1.4. EAEU Pharmaceutical Market: General Principles of Granting a Marketing Authorization - YouTube

Having addressed the basic documents laying down the legal infrastructure

for the Single Pharmaceutical Market of the Eurasian Economic Union,

let’s describe the marketing authorization and related procedures in more detail.

We will start with general provisions.

According to paragraph 23 of the Rules for granting a marketing authorization

and assessment of medicinal products for human use

(which will be referred to from now on as merely the Rules),

the applicant may choose a reference Member State and Member States concerned

when applying for granting a marketing authorization for a medicinal product.

Thus, the number of Member States where the product may be authorized is determined by the applicant.

Minimally, limiting the scope of authorization to one Member State only is also allowed.

This will be considered as the first step of a mutual recognition procedure,

and such a Member State becomes the reference Member State by default.

Contrary to this, it is allowed to initiate the procedure of granting a marketing authorization in all Member States,

specifying the reference Member State.

The reference Member State is the one who processes the application and carries out the assessment

whereas the Member States concerned only need to consider the assessment report

drawn up by the reference Member State.

Obviously, Member States have different levels of expertise

in processing applications and carrying out the assessment of medicinal products.

It is expected that in the beginning Belarus, Kazakhstan, or Russia

will be chosen as a reference Member State more frequently than Kyrgyzstan or Armenia.

Part III of the Rules contains general principles

for granting a marketing authorization for medicinal products.

The applicant may choose between two marketing authorization procedures,

namely a mutual recognition procedure and decentralized procedure.

Both resemble those envisaged in the EU as laid down in Directive 2001/83/EC.

According to these general principles,

an applicant should furnish the reference Member State with a completed application

either as a paper submission or electronically, confirmation that the relevant fees have been paid,

and a marketing authorization application dossier in the Common Technical Document format.

Also, in contrast to other regions and countries,

in all cases samples of a finished product need to be provided

to perform verification of test methods included in the finished product specifications.

The verification of test methods included in the finished product specification is a routine practice.

Although this approach is questionable and lacks scientific rigor,

applicants and marketing authorization holders should be ready to face this requirement.

Moreover, no method transfer is performed when the official laboratory verifies the methods.

This is why the applicants need to be prepared for observations like ‘method is not reproducible’

which is considered a major issue during the assessment.

Unlike the reference Member State,

Member States concerned need not be provided with the full marketing authorization application dossier.

In particular, the applicant should submit only Module 1 of the dossier and selected documents,

such as a draft SmPC, patient leaflet, labelling samples

drawn up using the official language of the Member State concerned

where this language differs from Russian.

It should be mentioned that the file itself should be drawn up using Russian language,

but some sections of the dossier may be in English.

The documents which must be in Russian are specified in Appendix 4 to the Rules.

As was mentioned, the file should be in CTD format

which fully reproduces conventions envisaged by the ICH,

i.e., the specifications for Modules 2 to 5 coincide with those recommended by ICH,

and Module 1 is EAEU-specific somewhat resembling that of the EU.

Where the ICH specifications allow some differences among regions for Modules 2 to 5,

such as Module 3.2.R (Regional information), specifications of the European Commission were used.

Module 2 and selected sections or subsections of Module 3,

as well as synopses of non-clinical or clinical study reports, should be in Russian.

The rest of the sections, i.e., many sections of Module 3 and non-clinical or clinical study reports

may be submitted in English. Use of other languages is not allowed.

A certificate of marketing authorization is a document issued by a competent authority.

It confirms granting an authorization for a medicinal product in the Member State.

In the EAEU, much attention is paid to this paper document;

issuing the certificate of MA in the EAEU is synonymous to issuing a marketing authorization in the EU.

Generally, the certificate of marketing authorization and marketing authorization have the same meaning.

It shall be drawn up using a single template which is laid down in Appendix 17 to the Rules.

Each Member State issues its own certificate.

Unless otherwise approved by the reference Member State, the period of validity is five years.

The renewal policy of marketing authorization follows the rules

similar to those specified in EU Directive 2001/83/EC.

At the same time, within the transition period,

a marketing authorization of nationally authorized products,

within the procedure of bringing into compliance,

may be renewed to have unlimited validity if certain conditions are fulfilled.

Transition to the Single Market

allows the existence of several marketing authorization procedures simultaneously.

Obviously, before the Rules became effective,

only national procedures had been effective for bringing medicinal products to the market.

After the EAEU procedures were put into force on May 6th, 2017, and by the end of 2020,

both national and EAEU procedures can be used to authorize products for marketing.

As from January 1st, 2021, only EAEU procedures may be used.

However, nationally authorized products

may be marketed in accordance with national marketing authorization up until December 31st, 2025.

All marketing authorization holders of nationally authorized products

which wish to remain on the Member States pharmaceutical markets

must undergo the procedure of bringing a marketing authorization dossier

of a nationally authorized product into compliance with the Rules.

The period of validity of all national certificates of marketing authorization lapses on January 1st, 2026.

At the same time, stocks of products subject to a national marketing authorization

may be sold up until their expiry date

even if corresponding products have been successfully brought into compliance.

Development, investigation, manufacturing, and marketing of medicinal products for human use

in the Eurasian Economic Union are subject to GMP, GCP, GLP, GDP, and GVP.

Those practices are collectively called good pharmaceutical practices.

The sources for the Union GxP rules were discussed previously.

