Expertise · Clinical & Preclinical Studies

When EAEU Registration Requires Clinical or Bioequivalence Evidence

Development programmes supporting medicinal product registration

This section brings together clinical, bioequivalence and preclinical evidence used to support medicinal product registration, including local-study strategy, foreign-data usability, GCP/GLP inspection risk, biowaivers and biological products.

Detailed guidance across the evidence programme is available in the current technical library.

Clinical and bioequivalence evidence supporting EAEU registration

For a medicinal product entering Russia or another Eurasian Economic Union market, the question is not whether a “local clinical study” is required. That formulation belongs to an older national-regulation mindset and is one of the most persistent sources of unnecessary development work.

Under the EAEU registration system, the evidence requirement depends on what type of medicinal product is being registered, what claims are being made, what reference product or scientific bridge is available, and whether the existing quality, nonclinical and clinical package is sufficient under the Union rules.

For many foreign manufacturers, especially generic and hybrid-product companies, the highest-value regulatory decision comes before any new study is commissioned:

Can the existing global evidence support EAEU registration as it stands, can an in-vivo study be replaced by a biowaiver or another equivalence approach, or does the product genuinely require additional clinical evidence?

The wrong answer can add months, substantial cost and unnecessary patient exposure. The correct answer can remove an entire study from the critical path.

There is no universal requirement for a Russian local clinical trial

New medicinal products in Russia are registered under EEC Council Decision No. 78 as EAEU products. The registration dossier is assessed for quality, safety and efficacy according to the applicable EAEU framework.

The fact that a clinical, pharmacokinetic or bioequivalence study was performed outside Russia does not, by itself, make the study unusable for EAEU registration.

The relevant questions are whether:

  • the study design is appropriate for the regulatory purpose;
  • the study was performed under acceptable Good Clinical Practice;
  • the population, comparator and treatment conditions support extrapolation to the proposed EAEU use;
  • the bioanalytical and statistical methods are valid;
  • the study product corresponds to the product proposed for registration;
  • the data are complete enough for expert assessment;
  • any product-specific EAEU requirement has been met.

EAEU Good Clinical Practice is established by Decision No. 79 and was further updated in 2025. Decision No. 78 also gives expert organizations mechanisms to verify clinical-trial compliance where the reliability of submitted data is questioned.

The practical implication is straightforward:

Pharegis does not recommend a study because it is “customary in Russia”. We recommend a study only where the EAEU regulatory bridge requires it.

Start by qualifying the application type

The amount of nonclinical and clinical evidence is determined first by the legal/scientific nature of the application.

The main pathways include:

  • original medicinal products;
  • generic medicinal products;
  • hybrid medicinal products;
  • biological and biosimilar medicinal products;
  • products relying on well-established medicinal use or another specific legal basis where applicable;
  • fixed-combination and other product-specific development pathways.

A product should not be called a “generic” merely because the active substance is old or another company already sells something similar.

For a conventional generic, the applicant relies on the established safety and efficacy of an appropriate reference medicinal product and demonstrates equivalence, normally through pharmaceutical equivalence plus bioequivalence where required.

If the proposed product differs in a way that prevents a standard generic bridge—for example in strength, route, pharmaceutical form, indication or another clinically relevant characteristic—the correct route can become hybrid, with additional nonclinical and/or clinical evidence required to bridge the difference.

For a biosimilar, a conventional small-molecule bioequivalence study is not the governing evidence model at all. The applicant must establish biosimilarity through a stepwise comparability programme under the EAEU biological-medicinal-product rules.

Classification therefore comes before protocol design.

For a conventional generic, the first clinical question is usually bioequivalence

EEC Council Decision No. 85 establishes the EAEU rules for bioequivalence studies of generic medicinal products.

For a systemically acting immediate-release generic, the usual regulatory objective is to demonstrate that the test and reference products do not show a clinically meaningful difference in the rate and extent of active-substance availability under the defined study conditions.

A well-designed programme may require decisions on:

  • selection of the reference medicinal product;
  • fasting and/or fed conditions;
  • single-dose versus another justified design;
  • parallel versus crossover design where relevant;
  • analyte to be measured;
  • washout period;
  • sampling schedule;
  • bioanalytical method;
  • statistical model;
  • treatment of outliers or protocol deviations;
  • handling of highly variable products;
  • whether one study can support additional strengths.

