Overview of Biosimilars

 

S. Janani, K. Manikandan, R. Kamaraj*

SRM College of Pharmacy, SRM Institute of Science and Technology, SRM University, Chennai

 

ABSTRACT:

Biosimilar is a biologic product that is similar to the original innovator product that has been manufactured by a different company.Though, biosimilar and biologics are analogous to each other, biosimilar is the generic version of biologics. Unlike generics where the active ingredients are identical to the reference drug, biosimilar is not identical, rather similar to the reference biologics. Due to post-transcriptional changes, the manufacture of biosimilar is difficult. These complexities that occur in the manufacture of biosimilar make it hard to claim patent. The Patient Protection and Affordable Care Act vindicate the future for granting biosimilars in the U.S through its subtitle, the Biologics Price Competition Innovation Act (BPCIA). 351 (a) application is used for getting approval of new biosimilar while 351 (k) is the biologic license application. For Europe, approval of biosimilars occurs through EMA via centralised procedure. The pilot study can be conducted by the sponsor for scientific advice needed in the filing of biosimilar. The GCC (Gulf Cooperation Council) is an economic and political confederation of six Middle Eastern countries- Kuwait, Oman, Saudi Arabia, UAE (United Arab Emirates), Qatar, Bahrain.Therefore, technically, patent infringement is no big concern as there are no patents for these products in India.

 

 

 

INTRODUCTION:

With recent advancement in drugs, biological drugs or biologics has gained paramount importance in many medical fields including haematology, rheumatology, oncology,multiple sclerosis, and various other diseases. The first generation of biopharmaceutical product, Humulin was launched in 1982, and now it is at the end of patent expiration. Genetic recombination technique in living cells is applied in the production of biosimilar and then purified by complex procedures. Biosimilars are mostly polypeptides or monoclonal antibodies. Biosimilar involves a wide range of substances, including growth factors, recombinant hormones, monoclonal antibody-based products, blood products, recombinant vaccines and advanced technology products (cell and gene therapy biological products)¹.

 

 

Biosimilar is also called as similar biologics, follow-on-biologics, similar bio-therapeutic product and subsequent-entry biologics². Follow-on-biologics is used in the U.S.A while biosimilar is used in the European Union. Biosimilars are largely approved in Europe.

 

Three determinants in biosimilar definition:

 

 

 

CHALLENGES FACED BY BIOSIMILAR:

A biosimilar drug is a biological drug manufactured by a different company that is targeted to mimic the reference product³. Though the peptide sequence is same in biosimilar, they are non-identical due to alterations or post-transcriptional changes, happened during the purification process. The area of concern of physicians is the approximation of biosimilar to the prototype drug ⁴ and therefore legislation and procedure have to be followed post-marketing ⁵. It can be seen from,

·         A high range of molecular complexity is exhibited by biologics

·         A minor change in the product can cause a major change in the product ^6,7, and

·         They are produced in whole organisms or in culture by cells.

Complexities in the approval of a biosimilar:

 

 

Differences between generics and biosimilar:

Process	Generics	Biosimilar
Manufacturing	They are produced by chemical synthesis   Reproducibility easy to establish	They are formulated by genetic recombination method. Reproducibility difficult to establish
Clinical development	In some cases, requires all phases of clinical studies.	Vigorous clinical studies from Phase I-III are conducted.
Regulation	Bioequivalence should be shown Abbreviated registration methods are followed in Europe and U.S Automatic substitution is allowed	Similarity should be demonstrated Regulatory pathway for biosimilar is defined byEMEA- European Medicine Agency Automatic substitution is not allowed.

 

BIOEQUIVALENCE OF BIOSIMILAR:

Based on EU legislation, European Medicine Evaluation Agency (EMEA) is the only agency to have proposed guidelines for biosimilars. The guideline discusses the production process requirements, analytical methods, and quality to assess comparability, elements to look while choosing an innovator product and physiochemical and biological characterization of biosimilars. Along with these guidelines, there is four product classificationpublished for the manufacture of biosimilars that contain recombinant epoetin, somatotropin human insulin and human granulocyte colony-stimulating factor. These indentures sketch out the pre-clinical and clinical data requirements for marketing approval, describing the design and size of the trials and the best way for proving equivalence for each product, in comparison with an original drug.

