Formation of patent strategy at all stages of biosimilar development and Implementation

 

Elena Vyacheslavna Litvinova^1*, Olga Viktorovna Posilkina², Nataliia Fedorovna Maslova³

¹Candidate of Biology (PhD), Associate Professor of the National University of Pharmacy,

National University of Pharmacy, Ukraine, 61002, Kharkov, 53 Pushkinska str.

²Doctor of Pharmacy, Professor of the National Pharmaceutical University,

National University of Pharmacy, Ukraine, 61002, Kharkov, 53 Pushkinska str.

³Doctor of  Biology, Professor of  the State Enterprise “State Scientific Center of  Drugs”, State Enterprise “State Scientific Center of Drugs”, Ukraine, 61085, Kharkov, 33 Astronomicheskaya str.

 

ABSTRACT:

The aim of this study is to analyze the specificities formation of patent strategy at all stages of biosimilar development and implementation. Due to the complexity of biological medicinal product structure and the impossibility of accurate reproduction of technology, biosimilar can not be identical to a copy of the original biological medicinal product. The dependence of biological medicinal product from living cells, the functions of which inevitably vary, as well as the presence of impurities can significantly change the properties of biological medicinal product of different manufacturers. On the basis of the above, it follows that when creating a biosimilar there is a possibility of obtaining a new invention. It has established the possibility of biosimilar patent protection at all stages of the life cycle depending on the stage of preparation of registration dossier. It contributes to rational management of the intellectual capital of pharmaceutical companies and more effective drug provision of the population. It has been proved that various stages of the development and implementation of biosimilars should be accompanied by different types of their patenting (pharmaceutical composition, new dosage form, delivery method, optimization of the purification process, increase of stability, new indications for application or new treatment), etc. It has proposed author's algorithm for the formation of patent strategy of biosimilar development and implementation depending on the stage of preparation of the registration dossier.

 

 

 

INTRODUCTION:

The world market of biological medicinal products is actively developing. According to «GBI Research» company today the sales of biological medicinal products are about $200 billion. USA is accumulating an average of 17-20% of the global pharmaceutical market [1].

 

According to the directive of the European Parliament and the Council of the European Union 2001/83/EC, biological medicinal products include: immunological drugs; drugs are obtained from donor blood and donor plasma; medicines are obtained with the help of biotechnological processes; medicines of advanced therapy (gene therapy preparations, somatic cell therapy drugs, tissue therapy products).

 

Biological medicinal products have opened new possibilities for the treatment of diseases that are difficult to treat: oncological pathology, diabetes, multiple sclerosis, etc., resulting in a significant improvement in the quality of life of these patients, increasing its duration and giving hope for a cure. However, due to the complexity of their development and production, the cost of such drugs is usually quite high. One of the ways to increase their economic accessibility for patients is the replacement of biological medicinal products with biosimilars. From the regulatory authorities' point of view, in particular the FDA and EMA, these drugs should be called biosimilars [2, 3].

 

The aim of this study is to analyze the specificities formation of patent strategy at all stages of biosimilar development and implementation.

 

EXPERIMENTAL:

Studies were conducted using a databases on the Internet: Ukrainian patent office, the European patent office, the US patent office, the Food and drug administration, European Medicines Agency (EMEA), State enterprise “The State Expert Center” of the Ministry of Health of Ukraine. It has used retrospective, logical, systematic and analytical methods.

 

RESULTS AND DISCUSSION:

One of the important problems in the creation of biological medicinal products is their high cost, due to the complexity of their development and production. Given the duration of the treatment of these pathologies, the total cost becomes “unacceptable” not only for the patient but for the state. The average annual cost of treatment with certain biological medicinal products is given in table 1 [4].

 

Table 1. Cost to US consumers of some commonly used biologic medicines*

Drug Name	Indication	Annual Cost ($)
Etanercept (Enbrel, Amgen and Wyeth)	Rheumatoid arthritis	26,247
Trastuzumab (Herceptin, Genentech)	Breast cancer	37,180
Interferon beta‐1a (Rebif, EMD Serono and Pfizer)	Multiple sclerosis	39,505
Adalimumab (Humira, Abbott)	Rheumatoid arthritis and Crohn’s disease	50,933†
Imatinib (Gleevec, Novartis)	Leukemia and gastrointestinal Stromal tumor	56,424†
Epoetin alfa (Epogen, Amgen)	Anemia of chronic renal disease	8,447
Imiglucerase (Cerezyme, Genzyme)	Gaucher’s disease	200,000

*Full cost estimates were annualized on the basis of a reasonable course of therapy for the given indication (2009); † costs are for the treatment of Crohn’s disease and gastrointestinal stromal tumors

 

 

It should be noted that the next 5-7 years are very important for many pharmaceutical companies, as patents expire on a number of foreign biological medicinal products, so the work in the biosimilar sector provides competitive advantages and opportunity to generate significant profits.

