From complexity to cohesion: EAEU's role in CIS pharmaceutical regulations

Posted on the 6th August 2024

Giannis Tsogkas, Senior Manager at G&L Healthcare Advisors examines the impact of Resolution No.78 and how it is aligning market authorization across member states and paving the way for a unified approach in this diverse regulatory environment.

The term “CIS” (Commonwealth of Independent States) encompasses countries that were once part of the Soviet Union.

These include Azerbaijan, Armenia, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Moldova and Ukraine. While the Russian Federation is also considered a CIS market, it is often discussed separately due to its significant size and economic influence.

Unlike the European Union, the CIS markets do not form a cohesive actual union. Instead, each country maintains its own set of laws and regulations governing medicinal products. This decentralized approach creates a complex regulatory landscape for the registration and maintenance of such products.

Navigating these regulations becomes even more challenging because of linguistic diversity and variability in regulatory expertise among the individual CIS markets.

The establishment of the Eurasian Economic Union (EAEU or EEU), comprising Armenia, Belarus, Kazakhstan, Kyrgyzstan, and the Russian Federation, has introduced new regulations aimed at streamlining the registration process for medicinal products.

These regulations offer a harmonized approach across all five Member States, reducing the regulatory burden.

Resolution No. 78 of November 3^rd, 2016, and subsequent amendments, titled “On the Rules of Marketing Authorization and Assessment of Medicinal Products for Human Use”, outlines the procedures for the registration and renewal of medicinal products, as well as for variations to authorized medicinal products within the EAEU.

It also guides Marketing Authorization Holders (MAHs) to ensure compliance with the new EAEU regulations, including transitional provisions for bringing existing nationally approved products in line with the new EAEU regulation.

Resolution No. 78, as amended, introduces several significant changes, including the requirement that all new Marketing Authorisation Applications (MAAs) submitted after January 1st, 2021 align with the procedures outlined in the resolution.

As of this date, purely national MAAs are no longer accepted in the Russian Federation, and as of July 1st, 2021, the same applies to the other EAEU member states.

The Resolution also mandates that new MAAs adhere to either the EAEU Mutual Recognition Procedure (MRP) or the Decentralized Procedure (DCP), both of which are outlined in the resolution.

These procedures bear similarities to those established in the EU.

Applicants are required to designate an EAEU Member State to serve as the Reference Member State (RMS), with the selection based on the expertise level of the Health Authority in each EAEU country.

In the case of the EAEU MRP, the MAA dossier is submitted to the RMS and is assessed using the same defined steps as would be encountered in the EU MRP (validation phase, assessment phase with clock stop(s) for the Applicant to respond).
Upon approval by the RMS, the MAA dossier is submitted to the Concerned Member States (CMS) who review and approve the MAA. CMS can ask for additional information (with CMS and Applicant timelines defined). Procedures are also defined in case of disagreement between the CMS and the RMS on the approval of the MAA. Resolution No. 78, as amended, defines specific timelines for each step of the MRP for the RMS, the CMS, and the Applicant.
For the EAEU DCP, the same defined steps are also established in the regulation as encountered in the EU DCP (validation phase, assessment step with clock stop for Applicant to provide responses, second assessment step, procedure for resolving disagreement between RMS and CMS).
Timelines for the RMS, CMS, and Applicant are also defined for each step of the DCP.
The regulation also provides for consultation between the CMS and RMS to obtain advice for new MAAs submitted using the MRP or DCP.
Specific documentation needed for different types of applications (full applications, generic, hybrid, well-established use, combination products, biological products, biosimilars) is also defined in the regulation.
The regulation determines the Module 1 and the Module 3 documents that need to be translated to Russian.
Any clinical trials conducted before January 1^st, 2016, which were used to generate clinical study reports included in the dossier, will be accepted if they were conducted in ICH countries and were used to obtain a Marketing Authorisation in these ICH countries.
If Clinical trials were initiated after January 1^st, 2016, then at least one of these trials must be conducted partially or fully in EAEU countries. If these requirements are not met, then an inspection of one clinical trial site where the trials have been conducted will be performed as part of the MAA assessment process.
The results of consultation with target patient groups for the Patient Leaflet (readability test) also need to be provided in Russian, since the Product Information is provided in the Russian language.
Decision No. 88 of November 3^rd, 2016 “on the Adoption of the Requirements for the Medication Guide and Summary of Product Characteristics of Medicinal Products for Human Use” defines the requirements and the circumstances under which this consultation will need to be performed.

Decision No. 88 does not provide any specifics on whether the readability testing is required in any other language of the EAEU markets, so consultation with the RMS/CMS should be sought.

All existing nationally authorized medicinal products in individual EAEU member states must be brought to compliance with the EAEU regulation by December 31st, 2025.

Bringing these national licenses into compliance with the EAEU regulations will result in new licenses which, if granted before the specified date, will supersede the purely national licenses in each EAEU Member state.

After December 31^st, 2025, purely national medicinal product licenses will no longer be valid within the EAEU.

The procedure for bringing existing nationally authorized medicinal products into compliance with EAEU regulations closely mirrors the EAEU MRP. If an Applicant holds a medicinal product nationally authorized in one or multiple EAEU Member States (MS), they must select one of these as the RMS.

Subsequent steps align with the MRP, including necessary variation(s) submission to update the existing nationally approved dossier up to date before MRP initiation.

