Biosimilars in the EAEU may not need a comparative clinical study. For monoclonal antibodies, one is always required
Decision of the Eurasian Economic Commission (EEC) Council No. 89 of 3 November 2016 “On Approval of the Rules for Conducting Studies of Biological Medicines of the Eurasian Economic Union” (hereinafter Decision No. 89) allows a confirmatory clinical study of a biosimilar (similar biological medicinal product) to be omitted in certain cases. A biosimilar is a biological medicinal product that contains a version of the active substance of a registered originator (reference) product. To omit the study, efficacy and safety must follow unequivocally from the similarity of physicochemical characteristics, biological activity, and pharmacokinetic and (or) pharmacodynamic profiles.
For monoclonal antibodies (mAbs), Decision No. 89 requires comparative clinical studies in all cases. If comparability studies reveal significant differences that cast doubt on biosimilarity, the product cannot be registered as a biosimilar.
What qualifies as a biosimilar and what it is compared with
Federal Law No. 61-FZ of 12 April 2010 “On the Circulation of Medicines” (hereinafter Federal Law No. 61-FZ) defines a biosimilar (similar biological medicinal product) as a biological medicinal product similar in quality, efficacy and safety to the reference biological medicinal product, in the same dosage form and with an identical route of administration.
Decision No. 89 adds the following conditions:
the dosing regimen and route of administration of the biosimilar and the reference product are the same, and any difference in strength, dosage form, composition, excipients or presentation requires justification and additional data;
deliberate changes made to improve efficacy, for example optimization of the glycosylation profile, are incompatible with the biosimilar approach, whereas differences that may improve safety (fewer impurities, lower immunogenicity) may not conflict with it;
as a rule, the same type of cell line is used in manufacturing, and a different type of cell line needs justification.
The reference product must be registered in the Union on the basis of a complete registration dossier, and the same product is used throughout the program of quality, safety and efficacy studies. A product registered outside the Union may be used for comparison in certain clinical studies and in non-clinical in vivo studies (in animals). In this case, the manufacturer is responsible for confirming that the product corresponds to the reference product registered in the Union, and the mandatory part of the bridging data is the results of analytical studies comparing three products: the biosimilar under study, the reference product registered in the Union, and the comparator product not registered in the Union. The acceptability of this approach is determined separately for each product, discussed in advance with the authorized bodies, and finally accepted during assessment of the dossier. If the originator product is not registered in the Union, the authorized body of the member state asks the Expert Committee on Medicines under the EEC for a recommendation on the choice of the comparator product.
The choice of the reference product is justified in the dossier. Module 2 of the Common Technical Document (CTD) contains the selection criteria and their justification, and confirmation of the choice is given in the study report or in a separate official letter. For the reference product, the dossier states the trade name, strength and dosage form, the registration holder, the registration date and certificate number, the member states where it is registered, the number of the batch used in the studies, the manufacturer, the shelf life and the country of purchase. The recommendation of the Expert Committee on Medicines is attached if available, and copies of the certificates of analysis of the batches of the reference and study products are attached to the study report. This is a requirement of Decision of the EEC Council No. 78 of 3 November 2016 “On the Rules for Registration and Assessment of Medicines for Human Use” (hereinafter Decision No. 78).
In what order studies are conducted
Decision No. 89 recommends a stepwise approach: first a comprehensive establishment of physicochemical and biological characteristics, then non-clinical in vitro studies (under laboratory conditions, on cells and molecules), then, where necessary, in vivo studies and clinical studies. The scope and nature of the last two stages depend on the quality of the evidence obtained earlier, including the reliability of physicochemical, biological and non-clinical in vivo data.
Clinical data are not permitted as a basis for justifying substantial differences in quality attributes. If comparability studies point to significant differences that cast doubt on biosimilarity, the product cannot be registered as a biosimilar, and development is started afresh to compile a complete registration dossier. The design, conduct, endpoints and target population of the studies must be sensitive enough to detect clinically significant differences.
What quality data are required
Comparing a biosimilar only with a publicly available standard, for example a pharmacopoeial monograph, is insufficient for comparability purposes. Quality analysis must be comprehensive, use sensitive orthogonal methods (methods based on different principles) and, unless otherwise justified, include side-by-side comparative studies. Several batches of the reference product are used for comparison, and their age relative to shelf life is taken into account.
Acceptance ranges for quality attributes are based primarily on the experimentally determined ranges of the reference product. Unless otherwise justified, they are no wider than the variability of its representative batches, and the choice of ranges is justified by the number of batches tested, the attributes studied, the age of the batches and the analytical method. If significant quality differences are found and the absence of a clinically significant effect cannot be justified, the claim of biosimilarity raises doubts.
