Biosimilars: the paradox of sharing the same pharmacological action without full chemical identity

Abstract

The use of biotech medicines is increasing, with consequent mounting expenses for National Health Systems (NHSs). Biosimilars should be considered an opportunity to improve access to care. On the other side, the general public might suspect to receive low-quality medicines to save money. Actually, no drugs with a lesser degree of pharmaceutical quality with respect to existing alternatives can be authorized on the ground of a lower price. Biosimilars can be authorized only if their quality is of the same level as that of the originator. There is no chemical identity between biosimilars and the originators: any differences in quality attributes must be justified and shown not to impact on the safety and efficacy of the biosimilar by scientific investigations including pre-approval nonclinical and/or clinical studies. The biosimilar safety profile may be different from the originator or change over time for the same product. Hence caveats limiting the widespread use of biosimilars yet exist and should be solved by education on the main biological issues of biotech medicines, and on continuous update of the rules set up by the Regulatory Authorities to assess biosimilarity and to monitor post-approval safety.

Keywords::

• biosimilars
• biotechnology
• interchangeability
• quality by design

1. Introduction

Owing to the long working time required to manufacture one batch, to the number of expensive controls required during the process, the price of biotech products is so high that access for patients is often limited and will be even more limited in the future, due to increased complexity and economic constraints.

In a world where biosimilars are now conquering their position in the pharmaceutical market, broad education on the main biological issues of biotech medicines is becoming imperative in order to fully understand that despite evidence of small differences in the chemical structure, a biosimilar shares the same biological activity of the reference product, and that the originator itself is something dynamic changing over time.

Increased licensing of new biotech medicines is leading to an augmented demand of these products, with consequent mounting expenses for National Health Systems (NHSs). Even in fully developed countries, the feeling of unsustainable access to biotech therapies due to high costs for NHSs is growing more and more [1]. On the other hand, the economic aspects represent a challenge also for pharmaceutical companies due to the long time necessary to develop original biotech or biosimilar molecules, high manufacturing costs, and waiting times to obtain authorizations [2]. Other forms of investment such as stocks, real estate, electronics, web design apparently seem to offer investors more rapid wages with less economic burden.

The mission of Health Authorities is to grant a sustainable access to therapies to all patients ensuring at the same time the appropriateness of care. The use of biosimilars, when economically advantageous, should be considered an opportunity to improve access to care (12 patents of biotech drugs will expire before 2020) [3]. On the other side, this may cause in the general public the suspect to receive low-quality medicines to save money (what costs less is usually perceived of lesser value). Moreover, the complexity of the manufacturing process of biotech medicines may generate the wrong perception of excess uncontrollable variability in the biosimilar molecules, resulting in a feeling of uncertainty and uneasiness in the prescribing physician, and further raising suspects toward biosimilars.

Biotech medicines pose not only economic issues but may also require, in the clinical practice, benefit/risk evaluation in the single patient; hence they need to be used in an appropriate way. Patients need to be fully aware of the adequacy of the treatment they are receiving with respect to quality, safety and efficacy. At the same time, clinicians need to properly know and utilize them.

The knowledge of problems linked to biochemical aspects and manufacturing processes of biotech medicines allows a better comparison among different products and enables clinicians to offer the best choice to patients. This was already necessary in the past, for example, to choose an albumin-free vaccine or a biotech product free from the use of human serum in the manufacturing process to treat naïve patients, especially children, in order to avoid exposition to viruses or other transmissible pathogens (e.g., transmissible spongiform encephalopathies) [4].

