Local Clinical Trials in the EAEU Are Not Required for Most Drugs. Here Is What Determines the Scope.
Regulatory managers often include a dedicated budget line for local clinical trials in their registration plans without first evaluating whether they are actually necessary for the specific medicinal product. In most cases, such a budget allocation is not required. Where expenditure is genuinely needed, it most frequently involves a bioequivalence study. A bioequivalence study is structured completely differently from a full-scale clinical trial: it has different timelines, different sample sizes, and a distinct methodology.
The term «local clinical trials» is not formally defined in the regulations of the Eurasian Economic Union (EAEU). It is a colloquial expression encompassing several distinct regulatory pathways: mandatory local or partially local clinical trials for certain innovator (originator) drugs, comparative clinical studies for biosimilars, pharmacodynamic studies, bioequivalence studies, and complete exemptions from local data for orphan drugs and well-established medicinal products. Each pathway is triggered by its own set of conditions, and they cannot be consolidated into a single generic budget or study protocol.
Structure of the Evidentiary Base for EAEU Registration
The Rules for Registration and Examination of Medicinal Products for Human Use were approved by Decision No. 78 of the Eurasian Economic Commission (EEC) Council dated 3 November 2016 (hereinafter referred to as Decision No. 78). The requirement to register new medicinal products exclusively under Union rules came into mandatory effect on 1 July 2021, while a separate deadline of 31 December 2020 applied to the Russian Federation; prior to these dates, applicants had the option to choose between national procedures and EAEU regulations.
The deadline for aligning previously authorized medicinal products with Union law warrants particular attention. Decision No. 78, as amended by EEC Council Decision No. 34 dated 22 May 2025, established this alignment deadline as 31 December 2025. This deadline has now passed: alignment applications submitted prior to that date maintain the validity of their marketing authorizations during the transitional period, whereas marketing products on general terms without such an application is no longer permissible after 31 December 2025. For the purposes of this article, another implication is key: the pool of medicinal products whose dossiers are compiled anew under EAEU rules continues to expand, and the question regarding the required volume of clinical data arises for every applicant.
The overarching principle is straightforward. EAEU regulations are built around the acceptance of foreign data. Mandatory replication of clinical trials within the Union territory is not envisioned as the baseline scenario. The required volume of evidence depends on which of four categories the product falls into: innovator, generic, biosimilar, or orphan.
Innovator Products and the Necessity of Local Studies
The efficacy and safety of an innovator product are established through a comprehensive package of non-clinical and clinical studies conducted during pharmaceutical development. Decision No. 78 does not contain a blanket requirement to conduct a standalone clinical trial within the territory of EAEU member states. The applicant submits a full clinical section in the marketing authorization dossier (Module 5), including data from multi-regional clinical trials (MRCTs), if available.
In practice, assessors of the reference member state’s competent authority evaluate whether the submitted data are sufficient to reach a conclusion on the benefit-risk balance for the Union population.
There is an explicit formal criterion for this evaluation. Paragraph 36 of Decision No. 78 accepts Module 5 clinical data without supplementary conditions in only three cases:
The studies were conducted within member states prior to 1 January 2016;
The studies were conducted in countries of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) region prior to that date, and the product was authorized in those countries based on those data;
At least one of the studies initiated after 1 January 2016 was conducted entirely or partially within the territory of the Union.
If none of these conditions are met, the applicant is obligated to conduct at least one clinical study entirely or partially within the Union before submission. The alternative is to agree to an unscheduled inspection of one of the overseas clinical trial sites. This constitutes the formal mechanism that occasionally makes a local clinical trial necessary for an innovator drug. In practice, this narrows the scope significantly: for the majority of modern multi-regional clinical trials that include study centers in Union member states, this condition is satisfied automatically.
Real-World Evidence (RWE) is beginning to be applied in the EAEU as an additional source of data; however, the regulatory framework governing this area is currently evolving and warrants a separate analysis.
Generic Products and the Role of Bioequivalence Studies
For generic drugs, the regulatory framework is different. The Rules for Conducting Bioequivalence Studies of Medicinal Products were approved by EEC Council Decision No. 85 dated 3 November 2016 (hereinafter referred to as Decision No. 85) and apply to generic and hybrid medicinal products. A bioequivalence study addresses a different objective.
It demonstrates that the generic drug is equivalent in quality to the reference product, allowing the reference product’s safety and efficacy data to be extrapolated to the generic. It does not require demonstrating efficacy from scratch.
This study is almost always pharmacokinetic (PK). It cannot be classified as a conventional clinical trial. The standard design is a randomized, single-dose crossover study involving at least 12 evaluable subjects included in the statistical analysis.
Participants must be at least 18 years of age, preferably with a Body Mass Index (BMI) within the range of 18.5-30 kg/m². This is a standard subject selection criterion for all bioequivalence studies and is not tied to a specific product category.