 

Among the main factors in the development of the biosimilar market, experts highlight their high efficiency; the presence of evidence base, relatively moderate price compared with original products, the broad scope of application, social significance and increased interest of state and pharmaceutical companies from their production.

 

In 2004-2005 the controlling body of EU and WHO have developed a scientifically-based legal framework and began registration of biosimilars.

 

A distinctive feature of biosimilar development is that at the stages of its life cycle it is necessary to determine the similarity, the formation of a scientific bridge leading to the clinical experience of the original drug, and the main goal of biological medicinal product development is to prove the clinical effect. The most sensitive tool is analytical methods to form this scientific bridge in the biosimilar development.

 

In biosimilar study the extensive comparison is made in comparison with the reference biological medicinal product: its physicochemical characteristics and production process, functional characteristics, pharmacokinetics and pharmacodynamics, the study of immunogenicity, efficacy and safety. The principle of a step-by-step methodology for proving the similarity of the biosimilar and reference biological medicinal product is justified to reduce the amount of research at the stages of preclinical and clinical study of the reproduced drug in normative documents. The more fully and faithfully demonstrated the similarity of the biosimilar and reference biological medicinal product at each stage, the less the amount of research is required at subsequent stages.

 

It is necessary to monitor biosimilar compliance with the original biological medicinal product, their safety, bioequivalence, the quality of the active pharmaceutical ingredient, the determination of the methods of synthesis of active pharmaceutical ingredient, the characteristics of the excipients and packages in biosimilar production.

The high molecular weight of biosimilar, its heterogeneity and the change in the methods of synthesis may be the reason for the preparation of a drug that differs in its properties from the original biological medicinal product. The factors that determine the complexity of biostimilar reproduction also include: purity of active pharmaceutical ingredient, content of by-products, isomers, degradation products, multi-stage and high-intensity production. The safety problems of biosimilar are associated with immunogenicity.

It has conducted the analysis and systematization of literature data revealed the effectiveness and safety of a number of registered biosimilars according to clinical trials, including meta-analysis (Table 2).

 

Due to the complexity of biological medicinal product structure and the impossibility of accurate reproduction of technology, biosimilars can not be identical to a copy of the original biological medicinal products. The dependence of biological medicinal product from living cells, the functions of which inevitably vary, as well as the presence of impurities can significantly change the properties of biological medicinal products of different manufacturers. On the basis of the above, it follows that when creating a biosimilar there is a possibility of obtaining a new invention [13]. It has conducted analysis and systematization some patents for biosimilars (Table 3).

 

Analysis of literature data, regulatory framework in the field of biostimilar registration, systemization of patents, the object of which is biosimilar, has allowed proposing an author's algorithm for the formation of patent strategy of biosimilar development and implementation depending on the stage of preparation of the registration dossier (Figure 1).

 

At the first stage of biosimilar development it is necessary to conduct patent research on the patent purity of the investigated object, to obtain data confirming the expiration of the patent on the original biological medicinal product.

 

Before starting to biosimilar development, especially if third parties are involved as partners or as sponsors, it is necessary to conclude an agreement on creative cooperation with indication of the percentage of each person's participation and the distribution of property rights. If this is not taken into account in advance, this may lead to a conflict of interest.

 

Table 2. Analysis of the effectiveness and safety of some registered foreign biosimilars