The study is therefore not an isolated CRO activity. It is part of the registration strategy and has to be designed against the intended EAEU dossier.

Reference-product selection can determine whether the whole programme is usable

A technically excellent bioequivalence study can still become unusable if the wrong reference product was selected.

The EAEU rules establish principles for choosing an appropriate reference medicinal product. The preferred comparator is linked to the original/reference product recognized for regulatory purposes. Where the ideal comparator is not available on the relevant market, additional selection logic and, in some situations, recommendations of the EEC Expert Committee on Medicinal Products may become relevant.

The Commission maintains a substantial body of Expert Committee recommendations dealing with comparator selection for specific active substances and dosage forms.

Before procurement of the comparator, Pharegis therefore verifies:

regulatory identity → market source → dosage form → strength → batch → shelf-life window → documentary traceability.

Comparator procurement should be treated as a controlled regulatory step, not as ordinary purchasing.

Bioequivalence is not automatically required for every generic

Decision No. 85 allows several circumstances in which in-vivo bioequivalence may be replaced by another scientifically justified approach.

The most commercially important is the BCS-based biowaiver for eligible immediate-release oral products.

The 2024 amendments to the EAEU bioequivalence rules expanded the biowaiver framework. Among other changes, they broadened the possibilities for certain prodrugs and for medicinal products with active substances belonging to BCS Class III, subject to the applicable conditions.

A biowaiver does not mean “no evidence”. It replaces an in-vivo pharmacokinetic study with a stringent pharmaceutical and biopharmaceutic equivalence argument.

The assessment can include:

  • BCS classification of the active substance;
  • solubility across the required pH range;
  • permeability/absorption justification;
  • comparative dissolution profiles;
  • dosage-form characteristics;
  • excipient composition and quantitative similarity where required;
  • potential effect of excipients on gastrointestinal transit, absorption or stability;
  • manufacturing consistency;
  • product-specific risk factors.

For a Class III product, excipient similarity and dissolution behaviour can become particularly important because high permeability cannot be relied on to neutralize formulation differences.

A biowaiver should therefore be decided during pharmaceutical development, not after a failed or inconvenient BE study.

Some formulations can be exempt from in-vivo BE for reasons other than BCS

Certain medicinal-product configurations may not require a conventional in-vivo bioequivalence study because equivalence can be established more directly.

Examples can include specific aqueous solutions or other dosage forms where the active substance is already in solution and the test and reference products meet the relevant composition and administration conditions.

The exact exemption is product-specific. Excipients, concentration, route and the possibility that formulation differences could affect safety or bioavailability must be assessed.

The mistake is to reason from dosage-form name alone:

“It is a solution, therefore no BE is needed.”

The correct reasoning is:

“This formulation meets the regulatory conditions under which in-vivo BE is unnecessary, and the dossier contains the evidence demonstrating those conditions.”

Additional strengths can sometimes be bridged—but only if the pharmaceutical development supports it

A manufacturer registering several strengths often does not need to conduct a full in-vivo BE study for every strength.

The EAEU rules permit waiver of additional-strength studies where the relevant conditions are met, including factors such as:

  • proportional or otherwise acceptable formulation relationships;
  • common manufacturing process;
  • suitable dissolution behaviour;
  • linear pharmacokinetics or another acceptable scientific basis;
  • selection of the most sensitive/appropriate strength for the in-vivo study.

This should be designed before pivotal batches are manufactured.

If strengths are developed independently and their formulations drift apart, the opportunity to bridge them may be lost.

For portfolio economics, the strength strategy is therefore part of the clinical evidence strategy.

Topical generics use a different equivalence toolbox

Conventional plasma pharmacokinetic BE is not always scientifically meaningful for a locally acting topical medicinal product.

In 2023 the EAEU supplemented Decision No. 85 with specific approaches to establishing equivalence for generic and hybrid topical products. The new framework created several routes based on route of administration and product characteristics, allowing appropriate comparative pharmaceutical, pharmacodynamic, pharmacokinetic or other specialized models to replace broad confirmatory clinical trials where scientifically justified.

This is a significant development for manufacturers of creams, gels, ointments and other locally acting formulations.

