EAEU Bioequivalence Rules Changed in 2024. The New RMP Hierarchy Every Generic Developer Must Follow
A manufacturer of a generic medicinal product can complete a bioequivalence study, spend six months and several million rubles on it, and then receive a deficiency notice from experts: the justification for selecting the reference medicinal product does not comply with current rules. The company is then forced either to supplement the dossier with extensive additional justification or, in the worst case, to redo the study with a different reference standard.
This risk is especially relevant right now.
By December 31, 2027, companies are required to bring their national registration dossiers into compliance with Eurasian Economic Union (EAEU) requirements — the transition period was extended by Decision of the Council of the Eurasian Economic Commission (EEC) No. 34 dated May 22, 2025. The workload is substantial, the pace is demanding, and the question of reference medicinal product (RMP) selection comes up for every drug whose dossier is being prepared or updated under the unified EAEU rules.
Since June 13, 2024, the rules for RMP selection in the EAEU have been updated. EEC Council Decision No. 30 dated April 12, 2024 rewrote paragraph 18 of the Rules for Conducting Bioequivalence Studies of Medicinal Products within the EAEU, approved by EEC Council Decision No. 85 dated November 3, 2016 (hereinafter the Rules). The main change: a five-step hierarchy has been established, with a clear order of priorities and an expanded role for the Expert Committee on Medicinal Products (hereinafter the Expert Committee).
Let us look at what exactly changed and how to structure work under the new rules.
Why RMP Selection Matters From Day One
A bioequivalence study proves that a generic behaves in the body the same way as the pioneer product — the drug backed by years of clinical trials. That pioneer product, the original medicinal product, serves as the benchmark: the RMP. Once bioequivalence is demonstrated across two primary pharmacokinetic parameters — area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax) — the efficacy and safety data of the original are extrapolated to the generic.
If the wrong product is taken as the benchmark, the chain of evidence breaks. The regulatory authority cannot accept such a study: it is unclear what the new product is being compared against and which data are being extrapolated to it. This is why the rule «select the correct RMP first, then plan the study» must be followed without exception.
What Selection Looked Like Before the Amendments
Before Decision No. 30, paragraph 18 of the Rules stated a general principle: priority went to the original medicinal product registered in the EAEU, and in its absence, companies were to look to international practice. No detailed multi-step scheme existed.
In practice, this created uncertainty. Companies interpreted «absence of the original» differently: some considered the lack of Russian registration sufficient, while others required proof of absence across the entire International Council for Harmonisation (ICH) market. Generic products were used as RMPs without any coordination with the Expert Committee — often without issue, but sometimes resulting in deficiency comments. Different EAEU member states applied the rules differently, creating an uneven playing field within the unified market.
What Changed in June 2024
Paragraph 18 of the Rules now establishes a five-step hierarchy. Moving to the next step is permitted only upon documented proof that the previous step is unavailable.
| Step | RMP Category | Conditions and Restrictions |
|---|---|---|
| a | Original product registered in the EAEU | Priority. Safety, efficacy, and quality confirmed upon registration in the EAEU or under the legislation of member states |
| b | Original product from ICH countries; or a generic (hybrid) product if no ICH original is available | Applicable when step a is impossible. A generic is permitted only if the ICH original is unavailable, the generic is registered in at least one EAEU member state, has confirmed bioequivalence to the original, and has received Expert Committee approval |
| c | Product from the Expert Committee’s published list | Applicable when steps a and b are impossible. The current list of decisions is published on the EAEU official website |
| d | Product with at least 20 years of medical use experience | Applicable when steps a through c are impossible. Use experience must be in at least one member state; Expert Committee approval required |
| e | Combination product | Applicable when steps a and b are impossible (not the entire a–d chain). Requires Expert Committee approval with an assessment of the rationality of the fixed combination |
Step e applies only when steps a and b are unavailable. The a–d chain is not involved here. Combination products occupy a distinct position in the system: their status as an original is often less straightforward, and a separate evaluation logic applies.
A note on which countries fall under «ICH region»: these are the jurisdictions and associations participating in the International Council for Harmonisation — the European Union (EMA), the United States (FDA), Japan (PMDA), Canada (Health Canada), Switzerland (Swissmedic), and Australia (TGA). An «ICH original» means a product registered in one of these jurisdictions under a full dossier. A product registered only in India or China, for example, does not qualify for step b.
A separate provision covers cases where a combination product cannot be recognized as an RMP: if the combination is irrational or its efficacy and safety are unproven, the applicant will need to conduct a full program of preclinical and clinical studies.
The Role of the Expert Committee in Practice
The Expert Committee features in three of the five hierarchy steps. Before reaching out, check whether a decision already exists: the list is published on the official EAEU website. Published decisions include, for example, recommendations on ethosuximide and on the azelastine–mometasone combination — cases where identifying the original is particularly difficult.