Active pharmaceutical ingredient	Results	Ref
Adalimumab	It has investigated comparative efficacy and safety of biosimilar adalimumab and originator adalimumab in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA). Biosimilar and originator adalimumab, in combination with MTX, represent an effective intervention for active RA despite treatment with MTX. No significant difference was found between biosimilar and originator adalimumab in terms of efficacy and safety.	5
Erythropoietin	It has investigated a comparison of the safety and efficacy of HX575 (epoetin alfa proposed biosimilar) with epoetin alfa in patients with end-stage renal disease. This randomized, double-blind, parallel-group, multicenter study was conducted at 49 US clinical sites. HX575 in dialysis patients with renal anemia was therapeutically equivalent to the reference medicine in terms of maintaining stable Hb levels and safety.	6
Etanercept	To evaluate the efficacy and safety of biosimilars of anti-tumor necrosis factor (TNF)-α agents compared to their reference agents in immune mediated diseases. Nine studies reporting outcomes in 3291 patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) were identified (5 infliximab, 2 adalimumab, and 2 etanercept). In the present study, biosimilars of anti-TNF-α agents had an overall comparable efficacy and safety profile compared to their reference agents in RA and AS supporting their use for these conditions.	7
Filgrastim	It has compared the clinical efficacy and safety of approved or proposed G-CSF biosimilars (filgrastim or pegfilgrastim) with reference G-CSF in patients with breast cancer. Eight eligible randomised clinical trials were included in this meta-analysis. This meta-analysis showed no significant differences in clinical efficacy and safety between biosimilar and reference G-CSF in BC patients.	8
Imatinib	It has evaluated the efficacy and safety of generic imatinib (Genike, Chiatai Tianqing Pharmaceutical Group Co., Ltd.) and imatinib (Glevic, Novartis, Switzerland) in 323 newly diagnosed patients with chronic myeloid leukemia in chronic phase (CML-CP). There were no statistically significant differences in efficacy and safety between Glevic and Genike treatment in newly diagnosed patients with CML-CP.	9
Infliximab	Eleven observational studies reporting outcomes in 829 patients treated with biosimilar of infliximab (CT-P13) were identified. CT-P13 was associated with excellent clinical efficacy and safety profile, supporting its use in the treatment of inflammatory bowel diseases.	10
Somatropin	Data from clinical development studies and 10 years of postapproval experience affirm the clinical efficacy and effectiveness of biosimilar recombinant human growth hormone (rhGH) across all approved indications. Biosimilar rhGH is an effective treatment option for children who require therapy with rhGH.	11
Trastuzumab	It has investigated the overall response rate and assess the safety of a proposed trastuzumab biosimilar (n=230) plus a taxane or trastuzumab (n=228) plus a taxane in patients without prior treatment for ERBB2-positive metastatic breast cancer in multicenter, double-blind, randomized, parallel-group, phase 3 equivalence study. Among women with ERBB2-positive metastatic breast cancer receiving taxanes, the use of a proposed trastuzumab biosimilar compared with trastuzumab resulted in an equivalent overall response rate at 24 weeks.	12

 

Table 3. Analysis of patent protection of some registered foreign biosimilars

Active pharmaceutical ingredient	Pharmaceutical company	Patent Number	Title of invention
Adalimumab	Lupin ltd	WO2016162819	Stable aqueous pharmaceutical composition of anti-TNF alpha antibody
Erythropoietin	Sandoz	SI1453857	Chromatographic purification of recombinant human erythropoietin
Etanercept	Sandoz	CA2833427	Stable pharmaceutical liquid formulations of the fusion protein TNFR:FC
Filgrastim	Teva pharma	ZA201105171	New stable formulations of recombinant human albumin-human granulocyte colony stimulating factor fusion protein
Imatinib	Teva pharma	JP2011140508	Stable imatinib composition
Infliximab	Avesthagen ltd	WO2011015919	A highly efficient process of purification and production of recombinant infliximab
Peginterferon alpha-2b	Lupin ltd	MX2015005230	Stable pharmaceutical composition of peginterferon alpha-2b.
Somatropine	Sandoz	WO2004004781	Liquid formulations with high concentration of human growth hormone comprising 1,2-prolpylene glycol
Trastuzumab	Avesthagen ltd	WO2011015920	A highly efficient process of purification and production of recombinant trastuzumab

 

Figure 1. Algorithm for the formation of patent strategy of biosimilar development and implementation depending on the stage of preparation of the registration dossier

 

At the first stage, it is important to choose the reference biological medicinal product that must be approved for use in the European Union, on the basis of a complete dossier in accordance with the requirements of Article 8 of the EU Directive 2001/83, as amended. The selected reference biological medicinal product should be used throughout the entire program of comparative studies.

At the WHO seminar, which took place on July 5, 2017 in Copenhagen, it has raised the issue of a global reference biological medicinal product for biosimilar development. Most health authorities, including the European Medicines Agency and bodies in the Euroasian Economic Union allow the use of foreign reference biological medicinal product in biosimilar development. If a local reference biological medicinal product is needed, then, to facilitate global development, it is possible to link the data on the analyst generated in the process of working with reference biological medicinal products from different countries.