Acceptance criteria depend on the nature of the drug and active substance variability:
| Drug Category | Acceptance Interval for AUC and Cmax | Condition |
|---|---|---|
| Standard | 80.00-125.00% | 90% confidence interval |
| Narrow Therapeutic Index (NTI) | 90.00-111.11% | Same confidence interval, narrowed range |
| Highly Variable (intra-individual CV above 30%) | Up to 69.84-143.19% for Cmax at CV = 50% | Widening scales with variability, maximum at CV 50% |
The acceptance limits for AUC are not subject to widening regardless of variability; they are maintained strictly within the 80.00-125.00% interval.
Certain formulations are entirely exempt from in vivo testing. The biowaiver procedure, based on the Biopharmaceutics Classification System (BCS), allows in vivo human studies to be substituted with in vitro comparative dissolution profile testing if the active pharmaceutical ingredient is highly soluble and highly permeable (BCS Class I), or highly soluble with low permeability (BCS Class III), provided the excipient composition is comparable to the reference product. Dissolution profiles are deemed equivalent if the similarity factor (f2) falls between 50 and 100. If the calculation of f2 is not valid, alternative approaches are permitted: the difference factor (f1), the Weibull distribution function, or comparisons at individual time points (such as Student’s t-test).
Biosimilars and the Limits of the Pharmacokinetic Approach
The framework of Decision No. 85 does not apply to biological and biosimilar medicinal products: Paragraph 7 of the Rules explicitly excludes biological products from its scope, referencing standalone rules for comparing biological medicinal products with reference products. The rationale lies in molecular complexity: minor differences in tertiary structure or glycosylation can alter immunogenicity in ways that pharmacokinetic similarity alone cannot address.
These dedicated rules are established in EEC Council Decision No. 89 dated 3 November 2016, «On Approval of the Rules for Conducting Studies of Biological Medicinal Products of the Eurasian Economic Union» (hereinafter referred to as Decision No. 89). The regulation introduces the concept of a «comparability study within the biosimilarity assessment» (biosimilarity exercise): a set of pharmaceutical and biological tests, non-clinical and clinical studies designed to confirm the absence of clinically meaningful differences between the biosimilar and the reference biological product. The wording directly includes clinical trials in the mandatory package. An applicant cannot limit itself to a pharmacokinetic comparison at its own discretion.
For a biosimilar, the standard pathway for demonstrating equivalence includes comparative clinical trials in addition to a bioavailability study. This is the scenario where the term «local clinical trial» comes closest to the actual content of the work: the regulator expects comparative clinical data, and pharmacokinetics serves only as one part of the overall picture.
Locally Acting Products: Moving from Pharmacokinetics to Clinical Endpoints
Annexes No. 2 and No. 3 to Decision No. 85 describe situations where the pharmacokinetic approach is not applicable at all, typically for locally acting formulations with minimal systemic absorption (such as topical corticosteroids, dermatological preparations, or ophthalmic drops). In these cases, the regulation provides for two backup levels of evidence.
The first level consists of pharmacodynamic studies. Here the pharmacological effect comes to the forefront. Blood concentration of the substance is not suitable for evaluating such a product. A placebo-controlled arm is mandatory because pharmacodynamic endpoints are highly susceptible to placebo effects. Participants are screened in advance for their ability to demonstrate a measurable response, and non-responders are excluded from the primary analysis.
The second level, a full comparative clinical trial, is required if pharmacodynamic markers are absent or insufficiently reliable. This level carries a practical feature rarely discussed openly: clinical endpoints are considerably less sensitive to differences between products than pharmacokinetic ones, so the sample size becomes enormous. Annex No. 3 to Decision No. 85 gives a characteristic example: confirming a 20% increase in response to the studied product compared with placebo requires around 8,600 patients, while showing a 16% risk reduction in patients with myocardial infarction requires around 2,600 participants. This is precisely why the regulation states directly that the pharmacokinetic approach is preferable to the clinical one wherever possible.
Orphan Products and Simplified Registration Pathways
For orphan products, the regulatory logic of the EAEU and Russia overall moves toward simplified registration pathways, and here direct confirmation was found for the rule already mentioned: Paragraph 36 of Decision No. 78 directly exempts orphan products from the requirement to conduct a local clinical trial when foreign data are insufficient. For this category, no such obligation exists at all.
In Russia, rare (orphan) diseases are considered those with a prevalence of no more than 10 cases per 100,000 population (Part 1, Article 44 of Federal Law No. 323-FZ dated 21 November 2011). The accelerated review procedure for orphan products is established by Article 26 of Federal Law No. 61-FZ and takes no more than 80 working days: 10 working days to check dossier completeness and 60 working days for the quality and benefit-risk evaluation. At the EAEU level, orphan products are eligible for a separate accelerated review under Paragraph 120.11 of Decision No. 78: the registration timeline in the reference member state is reduced from the standard 140 to 100 working days, and the procedure for requesting such review is described in Annex No. 27 to Decision No. 78.
