BioRationality: The Revised Indian Biosimilar Guidelines Finally Bring Rationality

The Indian Central Drugs Standard Control Organisation (CDSCO) has recently issued a draft guideline for biosimilars, which is a significant change in its perspective. The 2025 CDSCO Draft Guidelines on Similar Biologics¹ represent a progressive shift toward harmonizing Indian regulatory requirements with global standards set by the European Medicines Agency (EMA)², FDA, and the UK’s Medicines and Healthcare products Regulatory Agency (MHRA).³

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A comparative analysis reveals significant alignment with the World Health Organization Technical Report Series 1043⁴ and recent practices of EMA and MHRA, particularly in minimizing animal testing, streamlining efficacy requirements, and emphasizing the totality of evidence from quality and in vitro assessments. However, some places still show room for refinement and clarification to match current global regulatory trends fully.

One of the most notable strengths of the CDSCO draft is its explicit de-emphasis on in vivo animal testing. The document strongly encourages using in vitro assays to establish comparability in nonclinical assessments. It introduces a tiered decision framework where in vivo studies may only be requested under specific conditions of residual uncertainty. This aligns closely with the EMA’s 2022 update, which allows for complete waiver of animal studies when in vitro and analytical data are sufficient to exclude safety or efficacy concerns, and with the MHRA guidance, which promotes the 3Rs principle (Replace, Reduce, Refine) to the point of near elimination of animal requirements.

Although slightly more conservative, the FDA has also begun to permit waivers for animal testing in specific biosimilar applications based on strong in vitro and analytical data. Thus, CDSCO’s updated stance reflects a marked philosophical convergence with these agencies, confirming India’s move toward a scientifically justified and ethically modern regulatory posture.

The CDSCO’s position on clinical efficacy testing also reflects a significant evolution. Like EMA and MHRA, the new CDSCO draft permits waivers of confirmatory phase 3 efficacy trials under defined conditions. These include high structural and functional comparability, PK/PD equivalence demonstrated using validated biomarkers, and robust immunogenicity and safety monitoring plans. This reflects a substantial shift from CDSCO’s earlier 2016 guidelines, which generally mandated confirmatory efficacy studies for most biologics. EMA had already moved in this direction with its 2014 update, and the MHRA removed the requirement for confirmatory efficacy studies in 2022 for products that meet high comparability standards.

Although historically slower, the FDA issued a draft guidance in 2023, strongly suggesting that comparative efficacy trials may no longer be needed in most biosimilar applications if PK, PD, and immunogenicity data are convincing. In this respect, the CDSCO guidelines are both timely and scientifically justified. However, greater emphasis on biomarker validation, statistical justification of margins, and standardized PD endpoint use could bring further clarity and alignment with EMA’s robust sample size and statistical criteria guidelines.

Regarding immunogenicity testing, the CDSCO draft provides a detailed, multi-tiered framework that includes antidrug antibody incidence, neutralizing antibody titers, persistence, and clinical impact. The guidelines recommend risk-based immunogenicity testing, acknowledging that highly similar biologics like insulin or filgrastim with a long history of low immunogenicity may not require pre-approval immunogenicity studies.

This is consistent with the EMA’s 2017 guideline on immunogenicity assessment, which classifies products based on immunogenicity risk and allows waivers for low-risk categories when paired with rigorous analytical comparability. The FDA and MHRA also take a risk-based view but often still expect immunogenicity data for higher-risk categories, such as monoclonal antibodies. CDSCO’s adoption of the same principles and its provision for post-marketing immunogenicity surveillance when pre-market data are waived reflect regulatory maturity and ethical responsibility.

However, some ambiguities remain in the CDSCO document. For example, the statistical methodology recommended for analytical similarity assessments includes a preference for min–max intervals due to the practical constraint of batch availability. Still, the statistical justification and interpretation of outliers require more precise articulation.

EMA generally prefers tolerance or equivalence interval testing based on sample size and criticality, and the FDA often requests equivalence testing using 90% confidence intervals with predefined acceptance margins for all key quality attributes. CDSCO allows these methods but does not mandate them or provide firm criteria for sample size justification, leaving room for potentially inconsistent applications across applicants. Greater specification would enhance regulatory predictability and alignment.

Another area that would benefit from enhancement is the explanation of the rationale behind the extrapolation of indications. While the CDSCO guideline broadly permits extrapolation if analytical similarity, mechanism of action, receptor engagement, and immunogenicity profile are sufficiently established, there is minimal discussion on how divergent clinical populations or routes of administration should be factored into this decision. EMA’s guidance is more explicit, often requiring justification based on receptor expression, disease pathology, and clinical similarity across indications. MHRA and FDA follow similar principles. More prescriptive language from CDSCO would ensure consistent decisions across therapeutic areas and reduce sponsor uncertainty.

In conclusion, the 2025 CDSCO draft guidelines represent a meaningful and commendable step toward global regulatory alignment in the oversight of biosimilars. The agency has embraced major global trends—especially the reduction of animal and human efficacy testing—in favor of a scientifically robust, risk-based, and ethically sound framework.

While the guidance is harmonized mainly with EMA, MHRA, and emerging FDA positions, further refinement is needed in statistical testing, PD biomarker validation, immunogenicity risk stratification, and extrapolation justification to ensure clarity, consistency, and global acceptability. With these improvements, CDSCO’s framework could serve as a model for emerging markets seeking to modernize their biosimilar regulatory pathways.

References

1. Draft guidelines on similar biologics 2025. Directorate General of Health Services CDSCO. Accessed May 19, 2024. https://cdsco.gov.in/opencms/resources/UploadCDSCOWeb/2018/UploadPublic_NoticesFiles/Draft%20Guidelines%20on%20Similar%20Biologics%202025.pdf

2. Reflection paper on a tailored clinical approach in biosimilar development. EMA. January 2, 2025. Accessed May 19, 2025. https://www.ema.europa.eu/en/reflection-paper-tailored-clinical-approach-biosimilar-development

3. Guidance on the licensing of biosimilar products. MHRA. Updated February 27, 2025. Accessed May 19, 2025. https://www.gov.uk/government/publications/guidance-on-the-licensing-of-biosimilar-products/guidance-on-the-licensing-of-biosimilar-products

4. Guideline for the production and quality control of monoclonal antibodies and related products intended for medicinal use. WHO. April 22, 2022. Accessed May 19, 2025. https://www.who.int/publications/m/item/trs1043-annex4