 

Prospective manufacturers can come up with more number of scientific evidence on the bioequivalence of biosimilar giving special focus on quality, safety, and efficacy which can lead in increase of biosimilar in the market for patients’ use ⁸.

 

PATENTING BIOSIMILAR?                                                                                                    

Are there any consequences for patenting biosimilar considering their complexities? In a narrow sense, if biosimilars are considered as bio-generics, these biologic drugs can enter the market right after the patentexpiration and there no patent-related problems that need to be solved, however, they are open to regulatory interpretations. If seen in a broader sense as inventions or patent applications, patent-related problems arise. In some instance, biosimilar patents may be filed even when the original patent is still valid rather than filing it after the expiration. In such a case, the pioneer manufacturer should draft the claim in the original patent broadly enough to prevent biosimilars from entering the market. Thus the scope of the assertion should include a broad coverage of all sequences that are at least in a range of 80 and 100 percent identity in comparison to the sequence of the biopharmaceutical (original). So, for the biosimilar patent applications, novelty and invention are the prime focus⁹.

 

Some approved biosimilar:

Manufacturer	Product	Brand name	Approved in
Sandoz	Human growth hormone	Omnitrope	EU, US, Australia
Biopartners	Human growth hormone	Valtropin	EU
Sandoz	Erythropoietin	Binocrit	EU
Hexal	EPO Versions		EU

 

REGULATORY CONSIDERATIONS IN UNITED STATES FOR BIOSIMILAR:

From the global point, U.S lags its regulatory counterparts in approving biosimilars ¹⁰. Committee for Medicinal Products for Human Use (CH0MP) European Medicines Agency (EMA) framed a regulatory pathway for approving biosimilars.Until now, 14 biosimilars has been approved by the European Agency^11,12. To improve research and development of newer biosimilars, U.S.A granted a twelve-year exclusivity period for biologics. Under this exclusivity period, a new biosimilar cannot be submitted to the FDA for approval, until four years after the innovator product has been approved andit is only after 12 years of theinnovator product license, a new biosimilar can be approved ¹⁰.

 

The Biologics Price Competition Innovation Act (BPCIA) metamorphosed the approval process of biosimilar through, Patient Protection and Affordable Care Act of 2010 (ACA). Public Health Service Act (PHSA) that grants license to biopharmaceuticals was amended by the BPCIA; traditional drugs are licensed by Food, Drug and Cosmetics Act (FDCA). An abbreviated approval pathway for biosimilar products has been created by BPCIA that allowedthe license of biological products which are in the U.S drug market^{13, 14, 15}.  Lately, Biosimilar User Fee Act of 2012 (BsUFA) was enacted that paved way for the FDA the authority to charge fees for giving the required resources to process and evaluate biosimilar products^{10, 16}.

 

Comparatorproduct with U.S.A licensed product:

To acquire license, the sponsor must prove that the proposed product which has been approved by the FDA is similar to the reference product as per section 351 (k) of the PHS Act. A sponsor can demonstrate data for proving biosimilarity by comparing the proposed product directly with the reference product. According to section 351 (k) of the PHS Act, to demonstrate biosimilarity, one clinical pharmacokinetic and pharmacodynamic study and analytical study between the proposed and reference product has to be submitted unless it can be proved scientifically that such a study is not needed. To fulfil the requirements under section 351 (k) (2) (A) of the PHS Act, a sponsor can use the data obtained from clinical and non-clinical studies to compare the proposed product with U.S licensed reference product. An adequate information or data is required for scientific justification of assessment of biosimilarityof the comparative data that can build an acceptable bridge with the U.S licensed reference product.However, during the drug’s developmental program, a sponsor can discuss directly with the FDA about their ways to bridge to the reference product by providing adequate scientific justification. The final decision will be made by FDA regarding the adequacy of justification and bridge during review of the 351 (k) of the application¹⁷.

