EAEU Biosimilar Registration Under Decision No. 89 — Evidence Requirements and 2024–2025 Updates
Most teams tackling biosimilar registration for the first time eventually receive a deficiency letter from the expert body. The dossier, it turns out, was assembled along the lines of a generic — simply with a protein molecule description added. Experts return it with a multi-page list of missing data. The missing studies cannot be conducted quickly. Timelines slip by a year or more.
This is not an isolated situation. The regulatory pathway for biosimilars is fundamentally different from that of small molecules. Proving bioequivalence is not enough. A step-by-step comparability exercise with the reference product must be completed across the entire evidence chain — from physicochemical characteristics to clinical data. Below is an examination of how this system works in the EAEU, what has changed over the last two years, and what to factor in when planning registration.
How It Began: National Rules and Their Limitations
Before the creation of the unified pharmaceutical market of the Eurasian Economic Union, each member state regulated biosimilar registration independently. In Russia, the first requirements for such products appeared in Ministry of Health Order No. 757n as early as 2010. Kazakhstan and Belarus relied on their own national frameworks, often lagging behind Russian requirements by several years.
In practice, this created predictable problems. A product registered under the requirements of one country did not receive automatic recognition in a neighboring one. Manufacturers either had to duplicate dossiers with minor adaptations or abandon part of the market altogether. For companies oriented towards biosimilar exports, this increased development costs and extended time-to-market.
The volume of similarity evidence required also varied. Some regulators confined themselves to a basic quality data package and comparative pharmacokinetic studies. In-depth analytical characterization of the molecule — including glycosylation assessment, peptide mapping, and a multi-tiered immunogenicity evaluation strategy — was practically not required at the national level. Manufacturers took advantage of this, and products with minimally demonstrated similarity to the originator reached the market.
This gap between European standards of evidence and the actual state of registration dossiers in the EAEU was one of the primary arguments for establishing unified rules.
The EAEU Regulatory Framework
The regulatory foundation rests on two Decisions of the Council of the Eurasian Economic Commission adopted on 3 November 2016. Decision No. 78 establishes the general procedure for the registration of medicinal products. Decision No. 89 sets out the specialized requirements for demonstrating similarity for biological products and defines the scope and content of the biosimilar registration dossier (hereinafter — Decision No. 89).
How does a biosimilar differ from a generic at the legal level? Under Article 4, Clause 12.2 of Federal Law No. 61-FZ «On the Circulation of Medicines,» a biosimilar is recognized as a biological medicinal product similar in quality, efficacy, and safety parameters to a reference biological medicinal product in the same dosage form with an identical route of administration. The word «similar» is fundamental here: it refers to proven similarity, not identity.
Why is identity unattainable? A biological product is manufactured in living cells. The final product depends on the host cell line, nutrient medium, cultivation conditions, and purification regimes. Two different manufacturing processes yield molecules that are similar but not identical. A phrase that has long been established in the professional community captures this: «the process is the product.» No biosimilar manufacturer reproduces the originator’s manufacturing process; they develop their own and then demonstrate that the resulting molecules are sufficiently close.
A generic requires only a bioequivalence study. A biosimilar undergoes a multi-level comparability exercise, which Decision No. 89 organizes according to a step-wise, top-down principle:
| Level | What Is Demonstrated | Primary Methods |
|---|---|---|
| Quality | Physicochemical similarity | Mass spectrometry, peptide mapping, glycan analysis, Surface Plasmon Resonance kinetics |
| Non-clinical | Functional similarity in vitro | Biological activity assays, receptor binding studies |
| PK/PD | Comparable behavior in the body | Pharmacokinetic/Pharmacodynamic studies, typically in healthy volunteers |
| Clinical | Absence of clinically meaningful differences | Comparative clinical trials (if preceding levels did not resolve all uncertainties) |
Crucially, if analytical similarity is demonstrated convincingly, the regulator may agree to reduce the volume of non-clinical and clinical data required. This approach is referred to in the professional community as the «totality of evidence»: all data levels are assessed as a coherent whole rather than in isolation.
