Modules 4 and 5 of the EAEU Registration Dossier. When Non-clinical and Clinical Study Reports Can Be Submitted Without Rework
The statutory deadline for submitting applications for dossier alignment with the requirements of the Eurasian Economic Union (EAEU) expired on 31 December 2025. For companies that submitted their documentation on time, work on Modules 4 and 5, the non-clinical and clinical study reports, is still ongoing for many. An applicant has up to 180 working days in total to respond to all regulatory queries, which means procedures launched in the autumn of 2025 may well only be wrapping up now.
Companies generally do not anticipate this extended correspondence. Modules 4 and 5 are often assumed to be the simplest part of the dossier: since the studies have already been performed, it is assumed the reports merely need to be moved into a new folder. Union rules do provide an exemption for this part of the dossier, but it does not apply to every procedure or to every medicinal product. A misjudgment about where this concession applies results in a regulatory query, with a 90-working-day response window, and the risk of being issued a time-limited marketing authorization (MA) instead of an unlimited-term one.
Structure of Modules 4 and 5 in the CTD Format
The EAEU registration dossier is structured in the Common Technical Document (CTD) format, harmonized with the ICH CTD standard. Module 4 contains non-clinical study reports: primary and secondary pharmacodynamics, safety pharmacology (effects on the cardiovascular, respiratory, and central nervous systems), pharmacokinetics in animal models, and toxicology, including acute and repeat-dose toxicity, genotoxicity, carcinogenicity, and reproductive toxicity. The section concludes with a list of literature references.
Module 5 compiles data on all clinical trials of the drug: from bioavailability and bioequivalence studies to pivotal efficacy and safety studies and post-marketing experience reports. For generic medicinal products, the primary document here is the bioequivalence study report. It must contain the bioanalytical method validation, raw concentration data, and statistical analysis.
Module 4 and Module 5 are checked against a single principle. Under the Union’s rules, a study is accepted only if it meets the requirements of Good Laboratory Practice (GLP) for Module 4 or Good Clinical Practice (GCP) for Module 5. The mere fact that a study was conducted at some point does not persuade the assessor.
GLP rules are approved by EEC Council Decision No. 81 dated 3 November 2016. GCP rules, contrary to the widespread assumption that this number belongs to pharmacovigilance, are enacted by a separate EEC Council Decision No. 79, also dated 3 November 2016. For generics, these two frameworks are supplemented by the Rules for Conducting Bioequivalence Studies of Medicinal Products (EEC Council Decision No. 85, dated 3 November 2016). All three legal acts were signed on the same day, 3 November 2016, which makes them easy to remember and just as easy to mix up when searching for the relevant text.
Within Module 4, reports are organized into three clusters: pharmacology (primary and secondary pharmacodynamics, safety pharmacology), pharmacokinetics (ADME profiles in animal models), and toxicology (acute and chronic toxicity, genotoxicity, carcinogenicity, reproductive toxicity). Module 5 is divided into seven subsections: biopharmaceutical studies, pharmacokinetics using human biomaterials, human pharmacokinetics and pharmacodynamics, efficacy and safety reports, post-marketing experience data, and patient case report forms, which are submitted upon separate request. For generic drugs, the primary burden falls on subsection 5.3.1, the bioequivalence study report.
Within the Union, non-clinical and clinical data are mutually recognized when they meet a single quality standard. If a study was conducted in a laboratory or clinical center that operated under national rules diverging from Decisions No. 79 and No. 81, the assessor is entitled to request additional proof that the results are comparable.
When Study Reports Can Be Submitted Without Reformatting
EEC Council Decision No. 78 dated 3 November 2016, «On the Rules for Registration and Examination of Medicinal Products for Human Use» (hereinafter, Decision No. 78), separately governs the dossier alignment procedure, available for drugs already circulating on the market under the national rules of member states.
For this procedure, Decision No. 78 explicitly permits submitting non-clinical and clinical study data in Modules 4 and 5 as existing reports, without bringing their formatting into line with GLP, GCP, or bioequivalence rules. A 2008 report can be attached as is, even if it was prepared to a national GOST standard and was never rewritten into an international format. The same rule applies when expanding the registration to new recognition states under the same alignment procedure.