 

 

REGULATORY CONSIDERATIONS IN GULF COOPERATING COUNCIL:

Legal basis for quality documents:

A complete quality dossier is required as per GCC Data Requirements for Human Drug Submission along with biosimilar comparability. Applicants must make sure that the quality target product profile (QTPP) of a biosimilar comparability for the reference product versus biosimilar product are an additional information to the normal specifications of the quality dossier. QTPP of a biosimilar must be discussed separately in section 3.2.R when giving the data in Module 3.

 

Manufacturing process of a biosimilar product:

The documentation and development of biosimilar products must cover two aspects:

1.       Both the quality attributes and molecular characteristics of the targeted proposed drugand the reference product should be comparable;

2.       Consistency and performance of the manufacturing process of the biosimilar on its own.

 

The QTPP of a biosimilar can be construed based on the data collected from the reference product, by extensive characterization and also by information available publicly. For the development of the biosimilar and its manufacturing process, quality target product profile (QTPP) serves as the basis.

 

As the biosimilar need not to be identical to its reference counterpart, the formulation can be done on the basis of state-of-the-art technology. The stability of the biosimilar product should be based on the GCC Guidelines for Stability Testing. The stability and compatibility data should be explained by the drug and cannot be extrapolated from the reference medicinal product (RMP). It is proclaimed that the biosimilar has its own lifecycle. Process changes that occur during the formulation of the biosimilar is inevitable, however, it is highly recommended to generate the required efficacy, safety, and quality data for the demonstrating biosimilarity against the reference product^{18, 19}.

 

REGULATORY CONSIDERATIONS IN EUROPE:

All medicines manufactured by biologic process and those used for specific indications (e.g,, neuro-degeneration, auto-immune diseases, and cancer) must be approved via centralised procedure throughEMAin EU.

 

EMA’s scientific committee on human medicine and safety (the CHMP and PRAC) and European Union’s biologic party evaluates the data when a pharmaceutical company files for marketing authorization at EMA.

An EU wide marketing authorization is obtained when EMA reviews the data and gives a scientific opinion which is accepted by European Commission.

Comparison between the data required for approval of a biosimilar product and the reference product

 

 

Guidelines for biosimilar:

Applicable to all biosimilars
Quality   Immunogenicity   Clinical and non-clinical     Overarching	guideline on similar biologic medicinal products containing biologically derived proteins as active substance: quality issues20 guideline on immunogenicity assessment of Biotechnology-derived therapeutic proteins 21. guideline on similar biologic medicinal products containing   biologically derived proteins as active substance: non-clinical and clinical issues22 guideline on similar biological medicinal products23.
Product specific- annexes non-clinical and clinical Guidance on similar medicinal products containing somatropin24 Guidance on similar medicinal products containing recombinant erythropoietins25 Guidance on similar medicinal products containing recombinant granulocyte-colony stimulating factor26 Guideline on non-clinical and clinical development of similar biological medicinal products containing low molecular weight heparins 27. Non-clinical and clinical development of similar medicinal products containing recombinant interferon alpha 28 Guidance on similar medicinal products containing recombinant human insulin29

 

SAFETY OF BIOSIMILARS:

General considerations:

Since the introduction of the first biosimilar in 2006, an increasing number of biosimilars have been approved and safely used in the E.U. Apart from reactions of an immunological reaction, most of the adverse drug reactions (ADR) can be figured out from the pharmacological action, and occur with both the biosimilar and reference medicine. Of the 25 biosimilar approved in the E.U, none has been suspended or withdrawn for reasons of safety and efficacy. Safety monitoring of biosimilars is the same as that of the biological products ³⁰.