In practice, the most demanding part of the dossier is the Quality Module. For a monoclonal antibody, confirming the amino acid sequence is not enough. A contemporary dossier includes an analysis of charge variant distributions (isoform profile), a detailed characterization of glycan structures and their functional significance — fucosylation and sialylation directly determine the effector functions of the molecule, including antibody-dependent cellular cytotoxicity (ADCC). Peptide mapping to confirm primary structure identity at the level of individual peptide fragments, and receptor binding force analysis using Surface Plasmon Resonance, are mandatory. All of this requires specialized laboratory capabilities and 12 to 18 months for method development and validation.
Immunogenicity presents its own set of challenges. For any biological product, there is a risk of forming anti-drug antibodies (ADA). These antibodies can reduce therapeutic efficacy, cause serious adverse reactions, or cross-react with endogenous proteins. Decision No. 89 requires the development of a multi-tiered ADA detection strategy, encompassing screening, specificity confirmation, and neutralizing capacity assessment. The immune response observation period must be at least 6 to 12 months, and this must be built into the clinical study design from the outset. Introducing this requirement into an already-running study is generally not possible without a full restart.
The data protection period for biosimilars is established by Article 13, Part 5.2 of Federal Law No. 61-FZ (introduced in 2024): a registration application may be submitted no earlier than 3 years from the date of state registration of the reference product. For chemically synthesized generics, this period is 4 years. Biosimilars appear to have an advantage at first glance — but this is not the case. Those three years are consumed entirely by the studies that generics do not require.
What Changed in 2023–2025
Decision of the Council of the Eurasian Economic Commission No. 77 dated 4 July 2023 entered into force in February 2024. It introduced significant amendments to Decision No. 89 in two directions.
The first concerns low molecular weight heparins (LMWH). These are complex polysaccharide mixtures obtained from natural raw materials by chemical or enzymatic depolymerization. The heterogeneity of their composition makes it impossible to characterize them as standard proteins; specialized approaches are required. The new version of Chapter 15.6 of Decision No. 89 requires comparative analysis of physicochemical properties (molecular weight distribution, disaccharide composition profile) and pharmacodynamic comparison of anti-Xa and anti-IIa activity. The ratio of these two activities has become a mandatory comparability marker. Where analytical and pharmacodynamic similarity is convincingly demonstrated, large comparative efficacy studies for LMWH biosimilars are no longer required.
The second direction concerns Factor IX preparations for the treatment of hemophilia. Decision No. 77 established detailed clinical study design requirements organized by patient group:
| Patient Group | Minimum Participants | Special Requirements |
|---|---|---|
| Previously treated (12+ years) | 12 | Pharmacokinetic evaluation, repeat at 3–6 months |
| Children 6–12 years | 10 | Activity recovery profile |
| Children under 6 years | 10 | Age-adjusted clearance consideration |
For all groups, strict monitoring of inhibitors is required — neutralizing antibodies whose development in hemophilia poses a direct threat to life. An interim post-registration study report is submitted 2 years after registration; the final report is due after 4 years.
Decision of the Council of the Eurasian Economic Commission No. 18 dated 21 February 2025 introduced new standards for the Summary of Product Characteristics (SmPC) and the package leaflet. Among the new requirements is the placement of an additional safety monitoring symbol — a black inverted triangle. This symbol is intended for products requiring enhanced pharmacovigilance, including those with incomplete post-registration data. The decision to assign this status rests with the regulator. For healthcare professionals, the symbol means one thing: all suspected adverse reactions must be reported to the pharmacovigilance system. The SmPC must now also explicitly state the registration status — conditional, or under exceptional circumstances.
In 2025, the Eurasian Economic Commission made a concession for foreign manufacturers on the matter of Good Manufacturing Practice (GMP) certification. A company may now submit a registration dossier without an EAEU GMP certificate, replacing it with a certificate from the country of manufacture and a written commitment to undergo an inspection under Union rules within 3 years of registration. For imported biosimilars, this has significantly eased market access.
Future Directions of Regulation
In October 2025, the US Food and Drug Administration (FDA) published a draft guidance that changes the logic of biosimilar development. The agency proposes abandoning comparative efficacy studies (Phase III) for products with compelling analytical data and PK/PD results. Large-scale clinical trials, in FDA’s assessment, add little meaningful safety information while substantially increasing development costs. Additionally, the proposal would eliminate the legislative distinction between a «biosimilar» and an «interchangeable biosimilar»: all approved biosimilars could be recognized as interchangeable without dedicated switching studies.
