India Releases New Biosimilars Guidance

Regulatory NewsRegulatory News | 28 March 2016 |  By 

India’s Central Drugs Standard Control Organization on Saturday released new guidance for biosimilar developers as new biosimilars come to market there before other regions, and as India's regulators look to develop more specific guidance on postmarketing studies.

The new document is a slight tweak of previous guidance issued in 2012, but includes several important changes that are now up for discussion through 30 April. India's biosimilars market currently includes eight biosimilars, including one for AbbVie's blockbuster Humira (adalimumab) and two biosimilars for Roche's breast cancer treatment Herceptin (trastuzumab), which are not approved in any other countries (though Korea's Food and Drug Administration has approved a different Herceptin biosimilar), according to the industry blog Biosimilarz (the Generics and Biosimilars Initiative lists more than 60 approved biosimilars in India).

Among the most major changes, CDSCO now says that if the reference biologic (for which the biosimilar is being developed) is not marketed in India, the reference biologic can be licensed in any ICH country (i.e. EU, Japan, US, Canada and Switzerland).

Postmarket Updates

One of the biggest differences between the 2012 guidance and the document issued this week is the section on postmarketing studies, which CDSCO says are intended “to further reduce the residual risk of the Similar Biologic” and which now includes a timeline for such studies.

CDSCO is calling for specific postmarketing safety data “through a pre-defined single arm study of generally, more than 200 evaluable patients and compared to historical data of the Reference product. The study should be completed preferably within 2 years of the marketing permission/manufacturing license unless otherwise justified.”

The primary aim of the Phase IV study is safety, CDSCO says, noting that the primary endpoint should be safety while the secondary endpoint should be efficacy and immunogenicity.

“If immunogenicity is evaluated in clinical studies, it is not mandatory to carry out additional non-comparative immunogenicity studies in post marketing studies,” CDSCO adds in the updated section. “The immunogenicity of the Similar Biologic should be evaluated using appropriately designed studies with state-of-the-art methods, taking into consideration the potential impact on both safety and efficacy.”

In addition to the new postmarketing guidance, CDSCO says that “if the firm conducts pre-approval studies that included more than 100 patients on the proposed Similar Biologic drug, the number of patients in phase IV study can be reduced accordingly so that the safety data (from both Phase III and IV) is derived from a minimum of 300 patients treated with the Similar Biologics.”

The regulator also added a new section on non-comparative safety and efficacy studies, noting that if a product is found to be similar “in pre-clinical, in vitro characterization having established PK [pharmacokinetic] methods and a PD [pharmacodynamic] marker that is surrogate of efficacy, the residual risk is significantly reduced in the Phase I study if equivalence is demonstrated for both PK and PD. Phase III clinical trials of such a Similar Biologics product may be waived...[and] where considered necessary, an appropriate single arm study in at least 100 evaluable subjects may be carried out in the most sensitive indication to address any residual uncertainty.”

CDSCO also added new information on when a confirmatory clinical safety and efficacy study can be waived, noting: “In case the safety and efficacy study is waived all the indications approved for reference product may be granted based on comparable quality, non‐clinical as well as convincing PK/PD data. Wherever the phase III trial is waived, the immunogenicity should have been gathered in the PK/PD study and will also need to be generated during post-approval Phase IV study.”


As far as the manufacturing of biosimilars, CDSCO has altered the section on “Fermentation Process Development,” which it now calls “Upstream Process Development,” though the requirements under the changed name are the same:

“Upstream process should be described in detail including media components used for cell growth:  • At least three batches of reproducible fermentation data at pilot scale (batch size adequate to give enough purified product to generate preclinical data) • Upstream process should be well controlled and monitored,” CDSCO says.

The regulator also says manufacturers should include details of “upstream process kinetics data from consistency batches indicating cell growth, product formation, pH, temperature, dissolved oxygen, major nutrient consumption pattern and agitation rate.”

The rest of the guidance is nearly identical to the document from 2012 though there are some slight language tweaks.

Guidelines on Similar Biologic: Regulatory Requirements for Marketing Authorization in India


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