lot-to-lot variabilities, to evaluate the biosimilarity to the reference product [100]. The approval of biosimilars places more emphasis on extensive characterization of the API [101], with supplementary data from animal studies, clinical pharmacology or clinical trials to rule out any residual uncertainty from the characterization process [102]. Compared to chemical-based pharmaceuticals, the evaluation process clearly demands more time and expertise for the RAs. In addition, doubts have been cast on the suitability of the guidance for biosimilarity evaluation in assessing more complex biopharmaceuticals such as ATMPs [103]. Such uncertainty thus raises the need for more harmonization between different regulatory perspectives.

Differing perspectives on interchangeability
Differences exist between FDA and EMA perspectives on interchangeability. For FDA, biopharmaceuticals that are highly similar to the reference product can be classified as biosimilar product or interchangeable product. For the product to be classified as interchangeable, additional data on the safety and efficacy of switching from the reference product must be provided [104]. Once an interchangeable product is approved, the reference product may be substituted with the interchangeable product by the pharmacist without consulting the prescriber. In comparison, EMA does not require additional studies to determine if a biosimilar is interchangeable. However, EMA distinguishes the act of interchanging between reference product and biosimilar, or between biosimilars, into switching and substitution: switching is done at the prescriber level while substitution is done at the pharmacy level [14]. Differences in definition can lead to unnecessary confusion when manufacturers want their products approved for use in different countries. While the requirement for a switching study can provide better safety assurance of the interchangeable product, this also increases the production cost and possibly negate any cost savings it has over the reference product. This may also explain why there has been no interchangeable products approved by FDA currently [105, 106]. In addition, the vast clinical experience of EMA in approving biosimilars has demonstrated that biosimilars have similar efficacy and safety profiles as their reference product [107]. This is also supported by a systematic review which did not show any safety or efficacy risk from switching between reference products and biosimilars [108]. Thus, the requirement by FDA for a switching study to demonstrate interchangeability is debatable.

Growing number of data integrity lapses
‘Data integrity is the degree to which a collection of data is complete, consistent and accurate throughout the data life cycle. The collected data should be attributable, legible, ­contemporaneously recorded, original or a true copy, and accurate (ALCOA). Assuring data integrity requires appropriate quality and risk management systems, including adherence to sound scientific principles and good documentation practices’ [109, 110]. FDA has noted an increasing number of GMP violations pertaining to data integrity in recent years [111]. Compromised data integrity can lead to missing and inaccurate information that are vital considerations in the regulatory approval for market authorization [112], as well as jeopardising product quality assurance [113]. Lapses can be due to unintentional errors such as lack of awareness as well as inadequate standard operating procedures (SOPs) [114]. In more serious cases, deliberate data manipulations, such as data falsification instructed by upper management, have been reported [115, 116]. A review of the warning letters issued by the Center for Biologics Evaluation and Research (CBER) reveals that data manipulation can occur despite the implementation of legislative guidelines, SOPs and controls [117–119], hinting a possible lack of a quality-focused culture within these organizations.

Proposed solutions to challenges of biopharmaceuticals

Optimizing biopharmaceutical manufacturing with ­Industry 4.0
Industry 4.0, or the Fourth Industrial Revolution, is a broad concept that involves the amalgamation of physical and digital technologies to generate a constant flow of information, allowing real-time data access [120]. These data can then be applied to generate analytical tools such as algorithms and models to allow better process and product understanding [121]. Consequently, this allows more effective implementation of Quality-by-Design (QbD) approach in process development and optimization [122]. According to ICH, QbD is a ‘systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management’ [76]. With QbD, process capability is improved with better product and process understanding, which in turn reduces the inherent variation in quality of biopharmaceuticals [123].

Real-time data access can be achieved with process analytical technologies (PAT). FDA considers PAT as ‘a system for designing, analysing, and controlling manufacturing through timely measurements, i.e. during processing, of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality’ [124]. The general methodology of PAT begins with the collection of data using robust, rapid and sensitive analytical tools and sensors, such as HPLC, dynamic light scattering, pressure gauge and flow meter [125]. This is followed by the modelling of these data to generate useful process-related information and ends with the goal of using the generated data to influence the manufacturing processes [126]. For instance, PAT has been used to optimize downstream processing. This is achieved by combining the screening of previously validated chromatographic conditions with scientifically sound experiments to generate a chromatographic model that is able to predict critical process parameters for downstream optimization [127, 128]. In addition, deviations captured during routine monitoring can also be used to generate algorithms that can better categorize human errors or facilitate more effective corrective actions and ­preventive actions (CAPAs), thereby reducing the occurrence of failed batches as well as the cost of implementing CAPAs [129].

Industry 4.0 has allowed greater interconnectivity through platforms such as the Internet of Things (IoT), providing worldwide access to data to facilitate better process understanding. For instance, a better understanding of the CHO cell genome is achieved by pooling data from various assemblies generated by the other researchers using sequencing technologies such as short-read Illumina and single molecule real time (SMRT) sequencing [130]. With a better understanding of the genome, manufacturers may manipulate the gene more effectively and improve host-cell stability, consequently leading to more consistent product quality.

Enhanced harmonization efforts on biosimilar guidelines
With the expected influx of biosimilars due to patent expiry of the reference product, there is a need for RAs to develop guidelines that facilitate the clinical decision to choose between the reference product and biosimilars, switching between reference product and biosimilars, or switching between biosimilars as a potential therapeutic option. Although EMA does not provide recommendations on interchangeability and leave the development of substitution policies to its Member States [131], countries such as Germany, The Netherland and Scotland have endorsed the interchangeability of biosimilars [132]. In general, these countries recommend that the decision of switching should be based on shared decision-making between the patient and prescriber on the potential risks of switching, along with appropriate monitoring for early detection of adverse event [14, 133–135]. Such perspective is logically sound as it ensures that any clinical decision made is in the patient’s best interest. It is worthwhile to encourage RAs of these countries to share their regulatory experience so that other RAs can make a more informed choice when developing guidelines relating to the use of biosimilars. Such concerted efforts will promote harmonization of guidelines.

Enhancing data integrity with a culture of quality (quality culture)
Without a culture of quality, even the simplest and preventable data integrity-related violations can occur [136]. This is because the organizational culture directly impacts routine operations which have a downstream influence on data and product quality, and senior management is responsible for creating a culture of quality [137]. A critical element of quality culture is the ‘transparent and open reporting’ of data integrity-related violations at all organizational levels [109]. Measures such as an independent reporting channel, anonymous or identifiable, or rewarding employees who report quality-related issues can help to incentivise employees to voice out their concerns [138]. A culture of quality can be created by first incorporating the ‘Leader 5Vs’ that correlate with a positive influence on quality culture [139], which are further explained in Table 4 [140]. In essence, the table emphasizes on the importance of senior management in creating a vision, leading by example, empowering their employees towards quality excellence. Senior management is encouraged to look at WHO guidance on data integrity as it provides practical recommendations on building a quality ­culture [138].

Table 4

In facilitating a behavioural change, employers may consider the ABC (antecedent, behaviour, consequence) model: where an antecedent encourages a behaviour and leads to a consequence, which in turn influences the recurrence of behaviours [141], see Figure 3. While antecedents are essential in triggering a behaviour, it is the consequence that significantly motivates or demotivates the latter [142]. As such, in the implementation measures to effectively correct a behaviour, consequences should be emphasized over antecedents. In addition, a ratio of positive to negative consequences at 4:1 is recommended to sustain performance outcomes [141].

Figure 3

Employees are also crucial in transforming the organizational culture [143]. Training for employees should help them understand the organization’s quality objectives, SOPs and their individual role in achieving said objectives [144]. In addition, they should leverage on the ‘speak up’ culture to provide feedback on how the senior management can customise the quality culture messages to be more relevant to their work [145].

Developing a culture of quality excellence is not an instantaneous process as it requires a change of mindsets: senior management must drive the change while employees must be motivated to change. An effective collaboration at all organizational levels will ensure that the change can be expedited, and the culture remains sustainable in the long term.

List of abbreviations

Conclusion

With the patent expiry of innovator biopharmaceuticals, more biosimilars will be developed for use. In general, this paper has shown that most biopharmaceuticals share similar manufacturing processes and considerations, providing useful insights for manufacturers who are interested to include biosimilars in their pipeline. However, it is still highly advisable for manufacturers to demonstrate an extensive product and process understanding as there may be certain methods that are not suitable or relevant for their product. Due to their inherent complexity, biopharmaceuticals present challenges in assuring product quality. This can be addressed with real-time monitoring and better predictive modelling, as well as other solutions that are not discussed in this paper.

For the RAs and IOs, the outlook on GMP harmonization for biopharmaceuticals is highly promising. As countries improve and harmonize their GMP standards, there will be a greater assurance of quality and safety of biopharmaceuticals. However, more effort is needed in providing guidelines on the interchangeability of biosimilars to encourage their use. With greater collaboration among RAs and IOs, practical experience can be shared, and this can facilitate improvement of existing guidelines. The challenges presented by biopharmaceuticals, although daunting, are not insurmountable. With technological advances and better collaboration between key stakeholders, these challenges can be effectively managed.

Competing interests: None.

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

Authors

Adjunct Associate Professor Sia Chong Hock, BSc (Pharm), MSc
Sia Ming Kian, BSc (Pharm) (Hons)
Associate Professor Chan Lai Wah, BSc (Pharm) (Hons), PhD

Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543

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Author for correspondence: Adjunct Associate Professor Sia Chong Hock, Senior Consultant (Audit and Licensing) and Director (Quality Assurance), Health Products Regulation Group, Health Sciences Authority Singapore, 11 Biopolis Way, #11-01 Helios, Singapore 138667

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Current trends for biosimilars in the Latin American market

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Author byline as per print journal: Esteban Ortiz-Prado1,2, MD, MSc, MPH, PhD; Jorge Ponce-Zea3, MSc; Jorge E Vasconez1, MD; Diana Castillo,1, MD; Diana C Checa-Jaramillo1, MD; Nathalia Rodrí­guez-Burneo1, MD; Felipe Andrade2, MD; Damaris P Intriago-Baldeón4, MSc; Claudio Galarza-Maldonado5, MD, PhD

Abstract:
The number of approved biological medicines in the global pharmaceutical market has increased in recent decades. However, their high costs have also promoted the development of biosimilar medicines, following the expiry of the patent of the reference drug. Biosimilars are approved medicines of biological origin which have no statistically significant differences in terms of quality, safety and therapeutic efficacy in comparison with the reference biological. Drugs marketed as biomimics meanwhile are copies of monoclonal antibodies and fusion proteins that have not demonstrated bioequivalence to their reference biologicals. Across the world, regulations have been developed to ensure the safety and efficacy of biosimilar products, which can reduce public health expenditure and improve patient access to biological medicines. As a result, Latin America has begun to invest in the development of these drugs. The objective of this literature review is to describe the development of the biosimilar and biomimic market in Latin America.

Submitted: 7 January 2020; Revised: 10 April 2020; Accepted: 23 April 2020; Published online first: 6 May 2020

Introduction

Biological medicines have become a major market for the pharmaceutical industry, the biologicals market was valued at US$ 254.9 billion in 2017 and is expected to reach US$ 580.5 billion by 2026 at a compound annual growth rate (CAGR) of 9.5% during the forecast period from 2018 to 2026 [1]. In the coming five years, the patents of many essential biological medicines such as Cosentyx, Kadcyla, Removab or Soliris will expire, providing opportunities for biosimilar development [2–4].

Biosimilars can be defined as biotherapeutic products which have no statistically significant differences in quality, safety and efficacy to an already licensed reference biotherapeutic [5]. Unlike small molecule generics, biologicals are larger and more complex and therefore production can be difficult to standardize, even within the same manufacturer [6].

The first biosimilar approved in the European Union (EU) was the human growth hormone Omnitrope (somatotropin) in 2006. By end of 2019, 64 biosimilars within the product classes of (1) human growth hormone; (2) granulocyte colony-stimulating ­factor; (3) erythropoiesis stimulating agent; (4) insulin; (5) follicle-stimulating hormone (FSH); (6) parathyroid hormone; (7) tumour necrosis factor (TNF)-inhibitor; and (8) monoclonal antibodies have been approved in the EU [7]. In contrast, 26 biosimilars within the product classes of (1) anti-tumour necrosis factor-alpha (TNF-α); (2) monoclonal antibodies; and (3) granulocyte colony-stimulating ­factor, plus four follow-on biologicals in the product classes of insulin (Admelog, Basaglar and Lusduna) and teriparatide (PF708), have been approved in the US [8], while 94 biological and ­biosimilar products including biomimics for 27 biological molecules have marketing authorization in Latin America, see Table 1.

Table 1

Biosimilars have changed the dynamics of the biologicals market and lowered healthcare costs. They also represent a market opportunity for small and medium-sized pharmaceutical companies that cannot afford to develop new biological medicines. Generally, the development of biosimilars involves lower production costs; the estimated cost of developing and gaining approval for a biosimilar ranged between US$100 million and US$200 million [9, 10], compared to an average cost of US$1.3 billion of bringing a new originator drug to market [11].

