Biosimilars in India – Things You Need to Know

Biosimilars in India – Things you need to know

Biological agents show significant clinical benefits, but their high cost limits their accessibility. The demand for cost-effective options and the patent expiry of biologics have propelled the development of biosimilars or similar biologics.

This article covers the key takeaways from the Indian regulatory guidelines for the approval of similar biologics in India.

Guidelines for similar biologics in India

The guideline for similar biologics in India was released in 2016 by the Central Drugs Standard Control Organization (CDSCO) and the Department of Biotechnology (DBT).

The 2016 guideline are an update to previous guidelines published in 2012. The authorities revised the guidelines to provide a clear regulatory pathway at par with international regulations for the approval of similar biologics in India.

As per the guideline, a similar biologic product is that which is similar in terms of quality, safety and efficacy to an approved reference biological product based on comparability.

The guideline enumerates the various regulatory requirements for the manufacturing, preclinical studies, clinical studies and post-marketing requirements for similar biologics.

The approval of similar biologics follows a sequential process and involves the following authorities:

  • Institutional Biosafety Committees
  • Review Committee on Genetic Manipulation (RCGM)
  • Genetic Engineering Advisory Committee

Reference biologic

A product can only be considered similar biologic if proven similar using extensive quality characterization against the reference biologic. The dose, strength, dosage form and mode of administration of similar biologics need to be similar to that of the reference product.

Companies planning to develop similar biologics are required to submit the rationale for selecting the reference product to the regulatory authorities. The reference product should have been approved in India using a complete data package. When the reference product is not authorized in India, it should be approved/licensed and marketed in an ICH (The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) country.

Requirements for manufacturing and characterization studies

Similar biologics should be manufactured following good manufacturing practices. The manufacturing process should be robust, consistent and reproducible.

Companies need to provide a complete description of the manufacturing process, including details regarding the host cell cultures, vectors and gene sequence. The post-translational modifications, if any, should also be enumerated.

Data for submission should include:

  • A complete description of the drug product and the associated processes
  • Critical and vital quality features of the product
  • Manufacturing process controls
  • Variables affecting the production process (Critical process parameters)
  • Data from stability studies
  • Comparability of product manufactured at clinical scale against reference biologic
  • Data from consistency batches and/or process validation batches as applicable

Analytic characterization is required to demonstrate similarity between the similar biologic and the reference drug. Indian guidelines recommend characterization studies to evaluate immunological and biological activities, physical/chemical properties, content, purity, contamination and content.

Real-time stability studies, accelerated studies, and stress studies should be conducted to evaluate the product's shelf life, storage conditions, and degradation profile.

Variability between the similar biologic and the reference product should be evaluated to assess the potential impact on the safety and efficacy of similar biologic. Additional characterization studies may be necessary in such cases.

Conducting preclinical and clinical studies

Once the analytical studies characterize the similarity between similar biologic and the reference product, companies need to conduct preclinical and clinical studies to test the safety and efficacy of the similar biologic.

Comparative pharmacokinetic (PK)/ pharmacodynamics (PD) studies are required to establish similarities in PK/PD characteristics between the similar biologic and the reference product. The type may vary case by case - Drug developers can combine PD and PK studies, or PD study can also be conducted together with phase III studies as appropriate.

A phase III comparative clinical trial is required to establish the similarity in efficacy and safety between the similar biologic candidate and the reference product. In recombinant human-soluble insulin products, only a comparative safety study is required.

Equivalence or non-inferiority studies may also need to be conducted. Before study initiation, the manufacturer must consult the CDSCO and justify the rationale for the sample size estimation and define the comparability limits.

The confirmatory safety and efficacy study can be waived if the similar biologic demonstrates high similarity with the reference biologic regarding the structural and functional characteristics, preclinical and PK/PD outcomes. However, confirmatory phase 3 clinical studies cannot be waived for large molecular weight biologics like monoclonal antibodies.

To ensure the absence of any unexpected safety concerns, clinical studies to evaluate the immunogenicity and adverse events are mandatory. The immunogenicity profile of the similar biologic should be compared to the reference biologic. Pre-approval comparative safety data should be based on adequate patient exposure and presented along with published data on the reference biologic.

When can extrapolation of indication be considered?

Extrapolation of indication can be considered if similarity has been established between the similar biologic and the reference product with respect to the quality or preclinical assessment. Additionally, demonstration of efficacy and safety in one indication allows extrapolation for other indications if the exact mechanism of action or receptor is involved. It should be noted that new indications that are not specified by the innovator require a separate application.


  1. Department of Biotechnology and Central Drugs Standard Control Organization. Guidelines on Similar Biologics: Regulatory Requirements for Marketing Authorization in India,2016. Available from: 6.pdf . Accessed: 18April 2021.

Frequently Asked Questions

In which cases the extrapolation of the safety and efficacy data of a particular clinical indication (for which clinical studies has been done) of a similar biologic to other clinical indications may be possible?

The extrapolation of the safety and efficacy data of a particular clinical indication (for which clinical studies has been done) of a similar biologic to other clinical indications may be possible if following conditions are met: Similarity with respect to quality has been proven to reference biologic Similarity with respect to preclinical assessment has been proven to reference biologic Clinical safety and efficacy is proven in one indication Mechanism of action is same for other clinical indications Involved receptor(s) are same for other clinical indications New indication not mentioned by innovator will be covered by a separate application.

The permission to initiate clinical trial granted in Form CT-06 or automatic approval in Form CT 4A shall remain valid for a period of 2 years from the date of its issue, unless extended by the CLA.

FORM MD-24 is an application for grant of permission to conduct, clinical performance evaluation of new in vitro diagnostic medical device.

Yes. Clinical trial at each site shall be initiated after the approval of the clinical trial protocol and other related documents by the Ethics Committee for that site, registered with the CLA.

Yes. Before enrolment of first participant in any clinical trial, registration in CTRI is mandatory

The three tier mechanism comprises the following authorities: 1. Institutional Biosafety Committee (IBSC) at the Institute/ company – To ensure biosafety on-site 2. Review Committee on Genetic Manipulation (RCGM) in the Department of Biotechnology - Managed genetically engineered cell banks 3. Genetic Engineering Appraisal Committee (GEAC) in the Ministry of Environment & Forests (MoE&F)- for genetically modified organisms/ living modified organisms

Any person or institution or organisation having permanent establishment in India who intends to conduct clinical trial of a biological product can submit application for clinical trial.

The clinical performance evaluation shall be initiated within a period of one year from the date of grant of permission.

After obtaining permission in CT-11 or CT-14 or CT-15 as the case may be, the person, who intends to manufacture the biological product for CT, shall make an application for grant of license to manufacture the biological product by the respective State Licensing Authority (SLA) in accordance with the provisions of the Act and the Drugs and Cosmetics Rules, 1945.

No. For biological product and substances discovered or developed in countries other than India, Phase I data should be submitted along with the application. After submission of Phase I data generated outside India to the Central Licensing Authority, permission may be granted to repeat Phase I trials or to conduct Phase II trials and subsequently Phase III trial concurrently with other global trials for that biological product.

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