This concession applies to the format of the reports, not to their substance. The expert body of the reference state evaluates data completeness on the merits, and if Modules 4 and 5 lack specific studies, for example carcinogenicity data for a chronically administered drug, it may request the missing evidence. If part of the data is missing, or new safety information emerges, the competent authority may impose additional obligations on the MA holder, including a time-limited registration certificate instead of the unlimited-term one otherwise granted to products with a market history of five years or more.
The logic behind this exemption follows from what actually happens during the review. During dossier alignment, the benefit-risk ratio is not reassessed, except in specific cases such as newly identified safety risks. The assessor checks the completeness and internal consistency of the data rather than revisiting whether the drug should be authorized at all. That determination was already made at national registration. Requiring a full reformatting of legacy reports to GLP and GCP in this situation would mean spending the applicant’s resources on the layout of a document that does not change the final outcome.
A separate, more extensive exemption applies to medicinal products registered and marketed in only one member state. For these, Decision No. 78 allows submitting only Modules 1 to 3 and the overview sections 2.3 to 2.5 of Module 2 during alignment, without a Russian translation if the official language of the country of registration differs. In this case, reports for Modules 4 and 5 are not required at all by default. The competent authority retains the right to request them separately, but they are not part of the standard filing.
For new registrations under the Mutual Recognition Procedure (MRP) or the Decentralized Procedure (DCP), and for line extensions (new indications) filed together with alignment, this exemption does not apply: reports in Modules 4 and 5 must meet the formatting requirements set out in the GLP, GCP, and bioequivalence rules. An existing report in the old format is not enough here; a full gap analysis is required.
| Registration pathway | What happens to Modules 4 and 5 | Legal basis |
|---|---|---|
| Dossier alignment, drug registered in several member states | Existing reports are submitted as is; reformatting to GLP, GCP, or bioequivalence rules is not required | Decision No. 78 |
| Dossier alignment, drug registered in only one member state | Modules 4 and 5 are not submitted by default; the authority may request them separately | Decision No. 78 |
| Alignment extended to new recognition states | The same formatting exemption applies as for the initial filing | Decision No. 78 |
| New registration under MRP or DCP; new indication | Reports must meet the formatting requirements of GLP, GCP, and bioequivalence rules | Decisions No. 78, 79, 81, 85 |
How to Run a Gap Analysis When the Exemption Does Not Apply
When a drug goes through standard registration or a label extension rather than dossier alignment, the gap between what the company already has on file and what Union rules require becomes a matter for dedicated analysis. For Modules 4 and 5 this runs along two separate tracks, non-clinical and clinical, and it almost never comes down to a simple check of the table of contents.
On the non-clinical side, the first common gap is safety pharmacology data, in particular a missing dedicated study of QT interval effects, if it was not carried out separately from the main pharmacodynamics program. A second recurring issue is a genotoxicity battery limited to a single test, usually the Ames test, when the regulator expects results from at least two or three independent tests. A third is missing or outdated reproductive toxicity data, which for older active substances is sometimes covered by a literature review rather than a new animal study.
On the clinical side, the main questions concern methodology rather than efficacy itself. Assessors rarely revisit whether an established active substance actually works. For generics, review starts with the choice of reference product. For many active substances, the EEC Expert Committee on Medicines has already issued a recommendation naming the reference product, and the comparator must match it. Where no such recommendation exists, a comparator sourced in a country with a well-developed regulatory system is acceptable.
Bioanalytical method validation is checked next; older reports often lack data on sample stability through freeze-thaw cycles. Another point is whether the statistical parameters of the bioequivalence study meet the required limits. The ratio of geometric means for Cmax and AUC between the test and reference products must fall within 80.00% to 125.00% at a 90% confidence interval.
