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What are Biosimilars?

The USFDA defines biosimilars as follows: "The biological product that 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” [4]. The biologics or biosimilars are produced using a unique cell line and proprietary process which varies from manufacturer to manufacturer.

Why Biosimilars?

The significantly large increase in healthcare costs worldwide calls for less expensive analogous to the generic versions of original innovator product. The recent loss in patent protection with respect to a number of first generation innovator products and the probability that a few more such innovator products will face the same fate in recent years have opened the doors of pharma market to generic versions of biologics referred to as “biosimilars” [3]. The biologics industries spend a significantly high percentage of around 30% of their total revenue in research and development (R&D). This culminates into R&D cost for a biologic agent to be around $1.2 billion as against low R&D cost of around $500 to $800 million for a conventional synthetic drug. Further, the high investment time of around 10-15 years in biologic development as against shorter time period of 7-10 years for chemical drugs further adds to high costs of biologics. These high investments incurred on biologics development translates into high cost of biologics to patients. The pressure of high medical costs on patients as well as the desire to increase patient access by reducing the cost of drugs have created a significantly high demand for biosimilars. The biosimilars are expected to serve as a cost-effective alternative to costly biologics resulting in much needed reduction in medical treatment costs [5].


Clinical Advantages
Market Advantages
Many cancers today are curable at early stage, like early HER2 positive breast cancer by Trastuzumab
Quality of life has been enhanced with MABs, like Adalimumab in RA
Increased access
The relapse of the disease has ben reduced with Rituximab in NHL
Reduces the burden on Healthcare spending
Better patient compliance; for example, blood transfusion in CKD was overcome by Erythropoietin/ Darbepoetin
Offers a big market opportunity for Biosimilar companies
Wider treatment options for no drug/less option therapy in many diseases
Challenges the monopoly of innovator’s pricing models


A complex and proprietary process

1. The first step of the production process begins with cloning of the gene of interest into complementary DNA (cDNA) vector. The DNA vector is then transferred into a host cell as E. coli or yeast.

2. The cell line expressing the target protein is then expanded in fermentation medium resulting in production of protein defined by the vector.

3. In order to obtain the purified bulk drug, the protein of interest has to undergo complex purification and validation process [3].

How Similar is Similar Enough?

European Medicines Agency (EMA) has brought forward a well-planned process for regulatory approval of biosimilars with specific guidelines for different classes of biosimilars. The customized guidelines deal with various aspects of biosimilars as manufacturing quality, pharmacokinetics, clinical considerations as well as non-clinical pharmacology and toxicology.

Guidelines suggested by Current EMA for biosimilars approval [3]

Regulatory Approval Required
Preclinical studies
Non-clinical and toxicology studies such as 28-day toxicity is required
Pharmacodynamic similarity markers requires to be based on clinical efficiency for example G-CSF, absolute neutrophil count (ANC) and CD34 in patients
Single dose subcutaneous (SC) and intravenous (IV) in patients. The acceptance criteria are to be based on clinical judgement
Clinical trials
A minimum of single equivalence trial with respect to the reference drug is necessary.
Extrapolation to other disease sites
It could be permitted, however a final decision will be made on case-by-case basis.
Drug safety
It is essential to demonstrate safety in a minimum a single equivalence trial with regards to reference product in the control arm
Antibody testing is essential for all clinical trials
Post-approval requirements
In order to achieve efficiency in extrapolated indications specific monitoring is to be carried out. After approval, a pharmacovigilance programme is essential

EMA guidelines endorses safety, immunogenicity, clinical efficacy and extrapolation of indications as the major issues. In order to assess the biosimilars safety, exactly similar safety parameters applied in case of the reference agent is to be used in the development programme. The clinical trial programme should include a sufficient patient sample size in order to quantitate the adverse effects in relation to reference product. After approval of a drug, the EMA guidelines stresses on pharmacovigilance programme which will help identify rare as well as potential serious events [3].

The biosimilars being biologically active molecules could result in induction of an immune response. The factors conferring immunogenic potential to a drug is related to the biopharmaceutical itself, the host or a combination of both. The most common cause of immunogenicity is related to the manufacturing impurities originating from the producing cell line or components of the media. Apart from this, structural modifications owing to manufacturing process, inappropriate storage, patient related factors (age, human leukocyte antigen (HLA) expression, co-morbid conditions), previous biological agents exposure as well as route of administration leads to rise in immunogenicity risk [3].

The chances of immunogenicity could be decreased by strict tests on the drug during its development process. However, the major loophole is that such tests are conducted in the preclinically which hampers prediction of immunogenicity among individual patients. The biosimilars are produced using independent processes as against their reference drugs which may result in structural as well as biochemical changes in the actual molecule. This gives rise to concerns about the safety of biosimilars. The product safety issues coupled to associated disease in the aetiology of immunogenicity reduces the probability of extrapolating clinical safety data to other indications. Thus, there arises the necessity of pharmacovigilance programs following approval of the drug which has already been implemented by regulatory authorities of most countries [3].

In order demonstrate comparative safety and efficiency of the biosimilars, EMA document provides the drug manufacturers with complete instructions on pharmacokinetics, pharmacodynamics, toxicology and clinical studies which are essential for approval of biosimilars. The clinical development programme for biosimilar intends to reveal no clinically meaningful difference with respect to the innovator product. This is to be achieved by equivalence trials of adequate sample size which is preferably double-blinded. The first requirement of an equivalence trial is to establish a “minimally clinically important difference (MCID)” in primary trial endpoint. MCID is the minimum difference in a meaningful clinical endpoint between two treatments beyond which the two drugs will not be considered equivalent by the regulatory agencies. EMA guidelines suggest that for the equivalence trial the applicant defines the primary endpoint along with MCID justified on clinical grounds in the trial protocol [3].


  1. CFR-Code of Federal Regulations Title 21. Available on / Last accessed on January 27, 2018.
  2. Kinch MS. An overview of FDA-approved biologics medicines. Drug Discov Today. 2015; 20(4):393-98.
  3. Dranitsaris G, Amir E, Dorward K. Biosimilars of biological drug therapies. Drugs. 2011;71(12):1527-36.
  4. Rushvi P, Charmy K, Nirav C, Narendra C. Biosimilars: An Emerging Market Opportunities in India. Pharmaceut Reg Affairs. 2016; 5:1.
  5. Ventola CL. Biosimilars: Part 1: Proposed regulatory criteria for FDA approval. Pharm Ther. 2013; 38(5):270-76.