Introduction

India’s regulatory landscape for biologic and biosimilar medicines continues to evolve. In response to scientific advances and accumulated regulatory experience, the Central Drugs Standard Control Organization (CDSCO) and the Department of Biotechnology (DBT) have jointly released the Draft Guidelines on Similar Biologics – Regulatory Requirements for Marketing Authorization in India, 2025. These proposed guidelines revise the earlier 2016 version, building on the original framework published in 2012.

The 2025 draft aligns India’s regulatory pathway more closely with international norms by adopting a science-based, risk-proportionate approach to the assessment of biosimilarity.

Salient Features of the Revision

The draft guidelines aim to provide clear and updated guidance to applicants seeking marketing authorization for similar biologics in India. Key highlights include:

Key Principles for Licensing: The development of a similar biologic must begin with comprehensive characterization of the Reference Biological Product (RBP). A stepwise comparability exercise—covering structural, functional, and clinical parameters—must confirm biosimilarity. Any clinically meaningful differences that cannot be justified will disqualify the product as a similar biologic. This principle is aligned with international norms such as WHO TRS 1043.
Reference Standards: The draft clarifies the role of reference standards, often termed the ‘Gold Standard,’ which carry assigned international units to ensure consistent assessment of biologics. In the absence of established reference standards, the development of in-house standards derived from the manufacturing process is permitted. The RBP must be an innovator product licensed either in India or in ICH countries (such as the USA, UK, Japan, Australia, Canada, or EU) based on a complete data package. Ideally, the same RBP should be used throughout development.

Updated Evaluation Pathway

The sections on quality, preclinical, and clinical evaluation have been updated to reflect international best practices.

Quality Attributes: The draft emphasizes that analytical and functional similarity between the similar biologic and RBP is essential. Compliance with a pharmacopeial monograph is necessary—but not sufficient—for establishing biosimilarity. Use of either reference or in-house standards is vital for demonstrating product consistency and manufacturing alignment.
Manufacturing Process: Given its critical impact on product potency, the manufacturing process must be consistent and robust—matching the standards required for originator products. Detailed documentation is required, including molecular biology considerations, upstream and downstream processing, control data, kinetics, batch size, stability, and comparability data.
Statistical Considerations: The draft provides guidance on statistical approaches to defining similarity, including using statistical intervals and sample size calculations. The preferred method for establishing similarity acceptance criteria is the min-max approach, as it avoids the need for a large number of RBP batches. Annexure III contains practical examples and statistical illustrations.
Strengthened Analytical Tools: A notable advancement in the 2025 draft is the emphasis on next-generation analytical methods. The approach for isolating the RBP’s drug substance must be appropriate and justified with data. The use of orthogonal analytical tools and advanced physicochemical and biological characterization techniques is emphasized. Annexure II lists specific quality attributes recommended for r-DNA derived products. For antibody or antibody-derived products, comparison with the RBP must include specificity, affinity, binding strength, Fc function, and evaluation of post-translational modifications and process-related impurities. Animal studies may be conducted if necessary.

Data Requirements for Preclinical Studies

The draft emphasizes a stepwise approach to non-clinical development:

In Vitro Studies: These form the first line of evaluation and are emphasized over animal studies. A comprehensive list of recommended assays is provided, including binding and functional activity studies to assess pharmacotoxicological activity. These studies are often more sensitive and specific than in vivo evaluations.
In Vivo Animal Studies: The need for such studies is determined case-by-case, following the “3Rs” principles (Replace, Reduce, Refine). In vivo studies are only required when justified by residual uncertainty or safety concerns. The licensing authority may deny waivers under specific conditions, such as use of a novel excipient, new route of administration, or higher-than-approved human dose.

Clinical Evaluation

If biosimilarity cannot be sufficiently demonstrated through analytical, in vitro, and PK/PD data, then comparative clinical studies are required. However, confirmatory safety and efficacy trials may be waived under certain conditions—particularly when:

Analytical and in vitro data is strong;
PK/PD studies confirm comparability;
A robust Risk Management Plan (RMP) is in place.

If meaningful differences emerge at any point that cannot be justified, a standalone marketing application (rather than a biosimilar application) will be required. If clinical studies are waived and similarity is adequately demonstrated, all indications approved for the RBP may be authorized.

Post-Marketing Requirements

Given the possibility of reduced pre-market clinical data, a Risk Management Plan and Pharmacovigilance Plan are mandatory. Any remaining uncertainties—such as those arising from a novel excipient or device—must be addressed through ongoing pharmacovigilance.

This includes:

Submission of Periodic Safety Update Reports (PSURs),
Reporting of serious unexpected Adverse Drug Reactions (ADRs),
Phase IV studies focusing on safety and immunogenicity, typically involving single-arm study designs and comparison with historical RBP data.

Conclusion

The Draft 2025 Guidelines reflect India’s evolving approach to biosimilar regulation—rooted in scientific rigor, global harmonization, and practical experience. By strengthening analytical and in vitro standards and allowing conditional waivers for animal and clinical studies, the guidelines promote efficient market access without compromising on safety or efficacy. This update represents a forward-looking step in facilitating the development, approval, and availability of similar biologics in India.

The CDSCO has published the 2025 draft guidelines for public consultation. Stakeholders have a 30-day window from the publication date to submit comments and suggestions, emphasizing the importance of timely engagement.