2. Manufacturing optimization

The main issue in the manufacture of biological products is keeping the process consistent. When a biotech product is authorized, the manufacturing process has been characterized in its main aspects, but not all quality attributes have been fully studied, hence the variability of the specifications is very high. Due to the intrinsic complexity and variability of biotech products, the manufacturing process becomes mature and consistent only after years the product has been marketed and often following dozens of variations. This is similar to what happens for the estimation of the therapeutic effect between Phase II and III trials: the effect is already demonstrated after Phase II, but the quantitative estimate has larger margins of variability than after Phase III. A regulatory axiom is that no drugs with a lesser degree of pharmaceutical quality with respect to existing alternatives can be authorized on the ground of a lower price. Biosimilars can be authorized only if their quality is of the same level as that of the originator. During the biotech lifecycle, widespread demand leads Marketing Authorization Holders (MAHs) of originators to increase manufacturing scale, to add new manufacturing sites, to generate new working or, despite very rarely, new master cell banks. Variations may have ‘positive' and ‘negative' effects. On one side, for an originator biological drug major changes impacting on the manufacturing process would trigger new clinical trials comparing old and new lots, with a nearly identical regulatory process to that of the licensing of a new biosimilar product. On the other side, the MAH of originator products, at the time of patent expiring, have long and detailed experience with their manufacturing processes, and because of the regulatory obligation to update their dossier and use state-of-the-art techniques for quality control, have usually manufacturing processes highly optimized and operating under tight specifications. Thus, the similarity exercise that a biosimilar has to perform with the originator must ensure a quality level that is comparable to the current level of the originator.

3. Absence of chemical identity

Biosimilars are not chemically identical to the originator. Lack of chemical identity due to minor differences in amino acid sequence or post-transcriptional glycosylation pattern, different impurities profile and excipients may lead to increased immunogenicity resulting in safety and/or efficacy problems. Data on both analytical comparability and clinical comparability are thus needed in order to establish biosimilarity. Any differences in quality attributes must be justified and shown not to impact on the safety and efficacy of the biosimilar by scientific investigations including pre-approval nonclinical and/or clinical studies. Furthermore, the advances in manufacturing technologies and of more effective purification techniques often allow to achieve a better impurities profile for the biosimilar with respect to the originator.

The biosimilar safety profile may be different from the originator or change over time for the same product. In fact, the new Directive on Pharmacovigilance requires an additional monitoring for biosimilars with respect to chemical generics [5], in order to early detect any possible safety signal since the product is placed on the market.

To date no demonstration exists that a licensed biosimilar had a lower grade pharmaceutical quality or a worse risk/benefit ratio with respect to the originator. Indeed, the paradigmatic case of erythropoietins alpha and beta for whom, following a process modification, cases of pure red cell bone marrow aplasia were reported in Europe (in US the formulation and manufacturing process were different), involved the originators [6]. These cases have been investigated by the Marketing Authorization Holder and by the European Competent Authorities and minimized via modifications of the formulation and production process, in order to reduce immunogenicity. This is a further verification of the importance that the regulatory review process shall always be based on solid scientific grounds.

4. Immunogenicity

The clinical features of immunogenicity may affect both safety and efficacy. For instance, anti-drug antibodies may be induced, and adverse reactions such as hypersensitivity reactions or neutralization of endogenous proteins may occur.

The studies to demonstrate differences in immunogenicity may be complex because they can be influenced by concomitant therapies or disease severity (e.g., in case of immunosuppression). Hence, the therapeutic indication most sensitive for establishing equivalence in efficacy might not necessarily be the most suitable for establishing differences in immunogenicity. At the moment, an increase in the reporting rate of adverse effects for a biosimilar product due to immunogenicity with respect to the originator has not yet been documented in the EU [7].

5. Regulatory aspects

Biosimilars are thus multi-level verified scientifically acceptable therapeutic options to biotech originators representing strategic resources by which highly expensive treatments may be made available to large numbers of patients both in countries where the NHS reimburses high cost treatments and in nations where pharmaceutical assistance relies on insurance companies. On the other hand, caveats exist that may limit their broad use in the clinical setting.

The first one is that, despite patent expiration of the originator, the manufacturing processes of biosimilars need in any case advanced technologies. Biotech plants are widespread worldwide, including developing countries, but due to efforts of the European Medicines Agency (EMA), biosimilars that have undergone an exhaustive regulatory review are currently on the market only in the EU.

