BioRationality: What’s Wrong With the Indian CDSCO Biosimilar Guidelines?

CDSCO Guideline Recommendations and Requirements

Commentary and Suggestions for Revision

Reference biologics already authorized in India or an International Council for Harmonisation (ICH) country.

The reference product must be registered in one of the SRA countries or the same product registered in India; authorization in India should be removed, and the supply of the reference product should come from the country of origin.

Biosimilars must undergo preclinical studies, including pharmacodynamic (PD) and toxicological assessments in animals. [See Appendix I for details]

It is now well-established that animals do not necessarily have the receptor binding to induce a pharmacological and then pharmacodynamic and toxic response; this sentence should be removed.

When in vitro studies are insufficient to reflect pharmacodynamic activity accurately, animal models are required.

There is no correlation between in vitro and animal studies; this statement should be removed.

A minimum of 1 repeat-dose toxicity study in a relevant animal model is required, conducted over at least 28 days with a recovery period of 14 days.

Dosages should include a range (low, medium, and high) to cover safety margins, with the high dose being at least five times the human equivalent dose when feasible.

This entire section should be removed. The FDA Modernization Act 2.0 removes clinical toxicology testing of biosimilars since biological drugs do not show toxicity in animals.

The applicant should provide the scientific justification for the choice of animal model(s) based on the data available in the scientific literature regarding the animal models to be used. However, suppose the pharmacologically relevant animal species is not available and has been appropriately justified. In that case, toxicity studies need to be undertaken in rodent or non-rodent species as per requirements of Schedule Y with due permission from the Review Committee on Genetic Manipulation (RCGM).

Immunogenicity is assessed by comparing antibody responses in animals for both the biosimilar and the reference biologic

This section must be removed as it is not scientifically sound and irrelevant. The statement that if a suitable species is unavailable, another unsuitable species, such as rodents, can be used is irrelevant. It brings much of a lack of trust in the guidelines.

Additional toxicity studies, such as safety pharmacology, reproductive toxicity, and genotoxicity, may not be required unless significant differences arise during initial animal studies, indicating further investigation is warranted.

There is no correlation between animal and human immunogenicity; remove this requirement.

Multiple-dose comparative PK studies may be required if the product is intended for chronic use.

Remove all this discussion; it is irrelevant. Animal testing cannot reveal any difference in any property of a protein product, let alone repeating it.

Confirmatory phase 3 clinical efficacy studies: Following PK/PD studies, biosimilars generally require confirmatory phase 3 trials, which focus on demonstrating clinical efficacy and safety in a relevant patient population. [See Appendix II for details]

There is no justification for a multiple-dose study based on chronic use as it cannot reveal any more information since it is given concurrently with the previous dose; remove this section.

Phase III studies involve efficacy testing with placebo controls.

There is no phase 3 study regarding biosimilars; this is an incorrect terminology; it is comparative clinical efficacy testing.

Phase 3 studies involve efficacy testing with placebo controls. Remove this section and adopt the UK’s Medicines and Healthcare products Regulatory Agency statement on clinical efficacy testing: “In most cases, a comparative efficacy trial may not be necessary if sound scientific rationale supports this approach. Therefore, a well-argued justification for the absence of an efficacy testing is in order.