An estimated 182 companies around the world are trying to market biosimilars [12]. These companies are reshaping the global pharmaceutical market by lowering prices for biological drugs. Examples of world leading companies include Amgen, Biogen, Merck & Co, Pfizer, Sandoz and Teva; companies that are based in Europe, Israel and the US. Although most leading companies are based in high-income countries, Asian nations such as China, India and South Korea are gaining increasing market share [13]. The future may appear brighter for developed nations, due to their technical facilities, capital availability and market opportunities, however, biosimilar development in the Latin American region is also developing [14].

The context for the development of biosimilars in Latin America is highly diverse due to peculiarities related to economic, political, regulatory and cultural factors. The nature of government policies, regulatory agencies, public and private health providers, payers, multinational pharmaceutical companies, local companies, physicians and patients differ in every Latin American country, each of which has a unique market and regulatory landscape [15].

Methods

Study design and setting
This is a descriptive analysis of the evidence surrounding the market for biosimilars and biological products in Latin America. This review offers an insight into the biosimilar products being developed in Latin America and can be classified as an ‘expert literature review’, according to Grant’s classification [16]. The search and analysis were conducted from Ecuador, South America using the DelphiS cross-searching tool, which searches across the University of Southampton’s printed and electronic resources, as well as major subject databases and indexes.

Data sources
Information from primary and secondary sources were obtained via EBSCO research databases using the DelphiS library engine. Databases included the following: EBSCO, JSTOR, Clarivate Analytics, PubMed/Medline, OVID, ScienceDirect, Web of Science, EMBASE and Europe PMC.

Search strategy
Indexed manuscripts were retrieved using the Boolean operators AND/OR in combination with the words ‘biosimilar’, ‘biosimilares’ (Spanish), ‘biological drugs’ or ‘medicamentos biologicos’ (Spanish). This search combined the term ‘South America’ and the word ‘Latin’, using the truncation mark (*) to include all documents that contain the specified word at the beginning of the search with the word ‘market’, in both English and Spanish.

Inclusion and exclusion criteria
All manuscripts that described the biosimilar market in Latin America were included. Manuscripts that did not contain the word ‘market’ in the title or abstract were excluded.

Study selection and analysis
In addition to research papers, trade publications, government documents, official statistics and technical reports were also included in the analysis. With the collected data, a description and analysis of the current situation regarding the development of biosimilars in each Latin American nation were performed by the authors. Similarities between countries were discussed, and strategies for optimized biosimilar development were proposed. A separate search was performed for each country (Argentina, Bolivia, Brazil, Canada, Chile, Colombia, Cuba, Dominican Republic, Ecuador, El Salvador, Honduras, Mexico, Nicaragua, Panama, Paraguay, Perù, Uruguay, Venezuela and the US) included in this manuscript. After the results were obtained, we combined the search. All relevant scientific publications published between January 1990 to December 2017 were reviewed against the inclusion and exclusion criteria by four members of our team.

Appraisal of the literature
All manuscripts included in the literature review were critically appraised using the Critical Appraisal Skills Programme tool (CASP checklist) for the specific type of article. This tool aims to identify potential threats to the validity of the research findings while offering a quantitative evaluation of every study.

Leading players in the Latin American biosimilar market

Argentina, Brazil and Mexico have the largest number of approved biosimilars/biomimics in Latin America; with 44 products approved in total, see Table 2.

Table 2Argentina
The Argentinian biosimilar industry was established in 1983 with the creation of Biosidus, the company that made the first biosimilar in South America, erythropoietin, which was released onto the market in 1990. There is growing interest in the development of the biosimilar industry in Argentina, which is supported by government policies. This is described in the government’s Science and Technology plan, Argentina Innovadora 2020: Plan Nacional de Ciencia, Tecnología e Innovación, which outlines public strategies to support the development of the biosimilar value chain [17]. In 2011, Argentina produced 650 million doses of generic and biosimilar drugs, of which domestic laboratories manufactured 63%. Exports in the same period accounted for US$850 million in revenue [18–21]. PharmADN Laboratory of the Grupo Insud was the first facility in South America to produce biosimilar monoclonal antibodies. This achievement constituted a significant milestone for the Argentinian pharmaceutical ­industry, since such drugs were previously imported at the expense of US$250 million per year [22].

Brazil
In Brazil, biosimilar products represent 2% of the drugs paid for and distributed by the Brazilian government. However, the acquisition of these products accounts for 41% of the Ministry of Health’s total expenditure [23]. This mismatch is likely due to the fact that biosimilars are expensive drugs used to treat a small number of chronic diseases, diseases that are difficult to control if proper treatment is not administered at the right time. In 2011, the government spent US$4.9 billion on importing medicines from eight biopharmaceutical companies, which accounted for 18% of total expenditure [24]. In 2009, ­Brazil became the 10th largest drug producer in the world; retail sales increase by 82.2% between 2007–2011 and approximately US$5.8 billion–US$10.6 billion was made due to this trading trend [14]. Regarding the regulation of biosimilars, Brazil uses World Health Organization (WHO) guidelines as a foundation for its regulation, but with some adjustments. For example, the Brazilian guidelines include two approval regulations, which have been in force since December 2010, to oversee the registration of new biologicals either using individual development or development by comparability. These regulatory measures were developed to promote the local production of biological drugs and to reduce the cost of these medicines [25].

Mexico
In 2012, Mexico had 180 approved biotechnological medicines, representing more than US$2.3 billion dollars of biosimilars sales [26]. A decree that modified the provisions for the regulation of health supplies was published by the Mexican government in 2013. By November 2014, regulation for the registration of biological and biosimilar medicines was finalized. Mexico is home to the second-largest pharmaceutical industry in Latin America. In 2014, the earnings of the Mexican pharmaceutical industry were US$11,430 billion. In 2015, Mexico was the biggest exporter of pharmaceutical products among the Latin American countries [27].

Andean community of nations: Bolivia, Colombia, Ecuador and Perú

There are overall 14 biosimilars/biomimics approved in the Andean community of nations, see Table 3, which have been produced both within and outside of the Latin American region.

Table 3Bolivia
In Bolivia, despite the approval of similar biotherapeutic products (SBPs), the regulatory guideline for SBPs has not yet been formalized by the government [28]. Nevertheless, some companies, such as Biocad, have obtained marketing authorization for their SBPs. The first Russian-made non-originator biological drugs to be launched in Latin America took place in Bolivia and Honduras. No formal information about the profits and/or penetration of those products were found during our search.

Colombia
Sales from the Colombian biomimic market reached US$126,086,839 during 2015–16, according to the Drugs Price Information System (Sistema de Información de Precios de Medicamentos, SISMED) managed by the Government of Colombia [29]. The decree signed in September 2014 intended to reduce the costs of biologicals by 30%–60% [30]. The price difference between originator biological and biosimilars in Latin America can be significant, with some biosimilars being over 50% cheaper than the originator drug [29]. However, national medical information systems in Colombia contain very little information about biological and biosimilar medicines. Furthermore, the guide provided by the Ministry of Public Health and Social Protection (Ministerio de Salud Pública y Protección Social, MSPS) contains limited information regarding the classification and prices of biological and biosimilar drugs currently authorized by the National Institute for Food and Drug Monitoring (Instituto Nacional de Vigilancia de Alimentos y Medicamentos, INVIMA).

Ecuador
In Ecuador, the cost associated with the acquisition of biosimilars is unknown. Nevertheless, due to recent regulatory changes that have facilitated the entry of biosimilars into the country, it is estimated that Ecuador spends at least US$50 million on biological or biosimilar products every year, if both the public and private markets are included [31, 32]. According to the Ministry of Public Health in Ecuador (Ministerio de Salud Pública, MSP), the average selling price of biosimilars (per bottle of injectable product) in the country is US$218 [33, 34].

In 2014, the now closed government-owned pharmaceutical company Enfarma (EP) registered the first biosimilar version of infliximab in Ecuador [32]. Although there are no officially published reports, information suggests that the commercialization of this biosimilar was not successful. Consequently, the innovator product (MabThera) made sales exceeding US$20 million in Ecuador in 2015 [32].

Until recently, biosimilar products have been overtaken by innovators in Ecuador, mainly due to lack of market penetration of biosimilars but also due to unfair commercial practices [35, 36].

Perú
According to data provided by the Ministry of Health in Perú (Ministerio de Salud, MINSA), the National Police Health Directorate (Dirección de Sanidad de la Policia Nacional, DIRSAN) and the social health insurance system (Seguro Social de Salud, EsSALUD), the biotechnological market in Perú, which includes biosimilars, has grown over the last five years. In 2013, expenses related to purchases of biotechnological products reached US$35,561,725. This high expenditure may be related to the fact that there are no domestic manufacturers of biological medicines in Perú; domestic companies only sell finished products [37, 38]. In 2016, the Ministry of Health in Perú released the national biosimilar regulatory framework, which aims to boost the domestic biologicals market in the country.

MERCOSUR: Chile, Paraguay, Uruguay and Venezuela

There is a total of 17 biosimilars/biomimics approved in the MERCOSUR trade bloc, the vast majority of which are in Chile. Paraguay and Uruguay each has only one approved biomimic drug, as summarized in Table 4.

Table 4Chile
In 2014, the Technical Standard for the Sanitary Registry of Biotechnological Products derived from recombinant DNA techniques was approved. This landmark approval means biosimilar products may be registered in Chile using international regulations as reported in previous years for the evaluation and approval of these products [39, 40]. Between 2014–2018, the public sector made purchases of biological and biosimilar medicines, equivalent to 26% of the total number of drugs purchased at a value of over US$143,719,000 [41]. Currently, as in Perú, Chile only imports finished biosimilar products [23].

Paraguay
We were able to find limited reliable data regarding the biosimilar market in Paraguay. In 2011, Paraguay had a Total Pharmaceutical Expenditure of US$445 million, of which US$248 million was private expenditure [28]. In 2016, an agreement was signed between the Argentinian pharmaceutical laboratory Biosidus and Lasca for the production of recombinant human erythropoietin [28]. This alliance accelerates Paraguay’s plans for expansion and capture of new markets in high-tech medicines. Although the alliance was completed, no information about sales or product catalogues could be identified.

Uruguay
Only limited accurate data on the biosimilars market in Uruguay were found. However, in 2015 a reference guide for the control of these products was established. This guide states that it would be necessary to implement strategies to support the training of personnel, promote investments in R & D and update the legal framework in order to boost the biologicals market in Uruguay [42].

Venezuela
The Bolivarian Republic of Venezuela is part of the Mercosur trade bloc, however, in 2019 it was suspended from all the rights and obligations inherent in its statehood. This situation and the economic crisis that currently affects the country has caused local manufacturers, who once generated advanced chemical products, to cease production. There is consequently a lack of access to medicines in Venezuela and only those centres able to import medicines are distributing biosimilars (and even then, at low levels).

The current situation related to the local production of biosimilars in Venezuela is not particularly promising, and currently there are no records regarding the pharmaceutical industry or biosimilars commercialized in the country available [43]. The agency which regulates biosimilar medicines in Venezuela is the Ministry of the Popular Power for Health – National Institute of Hygiene ‘Rafael Rangel’; however, there is no information available regarding current regulation of biosimilars in the country.

Central America and the Caribbean: Costa Rica and Cuba

Several countries in Central America like Guatemala and Panama have legislation for the approval of biological and biosimilar products, [44, 45]. Others, such as El Salvador, have no specific regulation for biosimilars. However, the Salvadorian National Direction of Medicines published a statute for the recognition of foreign medicines regulatory agencies. This statue approves the use of drugs that have been registered in countries that ­fulfil the Pan American Health Organization (PAHO) accreditation process (Level IV certification) [46]. Table 5 provides a list of biosimilars/biomimics approved in Costa Rica and Cuba.

Table 5Costa Rica
In 2010, the Ministry of Health in Costa Rica issued RTCR 440: 2010 – Regulation on the enrolment and control of biological medications [17]. In 2015, the Costa Rican Social Security Fund made the most significant economic investment in purchases of biological drugs in the country’s history, which accounted for over 48% of total investment in medicines (equivalent to approximately US$24 million). The most expensive medicines that were purchased were anti-neoplastic and immunomodulatory drugs [47].

Cuba
In 2011, the Ministry of Public Health in Cuba issued Resolution number 56/2011: requirements for the registration of biological products [48]. This resolution stimulated growth in the biotechnology industry due to investments made by the State and by independent investors, as well as the creation of government-owned pharmaceutical company BioCubaFarma. In 2010, Cuba had a trade balance in the pharmaceutical sector of US$303,606,000 in raw materials [48]. Regarding exports in biopharmaceutical products, the country reached US$686 million in 2013 [49].

