Biosimilars: an Emerging Market Opportunities in India

In recent few years, there are many epic Biological products are going off patent which has generated an abridged route for the Biosimilars products which relies on the extensive comparability testing against Reference Biological Products (RBP) assuring product’s quality, safety and efficacy. Biosimilars are product similar to biologics but not indicate to them. Thus they require distinct marketing approval with abounding documentation as they are not generic version of biologics. These made regulatory and administrators of different countries to establish strict balance between the cost benefit and risk management of the product. The first draft guideline for Biosimilars was established by Europe, subsequently Japan and USA has developed the draft guidelines. While recently India has established the biosimilars guideline in June 2012. India has vigorous Pharmaceutical Industry for the generic drug while it can become an emerging market for the Biopharmaceutical drug. The regulatory structure for the biosimilars in India is depicted in this article with comparison of the biosimilars guidelines established by India and WHO. The approval process will be based authenticating a comparability quality between the biosimilars products and original product due to small alteration may lead to intolerable modifications in safety and efficacy. In many cases nonclinical studies are more difficult and potentially expensive to perform where biosimilars are highly species specific. Thus there is need for stringent regulatory guidelines. The biosimilar market will soon be thriving above $ 80 billion price of drugs in next seven years.


Introduction
Biosimilars or biologics or biopharmaceuticals are the major magnification driver for the ecumenical pharmaceutical market due to their cost-efficacy, elevating occurrences of various diseases, incrementing number of off-patented drugs, positive outcome in the perpetual clinical tribulations, and elevating demand for biosimilars in different therapeutic applications such as rheumatoid arthritis, oncology and blood disorders. Recently, in USA the biosimilars are also developed and approved for lower cholesterol level under class of PCSK-9 inhibitor [1].
At the end of 2015, it is estimated that patent worth $ 80 billion of biosimilars are expected to expired globally. While the global biosimilars market is expected to reach $ 6.22 Billion by 2020 from $ 2.29 Billion in 2015, as it is growing at a CAGR of 22.1% from 2015 [2]. Fundamentally, biosimilars are licitly approved subsequent versions of innovator biopharmaceutical products following patent and exclusivity expiry. Biosimilar products has different therapeutic classes, while the existing biosimilars are erythropoietin's, growth hormones, granulocyte-colony stimulating factors and low molecular weight heparins (LMWH) and emerging biosimilars are Alfa interferon's, Beta interferon's, follicle stimulation hormone, insulin's, monoclonal antibodies (Table 1).

Regulatory Bodies
Terminology used for Biosimilar  The leading challenges faced by biosimilar drug developers is proving the equipollence or similar attribute of their biological drug to the reference product because of great variation in properties and even miniature alterations can lead to unacceptable deviations in safety and efficacy resulting into the prerequisite of class-concrete guidelines for several intricate molecules of biological [3]. There are different terms used for biosimilar by different regulatory bodies as shown in Table 1 [4-7].
The different definitions of biosimilars are: Europe (EMEA) Definition: A biosimilar demonstrates similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise [8].
USA (USFDA) Definition: The biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components, " and "there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product [9].
Canada (Health Canada) Definition: A SEB is defined by Health Canada as ''a biologic product that would enter the market subsequent to, and similar to, an innovator product authorized for sale in Canada [10].
India (CDSCO) Definition: Similar biologics-A biological product/ drug produced by genetic engineering techniques and claimed to be "similar" in terms of safety, efficacy and quality to a reference biologic, which has been granted a marketing authorization in India by DCGI on the basis of a complete dossier, and with a history of safe use in India [7,11].  Selection of Reference Biologic: The following factors should be considered for selection of the reference biologic [7,11].

Regulatory Framework of India
• Active Ingredient and strength of reference product must be same with the biosimilar product. • Same reference product must be used throughout study of quality, safety and efficacy. • Must be approved and marketed in India with all Quality, Safety and Efficacy data. • If not authorized in the India, than it must be licensed and marketed for 4yrs. Post approval in Innovators jurisdiction.