According to paragraph 28 of the Rules, manufacturing of medicinal products and active substances

shall comply with the requirements of the Good Manufacturing Practice of the Eurasian Economic Union.

When applying for a marketing authorization via the EAEU procedure,

an applicant may submit either a national GMP certificate or Union GMP certificate

which is issued by the same competent authorities via different albeit similar procedures.

No centralized inspecting body is to be established in the near future.

Where a GMP certificate of the Union cannot be provided by the end of 2020, an applicant shall submit:

a valid GMP certificate for the manufacture of finished products

and release testing issued by the medicinal product manufacturer’s own country

information on the outcome of all inspections carried out within the 3 years preceding the date of application

information on quality complaints within the previous 3 years

a consent to be a subject of a GMP inspection

and a copy of the site master file(s).

In the absence of the EAEU GMP certificate,

a competent authority having received a marketing authorization application may decide

whether to initiate an unscheduled inspection within the procedure of granting a marketing authorization

or to put the applicant into the inspection waiting list and proceed with the authorization procedure.

The latter option is only allowed if the applicant can persuade the competent authority

that all applicant’s attempts to initiate an inspection was unsuccessful.

Non-clinical safety studies and all clinical trials

should be conducted in accordance with GLP/GCP rules of the Union, respectively.

Those conducted outside the Union should meet equivalent quality and ethical standards.

Based on the assessment of the dossier,

a competent authority may trigger a GLP or GCP inspection within the authorization procedure.

Such an inspection should be conducted within 3 years after the marketing authorization has been granted.

The Rules envisage specific criteria for accepting foreign clinical data.

These are laid down in paragraph 38.

Generally, at least one clinical trial needs to be conducted in any Member State or States.

However, in exceptional circumstances,

a competent authority may choose to conduct an unscheduled GCP inspection

and waive the requirement for local clinical data.

There are no formal criteria for making such a decision in the Union law.

At the same time, where trials were conducted in ICH countries before circa 2016, those may be accepted

if the investigational product had been eventually authorized in any of the ICH Member States.

Orphan drugs are exempt from these requirements,

i.e., no local clinical data is required unless specific concerns arise.

Those specific concerns will be clarified in a separate document

which will be adapted from ICH E5(R1) Ethnic Factors in the Acceptability of Foreign Clinical Data.

As mentioned before, Union pharmacovigilance rules were drafted based on the EU GVP guidelines.

Communications between competent authorities and marketing authorization holders

related to pharmacovigilance issues and the time limits thereof depend on the issue detected.

Single labelling rules is another aspect of harmonization between the Member States.

Labelling shall be in Russian and in the official language of the Member State

where a medicinal product is to be marketed if this is envisaged by the legislation of that Member State.

Additional languages may be used when the respective information is identical to what is approved in Russian.

In case of small containers, the amount of required information may be reduced.

In the EAEU, product information which includes Summary of Product Characteristics,

Patient Leaflet, and Labelling is regulated by two different documents.

Labelling regulations are mostly original while SmPC and PL regulations are very close to those of the EU.

It is important to note that the user testing has become mandatory in several situations

such as approval of new molecular entities.

However, for imported medicinal products, the foreign user testing data is acceptable

where the testing has been performed in accordance with requirements similar to those of the EAEU.

The user testing report shall be translated into Russian.

According to paragraph 20 of the Rules, a marketing authorization for medicinal products

may be granted at the request of an applicant in the several Member States

in accordance with the mutual recognition procedure performed successively

or in the several Member States in accordance with the decentralized marketing authorization procedure

performed simultaneously.

Authorization of active substances of medicinal products in the EAEU is not envisaged.

It is worth mentioning that within the Rules,

the wording ‘competent authority or assessment organization’ is used.

This is done to take into account different regulatory systems in place in the different Member States.

For instance, Belarus, Kazakhstan, and Russia have two-tiered systems

where both a Ministry of Health and an assessing body exist.

Moreover, in Belarus and Kazakhstan,

the assessing body or assessment organization

may directly communicate with an applicant or marketing authorization holder and send various requests.

In Russia, all communications with the applicant are carried out via the Ministry of Health,

so the wording takes into account this diversity in regulatory systems.

This procedure is based on the mutual recognition

by concerned Member State or States of a marketing authorization granted by the reference Member State.

The concerned Member State refers to the reference Member State

that issued the marketing authorization on which the mutual recognition procedure is based.

Such an authorization issued by the reference Member State

is based on the assessment conducted pursuant to the Union rules.

However, this is sometimes called a national marketing authorization,

emphasizing that the authorization is valid only for one national market.

The reference Member State should issue a marketing authorization within 210 days.

Where a mutual recognition procedure is triggered by an applicant in the concerned Member States,

granting a marketing authorization should be completed within 90 days in the relevant Member States concerned.

At the end of the mutual recognition procedure,

a national marketing authorization will be issued in the concerned Member States.

The harmonization is maintained through the procedures for the examination of variations

as laid down in Annex 19 to the Rules.

The decentralized procedure is conducted concurrently by the several Member States.

The list of the Member States and the reference Member State are determined by the applicant.

The whole procedure should be completed within a maximum of 210 days

beginning with the day the last of the applications for a marketing authorization for a medicinal product

is submitted to the Member States concerned.

At the end of the decentralized procedure where an agreement on a positive outcome has been reached,

a national marketing authorization will be issued by the reference Member State

and the concerned Member States.

The harmonization is maintained through the procedures for the examination of variations

as laid down in Annex 19 to the Rules.