For clinical studies, it is strongly recommended to use a product made by a commercial process that reflects the quality profile of batches released for sale. The main clinical data must be obtained on the product of the final manufacturing process. In case of a departure from this requirement, the applicant submits a justification and, where necessary, data from additional comparability studies with the final and the earlier composition (Decision No. 78).
What non-clinical studies are conducted
The first step of the non-clinical program, comparative in vitro studies, includes a target-binding test and a test of signal transduction, functional activity or cell viability. The studies must be sensitive, specific and sufficiently discriminatory (able to distinguish between the products), cover the concentration range in which differences are detected with the greatest sensitivity, and be conducted on a sufficient number of batches of both products. Decision No. 89 calls in vitro studies paramount (fundamental) for non-clinical comparability.
The second step, determining whether in vivo studies are needed, depends on factors that are assessed together: potentially significant quality attributes that the reference product lacks (for example, new post-translational modifications), quantitative differences in quality attributes and significant differences in composition. If comparability in physicochemical and biological characteristics and the in vitro studies are found satisfactory, and nothing prevents the transition to clinical studies, in vivo animal studies are, as a rule, not required. The chosen approach is justified in the non-clinical overview of the registration dossier (Module 2.4).
For mAbs, Decision No. 89 sets a separate list of in vitro tests: binding to the target antigen, binding to the isoforms of the relevant Fc receptors, to the neonatal receptor FcRn and to complement (C1q), Fab-associated functions (for example, neutralization of a soluble ligand) and Fc-associated functions (antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, complement activation). Toxicological studies in non-human primates are not recommended.
What clinical studies require
The clinical part includes the following steps: pharmacokinetics (PK), pharmacodynamics (PD), efficacy, safety and immunogenicity. Decision No. 89 describes them separately for biotechnology-derived proteins and for mAbs (Table 1).
Table 1. Clinical comparability steps for biotechnology-derived proteins and mAbs
| Step | Biotechnology-derived proteins | mAbs |
|---|---|---|
| PK | A comparative PK study is part of the development program. Comparability margins are set and justified before the study begins. A 90% confidence interval (CI) falling within a predefined range may in itself be insufficient: the position and width of the CI are also considered. A single-dose crossover study is preferable; with a long half-life and (or) a high risk of immunogenicity, parallel groups may be needed | The first step of the clinical program. A single-dose study in healthy volunteers is recommended, in whom target-mediated clearance plays a smaller role. A parallel design may be needed because of the long half-life and the effect on immunogenicity. With a toxic mechanism of action or insufficient information, a study in patients is preferable, and if single-dose administration in patients is not appropriate, a multiple-dose study is conducted |
| PD | PD markers are recommended to be added to PK studies and are selected by clinical significance | PD endpoints are included in PK studies where possible. PD markers are accepted as the primary confirmation of comparability under two conditions: a clear dose-response relationship has been shown, and at least one marker is accepted as a surrogate |
| Efficacy | In the absence of surrogate markers, a randomized parallel comparative study with sufficient power (with enough participants to detect differences), preferably double-blind, on efficacy endpoints is generally required. An equivalence design is recommended. A non-inferiority design is acceptable with rigorous scientific justification, and it is recommended to discuss it with the authorized bodies | If comparative PD studies that convincingly confirm comparability cannot be conducted, efficacy is confirmed in a randomized parallel equivalence study with sufficient power, preferably double-blind. For oncology mAbs, a homogeneous population and a primary endpoint that measures activity are acceptable, for example the overall response rate (ORR, the proportion of patients with a complete or partial response); progression-free survival (PFS) is preferable where it is more sensitive than ORR |
| Immunogenicity and safety | Immunogenicity is compared according to the principles that Decision No. 89 sets for immunogenicity assessment. The analysis is conducted side by side, with blinding, and must detect antibodies at least to the biosimilar molecule. For chronic use, data from one year of follow-up are generally needed before registration, and a shorter period, for example 6 months, is acceptable if justified | The type, severity and frequency of adverse reactions are compared carefully, especially those described for the reference mAb. Immunogenicity is compared systematically, generally in a clinical efficacy and safety study, with the same validated methods. Where possible, patients who previously received the reference mAb are not included, or an analysis of the subgroup of previously treated patients is planned in advance. An exploratory analysis in the subgroup without antibodies to the drug is also planned |
Decision No. 78 sets additional requirements for immunogenicity data. The study is conducted in the group of patients with the highest risk of an immune response, and neutralizing antibodies are determined. The follow-up period corresponds to the planned duration of treatment and the time of antibody formation and is at least 12 months, and a different duration needs justification. Antibody assay methods must be validated, and the sufficient sensitivity of the method is assessed in advance.