The bioequivalence rules require accounting for the ethnicity of volunteers alongside age, body weight, sex, and metabolizer status when forming comparison groups. For drugs with a narrow therapeutic index or a known genetic polymorphism in metabolism, for example CYP2D6 or CYP2C19, this point is worth checking first: an imbalance in cohort composition often triggers an assessor’s comment even when the statistical results themselves fall within range.
| Section | Typical gap | What is usually required |
|---|---|---|
| Safety pharmacology | No dedicated study of QT interval effects | An in vitro hERG assay or an in vivo study |
| Genotoxicity | Only one test, usually the Ames test | Adding a second and third test to the battery |
| Reproductive toxicity | Data missing or outdated | A literature review or a new study |
| Reference product selection | Comparator does not match the EEC Expert Committee’s recommendation | Justification of the choice, or a different comparator |
| Bioanalytical validation | No freeze-thaw stability data | Additional method validation |
Gaps are closed one at a time. The tool depends on the type of gap: a new study where data simply does not exist, or a scientific rationale in Section 2.4 or 2.5 of Module 2, where the assessor explains why accumulated clinical experience compensates for weaknesses in the design of older non-clinical tests. Rewriting the reports themselves in full is not required. It is Sections 2.4 («Non-clinical Overview») and 2.5 («Clinical Overview») of Module 2 that shape how the assessor reads the raw data in Modules 4 and 5, and the quality of these sections affects the outcome of the review as much as the completeness of the reports themselves.
Electronic Dossier Assembly and What to Rely On for Justifications
The CTD format means Modules 4 and 5 enter the dossier as part of a structured electronic package, not as a set of separate files. The requirements for the electronic form of applications and dossier documents are set out in a separate act, EEC Board Decision No. 79 dated 30 June 2017. Note the issuing body: this is a Board decision, not a Council one, and it has nothing to do with the GCP rules, which also carry the number 79 but were issued by the Council. Confusion between these two documents, which share only a matching number, comes up regularly in practice and is worth checking before filing.
When a non-clinical gap is closed with a scientific rationale rather than a new study, it helps to rely on more than the company’s own expertise. The EEC Board adopted a separate Guideline on Non-clinical Safety Studies for the Conduct of Clinical Trials and Registration of Medicinal Products (EEC Board Decision No. 202 dated 26 November 2019). It describes the expected scope of the non-clinical program for different classes of products and serves as a reference point when drafting Section 2.4, especially when the argument is that the volume of older studies remains sufficient.
Action Plan
Determine the registration pathway. Check whether this is dossier alignment, an extension to new recognition states, a new registration under MRP or DCP, or a new indication. This determines whether Modules 4 and 5 qualify for the formatting exemption.
Check the single-country status of the product. If the marketing authorization is valid in only one Union member state, confirm in writing with the reference authority whether Modules 4 and 5 need to be filed at all, or whether Modules 1 to 3 with overviews are enough.
Take inventory of reports on both tracks separately. Split the non-clinical and clinical blocks into three groups: data complete and in the original format; data complete but needs a scientific rationale in Section 2.4 or 2.5; data missing and a new study is needed.
Close substantive gaps one at a time. For non-clinical data, start with safety pharmacology, the genotoxicity battery, and reproductive toxicity. For clinical data, start with the reference product, bioanalytical method validation, and the ethnic and metabolic composition of comparison groups.
Update Sections 2.4 and 2.5 of Module 2 before filing. Even when Modules 4 and 5 are submitted without reformatting, the overview sections need to reflect the current safety profile and explain the reasoning behind the evidence to the assessor.
Modules 4 and 5 remain the largest part of the dossier. The full text of a study rarely causes a rejection on its own, provided the right registration pathway is chosen and the substantive gaps in non-clinical and clinical data are closed. Companies more often lose time to the assumption that old reports work in any case and in any format. It depends on the quality of the studies themselves far less often.
Regulatory Framework:
1. EEC Council Decision No. 78 dated 3 November 2016, «On the Rules for Registration and Examination of Medicinal Products for Human Use» (as amended 26 November 2025)
2. EEC Council Decision No. 79 dated 3 November 2016, «On Approval of the Rules of Good Clinical Practice of the Eurasian Economic Union»
3. EEC Council Decision No. 81 dated 3 November 2016, «On the Rules of Good Laboratory Practice»
4. EEC Council Decision No. 85 dated 3 November 2016, «On the Rules for Conducting Bioequivalence Studies of Medicinal Products»
5. EEC Board Decision No. 79 dated 30 June 2017, «On Requirements for the Electronic Form of Applications and Documents of the Registration Dossier»
6. EEC Board Decision No. 202 dated 26 November 2019, «On Approval of the Guideline on Non-clinical Safety Studies for the Conduct of Clinical Trials and Registration of Medicinal Products»