Table.

Comparison of different regulatory guidelines for the approval of biosimilars

Specification	India - Department of Biotechnology and Central Drugs Standard Control Organization7	United States - Food Drug Administration8	Europe - European Medical Agency9	World Health Organization10
Definition of biosimilars	“A similar biologic product is that which is similar in terms of quality, safety and efficacy to an approved reference biological product based on comparability”.	“A biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components”.	“A biosimilar medicine (‘biosimilar’) is a medicine highly similar to another biological medicine already marketed in the EU (reference medicine)”.	“SBP is a biotherapeutic product which is similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product”.
Reference product	Innovator product approved in India or ICH countries based on a full safety, efficacy and quality data.	Innovator product approved by the FDA. For comparison with a non-US approved product, the requirements under section 351(k)(2)(A) of the PHS Act need to be addressed.	Original product approved in EU based on a complete dossier.	Originator product that was approved based on a full registration dossier.
Pre-clinical studies	Comparative PD (in vitro and in vivo) and toxicological studies should be conducted before clinical studies and designed to identify if there any significant differences between the similar biologics and the reference product.	Demonstration of similarity based on evidence from pre-clinical studies (including the assessment of toxicity) is required.	Non-clinical studies should be performed in a step-wise manner before initiating clinical studies. In vitro studies should be conducted first, followed by in vivo, if deemed necessary. These studies should be comparative in design to detect differences between the similar biological product and the reference product.	Non-clinical evaluation of a new biotherapeutic normally encompasses a broad spectrum of PD, PK and toxicological studies to validate the efficacy and safety of an SBP and should be comparative in nature.
Clinical studies	Clinical studies (PK, PD studies, and confirmatory safety and efficacy studies) are required. Phase 3 should include appropriate primary endpoints and the patient population needs to be sensitive and homogenous. Studies should be conducted as per the Indian GCP guidelines, generally in ≥100 evaluable patients in the test group.	Comparative human PK, PD, clinical immunogenicity, or clinical safety and effectiveness are required. At least one study with equivalence design and adequate power is required to evaluate any clinically meaningful difference between the proposed biosimilars product and reference product.	PK/PD studies, followed by clinical efficacy and safety studies, confirmatory studies for demonstrating clinical biosimilars comparability are required. At least one study with adequate power and equivalence design in a sensitive population to detect potential differences with regard to efficacy and safety is required.	Clinical studies should be designed with testing strategies to detect differences between the SBP and the reference product. At least one study with equivalence design in a sensitive population is preferred.
Immunogenicity	Both pre-approval (comparative) and post-approval (non-comparative) of safety assessments including immunogenicity are required.	Safety studies including immunogenicity assessments are required.	Safety studies, including immunogenicity assessments, are required. A head-to-head comparative study of 12-month duration is recommended in the sensitive population to detect any potential difference in immunogenicity between proposed biosimilar and reference product.	Data on immunogenicity are obtained from the comparative efficacy studies. In case of chronic administration, a one-year pre-approval data are usually required.
Pharmacovigilance	Comprehensive pharmacovigilance plan should be prepared by the manufacturer to further evaluate the clinical safety. Post-marketing phase 4 study may be required, preferably within two years of approval.	Post-marketing safety monitoring and mitigation strategy for biosimilars are required. In addition, a post-marketing study or a clinical trial may be required to evaluate certain safety risks.	Pharmacovigilance and risk management plan should be submitted according to current EU legislation and pharmacovigilance guidelines. Potential risks, including immunogenicity, should be closely monitored.	Submission of safety specifications and pharmacovigilance plan is required during the submission of the marketing authorization application. All information on product tolerability should be included in post-marketing safety report. Such safety information must be evaluated along with the evaluation of the frequency and causality of adverse events.
Extrapolation	Extrapolation of indication is possible if there is a similarity in quality and pre-clinical assessments between similar biologics and reference product or if MoA or involved receptor is same for other indication or if clinical efficacy/safety is proven in one indication.	Extrapolation of indication needs sufficient scientific justification and is considered on case-by-case basis.	Extrapolation to other clinical indications of the reference product is possible, but needs scientific justification and could be considered on a case-by-case basis.	Extrapolation may be possible if sufficient scientific evidence is provided along with the benefit/risk information of that indication.
Interchangeability	Not addressed Usually made randomly by the prescriber or pharmacist based on the product cost and assumed patient affordability	Interchangeable product (approved based on the demonstration of interchangeability), may be substituted with the reference product by a pharmacist without the involvement of the clinician who prescribed the reference product.	The decision is delegated to the Member States in the EU.	Not addressed.
Nomenclature	Not addressed	INN, followed by a four-letter suffix that is unique and ‘devoid of meaning’.	Same INN as the original product for biosimilars. Trade name, packaging and appearance should be different.	BQ scheme, consisting of a unique 4 letter identification code is used along with INN.

EU, European Union; ICH, The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use; FDA, Food and Drug Administration; GCP, Good Clinical Practice; INN, International Nonproprietary Names; MoA, mechanism of action; PD, pharmacodynamics; PK, pharmacokinetics; PSURs, periodic safety update reports; SBP, similar biotherapeutic product; PHS, public health service; EU, European Union; BQ, biological qualifier