The regulatory strategy may involve:

  • qualitative and quantitative formulation comparison;
  • physicochemical characterization;
  • microstructure or rheological characterization;
  • in-vitro release or permeation approaches where applicable;
  • local pharmacokinetic/pharmacodynamic models;
  • comparative clinical endpoint studies only where simpler equivalence approaches are insufficient.

The correct pathway depends on the formulation and route. A global “generic topical” package should therefore be re-mapped to the specific EAEU equivalence framework before a new clinical study is commissioned.

Modified-release and other complex products require product-specific BE strategy

Not every generic fits the standard immediate-release model.

Modified-release products, liposomal products, inhalation/nasal products and other complex formulations can require additional or specialized equivalence approaches.

The EAEU has adopted product-specific and platform-specific guidance in these areas, including separate guidance for quality and bioequivalence of certain product groups and pharmacokinetic/clinical study of intravenous liposomal medicinal products.

The study programme can therefore require more than one comparison condition, more than one strength, or additional pharmacodynamic/clinical evidence depending on the product.

For these products, copying a protocol previously accepted in another jurisdiction is particularly risky.

The protocol should be reconciled against:

EAEU product-specific guidance → reference product → formulation characteristics → intended registration claims.

Hybrid medicinal products require a bridge, not necessarily a full new clinical programme

A hybrid product sits between a straightforward generic and a fully original product.

The safety and efficacy of the reference product can still provide part of the regulatory basis, but the proposed product differs in a way that prevents reliance on a conventional generic equivalence package alone.

The additional evidence should address the specific difference.

For example, a different route of administration, modified formulation, new strength outside the ordinary generic bridge or changed indication may require targeted pharmacokinetic, pharmacodynamic, nonclinical or clinical evidence.

The correct objective is not to “repeat Phase III”. It is to identify the uncertainty created by the difference and design the smallest scientifically adequate programme that resolves it.

Pharegis structures the assessment as:

reference-product knowledge → proposed difference → new uncertainty → evidence needed to bridge that uncertainty.

This prevents both under-development and unnecessary full clinical programmes.

Original medicinal products require a complete evidence strategy—but not necessarily EAEU-only trials

For an original medicinal product, the registration dossier requires the nonclinical and clinical evidence appropriate to the proposed indications, dosing, population and benefit-risk profile.

A foreign development programme can be used for EAEU registration when the studies are scientifically relevant and meet the applicable GCP and dossier requirements.

The expert assessment will consider whether the data support use in the EAEU population and whether clinically important intrinsic or extrinsic factors could affect extrapolation.

Where an additional study is needed, the reason should be explicit—for example:

  • inadequate representation of the target population;
  • insufficient evidence for a claimed indication or subgroup;
  • dose-selection uncertainty;
  • clinically relevant ethnic/sensitivity considerations;
  • interaction or organ-impairment data gaps;
  • inadequate long-term safety exposure;
  • concern about study quality or data reliability.

The absence of a Russian site in a global Phase III programme is not, by itself, a scientific deficiency.

GCP compliance and data integrity can become registration-critical

Clinical evidence is useful only if the authority trusts it.

Decision No. 79 establishes EAEU Good Clinical Practice. The Rules were amended again in 2025, reflecting the continuing modernization of the Union’s clinical-trial framework.

For a study submitted in Module 5, the registration team should be able to demonstrate:

  • ethics and regulatory authorization appropriate to the study location;
  • informed-consent compliance;
  • protocol and amendments;
  • investigator/site documentation;
  • monitoring and data-management controls;
  • statistical analysis traceability;
  • source/data integrity;
  • safety reporting;
  • consistency between the clinical study report and underlying data.

Decision No. 78 also permits regulatory verification/inspection where there are doubts regarding compliance or reliability of clinical-study data.

For a sponsor using studies conducted in several third countries, Pharegis therefore performs a regulatory usability assessment, not merely a check that a final clinical study report exists.

The 2025 GCP update matters for new development programmes

The EAEU GCP rules are not static.

EEC Council Decision No. 63 of 1 August 2025 amended the Union Good Clinical Practice framework. For manufacturers planning new studies in 2026, the study should therefore be designed against the current version of Decision No. 79 rather than an old national or pre-amendment GCP checklist.

For legacy studies, the regulatory question is different: whether the study was compliant with the applicable requirements at the time and whether its data remain suitable for the present registration claim.