 

Active substances that are part of the biological medicinal products are generally labile, complex in structure, which may change during the production of the dosage form, with further storage, which in turn may affect the efficacy and safety of the final product. In connection with the above, the biological medicinal products can not be identical, as their stability can vary from series to series. It should be borne in mind that in biosimilar industrial technology developing it is practically impossible to recreate in the new conditions and in full all stages of the biotechnological process of obtaining the original (reference) biological medicinal product and obtain an absolute copy thereof. In addition, it is possible to use other process equipment and reagents in relation to the technology of original (reference) biological medicinal product. In connection with the above, when comparing the quality indices of reproduced and reference biological medicinal products, differences can be established and, above all, mainly due to new intermediate products and impurities. When evaluating biosimilar it is important to establish the composition, degree of purity, compliance with the dosage form; similarity with the corresponding reference product; efficiency; profile of immunogenicity and, if necessary, to compare economic indicators. Thus, at the second stage (module 3 of biosimilar registration dossier), the following objects of patenting can be identified: pharmaceutical composition (improvement of consumer properties), a new pharmaceutical form (ease of application, increase of compliance), method of obtaining (simplifying the method, reducing the time of the method), optimization of the purification process (increasing the output of the target product, increasing the purification of the target product), increasing stability (increasing stability in storage, improving organoleptic characteristics), etc. Thus, the original biological medicinal product, the Genotropin (Pfizer), is released in the form of lyophilizate to prepare a solution for subcutaneous administration, while his biosimilar Omnitrope (Sandoz) is a ready-made solution for subcutaneous administration (new drug form).

 

In the third stage, in accordance with preclinical studies (module 4), the following objects of inventions can be identified: pharmaceutical composition (bioavailability increase, toxicity reduction, expansion of the spectrum of pharmacological action, increase of pharmacological activity, etc.).

 

At the fourth stage, clinical studies are carried out step by step and begin with a comparative study of the parameters of biosimilar and reference biological medicinal product. The optimal is the study of pharmacokinetic parameters in cross-examinations on healthy subjects, in scientific substantiation and in compliance with ethical norms. Studies of pharmacokinetic and pharmacodynamic indices are performed in patients with pathology included in the indications for the use of the reference biological medicinal product. In the case of clinical studies, the same doses, route of administration and treatment regimen indicated in the instructions for the use of the reference biological medicinal product should be used.

 

At fourth stage, the detection of the following objects of inventions is possible: a new indication for use or a new method of treatment (improving treatment efficacy, accelerating recovery, reducing toxicity, side effects, etc.), pharmaceutical composition (increasing bioavailability, reducing toxicity, expanding the spectrum of pharmacological action , increase of pharmacological activity, etc.). So, the company F. Hoffman-La Roche protects its biological medicinal product, Recormon (epoetin beta, Russian Patent No. 2305554) as a method of treating disturbances of iron distribution in diabetes. Thus, a new indication for the medical use of erythropoietin has been demonstrated.

 

On the fifth stage, a registration dossier is formed and the drug is submitted for registration. At the same time, a program of managing risks (a first to market plan) is presented for the purpose of continuous collection of safety and immunogenicity data after first to market. After biosimilar implementation the patent strategy does not stop, it includes constant monitoring of unlawful use of biosimilar, establishment of violations of property rights to intellectual property.

 

Thus, the presented analysis indicates that throughout biosimilar life cycle and preparation of the registration dossier, it is advisable to use the patent protection tactics.

 

Patenting and implementation of highly effective and safe biosimilars for the treatment of the most urgent diseases (diabetes, anemia, oncopathology, etc.) will allow pharmaceutical companies to take the leading position in the pharmaceutical market, effectively use the existing intellectual potential.

 

CONCLUSION:

1     It has established the possibility of biosimilar patent protection at all stages of the life cycle depending on the stage of preparation of the registration dossier. It contributes to rational management of the intellectual capital of pharmaceutical companies and more effective drug provision of the population.

2     It has been proved that various stages of the development and implementation of biosimilars should be accompanied by different types of their patenting (pharmaceutical composition, new dosage form, delivery method, optimization of the purification process, increase of stability, new indications for application or new treatment), etc.

3     It has proposed author's algorithm for the formation of patent strategy of biosimilar development and implementation depending on the stage of preparation of the registration dossier.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

 

REFERENCES:

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Accepted on 10.05.2018           © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(7): 3081-3086.