Summary

A summary of the approved biosimilars in each of the countries discussed in this manuscript is shown in Tables 1–5. Although most Latin American countries have their own regulations on biosimilars, there are two relevant international trade agreements: the Andean Community of Nations (Comunidad Andina de Naciones, CAN), which relates to countries in the Andean region (Bolivia, Chile, Colombia, Ecuador and Perú); and the Southern Common Market (Mercado Común del Sur, MERCOSUR), which relates to Argentina, Brazil, Paraguay, Uruguay and Venezuela. Both agreements aim to regulate the use of patents in terms of medicines and to control, in someway, the price of medicines in the region. [50, 51].

The most important aspect of these trade agreements lies in the possibility of single consolidated purchases, allowing countries with weaker economies to benefit from greater bargaining power, however, this has so far not been achieved. This means countries must negotiate individually, thus buying at higher prices.

Investment in biosimilars in Latin American countries is increasing year on year, see Table 6 and regulatory authorities in many Latin American countries have been redesigned and standardized for the approval of biosimilars. However, local regulations vary between country.

Table 6

Discussion

Biosimilars have revolutionized the global pharmaceutical ­market by increasing competition and driving down prices, however, difficulties have arisen in the path to commercialization. As it can be assumed that a biosimilar has the similar clinical performance as the innovator drug, and at reduced cost, the biosimilar should in principle always win against the innovator product. However, this is not always the case and in many parts of Latin America, patient access to biosimilars remains limited [52]. Although it is a requirement for a biosimilar to have the similar clinical performance as the innovator product, this is not demonstrable for some biosimilars in Latin America. This is because comparability exercises are not mandatory in the region, allowing many products to enter countries only with a list of homologated documents, a situation that may reduce patient trust in biosimilars.

Economic context, drug markets and marketing strategies vary among countries in Latin America. The availability of information on the market size and the volume of import/export are often lacking, whilst Brazil and Argentina generally will have more information available[13].

In terms of biosimilar availability, three main groups of ­countries in the Americas were identified. The first group includes countries with biosimilars markets that are continuously growing and have fewer barriers to market and commercialize biosimilars. These countries are Argentina, Brazil, Chile, Costa Rica, Colombia, Mexico and Perú. Of particular significance are Argentina, Brazil and Mexico, as these countries are manufacturers of ­biological products and therefore play a pivotal role in providing access to biosimilars in the region.

The second group of countries (Bolivia, Ecuador, Paraguay and Uruguay) have smaller markets that attract less investment from pharmaceutical companies, which in turn reduces access to biosimilars. These countries are consumers and exporters of biological products on a small scale and play a secondary role in the biosimilars market [45].

The final group of countries may be considered atypical due to their political situation; this includes Cuba and Venezuela. Due to the fact they have been forced to close commercial borders with the US and most of its allies, price variability and the lack of access to biosimilars are not uncommon [53].

Hurdles to biosimilar success vary among countries, but a number of common issues were identified. It is important to distinguish countries with advanced technical capabilities and mature markets from those in the development stages. The first group of countries may be in a more favourable position to increase patient access to biosimilars; however, market structure in these countries still favours innovator drugs. In this context, small biotechnology companies cannot compete against the big pharmaceutical companies. This occurs in Argentina and Brazil for example [54]. In addition, in countries like Colombia and Ecuador, prescribers often receive gifts, trips and other benefits from the pharmaceutical industry, which can lead to unethical prescribing, a situation that is very poorly controlled in the region [32].

Latin American countries have an unmet need for biological products at low prices. The main actors in these countries are government regulatory agencies and public healthcare providers. Some countries such as Argentina, Brazil, Cuba and Mexico have efficient procedures and incentives to enhance patient access to biosimilars; whilst others have not yet developed regulatory systems for biosimilars.

Most countries are working to decrease their expenditure related to drugs. However, this is more difficult in Latin America as the market is fragmented and only the larger countries, such as Argentina and Brazil, are attractive to international suppliers of biosimilars. These leading countries therefore determine the timing of biosimilars manufacturing and commercialization in the region.

The purpose of this literature review is to provide an overview of the current state of the biosimilars market in Latin America. Further analysis is required to identify trends in the commercialization of biosimilars in this region. However, we have identified a number of recommendations. To ensure a promising future for the region, Latin American governments should develop robust regulation for biosimilars. They must also strengthen the capacity of their regulatory agencies to assess biosimilar candidates and perform post-market pharmacovigilance on these approved biosimilar products, allowing the timely assessment of effectiveness and identification of adverse effects.

Conclusions

This literature review shows that information regarding the biosimilars market in Latin America is scarce. It appears that the majority of countries in the region have limited experience in the production of biological drugs. The region in general relies on imported products from North America, Europe and Asia. The future of the biosimilars market in the region will depend on the political and economic will of government, as well as private industry, to support the creation of biotechnology hubs in the region. The development of robust guidelines and regulation regarding the development of biological medicines would also benefit the region.

Competing interests: Dr Esteban Ortiz-Prado worked for Enfarma EP, a government-funded pharmaceutical company in Ecuador. This company was shut down in 2016 and manufactured no generic drugs during 2009-2016. The author declares that none of the comments made in this manuscript have been influenced by his employment at Enfarma EP. The remaining authors declare no conflicts of interest.
Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

Esteban Ortiz-Prado1,2, MD, MSc, MPH, PhD
Jorge Ponce-Zea3, MSc
Jorge E Vasconez1, MD
Diana Castillo1, MD
Diana C Checa-Jaramillo1, MD
Nathalia1, MD
Felipe Andrade2, MD
Damaris P Intriago-Baldeón4, MSc
Claudio Galarza-Maldonado5, MD, PhD

1One Health Research Group, Faculty of Health Sciences, Medical School, Universidad de las Americas, Av. de los Granados E12-41y Colimes esq, Quito 170125 Ecuador
2Department of Cell Biology, Physiology and Immunology, Universidad de Barcelona, Barcelona, Spain
3Universidad Estatal del Sur de Manabí­, Manabí­, Ecuador
4Universidad Internacional SEK, Quito, Ecuador
5Unidad de Enfermedades Reumaticas y   Autoinmunes, ­Hospital Monte Sinaí, 6-11 Miguel Cordero Dávila, Cuenca 10107, Ecuador

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Author for correspondence: Esteban Ortiz-Prado, MD, MSc, MPH, PhD, One Health Research Group, Faculty of Health Sciences, Medical School, Universidad de las Americas, Av. de los Granados E12-41y Colimes esq, Quito 170125, Ecuador

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Are there biosimilar orphan drugs for Gaucher disease? An overview in Mexico

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Author byline as per print journal: G Castañeda-Hernández, PhD; L Carbajal-Rodríguez, MD; M Cerón-Rodríguez, MD; Professor LC Correa-González, MD; A Esquivel-Aguilar, PhD; SJ Franco-Ornelas, MD; JE García Ortiz, PhD; CM Hernández-Guadarrama, MD; JI Navarrete-Martínez, MD; Y Santillán-Hernández, MD; E Terreros-Muñoz, MD

Abstract:
Enzyme replacement therapy (ERT) is the first-line treatment for Gaucher disease (GD). The ERT Cerezyme (imiglucerase) was approved by the US Food and Drug Administration (FDA) in 1994; however, its patents have expired allowing the development of non-originator biological drugs. The Group of Medical Specialists on Gaucher disease in Mexico claims there is a ‘regulatory gap’ in the definition of biosimilar orphan drugs which should be resolved before these drugs are approved and marketed.

In Mexico, Asbroder (imiglucerase; Abcertin in other countries) has been approved for the treatment of GD, but it does not meet the exact definition of a biosimilar described by the World Health Organization (WHO) and other international guidelines. However, it was recognized as an orphan drug for GD and approved by the medicines regulatory authority in Mexico with the same international non-proprietary name (imiglucerase), in order to increase national access to treatment. This regulatory practice opens up a debate surrounding the relationship between international guidelines, clinical medicine, scientific evidence, bioethical considerations, public health institutions, and local laws. The aim of this paper is to establish whether there are biosimilars of imiglucerase as a therapeutic option. Moreover, it describes the regulatory setting of non-originator biological drugs in orphan diseases based on the approval of the non-originator imiglucerase in Mexico.

Submitted: 8 February 2019; Revised: 19 May 2019; Accepted: 20 May 2019; Published online first: 3 June 2019

Introduction

Orphan drugs are biological or chemical drugs used for the prevention, diagnosis or treatment of rare diseases affecting no more than five in every 10,000 inhabitants [1–3]. Biological drugs (BD) are more complex molecules than chemical drugs; therefore, they should be assessed using specialized technical criteria and regulatory frameworks [4].

In Mexico, non-originator biological drugs should be approved according to the recommendations of the World Health Organization (WHO) and other international guidelines [1, 5–7]. However, the Mexican regulatory criteria to approve non-originator biological drugs for orphan diseases are unclear or unknown.

Objectives

This paper reviews the available scientific evidence relating to the non-originator imiglucerase in Gaucher disease (GD) to establish whether there are biosimilars of imiglucerase as a therapeutic option. In addition, the regulatory setting of non-originator biological drugs for orphan diseases is assessed, based on the approval of non-originator imiglucerase in Mexico.

Literature review

A bibliographic search in PubMed was conducted to gather information about GD and evidence regarding biosimilar orphan drugs and the regulatory framework. The keywords were limited to English language as follows: [Biosimilar Orphan Drug; Biosimilar Rare Orphan Disease; Biosimilar Gaucher disease, Biosimilar Imiglucerase]. The papers were discussed face to face in several academic sessions or electronically.

Additional or systematic analyses were not carried out. This may be a limitation because the inclusion and exclusion criteria were not delimited (with the exception of the keywords) and because, historically, data related to orphan drugs is scarce particularly for biological orphan drugs, compared with non-biological drugs in non-orphan diseases. Therefore, if the search criteria had been restricted to evidence-based medicine (or other accepted methods), it would have picked up less information.

A total of 47 articles were registered in the database. Only two publications were specifically related to non-originator imiglucerase, and two were related to the regulation of biosimilars in orphan diseases [8, 9]. The most relevant reports based on the keywords are described below.

Gaucher disease: an overview

Gaucher disease (GD, OMIM, #230800, #230900, #231000) is a lysosomal storage disorder. It is characterized by the accumulation of glucosylceramide (glucocerebroside) and other glycosphingolipids in the phagocyte mononuclear system cells in the liver, spleen and bone marrow. It is a genetic disorder with autosomal recessive mutations in the gene for glucocerebrosidase (OMIM, *606463), causing reduced or no activity of the acid-β-glucosidase enzyme (glucocerebrosidase or glucosylceramidase). This enzyme therefore has impaired catalytic function and/or diminished stability [10], enabling the accumulation of glucocerebroside in the Gaucher cells and monocytes. In the long term, this leads to hypertrophy of the cellular lysosomal system that infiltrates bone tissue, bone marrow, spleen, liver, lungs and brain, causing cell damage and organ failure.

The clinical manifestations in the visceral tissue and the vascular endothelium depend on macrophage density in the affected organs [10, 11]. One of the visceral manifestations of GD is splenic growth (to 1,500–3,000 cc, compared with the average 50–200 cc in adults), which causes splenomegaly-associated pancytopenia. The clinical spectrum is heterogeneous and often occurs at an early age. GD-related thrombocytopenia, a reduction in the number of mature blood cells (≤ 90 × 109 platelets/L), may be the result of hypersplenism, platelets splenic sequestration, infiltration, or medullary infarcts. Anaemia and leukopenia may coexist simultaneously or independently, and also depend on splenic growth. Anaemia may be secondary to hypersplenism, and, in the advanced disease, the result of medullary failure secondary to Gaucher cells infiltration or medullary infarcts. Hepatomegaly is a very common manifestation of GD, while cirrhosis and hepatic failure are rare. Bone disease is generally the most disabling aspect of GD. Patients frequently experience bone pain with some having bone crisis and more than 20% of cases having mobility disorders. Pathologic fractures or avascular necrosis in the femoral head may also occur [12].

Three clinical forms of GD have been described: a) type 1 (non-neuronopathic disease) which accounts for > 90% of cases; b) type 2 (acute neuronopathic); and c) type 3 (subacute neuronopathic). GD is caused by mutations in the gene for glucocerebrosidase, located in the 1q21 chromosome; it has 11 exons distributed along 7.6 kb. More than 350 pathogenic variants have been reported and approximately 80% of them are replacements of one single nucleotide. Three mutations prevail in Western populations: c.1226A>G (p.Asn409Ser, N370S allele), c.1448T>C (p.Leu483Pro, L4444P allele), and c.84dupG (84GG allele). Regarding phenotype-genotype correlation, it has been determined that the N370S allele predicts a non-neuronopathic phenotype (GD type 1), whereas the homozygous state for L444P allele predicts a neuronopathic phenotype (GD type 2 or 3). In some rare cases, mutations in the PSAP (Prosaposin) gene cause a saposin C (activator protein) deficit, which may cause GD [13–16].