 

Post marketing studies allow monitoring of known risks and also permit discernment of rare adverse drug reactions that unfold only when large numbers of patients have been treated for a long period. This is the reason why regulators may impose an obligation on the company to carry out a post authorisation safety study (PASS) at the time of approval of drugs. This makes the company to register the study publicly available at the EU PAS register: http://www.encepp.eu/ encepp_studies/indexRegister.shtml.

 

COLLECTING ADVERSE DRUG REACTIONS AND SUBMITTING PSURS:

As for all medicines, companies marketing biosimilars should collect all reports of suspected adverse drug reactions and submit periodic safety update reports (PSUR) to the regulatory authorities. Regulators then review the reports for any signal suggestive of a possible unwanted effect. If a signal is suspected, it is evaluated by EMA’s scientific committees, which will decide if any action is needed³¹.

 

BIOSIMILAR – INDIAN SCENARIO:

The Indian biotech industry which is a thriving industry had got its head-start from vaccine manufacturing.  The absence of product patent regulations for drugs marked a period in the country’ history where it was vital to make inexpensive medicinal products available to the masses – it did not matter to whether these products were innovator made or copies thereof. However, in the post TRIPS era (Trade-Related Aspects Intellectual Property Rights), there is need to offer and enforce adequate protections for patentable drugs, preferably biologics that inherently involve huge investments in R&D, manufacture, and clinical development. 

 

Currently, several biosimilars have been approved in India, including Recombinant human insulin, recombinant human erythropoietin, interferon, granulocyte colony stimulating factor. The versions of biologics available in India are either the expired patents or the ones that don’t exist in India. Therefore, from a technical standpoint, there is no concern about patent infringement regarding these as there are no patents for these products in India. If there is a 30% price drop of biosimilars, it may be significant to patients who can afford a life-saving generic version of these drugs. In many ways, the debate about biosimilars that rages across the regulated market and the developed market is irrelevant to India where the central concern revolves around access.

 

Partly due to the destitution of appropriate resources and experience, Indian regulators have sought to mimic regulations already in use in the developed world without customization³².

 

Requirements of reference product:

Regulatory requirements for marketing authorization of biosimilars in India were released in 2012 and require extensive quality/analytical comparative data in addition to abridged non-clinical/clinical studies are required for biosimilar approval.

 

Reference biologic product should be licensed in India and it should be an innovator product.

 

If reference biologic product is not marketed in India, then it must be licensed and widely marketed for four years post approval in innovator jurisdiction in a country with well-established regulatory framework.

 

In case if there is no medicine or only palliative therapy is available or in the case of national healthcare emergency, this period of four years may be waived or reduced^{35, 36, 37, 38}.

 

NEED FOR PHARMACOVIGILANCE IN BIOSIMILAR:

The pharmaceutical industry is required to buttress an active pharmacovigilance program for biosimilars that include both a PASS (post-authorization safety studies) and a PAES (post-authorization efficacy study). PASS are governed by a well-defined regulation of the EU (European Union, Directive 2001/83/EC, DIR) Art 1³³.  It is a structured method with pre-determined sample size along with specific aims and research questions. PASS are non-interventional studies as the drugs are used according to their indications. The results are closely monitored by the marketing authorization holder and are directly communicated to the national and international regulatory bodies. The inferences should be assessed in terms of severity and effect on the risk/benefit ratio of the drug. The aggregated data are analyzed centrally in order to determine whether the observed risks deter clinical usefulness. To complete this task, a well-trained and eligible person of the pharmaceutical company must be in charge of supervising the procedures as well as logistics. The market authorization holders must report promptly and in summation any important findings of the PASS to both the national and international authorities. Both the company and the authorities have the responsibility to raise alarms if in case, and also to make decisions concerning the safety of the product. PASS and PAES designed under the direct guidance of the authorities so that it over-spread the concerns and maximize the safety of the people.

 

The ability to path each biomedical medicinal product is closely associated to pharmacovigilance. The physicians or pharmacists are recommended to discourage biosimilar interchangeability. Preferably, a definite patient should always be administered with same biosimilar product. The primary concern of the medicinal community is the safety of biosimilars, medical systems ought to enable practitioner to continue the same brand of biosimilar for every single patient.