The European Medicines Agency (EMA), in a discussion document from April 2025, confirmed a similar course: priority to analytical comparability over clinical data. European experience with biosimilars had by that point exceeded 1 million patient-years — sufficient to draw safety conclusions. The question of automatic pharmacy substitution was left by EMA to national governments.
A comparison of the three regulators’ approaches to core dossier parameters:
| Parameter | EAEU (2025) | FDA | EMA |
|---|---|---|---|
| Batches for registration | Analysis of reference variability | 6–10 batches | Based on risk analysis |
| Comparative clinical efficacy trials | Required where PD uncertainty exists | Proposed to be abolished | Priority to analytics |
| Interchangeability | Not separately regulated | Proposed to be automatic | At the level of member states |
| Post-registration control | Mandatory for certain products | Standard | Standard |
The EAEU has not yet adopted analogous changes. At the RegLec regulatory conferences in 2024–2025, experts identified the liberalization of clinical requirements as the likely next step after 2026 — Union rules have traditionally tracked EMA approaches. This means that a robust analytical package today is an investment in tomorrow’s competitive position. When the regulator reduces clinical requirements, companies with strong analytics will be at an advantage.
What to Do Now
A biosimilar is among the most complex objects in regulatory practice. Below are practical steps for those planning registration in the EAEU.
Start with the originator’s Summary of Product Characteristics. Before planning studies, review the registered indications, special warnings, and immunogenicity data for the reference product. This will determine the scope of comparative data the regulator will require. If the originator holds indications protected by a current patent, including those indications in the biosimilar registration will not be possible even if clinical data exist.
Establish an analytical package strategy early. Method development and validation will take 12 to 18 months. This work must start in parallel with manufacturing process optimization. A standard scope includes mass spectrometry, glycan analysis, Surface Plasmon Resonance kinetics, and biological activity assays.
Build ADA assessment into the clinical study design from the start. The anti-drug antibody observation period must be at least 6 to 12 months. Adding this requirement to an already-running study is generally not possible without a full restart.
For LMWH: verify that the dossier complies with Chapter 15.6 of Decision No. 89 as updated in 2024. The new requirements are mandatory. The analytical plan must be revised to include the disaccharide composition profile and the anti-Xa/anti-IIa activity ratio. Approaches developed before February 2024 will not be accepted by the regulator.
Update the SmPC under Decision No. 18. If a biosimilar is already registered, check at the next dossier variation whether the additional safety monitoring symbol is required, and update the registration status section in accordance with the new format.
Biosimilar registration takes at least 160 working days at the expert evaluation stage under Federal Law No. 61-FZ — and that assumes a complete dossier at first submission. In practice, expert requests add a further 3 to 9 months. The total development and registration cycle for a new biosimilar in the EAEU ranges from 5 to 8 years. Planning must begin now, not after the patent has expired.
Regulatory Framework:
1. Decision of the Council of the Eurasian Economic Commission No. 89 dated 3 November 2016 «On Approval of the Rules for Conducting Studies of Biological Medicinal Products of the Eurasian Economic Union» (as amended 22 January 2025)
2. Decision of the Council of the Eurasian Economic Commission No. 78 dated 3 November 2016 «On the Rules for Registration and Evaluation of Medicinal Products for Medical Use» (as amended 2025)
3. Decision of the Council of the Eurasian Economic Commission No. 77 dated 4 July 2023 «On Amendments to the Rules for Conducting Studies of Biological Medicinal Products of the Eurasian Economic Union» (entered into force 25 February 2024)
4. Decision of the Council of the Eurasian Economic Commission No. 18 dated 21 February 2025 «On Amendments to the Requirements for the Package Leaflet and Summary of Product Characteristics of a Medicinal Product»
5. Federal Law of the Russian Federation No. 61-FZ dated 12 April 2010 «On the Circulation of Medicines,» Art. 4 Clause 12.2; Art. 13 Part 5.2