GD has a low prevalence, affecting approximately one in every 75,000 people in Western populations [17], and is therefore considered a rare disorder [1, 2]. There is a higher prevalence in some small populations where the level of consanguinity is high. In Mexico, this phenomenon has not been observed due to the large and diverse interbred population, except in some remote geographical areas [15].

Treatment of Gaucher disease in Mexico: Cerezyme and Asbroder

Treatment of GD aims to restore the activity of the glucocerebrosidase enzyme. Without treatment, the natural course of GD in any of its clinical manifestations is extremely adverse. Patients experience frequent complications as the diseases progresses, with high morbidity and mortality rates and decreased quality of life [13].

The available scientific evidence relating to non-originator biological orphan drugs was assessed in order to establish whether biosimilars are a therapeutic alternative treatment for GD in Mexico. ERT with alglucerase (mannose-terminated, human placental acid β-glucosidase, Ceredase, Sanofi Genzyme, Cambridge, MA) was approved in 1991 by the US Food and Drug Administration (FDA). The modified form of the acid-β-glucosidase enzyme, imiglucerase (Cerezyme, Sanofi Genzyme, Cambridge, MA), is produced by recombinant DNA technology in cultures of Chinese hamster ovary cells, and has been available since 1994 [18]. Cerezyme is recommended in Mexico for all patients with type 1 and type 3 GD [19]. Even though it is not curative, there is evidence supporting its safety and efficacy. It is proven to significantly diminish the haematological and visceral manifestations of GD, reduce bone marrow infiltration and improve skeleton quality as well as the quality of life of patients [20]. Reported benefits include restoration of haemoglobin concentration to normal levels or nearly normal levels within six to 12 months achieving a sustained response over five years, normalization of platelet count, reduction in hepatomegaly in 30% to 40% of cases, and reduction in splenomegaly in 50% to 60% of cases. In patients with bone pain or bone crisis, 52% had no pain after two years and 94% did not report further crisis [21].

Choi et al. conducted a switch-over clinical trial in 2015, ‘A phase 2 multi-center, open-label, switch-over trial to evaluate the safety and efficacy of Abcertin in patients with type I Gaucher disease’, to evaluate the efficacy and safety of Abcertin (ISU Abxis, Seoul, Korea) in five subjects with type 1 GD who were previously treated with imiglucerase [22]. Through indirect comparison, the results showed that the efficacy and safety of Abcertin was similar to that of the imiglucerase of reference.

Later on, the authors stated in an erratum that the product should not be regarded as a biosimilar (of imiglucerase), as defined by WHO [22–24]. In a second study conducted in 2017, ‘A multicenter, open-label, phase III study of Abcertin in Gaucher disease’, Lee BH et al. assessed the efficacy and safety of Abcertin in seven Egyptian patients with treatment-naïve type 1 GD. The results demonstrated the efficacy and safety of Abcertin in these patients [25]. However, the authors disclaim Abcertin as ‘another form of imiglucerase’, but not as a biosimilar according to the WHO definition [23].

Regulation of biological treatment options in Mexico

Asbroder is a new option for treating GD, however, it cannot be defined as a biosimilar of Cerezyme because it does not meet the WHO definition of a biosimilar. The regulatory setting in Mexico is complex, and the criteria to approve this non-originator imiglucerase for the treatment of GD are unclear. Mexican legislation of biological drugs was first discussed in Congress in 2007, and in 2009 a legislative procedure took place and reformed Mexican health laws. Following this, Article 222 Bis was enacted and outlined the general criteria that biological drugs including biosimilars must meet before reaching the market [26].

Regulation of biological and biosimilar drugs
In Mexico, the national health authority registers approved drugs. Both non-originator generic and biological drugs must meet legislation NOM-177-SSA1-2013 [27] ruled by Article 222 Bis in the Mexican General Health Law [28] (NOM-257-SSA1-2014 [29], and NOM-177-SSA1-2013, among others). Biological drugs must also be reviewed by two expert committees in the sanitary authority called Committee of New Molecules (Comité de Moléculas Nuevas) and Sub-committee of Biotechnological Drugs (Subcomité de Biotecnológicos).

Mexican law determines the requirements to validate innovative biologicals and biosimilars according to their characteristics and physiochemical complexity. Biosimilar drugs are not innovative according to legal definitions and, although advanced biotechnology allows adequate characterization of biomolecules, it is not always possible for a biosimilar drug to be identical to the originator drug (the ‘similar, but not identical’ paradigm) [5]. This is due to micro-heterogeneities in the raw materials and manufacturing processes. Manufacturers of biosimilar drugs must provide evidence from biosimilarity trials to prove that they meet quality, efficacy and safety criteria demonstrating their similarity to the originator biological drug [30–32]. It is noteworthy that the terms biosimilar and biocomparable are synonyms in Mexico, however, the correct legal nomenclature for non-originator biological drugs is ‘biocomparable’ to avoid any phonetic confusion that could be associated with a local generic drug brand.

The Mexican Official Norm NOM-257-SSA1-2014 (‘About biotechnological drugs’) specifies the requirements for evaluating technical and scientific information when registering a biological drug, as well as the criteria that the Mexican Health Ministry must follow to legalize the drug, general specifications for manufacturing, and the requirements that a biological drug must meet in order to be recognized as a reference biological drug. However, it is not specified in these laws that they apply to orphan drugs.

Non-originator biological orphan drugs
In Mexico, orphan drugs are not officially registered in the guidelines like other drugs are; instead, they are granted official recognition as an orphan drug. However, biological and biosimilar drugs for orphan diseases are not excluded from the aforementioned laws or regulations. This results in a complex situation because solid scientific evidence is not considered when demonstrating that non-originator drugs for orphan diseases have the same quality, safety and efficacy as the originator drug, and the health authority allows the import and trading of orphan drugs. This explains why the orphan biological drug Cerezyme for the treatment of GD did not undergo the same regulatory procedures as other drugs available in Mexico.

Since the Cerezyme patent expired, new products have been approved for the treatment of GD without an updated regulatory framework. In October 2015, an official communication of orphan drug recognition in Mexico authorized the commercialization of Asbroder, a presumed biosimilar drug of Cerezyme that shares the same international non-proprietary name, imiglucerase. Asbroder was the first of its kind to be approved in Mexico [33, 34]. Under the assumption of improving access for vulnerable patients, Asbroder did not need to apply to obtain a registry number (in Clave de Cuadro Básico y de Catálogo de Insumos del Sector Salud) to supply a health institution. Having the same international name implies recognition of biosimilarity in terms of quality, safety and efficacy. However, there is not sufficient analytic, preclinical and clinical trials evidence demonstrating such characteristics for Asbroder compared with Cerezyme. Therefore, the lack of standardized legislation for biosimilar treatments of rare diseases has a clinical impact on patients with GD [35].

The authors of the Korean study described above define Abcertin as ‘another form of imiglucerase’ [22]. The phrase ‘another form’ does not exist in any accepted international guidelines and therefore may confuse patients, physicians and health authorities. The drug contained in Abcertin should not be named ‘imiglucerase’; rather it should be identified with a different nomenclature, as is the case with velaglucerase and taliglucerase, where taliglucerase is identified as ‘another form’ of velaglucerase with differences in the chemical structure. This situation demonstrates the complexities surrounding biosimilar treatments for orphan diseases. There are significant legal gaps in the quality of the scientific evidence required for their approval and no source specifies the requirements a biosimilar drug must meet to obtain an official communication of recognition as an orphan drug. Consequently, the number and quality of tests required for orphan biosimilar approval are at the discretion of the health authority.

With this in mind, we must consider the issues that health authorities encounter when considering orphan biosimilar drugs. In Mexico, one of them is that scientific evidence relating to orphan products for rare diseases like GD do not have the endorsement of the health authority committee of experts, as Mexican legislation does not consider orphan diseases in its approval protocols. This means that the biosimilarity of a product is questionable when compared with the originator product. Likewise, the specific physicochemical characterization tests of orphan products, like imiglucerase, are not included in the Mexican Pharmacopoeia or in any other official document. This means that when the biosimilar manufacturer carries out in-house validations of the analytical methods and considers its specifications, there is no baseline scheme that underpins the comparisons. Thus, orphan drugs are not considered in the definitions of innovative and biosimilar drugs.

Proposed updates to regulation
In 2016, the Mexican health authority announced the establishment of a specialized group for orphan diseases and suggested that protocols on orphan drugs need to be updated in order to meet current scientific criteria [36].

In some circumstances, healthcare professionals may make the decision to switch without notifying the patient via informed consent; thus, the patients’ constitutional right to health protection is at risk [37]. Furthermore, pharmacovigilance – which requires adequate traceability systems – would be compromised. If two or more drugs share the same registry number to supply a health institution, it is impossible to know which drug is being administered. This could lead to a non-medical switch at the time of infusion without the physician or patient’s knowledge.

In light of these concerns surrounding orphan biosimilars, Asbroder must be thoroughly evaluated and given a new code in the Mexican List of Medications because it is not an interchangeable imiglucerase with Cerezyme. There is comprehensive data on the quality, efficacy and clinical safety of Cerezyme, but not for Asbroder; equivalent efficacy and safety following treatment switching to Asbroder have not been proven sufficiently.

Conclusion

Based on the literature, there are no biosimilars of imiglucerase for the treatment of GD. Asbroder is not a biosimilar of Cerezyme because it does not meet WHO’s definition or international guidelines. Further studies are required to show the efficacy and safety of Asbroder.

Position statement
Grupo de Especialistas Médicos en enfermedad de Gaucher expresses its position regarding biosimilar orphan drugs for the treatment of orphan diseases – using the case with Asbroder – as follows:

  • Biological drugs are complex, and their clinical outcomes cannot be extrapolated to biosimilar drugs when clinical trial data designed to demonstrate therapeutic equivalence are lacking.
  • For approval, biosimilar drugs need a different set of regulations from generics. They also need to provide evidence of quality, efficacy and safety equivalence versus the originator drug by means of proper analytical, preclinical and clinical trials. Biosimilar drugs are not interchangeable if efficacy and safety are not demonstrated.
  • In Mexico, there are legislations for biological drugs, but they do not specifically include the requirements for biosimilar drugs targeted at orphan diseases.
  • If therapeutic equivalence, efficacy and safety have not been demonstrated, indiscriminately switching to a biosimilar drug from an originator product represents a high risk for patients.
  • If patients with GD are stable with an originator drug, they should not be automatically switched to a biosimilar because that is not ethically acceptable. It puts the patient at risk and there is no evidence supporting switching, or evaluation of the product’s long-term safety.
  • Asbroder is a non-interchangeable biological drug and results cannot be extrapolated because there is not enough evidence available about its quality, efficacy and safety, compared to the originator drug. Thus, these biological products should not share the same naming and registration code to supply health institutions.
  • It should be noted that the authors of this review are not against the use of biosimilar drugs, as long as they meet the requirements of WHO Guidelines, Mexican Health General Law (DOF 12-07-2018) and the current Mexican legislation.

Acknowledgments

We thank Vesalio Difusión Médica for the editorial support.

Funding

We acknowledge Sanofi Genzyme for supporting only the medical writing and paying the journal fees.

Competing interests: The authors declare no conflict of interest. Sanofi Genzyme only helped paying for the translation of the manuscript.