A further caveat is that the licensing of biosimilar products can carry significant scientific and economic burdens to manufacturers, and can be resource and time consuming for Regulatory Authorities because of complex dossiers to evaluate. The EMA since 2004 has developed and revised quite a number of extensive guidelines (more recently also the Food and Drug Administration (FDA) has done the same) to ensure consolidated and harmonized scientific criteria to evaluate biosimilarity [8,9]. The assessment of biosimilarity requires class-specific science-based regulatory approval pathways, that evolves in light of the experience gained and involves specifically trained assessors.

If we choose two originators, one licensed in 2001 (Aranesp™ – darbopoetin) and another one licensed in 2006 (Tysabri™ – natalizumab), and check the number of variations related to the manufacturing process of the drug substance and of the drug product, the following results are obtained: for Aranesp™, 21 quality variations have been submitted to date [10], including the replacement of the existing Master Cell Bank; similarly, for Tysabri™, 22 quality variations have been presented since the initial commercialization [11]. These figures show the complexities and challenges of the regulatory process of biotech medicinal products also in the post-approval setting.

6. Quality by design

In modern pharmaceutical manufacturing, the Quality by Design (QbD) approach may reduce the need to submit continuous variations by establishing a ‘design space' [12]. This basically consists in a thorough characterization of the process in a pilot scale, in order to establish how the critical quality and process attributes vary, and to define ranges of variation per each parameter that can be modified inside the chosen range without submitting any regulatory variations. Even if the QbD approach may not eliminate completely the huge number of variations, typical of biotech products, it may reduce their number, allowing saving time and economic resources.

Despite mathematically complex, the QbD approach is beginning to be applied also to biological manufacturing processes, in particular monoclonal antibodies. Computer multivariate analysis, that allows to manage complex mathematical functions of multiple variables, is an innovative tool that will lead the modernization of pharmaceutical process characterization, and is predicted to favor in the next future also the widespread production of biosimilars. Of course, the reality is different from expectations: scale-down (pilot) model, mathematical simplification, unforeseen variables may render the model not fully representative of the real process, and focused on-site visits by Regulators to check site studies in order to demonstrate the correspondence between computer elaboration and physical process are needed. Indeed the first Marketing Authorization based on a QbD approach granted in EU for a monoclonal antibody (Perjeta™ – pertuzumab) did not include a process-wide design space, as further clarifications and implementations were considered necessary by the CHMP before the proposed design space could be considered approvable [13].

7. Interchangeability

Switching between biological medicinal products from different origins is a debated issue. At the moment, no robust studies demonstrating interchangeability among biosimilars or with the originator are available [14]. The clinical comparability exercise demonstrates statistical similarity in terms of efficacy and safety of the biosimilar and the reference product on the basis of PK/PD studies or small clinical trials that are not powered to highlight, for instance, a different immunogenicity. On the other hand, the same problem exists when a new manufacturing site is added for the originator, or an alternative process is introduced. When the corresponding variation is assessed, the competent authority evaluates the impact of the change and in case it has a significant impact, further clinical studies may be requested. In such cases only equivalence in efficacy is demonstrated, but trials may lack the statistical power to point out subtle differences in safety. Hence the regulatory effort is not yet finished: additional guidance is needed on the strength of evidence needed to demonstrate interchangeability.

Finally, another relevant aspect is the extrapolation of efficacy and safety data for indications of the originator not tested during the comparability exercise of the biosimilar. The assumption that based on the same mode of action and involved receptors no additional safety issues are expected for the extrapolated indication cannot always be considered automatically sufficient, particularly when the different indications involve the use of different dosages or target population.

8. Concluding remarks

In conclusion, biosimilars should be considered as valuable therapeutic options supported by comprehensive evidence of similarity with the originator assessed at the quality, preclinical and clinical level. Affordable prices and market competitiveness that can be obtained with their use are important achievements for NHSs that are required to ensure the largest access to care compatible with financial resources.

Caveats limiting their widespread use yet exist and should be solved by education on the main biological issues of biotech medicines, and on the rules set up by the Regulatory Authorities to assess biosimilarity and to monitor post-approval safety. At the same time, continuous updating of regulatory guidance, in light of the experience accumulating in time, is necessary to address unsolved issues as complexity in both approval and post-approval process and interchangeability.

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.