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Regulating Biosimilars: How India Fares?

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  Regulating Biosimilars: How India Fares?

After India flooded the world market with affordable medicine, it is now trying to its hand on biosimilars. These are medicines purposely designed to have the same action for the same disease as the original pharmaceutical drugs but are produced differently.

The world market for biosimilars is expanding very rapidly. According to Datamonitor, biosimilars is worth $245 million in 2010 and will easily reach $3.7 billion in 2015. But at present, only EU and the US have established regulatory guidelines for the approval to market these drugs. In the US, there are two ways for FDA drug approval. First is through the Public Health Service Act and the second is through the Food, Drug and Cosmetics Act. In 2010, President Obama sined into law the Biologics Price Competition and Innovation Act of 2009 which is considered as the legal pathways for biosimilar in the US. Unfortunately, a practical pathway defined by the FDA is not yet in place. Many doubt that the US regulatory and intellectual property barriers are not favorable to biosimilar pathways. The Biologic License Application will be used instead of the abbreviated BLA to get around the 12-years exclusivity requirement in the BPCI Act for biosimilars. BPCIA covers anything for which a BLA is filed; a virus, therapeutic serum, toxin, antitoxin, blood or blood component or derivative, allergenic product, or analogous product… applicable to the prevention, treatment, or sure of a disease or condition of human beings. Recently, proteins have been included except for chemically synthesized polypeptides.

According to the FDA’s reference products exclusivities, a biosimilar application will only be accepted 4 years after the approval date of the reference product. Approval of a biosimilar will happen only after 12 years from the date of first approval for reference product.

There are two biologic types in the US; a biosimilar product which is highly parallel to the reference product with no significant clinical differences in terms of safety, purity and potency; and an interchangeable biosimilar which may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.

A biosimilar product must have gone through analytical studies showing that the product is close to a reference despite differences in clinically inactive components, animal studies, clinical studies to demonstrate safety, purity and potency. Labeling must match the reference product’s approved indication, as well as route of administration, dosage form, and strength. Manufacturing facility must also be approved following criteria already set.

The 12-year exclusivity does not apply to a supplement for the biological product that is the reference product or subsequent application filed by the same entity for a change resulting in new indication, route of administration, dosing schedule, dosing form, delivery system, delivery article or strength or structural modification that does not change safety, purity and potency. Although it is not clear which FDA regulation applies to this, a structural modification to change safety, purity and potency is needed.

There are regulatory guidelines established in EU, with both general guidelines and product specific guidelines in place. For example, there is an 8-year data exclusivity for a reference product, a further 2-years marketing protection and an additional 1-year marketing protection for a new therapeutic indication during the first 8 years of exclusivity.

To date, 14 biosimilars have been approved by the Committee for Medicinal Products for Human Use(CHMP), taking into consideration the legislative guidelines under the DIRECTIVE 2001/83/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 6 November 2001 on the Community code relating to medicinal products for human use as amended by DIRECTIVE 2004/27/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL. Under this guideline, an applicant is not required to provide clinical and pre-clinical data if he can demonstrate that the medicinal product is a generic of the reference product. CHMP is further guided by the following guidelines  on biosimilars namely; guideline on similar biological medicinal products, guideline on similar biological medicinal products containing biotechnology-derived proteins as active ingredients, guideline on similar biological medicinal products containing biotechnology-derived derived proteins as active substance (currently under revision to take into account the lifecycle of biosimilars), and the guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins.

The specific guideline for biotechnology-derived proteins says that the product must demonstrate   comparable profiles in terms of quality, safety and efficacy. Possible safety issues in different subpopulations should be addressed, non-clinical studies must have been conducted, immunogenicity must have been investigated in humans using state-of –the-art methods to characterize immune response, clinical safety and pharmacovigilance.

EMEA/CHMP/42832/05/ also known as the Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: clinical and non-clinical issues lay down the non-clinical and clinical requirements for a biological medicinal product claiming to be similar to another one already marketed. The non-clinical section addresses the pharmaco-toxicological assessment. The clinical section addresses the requirements for pharmacokinetic, pharmacodynamic, efficacy studies. The section on clinical safety and pharmacovigilance addresses clinical safety studies as well as the risk management plan with special emphasis on studying the immunogenicity of the similar biological medicinal product.  

The regulatory frameworks for biosimilars are largely established in Europe, in fact, covering human insulin, somatropin, human growth hormone, erythropoietin, interferon-alpha, low-molecular weight heparin and monoclonal antibody. Currently, they are working on guidelines to include a number of other products like interferon-beta and follicle stimulating hormone.

In India, concerns have been expressed on the existing regulatory approval process for biosimilars. Manufacturing processes must strictly adhere to perfection as minor changes could greatly affect safety and efficacy. Biosimilar products must only be approved after a well established regulatory pathway in India. Due to the susceptibility of biologics, it is not impossible for two different manufacturers to come up with two identical biopharmaceutical drugs. Present marketing approval in the country follows bioequivalence model in the Schedule Y of the Drugs and Cosmetics Act for small molecule chemical entities only. Drugs and Cosmetics Act of India do not differentiate between large and small molecular drugs. It is the Central drugs Standard Control Organization and the Drugs Controller General of India who are responsible for approvals of new drug applications, however, each state regulatory authorities are responsible for granting manufacturing licenses. These practices may lead to regulatory oversight and weaker enforcement of the guidelines.

It is high time that India must come up with its own regulatory guidelines for biosimilar drugs to be enforced by a specific agency. In addition, regulatory control over mistakes and offences for manufacture of unapproved drugs are equally as important as the guidelines. The present Review Committee on Generic Manipulation discusses current guidelines by the EMEA and FDA. They take approvals of biosimilar drugs in case by case basis.

It is very urgent that India must have its own guidelines for biosimilars, both for manufacturing and marketing, which conforms to international safety and quality standards. A lot of people around the world depend on India to deliver safe and effective life-saving medicines. Painful, debilitating, and deadly diseases such as rheumatoid arthritis, chronic lymphocytic leukemia, vasculitis,


  1. Biosimilars in Europe, by Dr. Kati Hudson
  2. Biosimilars in the United States, Presented at the 10th Annual Forum on Pharma Patent Lifecycles (London), Dr. Rouget F. Henschel,
  4. McGraw-Hill Science & Technology Dictionary
  5. European Medicines Agency; Pre-authorization Evaluation of Medicines for Human Use



   Contributed by : Lisa Pineda Gacuma - Technical Expert
   Editor : Dixita N. Bhatt
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