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

Authors

Gilberto Castañeda Hernández, PhD in Pharmaceutical Applications
National Researcher Level III, National Research System, Fellow of Academia Mexicana de Ciencias; Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, #2508 Avenue Instituto Politécnico Nacional, Colonia San Pedro Zacatenco, CP 07360, Ciudad de México, Mexico

Grupo de Especialistas Médicos en enfermedad de Gaucher (Group of Medical Specialists on Gaucher disease)

Luis Carbajal-Rodríguez, MD
Paediatrician, Consejo Mexicano de Certificación en Pediatría AC, certificate number 2029, Mexico City, Mexico

Magdalena Cerón-Rodríguez, MD
Paediatrician, Internist, Consejo Mexicano de Certificación en Pediatría AC, certificate number 4525, Mexico City, Mexico

Lourdes Cecilia Correa-González, MD
Professor of Clinical Research Sciences, Haematologist, Paediatrician and Oncologist, certificate number 105 from Consejo Nacional de Oncología, certificate number 014-2016 from Consejo Mexicano de Hematología, San Luis Potosí, SLP, Mexico

Abdieel Esquivel-Aguilar, PhD
Pharmacology, certificate number 0877917 from Centro de Investigación y de Estudios Avanzados in Instituto Politécnico Nacional, Mexico City, Mexico

Sergio Joaquín Franco-Ornelas, MD
Consejo Mexicano de Certificación en Pediatría, certificate number 5500, Mexico City, Mexico

José Elías García Ortiz, PhD
Human Genetics, certificate number 234, Consejo Mexicano de Genética AC, National Researcher Level II, National Research System-CONACyT, Guadalajara, Jalisco, Mexico

César Martín Hernández-Guadarrama, MD
Paediatrician, Haematologist, Consejo Mexicano de Hematología R-2018, Consejo Mexicano de Pediatría, certificate number 5288, Guadalajara, Jalisco, Mexico

Juana Inés Navarrete-Martínez, MD
Specialist on Medical Genetics, certified by Consejo Mexicano de Genética No.15, Mexico City, Mexico

Yuritzi Santillán-Hernández, MD
Specialist on Medical Genetics, certificate number 137, Consejo Mexicano de Genética AC Medical Genetics, Centro Médico Nacional ‘20 de Noviembre’, ISSSTE, Mexico City, Mexico

Eduardo Terreros-Muñoz, MD
Haematologist, certified by Consejo Mexicano de Hematología, Fellow of Agrupación Mexicana para el Estudio de la Hematología AC de CV, Mexico City, Mexico

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25. Lee BH, Abdalla AF, Choi J-H, Beshlawy A El, Kim G-H, Heo SH, et al. A multicenter, open-label, phase III study of Abcertin in Gaucher disease. Medicine (Baltimore). 2017;96(45):e8492.
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29. SEGOB. Diario Oficial de la Federación. DOF:11/12/2014 [homepage on the Internet]. [cited 2019 May 19]. Available from: http://www.dof.gob.mx/nota_detalle.php?codigo=5375517&fecha=11/12/2014
30. Espinosa Morales R, Díaz Borjón A, Barile Fabris LA, Esquivel Valerio JA, Medrano Ramírez G, Arce Salinas CA, et al. Biosimilar drugs in Mexico: position of the Mexican College of Rheumatology. 2012. Reumatol Clin. 2013;9(2):113-6.
31. Xibille D, Carrillo S, Huerta-Sil G, Hernández R, Limón L, Olvera-Soto G, et al. Current state of biosimilars in Mexico: The position of the Mexican College of Rheumatology, 2016. Reumatol Clin. 2018;14(3):127-36.
32. Mayoral-Zavala A, Esquivel-Aguilar A, del Real-Calzada CM, Gutiérrez-Grobe Y, Ramos-García J, Rocha-Ramírez JL, et al. Update on biosimilars in inflammatory bowel disease: Position and recommendations in Mexico. Rev Gastroenterol México. 2018;83(4):414-23.
33. Secretaría de Salud. Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS). Resoluciones del Comité de Información, 2016 [homepage on the Internet]. [cited 2019 May 19]. Available from: http://sipot.cofepris.gob.mx/Archivos/juridico/RESOLUCIONES/2016/RES28EXT16.pdf
34. COFEPRIS. Comisión de Autorización Sanitaria. Dirección Ejecutiva de Autorización de Productos y Establecimientos, Obtención del Reconocimiento de Producto Huérfano, APROBADO 2015. Vol. 12. 2017.
35. Mistry P. Therapeutic goals in Gaucher disease. La Rev Médecine Interne. 2006;27:S30-3.
36. 8 millones de mexicanos padecen enfermedades raras. El Universal. 09/11/2016.
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Author for correspondence: Gilberto Castañeda Hernández, PhD in Pharmaceutical Applications, National Researcher Level III, National Research System, Fellow of Academia Mexicana de Ciencias; Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, #2508 Avenue Instituto Politécnico Nacional, Colonia San Pedro Zacatenco, CP 07360, Ciudad de México, Mexico

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Protein heterogeneity and the immunogenicity of biotherapeutics

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Abstract:
High resolution analytical techniques reveal structural micro-heterogeneity within endogenous proteins, however, they are ‘seen’ as ‘self’ molecules by the immune system and immunological tolerance is established. In contrast the protein biotherapeutics are produced in non-human cells and multiple downstream protocols are employed in the isolation and purification of drug product; consequent micro-heterogeneities may be ‘seen’ as ‘non-self’ and potentially immunogenic. In addition, extensive polymorphisms within and between outbred human populations suggests that any given protein biotherapeutic may be allogenic, and potentially immunogenic, when administered across different population groups. Further heterogeneity may result from differential intra-cellular processing and the addition of co-, trans-, and post-translational modifications. These processes are explored against reported incidences of immunogenicity for recombinant forms of human erythropoietin (EPO) and Immunoglobulin G (IgG).

Submitted: 7 February 2018; Revised: 28 March 2018; Accepted: 2 April 2018; Published online first: 16 April 2018

Introduction

The human genome (HG) is comprised of ~23,000 open reading frame (ORF) genes, however, the human proteome is orders of magnitude greater; due to alternate splicing (AS) of ORF genes, errors in transcription or translation, the addition of co- and post-translational modifications (CTM; PTM). A recent guestimate suggested that each ORF within the outbred human population might be translated to generate 100 structurally distinct proteins [1]. Protein and glycoprotein (P/GP) molecules exist in vivo as discreet entities within complex multi-component media, e.g. plasma, cell sap, and exert their function(s) through specific interactions with target/receptor molecules. In health each individual expresses a unique proteome and personal integrity demands immunological tolerance to all self-molecules. Ordered aggregation of monomer molecules may be essential for normal function; however, inappropriate (non-native) aggregation is implicated in the pathogenesis of numerous autoimmune diseases and the generation of autoantibodies [2, 3]. Similarly, denaturation and/or aggregation of P/GP biotherapeutics may render them immunogenic and result in the development of anti-drug/anti-therapeutic antibodies (ADA/ATA).

The thriving biopharmaceutical industry depends on the production of recombinant P/GPs exhibiting an essential structural fidelity with a selected endogenous molecule; therefore, structural variants generated during production, purification, formulation and/or delivery is a major concern as it may equate to potential immunogenicity [2, 3]. Pharmacovigilance must be exercised over the lifetime of an approved drug since incidences of adverse events are reported for drugs that have been long established in the clinic, e.g. insulin [4] and erythropoietin (EPO) [5]. The presence of ADA/ATA is frequently associated with onset of adverse events and/or loss of efficacy [6, 7] and suggests the presence of structurally altered/denatured molecules that are recognized as ‘foreign’ (non-self) by the patient’s immune system, i.e. immunogenic. This mini review enumerates structural parameters that have to be defined and maintained throughout the production, administration and clinical lifetime of recombinant P/GP therapeutics; illustrated for EPO and antibody therapeutics.

Structural heterogeneity: in vivo and ex vivo
Biosynthesis of P/GPs in mammalian cells employs error prone multistep processes and the end product(s) exhibits an inevitable structural heterogeneity. Lack of fidelity with the amino acid sequence encoded by a given ORF may be introduced at multiple stages, e.g. transcription, mRNA translation, miss-incorporation. Additionally, de nova secondary structures may be essential to allow co-translational modifications (CTMs) of the polypeptide as it is extruded from the ribosome tunnel, e.g. the addition of oligosaccharide, N-myristoylation. When released from the ribosome the P/GP transits to the endoplasmic reticulum where it is edited for correct tertiary/quaternary folding and initial oligosaccharide processing; further post-translational modifications (PTMs) are effected during passage through the Golgi apparatus [8–11]; P/GPs may be subject to further modifications throughout their life cycle in vivo, e.g. enzyme cleavage to release secondary bioactive products. It is presumed that all such molecular entities are recognized as ‘self’ by the immune system; therefore the first step in the quest to produce a recombinant P/GP therapeutic is determination of the structure of the natural (endogenous) molecule. However, the techniques employed to isolate and purify P/GPs from body fluids or tissues may result in denaturation and the introduction of non-native chemical modifications (CMs) e.g. deamination; proline isomerisation.

In practice a candidate recombinant P/GP therapeutic is evaluated, structurally and functionally in comparison with the fully characterized endogenous molecule. This approach cannot be realized for a potential recombinant monoclonal antibody (mAb) therapeutic since an endogenous anti-self antibody is not available for comparison. Candidate mAbs are sourced from inbred mice and engineered to generate chimeric or humanized mAbs; from transgenic mice expressing human immunoglobulin genes or random reassociation of human Immuoglobulin (Ig) heavy and light chain expressed within phage display libraries [12, 13]. The choice of production platform is a critical strategic decision since the processes involved in the addition of CTMs, PTMs and CMs are species and cell specific and production of a human P/GP in an alien cell line, e.g. CHO (Chinese hamster ovary) cell line, may result in the introduction of non-self structures and consequent immunogenicity with the generation of ADA/ATA responses [6–8]. Prior to clinical trials a candidate recombinant P/GP therapeutic has to be extensively characterized in comparison with the endogenous molecule, employing multiple orthogonal physicochemical techniques [14, 15]. Patent protection for numerous recombinant P/GP drugs has now expired and many more are approaching expiry, providing opportunities for the production of biosimilar drugs. Candidate biosimilars must be characterized in comparison with the approved innovator drug product [16, 17].

Protein folding: in vivo
Proteins are synthesized, within ribosomes, as a linear sequence (string) of amino acid residues covalently linked through the peptide bond; elements of secondary structure may form, de nova, and can include generation of an acceptor site for the addition of high mannose oligosaccharides N-linked to an asparagine residue present within a glycosylation sequon, i.e. the sequence asparagine-x-serine or threonine (asp-x-ser/thr; N-X-S/T), where x is any amino acid residue other than proline. Following release from the ribosome the protein transits to the endoplasmic reticulum where the high mannose oligosaccharide is truncated and exerts a quality control function for correct folding; miss-folded proteins being marked for proteasomal degradation [8–11]. Multiple PTMs may be effected during passage through the Golgi apparatus including further oligosaccharide processing, phosphorylation, sulphation. In this way a P/GP achieves its native, evolutionary determined, structure that ensures it traffics to the appropriate cellular compartment or is secreted [18–21].

It has been estimated that a protein of 100 amino acid residues undergoing random motion in search of the lowest energy form could pass through 1089 conformations, taking 1066 years, to sample all possible structures; however, within the cell the P/GP passes through intrinsic protein folding pathways to achieve the functional tertiary/quaternary conformation within seconds [22]. Our knowledge and understanding of P/GP structure/function relationships is mostly based on the results of X-ray crystallographic studies and tend to represent proteins as having a fixed (solid) structure [15]. Newer techniques show that proteins are ‘living, breathing’ entities that may exist in conformational equilibria, including intrinsically unstructured regions [23, 24]; ex vivo such regions, may act as focal points for aggregation [2, 3, 9, 23, 24]. Algorisms that attempt to analyse or predict structural parameters of P/GPs as they exist within in vivo environments are in their infancy [10, 24].

Protein folding: ex vivo
Proteins are comprised of amino acid residues that bear non-polar, polar uncharged and charged side chains and may fold to generate molecules having an overall hydrophobic or hydrophilic character. Proteins that are soluble in aqueous media have an overall hydrophilic character whilst hydrophobic amino acid side chains are orientated towards the internal space and form mutual interactions that stabilise structure; however, a scan of the surface exposed side chains may reveal hydrophobic patches that can act as centres for aggregation [2, 9–11]. This potential is underlined by diseases in which P/GP aggregation results in the deposition of insoluble fibrils in tissues, e.g. neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), transmissible spongiform encephalopathies (TSEs), and amyotrophic lateral sclerosis (ALS) [25–31]. Fundamental studies of protein folding and aggregation have focused on the hen egg white lysozyme molecule, the native form of which has high solubility in aqueous media. However, following exposure to denaturing solvents in vitro, followed by restoration to physiologic conditions it can miss-fold to form aggregates and fibrils, similar to pathogenic species seen in disease. Six spontaneous mutations in human lysozyme have been reported and all except one lead to systemic non-neurogenic amyloidosis involving kidney, liver and spleen [27–29]. Prion disease is an extreme example of the propensity for a soluble protein to form fibrils in vivo [30, 31]. In its soluble form the prion protein has a helical structure; however, in the disease state the protein converts to a beta sheet structure that aggregates to form fibrils; the denatured prion protein can act as a ‘catalyst’ to induce normal prion protein to convert to a beta sheet structure.

As previously stated we do not have means of determining the fine structure of P/GPs as they exist in vivo and are limited to extrapolation from structural studies of isolated P/GPs purified from human fluids and tissues employing multiple physicochemical techniques that may introduce further structural heterogeneity, e.g. deamidation of asparagine and glutamine residues, oxidation of methionine and tryptophan residues, glycation of lysine [10, 14, 24]. Additionally, proteins may undergo subtle reversible conformational changes that results in momentary exposure of hydrophobic regions that can be mutually attractive with formation of ‘partly unfolded clusters’, i.e. aggregates [3, 25–27], see Figure 1. Such clusters can act as nuclei for the formation of larger aggregates, possibly extending to precipitation. Structural heterogeneity is compounded by differing susceptibilities of individual amino acid residues to modifications depending on its position within the molecule and the immediate microenvironment.