A difference in immunogenicity also affects the efficacy analysis. If fewer neutralizing antibodies form against the biosimilar, an efficacy analysis of the whole population may give an erroneous conclusion that the biosimilar is more effective than the reference product. Decision No. 89 recommends providing in advance for an exploratory subgroup of patients in whom antibodies to the drug did not form.
When a comparative efficacy study is not conducted
For all biosimilars, confirmatory clinical studies may not be required if efficacy and safety follow unequivocally from the similarity of physicochemical characteristics, biological activity and PK and (or) PD profiles, and the impurity profile and the properties of excipients raise no concerns. Such simplified approaches should be agreed with the authorized bodies of the member states.
For biotechnology-derived proteins, comparative PK and PD data may be sufficient if the chosen PD marker is accepted as a surrogate and correlates with the patient outcome to the extent that a similar effect on the marker produces a similar effect on the clinical outcome. Decision No. 89 gives examples: the absolute neutrophil count for granulocyte colony-stimulating factor (G-CSF), the reduction of early viral load in chronic hepatitis C for alpha interferons and the euglycemic clamp test for comparing two insulins. If a PD marker is not confirmed as a surrogate but is significant for the pharmacological action and has a clear dependence of the effect on dose or concentration, a study of the dependence of response on dose and exposure with two or more doses may be sufficient. In exceptional cases, a confirmatory clinical study may not be required where comparability is reliably confirmed by physicochemical, structural and functional in vitro tests, PK studies in humans and a combination of PD markers. It is recommended to discuss such an approach (“fingerprints”) with the authorized bodies, and the plan must include the size of the equivalence margins with clinical justification and measures to confirm a comparable safety profile.
For mAbs, Decision No. 89 requires comparative clinical studies in all cases and rigorous scientific justification of their number and type. For mAbs, PD markers are accepted as the primary confirmation of clinical comparability under the two conditions stated in the “PD” row of Table 1, and if the conditions are not met, one should proceed to a clinical efficacy study. It is recommended to discuss the use of this approach with the authorized bodies, including the proposed equivalence margin and its clinical justification.
How results are extrapolated to other indications
If comparability is confirmed for one indication, the data can be extrapolated to other indications of the reference product with scientific justification. Extrapolation is carried out on the totality of quality, non-clinical and clinical data. Additional data are required, for example, if the active substance interacts with several receptors that act differently in different indications; if the substance has several active sites with different effects in different indications; or if the studied indication is not sensitive to differences in all significant aspects of efficacy and safety for other indications.
Immunogenicity depends on the route of administration, the dosing regimen, patient factors and the disease. Therefore, extrapolating immunogenicity from the studied indication or route of administration to others needs separate justification. For mAbs whose comparability is confirmed by PD markers, where the mechanisms of action differ across the claimed indications or this is uncertain, the applicant submits data that justify extrapolation to all indications and supports it with an analysis of the literature on antigen receptors and mechanisms of action.
What documents the dossier includes
Decision No. 78 sets separate requirements for the dossier of a biosimilar. For registration, data from comparative studies with the reference biological medicinal product are submitted, and quality, safety, efficacy and immunogenicity are compared with the same reference product at the manufacturing, non-clinical and clinical phases.
Module 1. The applicant submits a summary of the justifications and facts showing that the product is biosimilar to the originator, with a comparison of the active substance, dosage form, strengths, indications and route of use. The risk management plan is submitted together with information on the pharmacovigilance system. The absence of individual dossier elements is justified in the corresponding section of the module.
Module 2. The quality, non-clinical and clinical overviews give comparative information on the product and the reference product, the criteria for choosing the reference product and the justification of the scope of the comparative non-clinical and (or) clinical studies conducted.
Module 3. The applicant also submits confirmation of the similarity of the molecular and biological characteristics of the active substances (primary structure and higher-order structures, post-translational modifications, biological activity, purity, impurities), confirmation of the similarity of the characteristics of the medicinal product, an assessment of the effect of differences in impurities and excipients on clinical safety and efficacy, a description of the manufacturing process, pharmaceutical development data, a specification with the attributes of the reference product and stability studies. If the clinical significance of differences is unknown, especially for safety, additional studies are required before and after registration.
Modules 4 and 5. Module 4 contains the results of non-clinical studies in comparison with the reference product. Module 5 contains the results of clinical studies: single-dose PK studies and, if PK depends on dose and time, multiple-dose PK studies, PD studies, and data on adverse reactions and immunogenicity. For PD studies, doses are taken from the steep part of the dose-response curve obtained in non-clinical studies.