If the relevant decision is not on the list and you plan to use a product below step a, the request to the Expert Committee must be submitted before the bioequivalence study begins. Approval must be secured before the study is conducted. Running the study first and seeking approval afterward is a risk: reviewers will notice during dossier evaluation, and the validity of the entire procedure is likely to be questioned.
The request must include four blocks of information:
1. registration data for the proposed RMP: trade name, marketing authorization holder, registration certificate number in the country of registration;
2. confirmation of the product’s market availability or, conversely, documented justification of the original’s unavailability (letters from manufacturers, registry data from ICH jurisdictions);
3. comparative analysis: composition, dosage, dosage form, route of administration;
4. for step d: data on duration of medical use (at least 20 years in one EAEU member state).
When One INN Has Multiple Candidates
A particular difficulty arises when several products on the market share the same International Nonproprietary Name (INN), each claiming original status. This occurs with rebranding, multiple licensees, or parallel developments using the same active substance.
The Rules do not address this case directly, but the logic of the hierarchy provides a clear answer: priority goes to the product registered first with the most complete clinical evidence base. That product is the «source» of efficacy and safety data for the entire INN.
In disputed cases, the Expert Committee may issue a recommendation specifying a particular trade name as the RMP for that INN. The decision is binding for all subsequent registrations and removes uncertainty across the entire market.
Technical Requirements for the RMP Batch
Once the product is determined, the next step is selecting a specific batch for the study. Paragraph 20 of the Rules sets a limit: the active substance content in the investigational product batch must not differ from the RMP batch by more than 5% (unless adequately justified).
Here is how this works in practice. Purchase several RMP batches, run an assay on each, and select the one that falls within the acceptable range. Comparative dissolution testing (CDT) is also required for all batches under consideration, conducted in three buffer media (pH 1.2, 4.5, and 6.8). Dissolution profiles are included in the dossier and serve as justification for the batch selection.
If the active substance content difference exceeds 5%, bioequivalence study results can be adjusted mathematically — but regulators are reluctant to accept such corrections. It is better to resolve the issue by selecting a suitable batch before the study begins.
One more point concerns products available in multiple dosage forms. If the original is registered in both capsules and tablets (or in immediate-release and extended-release forms), the form used for the study should be the one first brought to market and used in the pivotal clinical trials. The fact that a different form is readily available commercially does not change this.
Biowaiver and Batch Requirements
A distinct situation arises with a biowaiver — the procedure for exempting a product from in vivo bioequivalence testing based on the Biopharmaceutics Classification System (BCS). For BCS Class I products (high solubility, high permeability), clinical studies can be replaced by in vitro pharmaceutical testing. This is significantly cheaper and faster.
Under a biowaiver, the requirements for the RMP batch are stricter. Dissolution profiles of the investigational product and the RMP must match across all three buffer media (pH 1.2, 4.5, and 6.8), with similarity assessed using the f2 factor (f2 ≥ 50). Requirements for the qualitative and quantitative composition of excipients are also more stringent than in a standard study. If any one of these conditions is not met, a biowaiver is unavailable and the study must proceed in vivo.
What to Do
Check the Expert Committee’s published decisions on the EEC website before anything else. If an approved RMP already exists for your INN, the question is settled without further approvals.
Work through the hierarchy step by step. Start with step a (EAEU-registered original). When skipping a step, document why the previous option was unavailable: official letters from manufacturers, registry screenshots, market availability certificates. Each skipped step must be justified in Module 3 of the registration dossier.
If selecting a generic as the RMP, contact the Expert Committee before the study begins. Prepare the full documentation package covering the four information blocks described above. Factor the review timeline into your overall project schedule.
Select the RMP batch within the 5% limit. Purchase multiple batches, run assays and CDT on each, and choose the batch within the acceptable range. Include data on all tested batches in the registration dossier.
Document the selection in Module 2.7.1 and in the bioequivalence study report. Paragraph 117 of the Rules explicitly requires the report to state the RMP’s trade name, dosage, dosage form, batch number, manufacturer, expiry date, and country of purchase. The justification must be traceable throughout: from correspondence with the Expert Committee to the final report.
The amendments introduced by Decision No. 30 made the RMP selection algorithm more transparent — but not simpler. Every step away from a standard EAEU-registered original now requires a documentary trail. Companies that build RMP hierarchy verification into the start of each generic registration project save months of work and protect costly studies from rejection.
Regulatory framework:
1. EEC Council Decision No. 85 dated November 3, 2016 «On Approval of the Rules for Conducting Bioequivalence Studies of Medicinal Products within the Framework of the Eurasian Economic Union» (as amended April 12, 2024)
2. EEC Council Decision No. 30 dated April 12, 2024 (amendments to Decision No. 85, including paragraph 18 on the RMP selection hierarchy)
3. EEC Council Decision No. 78 dated November 3, 2016 «On the Rules for Registration and Evaluation of Medicinal Products for Human Use» (as amended May 22, 2025)