Figure 1

Prediction of aggregation prone regions (APR)

Aggregation prone regions (APRs) may be classified as structural or critical. Structural APRs contribute to the stability of the native protein core structure but may be exposed following denaturation ex vivo and form aggregates under refolding conditions; critical APRs are exposed in the native state and may contribute to physiological protein/protein interactions in vivo and in vitro. Multiple physiochemical techniques and algorithms have been developed to identify APRs and inform protein engineering to reduce a propensity for aggregation [32–34]; a concomitant increases in recombinant proteins productivity has been reported [35]. Since hydrophobic binding contributes to protein/protein interactions APRs may be anticipated as a feature of functional sites and much attention has been focused on the antigen-binding site, i.e. the paratope, of antibody molecules [35, 36]. However, antibodies are multifunctional molecules and the formation of antigen/antibody complexes is an essential prelude to the activation of downstream effector functions activated by interactions of the Fc region with soluble and/or cell bound and ligands, e.g. cellular Fc receptors (FcγR, FcRn), the C1 component of complement [37, 38]. Interaction sites for these ligands have been identified and include the hydrophobic sequence 231-APELLGGPSVFLFPP-245 [15, 20, 37, 38]. Protein engineering has been employed to reduce the propensity for aggregation whilst retaining activation of effector molecules that determines their mechanism of action (MoA).

Immunogenicity

In health an individual is tolerant to their proteome, however, multiple autoimmune diseases manifest the potential for loss of tolerance to self-molecules or aberrant (mutant) forms of self-molecules arising in vivo. The potential for immunogenicity of biotherapeutics in humans may vary depending on the character of the disease being treated, three broad categories may be identified [39–41]:

  1. A disease in which a patient fails to express an essential P/GP or expresses a mutant inactive form, e.g. enzyme deficiencies. In each case an active therapeutic is ‘non-self’ and has potential to be immunogenic.
  2. Therapeutics that augment the patients endogenous production, e.g. insulin, erythropoietin. The patient may be expected to be tolerant unless there is a mismatch between P/GP polymorphic variants present in outbred population or the therapeutic has been subject to denaturation/aggregation, with exposure of altered structure during production, storage and/or delivery.
  3. Antibody therapeutics are a special case in that, in addition to polymorphisms within the ‘constant’ regions, the unique specificity is reflected in unique antigen binding site (paratope) structure that will be ‘non-self’ to a majority of patients in an outbred population.

 

Monoclonal antibodies: commercial evolution

The antibody response in humans is comprised of five immunoglobulin (Ig) classes: IgM, IgG, IgA, IgE and IgD; in addition IgG is comprised of four subclasses (IgG1, IgG2, IgG3, and IgG4) and IgA two (IgA1, IgA2) generating nine Ig isotypes [15, 42, 43]; each antibody isotype expresses a unique profile of effector mechanisms. The IgG1 subclass predominates in serum and has been the focus for structure/function studies and the predominant format adopted for approved mAb therapeutics. Following binding to its target, with the formation of antibody/antigen complexes, antibodies of the IgG1 subclass may trigger a cascade of inflammatory effector mechanisms that constitute its MoA. Activation of IgG1 mAbs provides natural protection in the killing and removal of bacteria and other ‘foreign bodies’; recombinant antibody therapeutics specific to cancer cells may similarly be activated, resulting in their killing and removal. Each IgG subclass may be exploited to offer a MoA profile appropriate to differing disease indications. The antibody landscape is developing rapidly, as new engineered constructs are customized to optimize treatment protocols, e.g. antibody fragments that enhance solid tumour penetration, antibody-drug conjugates that are internalized into target cells where drug release is effected [12, 13]. It should be noted that the binding of a divalent antibody to a multivalent antigen, e.g. a cancer cell, results in the formation of an immune complex (IC) that is itself an aggregated form of the antibody. ICs are removed and degraded by leucocytes that are also antigen-presenting cells and may therefore, present peptides derived from the paratope of a mAb [44].

The first GP approved by the European Medicines Agency and US Food and Drug Administration was the murine mAb Muromonab (1986, anti-human CD3 OKT3), produced in mouse hybridoma cells; it was administered to patients undergoing acute rejection of a liver transplant. Whilst successfully suppressing the rejection episode, vigorous anti-mouse IgG antibody responses developed in a majority of patients; excluding the possibility of exposing patients to the therapeutic on a subsequent occasion. Over succeeding years genetic and protein engineering techniques were employed to limit immunogenicity by successively increasing the human IgG character of mAbs and expression of selected IgG-Fc mediated MoA. The commercial mAb therapeutic era may be identified with the development of chimeric mouse/human mAbs comprised of the variable regions of a mouse antibody linked to the constant regions of human IgG1, generating a molecule that is ~30% mouse and ~70% human in structure [6–8, 15]. A significant reduction in immunogenicity resulted and a majority of patients could be repeatedly dosed with these mAbs. Further developments defined the amino acid residues of the mouse antibody that formed the antigen binding site (paratope) and transplanted them into selected human variable regions; generating a ‘humanized’ mAb [6–8, 15]. This technology is being superseded by protocols allowing the generation of ‘fully human’ antibodies. These mAbs are products of rearranged human variable region genes, however, by virtue of the fact that they are selected to be anti-self their unique paratope structure may provoke ADA/ATA responses [12, 13] in an outbred human population.

Meta-analysis of the incidence of ADA for the first approved ‘fully human’ anti-TNF-alpha (TNF-α), antibody (Adalimumab, Humira), generated by phage display, ranged from 1–54 %; when administered across multiple inflammatory diseases [6, 7]. The ADA responses may be transitory and/or of low titre and, with good patient management, do not necessarily result in significant adverse reactions [45]; a threshold for immunogenicity is evidenced by the fact that ADA responses are reduced when patients are concomitantly receiving a mild immunosuppressant, e.g. methotrexate [46]. Antibodies generated from phage display libraries depend on the pairing of VH and VL sequences that express anti-self specificities and would be forbidden in vivo, consequently they may express foreign (non-self) epitopes. The alternative technology for generating fully human antibodies from mice rendered transgenic for human immunoglobulin genes results in a natural pairing of VH and VL sequences and the incidence of ADA for the anti-TNFα Golimumab is reported as 0–19% [6].

Glycosylation: recombinant erythropoietin and IgG antibodies

A majority of proteins are generated utilizing the standard 20 amino acids linked through the peptide bond between alpha carbon atoms; in contrast oligosaccharides utilize multiple linkages with a potential to generate enormous glycome and glyco-proteome diversity; it is estimated that six sugar residues can be assembled to generate 1012 unique hexasaccharides [47]. The repertoire of sugars utilized varies between species, gender, cell line, etc.; to generate N-linked oligosaccharides, as previously discussed, or oligosaccharides O-linked through serine, threonine or mannose residues. Importantly, CHO and NS0 (murine) cell lines may add immunogenic non-human oligosaccharide structures to intended ‘fully’ human recombinant therapeutics [13, 48, 49]. Protein engineering and gene ‘knock-out’/‘knock-in’ techniques have been employed to modulate the glycoform profile of GPs; as illustrated in this text for EPO and IgG.

Erythropoietin: Recombinant EPO produced in CHO cells was initially shown to exhibit enhanced activity in vitro, in comparison with approved therapeutic isolated from urine. However, trials in vivo revealed a lack of therapeutic efficacy due to its rapid clearance from the circulation. It was later shown the attached oligosaccharides bore terminal galactose sugar residues, rather than the required sialic acid, resulting in clearance in the liver via the asialoglycoprotein receptor. Fractionation of the CHO-derived EPO allowed preparation of an active sialylated glycoform establishing this parameter as a Critical Quality Attribute (CQA); recombinant EPO, Epoetin received regulatory approval in 1989, is comprised of 165 amino acid residues and bears three N-linked and one O-linked oligosaccharide that accounts for ~40% of its mass [50–53].

Successful worldwide use of recombinant EPO followed but in 1999 a cohort of patients in Europe developed pure red cell aplasia (PRCA) (failure of erythrocyte production) due to the generation of ADA that neutralized not only the therapeutic but also endogenous EPO. Investigation showed that ‘minor’ changes had been introduced in the formulation of EPO produced in Europe, in contrast to the US, that were presumed to have resulted in denaturation/aggregation rendering the product immunogenic [51]. This illustrates the structural fragility of P/GPs and the need for pharmacovigilance throughout the lifetime of a drug. Incidences of PRCA continue to be reported around the world and include ‘biosimilar’ EPOs produced by multiple manufacturers and approved by regional or national regulatory authorities [52]. Experiences of Thailand are salutary, as of 1 January 2009, 14 EPO drugs were licensed in Thailand [53]; they originated from various countries and were not biosimilars as defined by the EU/USA/WHO (World Health Organization) requirements. The cost advantage for these versions of EPO resulted in widespread usage but was coincident with an increase in reports of PRCA due to the generation of ADA [53].

Anticipating expiration of patent protection and the advent of biosimilars the innovator company (Amgen) developed an improved (biobetter) product (darbepoeitin alfa), exhibiting increased efficacy and an extended in vivo half-life; it was approved and received patent protection [54, 55]. The improvement was achieved by the introduction of two additional N-linked oligosaccharide attachment sites resulting in the production of glycoforms bearing additional N-linked oligosaccharides expressing terminal sialic acid residues.

Antibodies: An IgG molecule is comprised of ~1,440 amino acid residues and two N-linked oligosaccharides each comprised of 7 to 13 sugar residues. For decades little account was taken of this ‘minor’ structural feature until it was shown that removal of the oligosaccharide resulted in loss of the ability of ICs to trigger MoAs mediated by activation of FcγR and the C1 complement component, i.e. glycosylation of IgG is a CQA [44, 45]. A minimum requirement for MoA activation is the presence of a seven-residue oligosaccharide on each heavy chain. Differential addition of sugar residues generates a multiplicity of IgG glycoforms that may each modulate the affinity of binding of ICs to effector ligands and hence MoAs, see Figure 2 [44, 45, 56–58].

Figure 2

The glycoform heterogeneity of human serum IgG is not mirrored by the glycoform profile of mAbs produced in CHO, NS0 or Sp2/0 cells; in contrast these cells express a restricted glycoform profile that may include immunogenic non-human glycoforms. The glycoform profile cannot be significantly manipulated by changes in culture conditions, therefore, the contribution of individual glycoforms to MoAs has been investigated by in vitro enzymatic modification of mAb or genetic engineering of the producer cell line. A dramatic outcome from these studies has been the demonstration that IgG antibodies that bear oligosaccharides devoid of fucose residues can exhibit a 10–102 folds increase in their ability to mediate killing of cancer cells by NK (natural killer) cells, similar increases can be achieved for mAb expressing a bisecting N-acetylglucosamine residue. New production CHO cell lines have been established following the ‘knock-out’ of the fucosyltransferase gene or ‘knock-in’ of the bisecting N-acetylglucosamine transferase gene [48, 56–58]. These cell lines have been used to generate approved ‘biobetter’ versions of previously approved mAbs.

Mechanism/Mode of action (MoA)

An antibody may be protective and deliver therapeutic benefit due to its binding specificity for target, e.g. neutralizing an exogenous bacterial toxin or endogenous TNFα, however, when the target is a bacterium or a cancer cell MoAs that result in killing and removal of debris are essential. [56–58]. The IC formed in turn become targets for leucocytes that bear cell surface receptors (FcγR) specific to the IgG heavy chain Fc region. The cross-linking of multiple FcγR results in leucocyte activation with the release of toxic agents and/or ingestion (phagocytosis), ICs may also activate the C1 component of the complement system to trigger a cascade of enzymatic reactions resulting in the formation of a membrane attack complex that inserts into the cellular membrane with the formation of pores that allow the ingress of water and egress of cellular constituents. Molecules released from the complement cascade also adhere to the IC and engage complement receptors expressed on leucocytes to further enhance cellular activation.

There are three families of FcγR (FcγRI, FcγRII, FcγRIII) that are differentially expressed on leucocytes and bind the IgG subclasses selectively, see Table 1; similarly, the C1 component of complement exhibits selective IgG subclass binding. An important parameter that contributes to mAb efficacy is the long half-lives of ~21 days, for IgG1, IgG2 and IgG4, this allows for extended intervals between administered doses; IgG3 has a shorter half-life of ~7 days [59]. Clearance of IgG is mediated via binding to the neonatal Fc receptor (FcRn) that is expressed on many cell types and is independent of the IgG glycoform, [56–58]. Antibodies of the IgG1 and IgG3 subclass have very similar functional profiles but the IgG2 and IgG4 subclasses exhibit unique profiles. It is important therefore when developing a mAb therapeutic to anticipate the preferred MoA in vivo and generate mAbs of an appropriate IgG subclass. To date, of the 160 mAbs listed in the international immunoglobulins database (IMGT: ImMunoGeneTics) 136 are IgG1, 8 IgG2, 2 IgG3 and 14 IgG4 [58, 60]

Table 1

Summary

It is posited that all recombinant P/GP therapeutics may be immunogenic, at least in a proportion of patients, resulting in loss of efficacy and/or the advent of adverse events. The significance of this outcome should be assessed with respect to the disease being treated, thus cancer and transplant patients will be receiving concomitant cytotoxic drugs that induce various levels of immunosuppression. By contrast patients with chronic diseases undergo long-term exposure to recombinant P/GPs and are at greater risk of developing ADA, that may be circumvented by treatment with mild immunosuppressive agents. Currently, an ever expanding armamentarium of biologicals is being developed that includes engineered IgG molecules that differ in structure to endogenous IgG and/or their fragments. Such manipulations increase the propensity for immunogenicity, however, outcomes may differ between acute conditions for which treatment may be within a relatively short time frame and chronic diseases that require long-term exposure.

