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.