This distinction matters because a registration dossier can contain studies generated over many years under different regulatory versions.

Biosimilars: quality comparability is the foundation of the clinical programme

Biosimilar development should not be approached as “generic BE plus a clinical trial”.

EEC Council Decision No. 89 establishes the EAEU rules for studies of biological medicinal products. The framework has been expanded repeatedly, including major additions in 2022, 2023 and 2025 for different biological-product groups and advanced therapies.

For a biosimilar, development is stepwise:

analytical/quality comparability → functional characterization → nonclinical evidence where needed → comparative PK/PD → comparative clinical efficacy/safety where needed → immunogenicity assessment.

The better the analytical comparability package, the more focused the later clinical programme can be.

Conversely, a weak quality-comparability package cannot be repaired by simply making the clinical study larger.

The clinical strategy should address residual uncertainty after quality and functional comparison.

Reference biological product selection is a separate regulatory decision

A biosimilar must be compared against an appropriate reference biological medicinal product.

The comparator used in analytical studies, nonclinical work and clinical studies should form one scientifically defensible bridge. If different sourced versions of a reference product are used during development, the bridging strategy must demonstrate that the comparison remains valid.

This can be particularly relevant for global programmes that use an EU-sourced reference product while seeking registration in the EAEU.

Comparator strategy should therefore be agreed before the comparative programme becomes difficult or impossible to reconstruct.

Fixed-combination products need evidence for the combination, not just for each component

For fixed combinations, existing knowledge about each individual active substance does not automatically establish the benefit-risk profile of the combination.

The EAEU has dedicated guidance for nonclinical and clinical development of combination medicinal products.

The required programme depends on factors such as:

  • whether the substances are already used together in clinical practice;
  • whether the proposed doses and regimen are established;
  • whether the combination changes exposure;
  • whether synergistic or antagonistic effects are expected;
  • whether the proposed indication is already supported by the individual components;
  • whether a new fixed combination is intended to replace free combination therapy.

The evidence may therefore range from focused pharmacokinetic bridging to a more substantial clinical efficacy/safety programme.

The clinical evidence and the CMC dossier have to describe the same product

One of the most underestimated registration risks is a disconnect between the product used in the pivotal clinical/BE study and the product proposed for commercial registration.

For a generic or hybrid product, the test batch used in BE should be linked to the intended commercial formulation and manufacturing process.

The dossier should allow the expert to understand:

  • formulation of the study batch;
  • manufacturing site;
  • batch size;
  • manufacturing process;
  • release specification;
  • dissolution profile;
  • stability status;
  • relationship to future commercial batches.

A major CMC change after the pivotal BE study can create a bridging problem.

The same principle applies to original and biological products: clinical batches must be connected scientifically to the commercial product through pharmaceutical development, process characterization and comparability where needed.

This is why clinical strategy and CMC strategy should not be managed by separate teams that meet only at submission.

Bioanalytical validation is part of the regulatory evidence

For a pharmacokinetic BE study, the bioanalytical method is not laboratory background documentation. It is part of the proof that the PK comparison is reliable.

The dossier should support:

  • analyte selection;
  • calibration range;
  • accuracy and precision;
  • selectivity;
  • sensitivity;
  • matrix effects where relevant;
  • stability;
  • incurred-sample reanalysis where applicable;
  • sample handling and chain of custody.

A statistically clean BE result generated with a poorly controlled bioanalytical method can still fail expert assessment.

Pharegis therefore reviews the bioanalytical package together with the protocol and clinical study report rather than treating it as an annex owned solely by the laboratory.

A pilot study can be a development tool, not wasted time

For some products, especially highly variable drugs, uncertain formulations or complex absorption profiles, a pilot PK study can materially reduce pivotal-study risk.

A pilot can help assess:

  • within-subject variability;
  • likely sample size;
  • adequacy of sampling duration;
  • formulation performance;
  • food effect;
  • analyte selection;
  • practical comparator behaviour.

The decision should be economic as well as scientific.

A pilot study is justified when the information it generates is likely to prevent a substantially more expensive pivotal failure or redesign.

It is not justified merely because “a pilot is usually done”.

The EAEU biowaiver framework should be assessed before protocol contracting

A recurring failure mode is commercial sequencing:

CRO selected → protocol quoted → study contracted → only then regulatory team asks whether a biowaiver was possible.