Advances in gene sequencing techniques are allowing identification of polymorphisms in ‘susceptibility’ genes that allows for stratification of patients. Stratification can contribute to the development of personalized medicine through identification of cohorts of patients responsive to a given therapeutic whilst similarly identifying patients that are not likely to benefit. Stratification of ‘common’ diseases may identify increasingly small cohorts of patients such that their condition may be classified as an orphan disease, indicative of a need for treatment with expensive customized biologicals, i.e. personalized medicine. This may result in a conflict between the high cost of development of specialist biologicals and the diminished market that stratification identifies. Some ‘respite’ may be offered by the development of biosimilars, however, they are currently providing only ~15–30% reduction in cost. The conflict between our ability to deliver ever expanding therapies for human health care, from conception to death, and to provide equity in delivery will continue and become ever more contentious.

Competing interests: None.

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

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Author: Professor Roy Jefferis, PhD, DSc, MRCP, FRCPath, Emeritus Professor of Molecular Immunology, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK

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Biosimilar infliximab introduction into the gastroenterology care pathway in a large acute Irish teaching hospital: a story behind the evidence

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Author byline as per print journal: Gary L O’Brien1, BPharm, MPharm; Donal Carroll2, BSc (Hon) Pharmacy; Mark Mulcahy3, BComm, MSc, PhD; Valerie Walshe4, BA, MA, PhD; Professor Garry Courtney2, MB, FRCPI; Professor Stephen Byrne1, BSc (Hon) Pharmacy, PhD

Background and aim: Biosimilar medicines are not considered exact replicas of originator biological medicines. As a result, prescribers can be hesitant to introduce such medicines into the clinical setting until evidence surfaces confirming their safety and effectiveness. In Ireland, a national biosimilar medicines policy is currently in development but the decision to prescribe biosimilar medicines remains at the discretion of the physician. The aim of this descriptive review is to tell the story of the evidence used by a large acute Irish teaching hospital to introduce biosimilar infliximab CT-P13 for the treatment of inflammatory bowel disease (IBD) in a safe and timely manner into routine care.
Methods: To explore the evidence supporting the effective introduction of biosimilar infliximab in a large acute Irish teaching hospital, a literature review was conducted. Evidence consisted of published studies, reviews, reports, position statements, articles, clinical guidelines, and recommendations from national bodies, regulatory authorities and professional organizations. All evidence was published in English.
Results and discussion: In September 2014, the accumulated evidence base provided physicians with reassurance to prescribe biosimilar infliximab CT-P13 for new patients suffering from IBD in this large acute Irish teaching hospital. In September 2016, as the evidence base grew, physicians began to safely and confidently switch patients from the originator infliximab product to the biosimilar product.
Conclusion: There was a significant time lag between regulatory approval and clinical acceptance given that the European Medicines Agency had granted market authorization for biosimilar infliximab CT-P13 three years prior to the initiation of this hospital’s switching process. Although conservative in their execution, the authors conclude that with the existential concern and uncertainty still surrounding biosimilar medicines, a distinct and individualized approach for biosimilar medicine implementation is required. It is with hope that the Irish biosimilar medicines policy will improve upon biosimilar medicine clinical acceptance once published.

Submitted: 29 January 2018; Revised: 11 February 2018; Accepted: 14 February 2018; Published online first: 27 February 2018

Background and aim

In 2014, six of the top 10 blockbuster medicines were monoclonal antibodies [1]. In recent times, small molecule chemical entity (SMCE) blockbuster drugs like Viagra® and Lipitor®, have been superseded by blockbuster biologicals such as Humira® and Enbrel®, demonstrating the newly acquired prominence of biological medicines [2, 3]. However, these large complex proteins (comprised of or derived from living cells or organisms) are more complicated than traditional SMCEs due to their unique manufacturing process [4]. Unlike generic drugs of SMCEs, biosimilar medicinal products (biosimilars) which aim to replicate originator biological products, have given rise to concerns related to their pharmaceutical quality, safety (especially immunogenicity) and efficacy (particularly in extrapolated indications) [5, 6]. This can create confusion around the practice of interchangeability which is not as lucid for biosimilars as it is for generic drugs of SMCEs [7].

Substitution, switching and interchangeability are terms often used when discussing biosimilars. Pharmacists can substitute generic drugs of SMCEs in Ireland and the UK on the proviso these medicines are deemed interchangeable [7–9]. The European Medicines Agency (EMA) defines substitution as ‘the practice of dispensing one medicine instead of another equivalent and interchangeable medicine at pharmacy level without consulting the prescriber’ whilst interchangeability refers to ‘the possibility of exchanging one medicine for another medicine that is expected to have the same clinical effect’ [10]. However, pharmacist substitution of biosimilars is not currently permitted in most countries [4, 11], although pharmacists practising in Australia can substitute some biological medicines [12]. In the majority of cases, it appears that pharmacists are bound by legislative constraints at the point of dispensing [13]. As a result, physicians are the key stakeholders to switch patients to and from different brands of the same or similar biological medicines, where switching is defined as ‘when the prescriber decides to exchange one medicine for another medicine with the same therapeutic intent’ [10].

There is no longer a dearth of evidence when it comes to the science and interchangeability status of biosimilar medicines. However, knowing when it is most appropriate and timely to implement these medicines into routine clinical practice can be difficult. In a large acute Irish teaching hospital, biosimilar infliximab CT-P13 was introduced in place of originator brand infliximab (Remicade®), to treat inflammatory bowel disease (IBD). As well as Crohn’s disease (CD) and ulcerative colitis (UC), Remicade® is licensed to treat a range of other autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and psoriasis [14]. In the absence of a national Irish biosimilar medicines policy and with perceived uncertainty surrounding biosimilar medicines, this descriptive review adds to the literature by illustrating the independent systematic evidence base behind the decision-making process to introduce biosimilar infliximab CT-P13 into secondary care treatment of IBD.

Methods

In June 2013, biosimilar infliximab was licensed by EMA [15]. The agency’s Committee for Medicinal Products for Human Use (CHMP) recommended the granting of marketing authorizations for the first two monoclonal antibody biosimilars, Remsima® and Inflectra®, both of which contain the same known active substance infliximab CT-P13. The decision to provide marketing authorization for both these infliximab biosimilar medicines was based on the same documentation. Their application dossiers demonstrated parallel similarity to the biological medicine Remicade®, which has been authorized in the European Union (EU) since 1999 [15]. Remsima® and Inflectra® are recommended for authorization in the same indications as Remicade®.

A few weeks after biosimilar infliximab CT-P13 was licensed, the European Crohn’s and Colitis Organisation (ECCO) released a position statement. In it, they articulated that post-marketing pharmacovigilance and unequivocal identification of infliximab CT-P13 as a biosimilar was in place. However, their overall stance on the issue was that the use of most biosimilars in patients with IBD should require testing in this particular patient population with comparison to the appropriate innovator product (Remicade®) before approval [16]. ECCO also considered the benefits of wider access with appropriate use of biological therapy in IBD and potential direct cost savings important but its primary concern was that rigorous testing was necessary in patients with IBD to ensure that appropriate efficacy and safety standards were met. The organization was of the opinion that final clinical decisions should always be made on an individual basis, taking into account both the circumstances of the individual patient and the prescribing physician. ECCO defied the practice of extrapolation for biosimilar infliximab at this time. In addition to stance taken by ECCO, several national physician societies initially questioned the marketing authorizations of biosimilars, including the extrapolation to IBD. Retrospectively, it became obvious that there was a lack of understanding of the biosimilar development concept [17].

Contrary to the guidance from ECCO, the chief pharmacist and consultant gastroenterologist of a large acute Irish teaching hospital decided to introduce biosimilar infliximab CT-P13 for use in new patients in September 2014. Both parties had been documenting the evidence trail since the licensing of this biosimilar in June 2013 and believed there was enough accumulated evidence from various sources to support their decision [15, 18]. This information was relayed to all prescribing physicians during an internal staff meeting where the chief pharmacist and consultant gastroenterologist explained the science behind their evidence-based decision. All physicians accepted this decision and agreed to prescribe biosimilar infliximab CT-P13 for new patients. Physicians agreed to report any adverse drug reactions (ADRs) to the Health Products Regulatory Authority (HPRA) in Ireland and to EMA. Hospital budget coordinators were pleased given that the biosimilar product was cheaper than the originator brand. With verbal reassurance to patients on the safety and efficacy at the point of prescribing, physicians faced no opposition from new patients.

Although this new prescribing practice could have been deemed hasty, the British Society of Gastroenterology (BSG) released a position statement with updated guidance two months later justifying the introduction of biosimilar infliximab CT-P13 in the clinical setting. The BSG recommended that infliximab should be prescribed by brand name [19]. This prescribing practice contradicts the trend for SMCE medicines where prescribing generically is encouraged [7]. This statement also proposed the use of a prospective registry of all biological use in IBD patients to capture safety data and side effects. For patients already on therapy, it was recommended to avoid switching from the originator product to the biosimilar, or vice versa, at least until safety data was made available [19].

During the summer of 2015, the National Institute for Health and Care Excellence (NICE) remarked positively on the topic of biosimilar prescribing. Their report concluded that EMA was content that the pharmacokinetics, efficacy, safety and immunogenicity profiles of biosimilars were similar to those of the originator product and concluded that the recommendations for infliximab could apply both to the originator product and its biosimilars [20]. In addition, the HPRA released a guide to biosimilars for healthcare professionals (HCPs) and patients in December 2015. This guide discussed the concept of extrapolation in the context of biosimilars where a clinical study is carried out in one of the approved indications of the biological medicine and the efficacy data are then extrapolated to all authorized indications [11]. As stated in this guide, extrapolation is not unique to the authorization of biosimilars; a similar approach may also be used to deal with post-authorization changes for reference biological medicines.

In February 2016, both NICE and the BSG updated their previous guidance on this subject. NICE reinforced that all HCPs should ensure biological medicines, including biosimilar medicines, are prescribed by brand name so that products cannot be automatically substituted at the point of dispensing. The choice of whether a patient receives a biosimilar or originator biological medicine should rest with the clinician in consultation with the patient [4]. The BSG however decided to go one step further, releasing a position statement on infliximab brand switching. Their guidance stated that there was sufficient evidence to recommend that patients who were in stable clinical response or remission on Remicade® therapy can be switched on the same dose and dose interval to biosimilar infliximab CT-P13. This switch should be carried out after discussion with individual patients with an accompanying explanation for switching (which is usually on the grounds of benefit to the overall service by reduction in costs of the drug and its administration) [19]. Despite the position statement from the BSG, this large acute Irish teaching hospital judged that it was premature to switch all of its patients from Remicade® to biosimilar infliximab CT-P13.

Two months later, a review entitled ‘Switching to biosimilar infliximab (CT-P13): evidence of clinical safety, effectiveness and impact on public health’ published in Biologicals concluded that whilst prudent switching practices should be employed, growing safety experience accumulated thus far with infliximab CT-P13 and other biosimilars was favourable and did not raise any specific concerns [21]. Similar evidence that was in favour of switching had also started to surface [19, 22]. In June 2016, ScienceDaily published a research article on their website entitled ‘Biosimilar switching not suitable for all patients’ [23]. At first, it appeared to the consultant gastroenterologist and chief pharmacist that this article, based on a study conducted in Spain [24], would counteract previous evidence in favour of switching. However, when examined closely, the results of the study showed that when anti-drug antibodies develop in response to Remicade®, these antibodies also cross-react with biosimilar infliximab CT-P13 as both biologicals share structural properties, including antigenic epitopes. These findings suggested that antibody-positive patients being treated with Remicade® should not be switched to biosimilar infliximab CT-P13 since these antibodies would also interact with the biosimilar and potentially lead to a loss of response. Despite its misleading title, the results of this research article actually emphasized the similarities between the originator and biosimilar brands of infliximab and reinforced the science behind the safety of switching. In fact, it should be reinforced that anti-drug antibodies prevent a switch only if the exposure or clinical effect of the reference product is fading.

July 2016 saw the European Commission (EC) release guidance stating that biosimilars, despite small differences, were expected to be as safe and effective as the reference medicine [25]. This publication followed previous documentation issued by the EC in 2014 explaining the concept of biosimilars to HCPs and the pharmaceutical industry [26]. Therefore, based on all the continually emerging evidence in favour of switching, the chief pharmacist and consultant gastroenterologist of the large acute Irish teaching hospital decided to switch all its patients from originator brand infliximab to biosimilar infliximab CT-P13 commencing in September 2016. This decision was relayed to all prescribing physicians during an internal staff meeting where the chief pharmacist and consultant gastroenterologist explained the science behind their evidence-based decision. All physicians accepted this and agreed to switch patients given the vast amount of evidence presented. Physicians agreed to report any ADRs to the HPRA and to EMA. Hospital budget coordinators were once again pleased. Although physicians found it more challenging to reassure patients of the switch at first, they reported that after informing and addressing all patient concerns at the point of prescribing, no opposition to switching arose.