A notable difference is that in this scenario, the Applicant has the option to submit variations before the procedure is finalized. This differs from an MRP, where variations can only be submitted after the procedure has been concluded and the application has been granted approval by the RMS and the CMS. In the procedure of bringing existing nationally authorized medicinal products into compliance with the EAEU regulations, the Applicant can submit variations to the RMS after the RMS has approved the application and before the submission of the dossier to the CMS for recognition. These variations will be assessed and approved by the RMS. The CMS will then receive and recognize the varied dossier approved by the RMS

Furthermore, the EAEU regulation clarifies whether the new marketing authorizations issued will be subject to renewal, contingent upon time and the number of Member States the medicinal product was initially approved (under purely national laws).

Decision No. 114 of the EEC Council dated October 20^th, 2023 “On Amendments to the Rules for Marketing Authorization and Expert Examination of Medicinal Products for Human Use”, which came into force on December 20^th, 2023, and amended Decision No. 78, brings significant updates to the documentation requirements for the procedure of bringing existing nationally authorized medicinal products in compliance with EAEU regulations.

These amendments aim to streamline the process, notably by eliminating the necessity for certain Module 1 documentation.

Additionally, specific sections of Module 3 are no longer mandatory for submission, except for biological products. These changes represent efforts to simplify the compliance procedure, facilitating the transition of existing nationally authorized medicinal products to meet EAEU regulations.

Once the marketing authorization alignment process is completed, the MAH will be given a maximum of 180 days to implement any changes such as importing medicinal products compliant with the newly aligned licenses in the EAEU.

Importantly, legacy nationally licensed medicinal products may continue to be marketed in that EAEU market until the product expires, in parallel to medicinal products approved under the EAEU MRP.

The EAEU MRP and DCP also require the submission of samples, reference standards, reagents, and any other related materials needed for local testing of the medicinal product.

Resolution No. 78, as amended, stipulates that for submissions made after December 31^st, 2020, documentation verifying GMP compliance with EAEU standards is required.

If such documentation is not available, a GMP inspection from the RMS will be necessary, which can be conducted concurrently with the MAA assessment.

Inspections for GVP and GCP compliance are also foreseen by the RMS, in the case where there are questions on the reliability of the management of the Pharmacovigilance System or the conducted clinical trials.

Another important key element for the EAEU markets is the presence of the Normative Document (ND).

Drafted by the Applicant, the ND is an integral part of the submitted dossier, encompassing specific details derived from various sections of Module 3. When applicable, it must also reference relevant EAEU Pharmacopoeia chapters and general monographs.

The ND is approved by the RMS and is eventually recognized/accepted by the CMS. Local laboratory testing conducted during the MRP, DCP, or the procedure of bringing into compliance with EAEU regulations needs to show alignment with the information presented in the ND

Resolution No. 78, as amended, outlines the structure of the submitted dossier, which follows the CTD format for Modules 2-5. It also defines the process for submission and assessment of the Active Pharmaceutical Ingredient Master File (APIMF) if utilized in the MAA process or the process of bringing into alignment existing authorizations with the EAEU regulations.

Furthermore, Decision No. 79 “On the Requirements for the Electronic Form of Applications and Documents of the Registration Dossier Submitted in the Course of Registration and Examination of Medicinal Products for Medical Use”, specifies the criteria for electronic submissions and the technical requirements for the XML files.

Since January 1^st, 2021, all new MAA submissions and submissions intending to bring existing licenses to compliance with EAEU regulations must be made in electronic format.

It is important to note that while electronic submissions use an XML file and share similarities to eCTD, they do not fully implement the existing ICH eCTD standards.

The approach to variations adopted by the EAEU markets in Resolution No. 78, as amended, is fully aligned with the EU variation guidelines (EC No. 1234/2008 and 2013/C 223/01). This alignment ensures consistency and facilitates regulatory processes across EAEU markets.

The resolution provides guidance for variation(s) submitted in one or more Member States, as well as for variations submitted alongside applications aiming to bring existing nationally approved medicinal products into compliance with EAEU regulations. Top of Form

Variations are classified as minor type IA or type IA_IN, type IB, and type II with the same definition and context as in the EU regulation.
A process for the classification of changes not provided in the EAEU variation classification (unforeseen variations) is described.
Grouping of variations is also described, in alignment with the grouping rules applied in the EU for type IA, type IB, and type II variations.
Work sharing procedure and urgent safety restriction process are defined, also fully aligned to the EU variation guidelines.
The changes that would render a variation a line extension are also described along with the process for assessing an extension application.

It is worth mentioning that certain EAEU markets (Armenia, Kazakhstan, Belarus) have re-instated the option to obtain new MAAs under purely national procedures.

This decision contradicts EAEU regulations but may be motivated by the need to expedite the availability of medicinal products of high importance for public health.

Although the EAEU guidelines intend to harmonize the requirements and, ultimately, the registered information for medicinal products across its Member States, diversity within the CIS region remains.

Several countries continue to operate under their purely national regulations, leading to different approval times and potentially varying levels of detail in registered dossiers.

The administrative requirements for regulatory activities in non-EAEU markets differ both among these markets themselves and in the EAEU markets.

This disparity necessitates additional time and resources for the preparation and submission of regulatory dossiers.

For instance, administrative tasks such as providing Power of Attorney to local representatives, may require legalization or notarization, submission in original hard copy or electronic form, or both, further complicating the regulatory process.

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