 

Clearly, these issues emphasize the need of freedom for physicians to decide the therapeutic use of biosimilars. The physician’ choice ought to be respected if supported by a medical justice, although payers and regulators are given preference to give a general guidance. For instance, it may not be significant to readily administer biosimilar to curable patients. Because of pharmacovigilance issues, it is not advisable to change biosimilar in the middle of the therapy. Qualified professionals help to elucidate the anomalies of biosimilar and the rationale for the above mentioned concepts. The Alliance for safe Biologic Medicines and the European Association for Bio-Industries conducted a research; the inferences were that clinicians opted for initial biosimilar treatment for their patients and not to be administered with a similar drug either by pharmacists or a colleague³⁴.  It is mandatory to maintain accurate data both at the clinic and dispensing pharmacy. The application of INN (International Non-Proprietary Name) for all the biosimilar has been proposed, if approved and implemented, it would help in elucidating the differences between biosimilars and the original drugs. If the pharmacists would maintain drug records including batch number, INN as well as the brand name, it is a great contribution for the pharmacovigilance program of the biosimilars³⁹.

 

Therefore a meticulous pharmacovigilance program subsuming PASS and supported by all health professionals involved, would reassure the community regarding their safety. Active engagement of patients and even health professionals would also be required. Biosimilars would then be in a position to achieve their goal, hopefully, which is cost containment through competition or regulation, enabling redistribution of funds to other public areas.

 

ROLE OF HOSPITAL PHARMACISTS:

It is of paramount importance that the hospital pharmacists should be aware that the biosimilars and innovator products are not interchangeable, because patients should be carefully monitored if their treatment is changed between products. Besides, patient safety is foremost and for pharmacists, the emphasis that biosimilars are not generics, and the possible implications for clinical outcomes when products are changed, will help in ensuring patient safety⁴⁰.

 

Furthermore, biosimilars are considered to contain a new active ingredient, whereas interchangeable products are not. Systematic checklists have been prepared for the evaluation of biopharmaceuticals coming on to the market, which have provided additional reassurance for the pharmacist. For example, the Pharmacy Checklist for Retacrit (epoetin zeta) gives information on protein and product formulation, manufacturing, supply reliability, batch consistency, clinical safety and tolerability, clinical efficacy, good handling practice⁴¹. 

 

CONCLUSION:

Around the globe, the complications of biosimilar are being actively debated. To make widespread availability of biosimilars, it is essential to critically evaluate the efficacy and cost effectiveness of biosimilar. By nature biosimilars are complex, factors such as robustness of manufacturing process, structural similarity to the parent molecule, level of understanding of mechanism of action, quality of pharmacodynamic assays utilized, demonstrated comparability in pharmacokinetics and immunogenicity, quality and quantity of clinical data, and the innovator’s experience with the parent product needs to be considered critically before marketing approval of biosimilars can be granted. Clinicians require thorough information on biosimilars and biopharmaceuticals in general to make knowledgeable treatment plans. Additionally, pharmacovigliance will be essential to track down any safety and efficacy problems that may arise from the use of biosimilars. Besides, the regulations for labelling and naming of biosimilar products should be the responsibility of single authorized body and that should be globally acceptable. In spite of the fact that biosimilars have entered the global market, the biosimilars manufacturers’ long-term capability to produce a consistent product still remains to be proven. Presently, even though European legislation is in place to assess and concede marketing approval for biosimilars, the EMEA guidelines only provide a road map and leave challenging areas still to be explored and monitored. The approval process of biosimilars should continue only on a case-by-case basis.

 

ACKNOWLEDGEMENTS:

The authors are thankful to SRM Institute of Science and Technology, SRM College of Pharmacy and the staffs for providing research facilities.

 

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Accepted on 10.07.2018           © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(11): 5152-5158.