In October 2016, explorative subgroup analyses of patients with CD and UC in the NOR-SWITCH study showed similarity between patients treated with originator infliximab and biosimilar infliximab CT-P13 with regard to efficacy, safety and immunogenicity [27]. Although this was one of the more large-scale controlled studies where biosimilar infliximab CT-P13 was tested in IBD patients, the small sample size of the IBD subgroup was too small to demonstrate any difference in ADR identification or minor differences in effect [27]. However, it was still an advancement on previous evidence for switching which was more so justified on the concept of extrapolation. ECCO released an updated statement in December 2016 that revised its previous guidelines. One of the prominent recommendations was that switching IBD patients from the originator brand to a biosimilar product was now deemed acceptable. It also stated that studies of switching can provide valuable evidence for safety and efficacy and that scientific and clinical evidence is lacking regarding reverse switching, multiple switching, and cross-switching among biosimilars in IBD patients [28]. In this rapidly moving field, the evidence is continuing to grow supporting the case that biosimilar infliximab CT-P13 is just as safe and effective as the originator biological. Figure 1 illustrates in diagrammatic form, the systematic trail of evidence behind the decision-making process to introduce and switch patients to biosimilar infliximab CT-P13 in this large acute Irish teaching hospital.

Figure 1

Results and discussion

The decision to treat new and switch existing patients to biosimilar infliximab CT-P13 in this large acute Irish teaching hospital was a multifactorial one underpinned by a robust and extensive evidence-based trail that ultimately convinced prescribing physicians. From September 2014, all new patients requiring infliximab therapy for the treatment of IBD were prescribed biosimilar infliximab CT-P13. In September 2016, all IBD patients receiving Remicade® were switched to biosimilar infliximab CT-P13. Switching from originator infliximab to biosimilar infliximab CT-P13 in IBD patients occurred in this hospital before any other Irish hospital and before the release of the NOR-SWITCH study data. Biosimilar infliximab CT-P13 was first licensed in June 2013 [15] but it was not until approximately three years later that prescribers in this large acute Irish teaching hospital decided to switch patients. It is evident that there was a significant time lag between regulatory approval and clinical acceptance. In fact, Ireland has the second lowest record of biosimilar use due to Irish HCPs being slow to accept biosimilars [29, 30]. This is possibly owing to a lack of confidence, unwillingness or knowledge to prescribe biosimilars which is also seen in other European countries [31]. Work which aims to enhance the understanding of biosimilar medicines amongst stakeholders and to encourage best practice of biosimilar use is currently being conducted by a collaborative organization of various interested parties [32, 33]. However, it could be argued that Ireland has exceptionally low biosimilar uptake because biosimilar prescribing is not mandated unlike in other countries [34]. In addition, the Irish biosimilar market does not appear very appealing to pharmaceutical companies. Despite the potentially huge cost savings to be made from switching, only 54 packets of the biosimilar product Benepali® were sold since its introduction to Ireland in August 2016 compared to almost 46,856 of the established originator brand Enbrel® (as of May 2017) [35]. Furthermore, various funding systems of different countries can too have an impact where, for example, in the UK, a major motivation for switching was reinvestment of some of the cost savings in improvements to patients’ care [20].

The decision by this Irish teaching hospital to switch patients to biosimilar infliximab could have been regarded as over cautious, delayed and conservative given that EMA had already licensed the biosimilar medicine three years earlier [15] and thus, one wonders why prescribers had not switched patients sooner. With regard to the current biosimilar medicine landscape, it is possible that prescribers may feel more comfortable issuing biosimilars if national authorities would actively enforce and implement individual EMA biosimilar-related decisions as they are published. EMA has the best knowledge of biosimilars amongst regulators but cannot influence interchangeability that is within the mandate of individual national regulatory agencies [10]. These authorities have different capacities to produce information on biosimilars and as a result, this situation contributes to the differential rate of acceptance of biosimilars within EU Member States. With continually emerging positive evidence, it is clear that a three-year time lag for the next biosimilar medicine, from market authorization to the patient switching process, should not occur. Flixabi®, biosimilar infliximab SB2 [36], received market authorization approximately three years after biosimilar inflixmab CT-P13 [37]. Given its late entry to the market relative to biosimilar infliximab CT-P13, it has been unsuccessful in penetrating the Irish market so far. The chief pharmacist and consultant gastroenterologist of this teaching hospital note that they would not be comfortable in switching patients from biosimilar infliximab CT-P13 to biosimilar infliximab SB2 without conducting a comprehensive review of the available evidence, (especially evidence from a switching study), even if the national regulator did declare all licensed biosimilars completely interchangeable [11]. Interestingly however, this large acute Irish teaching hospital was content to switch patients to Tevagrastim®, a biosimilar of filgrastim [38], from the originator brand without performing such a robust evidence review. With regard to the difference between these medicines and their respective disease states, the onset of response on neutrophil count from filgrastrim therapy occurs very quickly after administration and thus is routinely measured to ascertain treatment effectiveness. In contrast, there is no such clear-cut marker for assessing the onset of response from infliximab therapy at these very early stages so this is why an extensive evidence review was conducted prior to switching patients. The comparison between the implementation of these two biosimilars demonstrates that each biosimilar medicine requires a distinct and individualized approach when considering its introduction into the clinical setting; one approach does not suit all.

In the field of gastroenterology, biosimilar adalimumab, which is licensed to treat IBD, was recently granted market authorization [39]. In the Irish context to date, there have been no major efforts to introduce or switch patients to this biosimilar. However, adalimumab is predominantly dispensed by pharmacists in the primary care setting. This is in contrast to infliximab, which is commonly dispensed in the secondary care environment. This difference is quite interesting as it raises the issue that perhaps primary care pharmacists should be targeted by regulatory agencies to encourage patients to switch to biosimilar adalimumab in an effort to increase biosimilar medicine market penetration. However, as previously noted, this switch would have to be initiated by the prescribing physician [9] and be based upon appropriate evidence. Indeed, there are already many interesting and established approaches to biosimilar medicine implementation which demonstrate that just because a biosimilar medicine is licensed, does not mean that its use will be accepted by prescribers nor that all patients receiving the originator brand should be automatically switched. One such approach is whereby the American National Kidney Foundation sponsored a symposium entitled ‘Introduction of Biosimilar Therapeutics Into Nephrology Practice in the United States’ [40]. With anticipated increase in biosimilar products in the field of nephrology, mutually accepted lack of knowledge regarding the biosimilar approval process and development, and lack of trust with respect to biosimilar medicines’ safety and efficacy, this community of experts decided to meet at a nationwide level to discuss the introduction of biosimilars into their area of medicine. The colloquium highlighted several controversies but also made recommendations related to public policy, professional and patient education, and research needs [40]. With the introduction of new biosimilars set to increase on the market in coming years [41], this example of individual fields of medicine taking responsibility for biosimilar usage pertaining to their area may be a safe, feasible and effective approach to introduce biosimilars into the clinical setting. This strategy might be particularly suitable for fields like oncology and other inflammatory diseases where biosimilar usage is set to increase substantially [42, 43]. Another possible approach is that original biological and biosimilar medicines can be prescribed on the proviso that patients will be entered into disease-specific registries. These registries may be used as surveillance systems for monitoring ADRs, as well as to quantify and evaluate the risk-benefit ratio throughout a medicinal product’s life. Registries may be particularly effective for the evaluation of rare ADRs occurring in the real-world population of treated patients, as opposed to the highly selected populations in registration studies [44].

Following on from information released by the Medicine Management Programme (MMP) on biosimilars in the Irish healthcare setting in 2016 [45], and guidance issued by the National Cancer Control Programme (NCCP) on the use of biosimilar medicines in oncology in August 2017 [46], the Department of Health (DoH) disseminated a consultation paper in mid-August 2017 [29]. This paper indicates that the DoH is developing a national biosimilar medicines policy which aims to increase biosimilar use in Ireland by creating a robust framework where biologicals and biosimilars can be safely, cost-effectively and confidently used in the health service [13]. Table 1 reveals which topics of interest are being scrutinized. It is hoped this policy will address the inter-hospital variation to biosimilar medicine implementation in Ireland and shorten the acceptance process of using biosimilars in the clinical setting. An interesting issue raised by the consultation paper is that of inappropriate business practices [13]. Although this was not of concern for this large acute Irish teaching hospital, impact of the source of information and collaboration of prescribers with the pharmaceutical industry can in principle, have an influence on originator product and biosimilar product prescribing patterns. The consultation paper highlights that France and Germany have laws banning physicians from receiving gifts from pharmaceutical companies. For biosimilar medicine uptake to increase and be maintained, the information and evidence used by prescribers must not be tainted with commercial interests.

Table 1

One of the consultation paper’s recurring themes is that there is too much money being spent on originator biologicals when there are cheaper, equally effective alternatives available. It highlights that only 11 biosimilars are currently reimbursable by the Irish healthcare system, while over Euros 200 million is spent each year on biological drugs that already have approved biosimilars or that will have available biosimilars throughout 2018 [13]. It is clear that the potential cost savings to be accrued from switching to biosimilars can increase patient access to other new medicinal products. The Irish Pharmaceutical Healthcare Association (IPHA) framework agreement plans to save money on biological medicines [30, 47] where most of these medicines are reimbursed on Ireland’s high-tech medicine scheme. This scheme has seen an increase in expenditure from Euros 177.49 million in 2005 to Euros 562.29 million in 2015 [48, 49]. This prodigious level of pharmaceutical expenditure cannot be maintained. Research from the Irish National Centre for Pharmacoeconomics (NCPE) has shown that when pharmaceutical companies submit budget impact analyses (BIAs) for new high-cost medicines such as biologicals, the majority of these high-cost medicines have a greater cost burden on the budget than what is forecasted in their BIAs [50, 51]. This results in taxpayers spending more than anticipated. Thus, an increase in the uptake of biosimilar medicines would be a more sustainable approach to lower the Irish drug bill. One approach the DoH could take would be to establish gainsharing agreements at hospital level. Hospitals could be financially awarded for using biosimilars [20] or fiscally penalized for lack of utilization. Gainsharing agreements have already proven to be a powerful incentive in increasing biosimilar use at EU level [52]. With respect to the Danish biosimilar landscape, their initial passive approach to switching actually led to an administrative order [34]. Thus, another approach the DoH could adopt would be to introduce reference pricing of biological products which would accelerate the path to increased biosimilar usage [13]. Reference pricing of SMCE medicines has already resulted in savings of millions of euro in the Irish primary care setting [30]. Success of the use of biosimilar infliximab CT-P13 at University Hospital Southampton [53, 54] and in Denmark and Norway was observed, where biosimilar infliximab reached market penetration levels in excess of 90% (as of April 2016) [55]. Such uptake resulted in substantial drug acquisition cost savings and subsequently increased patient access to the biosimilar medicine [22, 53]. A recent report by QuintilesIMS™ has shown that the entrance of biosimilars into the market increases price competition while also generating price reductions for both biosimilar and reference products [56]. However, this report stresses that if the problem of low biosimilar uptake is not appropriately managed in the long term, this could lead to fewer new biosimilars being developed, reducing overall competitive pressure.

Conclusion

This review examines the evidence used by a large acute Irish teaching hospital to safely and effectively introduce biosimilar infliximab CT-P13 into the gastroenterology care pathway. There was a significant time lag between regulatory approval and clinical acceptance notwithstanding that EMA had granted market authorization for biosimilar infliximab CT-P13 three years prior to the initiation of this hospital’s switching process. However, the conservative approach to biosimilar infliximab implementation discussed in the review is justified given the conflicting and changing evidence disseminated from various sources over this three-year period. Alternative approaches that could be used to increase biosimilar medicine adoption into healthcare environments have been suggested. Undisputedly, this review demonstrates that increased biosimilar medicine usage is of benefit to all stakeholders: increased access for patients, more treatment options for prescribers, sustainable healthcare budgets for payers and more business opportunities for manufacturers.

Funding

This research was funded by the Irish Research Council GOIPG/2016/635.

Competing interests: The authors declare no competing interests in preparing this manuscript.

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

Authors

1Pharmaceutical Care Research Group, School of Pharmacy, University College Cork, College Road, Ireland
2St Luke’s General Hospital, Freshford Road, Kilkenny, Ireland
3Department of Accounting, Finance and Information Systems, Cork University Business Schools, University College Cork, College Road, Ireland
4Cost Accounting & Funding Team, National Finance Division, Health Service Executive, First Floor East, Model Business Park, Model Farm Road, Cork, Ireland

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Author for correspondence: Gary L O’Brien, BPharm, MPharm, Pharmaceutical Care Research Group, School of Pharmacy, University College Cork, College Road, Cork, Ireland

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