A separate mechanism, directly applicable to orphan products with a long history of use, is the medicinal product with well-established medical use. Decision No. 78 defines it in Section II: the active substance must have been used systematically and documented for at least 10 years in no fewer than 3 member states, and its efficacy and acceptable safety must be corroborated by bibliographic references to published post-marketing and epidemiological data. For such substances, the applicant may submit a well-established-use summary instead of the full volume of its own clinical data. The condition is strict, and it screens out genuinely new orphan products. For long-used active substances where only the indication or the dosage form changes, it works well.
For cases where an applicant is objectively unable to submit comprehensive efficacy and safety data because of the small size of the patient population, Decision No. 78 provides for registration in exceptional circumstances (Paragraph 120.1, grounds listed in Section 11 of Annex No. 1, procedure in Annex No. 25). The marketing authorization holder commits to an annual reassessment of the benefit-risk balance until the data are supplemented.
Product Categories and Required Scope of Evidence
| Product Category | Primary Evidence Type | Clinical Trial in EAEU Required? |
|---|---|---|
| Innovator product | Full clinical section, usually based on foreign or multi-regional data | Only if none of the conditions in Paragraph 36 of Decision No. 78 are met (no early national, ICH-region, or Union-inclusive data) |
| Generic product | Bioequivalence study (PK) or biowaiver based on dissolution data | No, a bioavailability study is required |
| Biosimilar product | Biosimilarity exercise under Decision No. 89, including a clinical stage | Yes, clinical trials are part of the mandatory package |
| Locally acting product without systemic absorption | Pharmacodynamic study; clinical trial if data are insufficient | Possibly, depending on the availability of reliable pharmacodynamic markers |
| Orphan product | Directly exempt from the local trial requirement (Paragraph 36 of Decision No. 78); well-established use, accelerated review, or exceptional-circumstances registration are available | No, the requirement does not apply under a direct provision |
What to Do
Determine the product category before calculating the budget. Establish whether the product is innovator, generic, biosimilar, or locally acting: this determines whether the discussion is about a clinical trial, a bioequivalence study, or a biowaiver.
For a generic, check biowaiver eligibility. Establish the biopharmaceutics class of the active substance and compare the excipient composition with the reference product before planning a study in humans.
For a locally acting product, gather pharmacodynamic markers in advance. If a reliable pharmacodynamic indicator is unavailable, plan for a sample size an order of magnitude larger than for a pharmacokinetic study, and include a placebo arm.
For a biosimilar, plan the biosimilarity exercise under Decision No. 89 as a single package that includes the clinical stage. Request scientific advice from the Expert Committee on Medicinal Products before starting the clinical program: the design of the comparative clinical stage is individual and requires agreeing on equivalence criteria in advance.
Document the justification for the chosen scope of evidence in Module 2, Section 2.5 of the registration dossier (clinical overview). The reference member state’s competent authority should see the rationale for the choice before the review begins. Obtaining this justification in response to an additional request works out more expensive in terms of time.
The scope of clinical data required for EAEU registration is determined by the product category and the availability of reliable surrogate endpoints. There is no general rule that «the local market requires local data.» For most applicants, this is good news: the actual volume of work is often smaller than what gets built into a conservative project plan. The exceptions are biosimilar products and locally acting products without reliable pharmacodynamic markers: for these, the scope of evidence turns out to be larger than expected.
Regulatory Framework:
1. EEC Council Decision No. 78 of 03.11.2016 «On the Rules for Registration and Examination of Medicinal Products for Human Use» (as amended 12.09.2025), Paragraphs 19, 36, 120.1, 120.11, Annexes No. 1, No. 25, and No. 27
2. EEC Council Decision No. 85 of 03.11.2016 «On Approval of the Rules for Conducting Bioequivalence Studies of Medicinal Products in the Eurasian Economic Union» (as amended 12.04.2024), including Annexes No. 2, No. 3, No. 4, and No. 5
3. EEC Council Decision No. 89 of 03.11.2016 «On Approval of the Rules for Conducting Studies of Biological Medicinal Products of the Eurasian Economic Union» (as amended 22.01.2025)
4. EEC Council Decision No. 34 of 22.05.2025 (regarding deadlines for aligning registration dossiers with Union law)
5. Federal Law No. 61-FZ of 12.04.2010 «On the Circulation of Medicines», Articles 20 and 26 (current version, reflecting the reform by Federal Law No. 1-FZ of 30.01.2024)
6. Federal Law No. 323-FZ of 21.11.2011 «On the Fundamentals of Health Protection of Citizens in the Russian Federation», Article 44