The risk management plan includes a safety specification that describes the important identified and potential negative aspects of the safety of the reference product, of the class of products and (or) of the biosimilar, as well as a pharmacovigilance plan with risk minimization measures. Decision No. 89 requires the risk management plan to take into account the risks inherent in the reference product and to consider immunogenicity separately. The risk minimization measures adopted for the reference product are, in principle, also included in the program for the biosimilar, and deviations are justified. For suspected adverse reactions, the biological product must be precisely identified by stating the trade name and batch number.
What rules on biosimilars exist in Russian legislation
An application for registration of a biosimilar may be submitted after three years from the date of registration of the reference product in the Russian Federation (under Federal Law No. 61-FZ). For six years from the date of registration of the reference product, the use for commercial purposes of information on the results of its non-clinical and clinical studies submitted by the applicant is not permitted without the applicant’s consent. The accelerated assessment procedure does not apply to biosimilars. The authorized federal executive body establishes the rules for assessment of biosimilars. The provisions of Federal Law No. 61-FZ on the three- and six-year periods contain no reference to Union law. The Law permits the circulation of medicinal products registered both under Federal Law No. 61-FZ and under acts that form Union law.
Order of the Russian Ministry of Health No. 558n of 24 August 2017 “On Approval of the Rules for Assessment of Medicines for Human Use and the Specific Features of Assessment of Certain Types of Medicinal Products for Human Use (Reference Medicinal Products, Generic Medicinal Products, Biological Medicinal Products, Biosimilar Medicinal Products (Biosimilars), Homeopathic Medicinal Products, Herbal Medicinal Products, Combinations of Medicinal Products), and the Forms of Expert Panel Conclusions” (hereinafter Order No. 558n) prescribes that, in the assessment of a biosimilar, its package leaflet is compared with the package leaflet of the reference product. If the package leaflet of the biosimilar states additional indications, a dosing regimen or a route of administration, the conclusion on the benefit-risk ratio is formed on the basis of the corresponding clinical studies. The assessment of the quality of a biological product is carried out taking Decision No. 89 into account.
Interchangeability is determined by the authorized federal body on the basis of the conclusion of the expert panel of the expert institution. The first criterion of interchangeability for biosimilars is formulated as comparability of the qualitative and quantitative characteristics of pharmaceutical substances.
What to do
Determine the reference product and the date for filing the application. Check that the product is registered in the Union on a complete dossier and that the same product is used in all studies (Decision No. 89). If the product is registered under Federal Law No. 61-FZ, check the filing date against the three-year period that Federal Law No. 61-FZ counts from the date of registration of the reference product.
Start with quality studies. Compare the biosimilar with several batches of the reference product by orthogonal methods, set acceptance ranges no wider than the variability of its batches, and choose the scope of in vivo and clinical studies on the basis of the results of this comparison (Decision No. 89).
Determine whether an efficacy study is needed. For biotechnology-derived proteins, check the product against the conditions of Decision No. 89 under which a comparative efficacy study is not conducted. For mAbs, proceed from the fact that Decision No. 89 requires comparative clinical studies in all cases and accepts PD markers as the primary confirmation under two conditions.
Agree the simplified approach with the authorized body. Decision No. 89 states that simplified approaches should be agreed with the bodies of the member states. Decision No. 78 classes scientific and pre-registration consultations at the applicant’s request, in accordance with the legislation of the member state, among the consultations of authorized bodies. In Russia, scientific consulting under Federal Law No. 61-FZ covers non-clinical and clinical studies and the assessment of quality, efficacy and safety.
Prepare the dossier under the biosimilar requirements of Decision No. 78. Plan immunogenicity follow-up of at least 12 months or a justification of a different period, and prepare a risk management plan that identifies the product by trade name and batch number (Decision No. 78; Decision No. 89).
Regulatory base:
1. Decision of the EEC Council No. 89 of 3 November 2016 “On Approval of the Rules for Conducting Studies of Biological Medicines of the Eurasian Economic Union” (as amended on 22 January 2025)
2. Decision of the EEC Council No. 78 of 3 November 2016 “On the Rules for Registration and Assessment of Medicines for Human Use” (as amended on 26 November 2025)
3. Federal Law No. 61-FZ of 12 April 2010 “On the Circulation of Medicines” (as amended on 4 August 2026)
4. Order of the Russian Ministry of Health No. 558n of 24 August 2017 “On Approval of the Rules for Assessment of Medicines for Human Use and the Specific Features of Assessment of Certain Types of Medicinal Products for Human Use (Reference Medicinal Products, Generic Medicinal Products, Biological Medicinal Products, Biosimilar Medicinal Products (Biosimilars), Homeopathic Medicinal Products, Herbal Medicinal Products, Combinations of Medicinal Products), and the Forms of Expert Panel Conclusions” (as amended on 31 March 2025)