The order should be reversed:

regulatory classification → biowaiver/exemption assessment → reference-product strategy → study design if still required → CRO/laboratory selection.

This can have a direct budget impact for generic portfolios.

The 2024 EAEU changes to Decision No. 85 make this particularly important because the biowaiver framework is broader than many legacy internal company SOPs still assume.

Real-world data can support some regulatory questions—but it is not a universal substitute for controlled evidence

In 2024 the EEC adopted general approaches for use of real-world clinical-practice data and evidence for registration, pharmacovigilance and extension of indications.

This opens additional evidence options in selected situations, particularly where conventional randomized evidence is difficult or where post-authorization data materially inform safety and effectiveness.

However, real-world evidence should not be treated as an automatic shortcut around a required BE study or a product-specific comparative clinical requirement.

The evidentiary question remains:

what uncertainty must be resolved, and is the proposed data source capable of resolving it with sufficient reliability?

Where evidence programmes most often lose time

The recurring problems are usually strategic rather than operational:

  • calling a product “generic” before confirming that it satisfies the EAEU generic bridge;
  • commissioning a Russian local clinical study that the EAEU pathway does not require;
  • selecting the reference product after the protocol has already been drafted;
  • overlooking an available BCS-based biowaiver;
  • assuming all strengths need separate in-vivo BE studies;
  • using a conventional systemic BE model for a topical or otherwise complex product;
  • failing to account for EAEU product-specific guidance;
  • treating a hybrid application as either a simple generic or a completely new drug instead of defining the evidence bridge;
  • assuming foreign Phase III data are unacceptable because no Russian center participated;
  • submitting a clinical study report without assessing GCP/data-integrity usability;
  • allowing the commercial formulation to diverge from the pivotal BE/clinical batch;
  • relying on a biosimilar clinical programme without a strong analytical comparability foundation;
  • procuring the wrong comparator batch or an inadequately documented comparator source;
  • separating CMC, clinical and regulatory planning until the dossier is assembled.

Each of these can be identified before a patient is enrolled.

What Pharegis manages in an EAEU evidence-strategy project

Pharegis can assess an existing global development package or design the EAEU evidence pathway before new studies begin. Typical deliverables include:

  • application-type qualification: original, generic, hybrid, biosimilar or other applicable basis;
  • clinical/nonclinical evidence gap matrix against Decision No. 78 and product-specific EAEU requirements;
  • determination of whether an additional Russian/EAEU clinical study is actually required;
  • bioequivalence strategy under Decision No. 85;
  • reference-product selection and procurement requirements;
  • BCS biowaiver assessment;
  • additional-strength waiver strategy;
  • topical/complex-generic equivalence pathway assessment;
  • protocol and statistical-design regulatory review;
  • bioanalytical-method and study-report review;
  • GCP/regulatory usability assessment of foreign clinical studies;
  • hybrid-product bridging strategy;
  • biosimilar comparability and residual-clinical-uncertainty strategy;
  • fixed-combination evidence strategy;
  • CMC-to-clinical-batch comparability assessment;
  • expert-question response strategy for clinical/BE evidence;
  • integration of evidence generation into the EAEU registration critical path.

For manufacturers entering the EAEU with an existing global dossier, the objective is usually not to create more data. It is to determine which existing data are usable, which gaps are real, and what is the minimum scientifically defensible additional programme needed for authorization.

Discuss a clinical or bioequivalence evidence strategy

For an initial assessment, prepare:

  • medicinal product, dosage form and strengths;
  • proposed EAEU application type;
  • intended indications and target population;
  • reference/comparator product used in development;
  • formulation and manufacturing-site information;
  • existing BE/PK studies;
  • dissolution and BCS data where relevant;
  • nonclinical and clinical study summaries/reports;
  • clinical-study countries and GCP documentation;
  • bioanalytical reports;
  • intended EAEU markets and filing date;
  • any planned formulation, site or process change before launch.

Pharegis can then determine whether the existing evidence is sufficient, whether an in-vivo study can be waived, whether a generic application should actually be hybrid, and which evidence-generating activity belongs on the registration critical path.

The objective is not to conduct a study in Russia. It is to generate—or avoid generating—the exact evidence required to support the EAEU regulatory bridge.

Regulatory basis

Regulatory status reviewed: August 2026.