Regulatory pathway for biosimilars in India
The decision time period taken by Regulatory Committee/ Competent Authorities is as per below Table 2  The general regulatory pathway for the approval of the biosimilar in India is as per below Figure 3  According to the recent update applicant can file the application for animal toxicity studies and clinical trial to RCGM and DCGI simultaneously to reduce the time frame of approval. Additional only after the approval of animal toxicity study reports, the applicant can conduct the clinical trial.
Competent Authorities: Major three competent authorities are involved in the approval process are as per below Figure 2 with their major functions [7,11]. In Guidelines by CDSCO have established five different protocols for approval of biosimilars. These protocols are as follow [12]: Protocol I: Indigenous product development, manufacture and marketing of pharmaceutical products derived from live modified organisms (LMOs), where the end product is not an LMO (Figure 4).
Protocol II: Indigenous product development, manufacture and marketing of pharmaceutical products where the end product is not an LMO ( Figure 5).
Protocol III: Import and marketing of pharmaceutical products in finished formulations where the end product is an LMO (Figure 6).
Protocol IV: Import and marketing of pharmaceutical products in bulk for making finished formulations where the end product is an LMO (Figure 7).
Protocol V: Import and marketing of pharmaceutical products derived from LMOs in bulk and/or finished formulations where the end product is not an LMO (Figure 8).    It gives worldwide worthy standards to authorizing biotherapeutic items that asserted to be like innovator result of guaranteed quality, safety, and efficacy that has been authorized on the premise of full dossier.
The key principles of WHO guidelines are (WHO): The permitting of SBPs will depend on the demonstrated comparability, to some degree, on non-clinical and clinical information created with an officially Licensed Reference Biotherapeutic Product (RBP).
The product won't likely qualify as biosimilar, if the applicable contrasts are found in the quality, non-clinical, or clinical studies.
It is connected to the all-around described and entrenched biotherapeutic product, for example, recombinant DNA-inferred restorative proteins, Vaccines, plasma determined product and their recombinant analogs.
It additionally states "International Nonproprietary Names (INNs)" served as helpful instrument for pharmacovigilance for biologicals.
Debates like compatibility or substitution and licensed innovation are unaddressed by WHO as these are not inside of its command as a consultant.
There is key distinction between the drafted guideline by India and WHO for endorsement of biosimilars which has been shown in Table 3 [4,12]. In vitro cell based assay or receptor based assay is needed.
In vivo evaluation is needed.

Clinical
Comparative PK/PD is required.
Phase III Comparative CT is not mandatory.
Scientific advice process is done by SEC, Apex committee, Technical Committee Exploration to other indication can be obtained PMS is mandatory for 4 years with 6 months PSURs for first 2 yrs.
Immunogenicity is not mandatory but expected.
Comparative PK/PD is required.

Comparative CT is required
Scientific advice process is not in place all WHO countries but it is for EMA Exploration to other indication can only be approved if clinical MOA is similar.

PMS is mandatory
Immunogenicity is mandatory.

Biosimilars market in India
India shares 75% of biosimilar market, in which 30 biosimilar products are marketed out of 40 biological products. First biosimilar was approved and marketed in India for a hepatitis B in 2000. In recent years more than 50 biopharmaceutical products have been approved for marketing in India, with more than half of them being biosimilars [13].  The path forward for biosimilars in Indian pharmaceutical markets is shown in Figure 9. The examples of the approved biosimilars are listed in Table 4 [14].

Conclusion
With lapse of the patent of biological product will made accessibility of the biosimilar product in the business sector with cost reduction as it is the worldwide need instead of the economy improvement. Biosimilars are bigger and more intricate than the chemical drugs. As they are not the generics, the generic approach won't be suitable for the biosimilar product. Biosimilars are like inventor yet not indistinguishable to the inventor product, prompting prerequisite of the comparability testing. Biosimilar maker needs to face extraordinary difficulties in the development, clinical improvement, manufacturing, registration and product marketing contrasted with customary generics. India's characteristic quality in pharmaceutical marketing has been the spine to end up one of the key player being developed and maker of biosimilars. Accomplishment of biosimilar relies on upon the satisfactory execution of the pharmacovigilance framework and administrative rule while India's pharmacovigilance framework is under upgradation. India needs to create particular enactment administering biosimilar, with stringent administrative guideline and compelling collaboration in the middle of originator and biosimilar producer. Along these lines India has long approach to go especially in connection to legitimate edge work.