Registration of Medicines

 

Anna Ivanova, Lawyer at BRACE Law Firm

BRACE Law Firm ©

June 29, 2022

 

According to the Federal Law dated April 12, 2010, No. 61-FZ "On the Circulation of Medicines" (hereinafter – "Law No. 61-FZ", "the Law on the Circulation of Medicines"), the production, manufacture, storage, transportation, import into the Russian Federation, export from the Russian Federation, advertising, dispensing, sale, transfer, use, and destruction of medicinal products are allowed in Russia only if they are registered by the relevant authorized federal executive body.

Medicinal Products Not Subject to Registration

At the same time, the aforementioned law establishes that the following are not subject to state registration:

• medicines manufactured by pharmacy organizations, veterinary pharmacy organizations, and individual entrepreneurs who have a license for pharmaceutical activity, based on prescriptions for medicinal products and requirements of medical or veterinary organizations;
• medicinal products purchased by individuals outside of Russia and intended for personal use;
• medicines imported into Russian territory for the provision of medical assistance for life-saving indications of a specific patient based on a permit issued by the authorized federal executive body;
• medicinal products imported into Russia on the basis of a permit issued by the authorized federal executive body and intended for conducting clinical trials of medicinal products and (or) conducting expertise of medicines for the purpose of state registration of medicines;
• pharmaceutical substances;
• radiopharmaceutical medicinal products manufactured directly in medical organizations;
• medicinal products produced for export.

Thus, as a general rule, all other medicinal products that do not fall under the specified list are subject to state registration.

According to the Rules for Registration and Expertise of Medicines for Medical Use, approved by the Decision of the Council of the Eurasian Economic Commission dated November 3, 2016, No. 78 (hereinafter – "EAEU Registration and Expertise Rules"), compared to national legislation, the list of cases in which medicinal products are not subject to registration has been expanded to include:

• medicinal products manufactured in pharmacies;
• pharmaceutical substances;
• medicinal products intended for conducting preclinical and clinical studies;
• medicines imported by individuals for personal use;
• radiopharmaceutical medicinal products manufactured directly in medical organizations in the manner established by the authorized bodies of member states;
• medicinal products not intended for sale on the customs territory of the EAEU;
• samples of medicinal products intended for registration, and standard samples;
• medicinal products intended for use as exhibition samples.

Confirmation of State Registration Issued Under the National Procedure

It is important to note that as of July 1, 2021, in all countries of the Eurasian Economic Union (in Russia since January 1, 2021), the first stage of the transition to a unified registration under EAEU rules was completed. Thus, applications for the registration of new medicinal products are accepted only under EAEU rules.

At the same time, medicines already registered in Russia may remain in circulation until the end of 2025. Manufacturers of such medicines have the right to extend the validity of their registration dossiers until the end of 2025.

Specifically, according to Articles 28–29 of the Law on the Circulation of Medicines, a registration certificate is issued indefinitely, with the exception of a registration certificate for a medicinal product issued for a term of 5 years for medicinal products being registered in the Russian Federation for the first time. Upon expiration of the specified five-year term, an indefinite registration certificate is issued, provided that its state registration is confirmed.

Consequently, the validity of registration certificates issued under the national procedure is maintained until 2025 through the confirmation of state registration (if such a certificate was issued for a term of 5 years and its validity expires before 2025).

Confirmation of state registration is carried out upon the issuance of an indefinite registration certificate. An application for confirmation of state registration is submitted to the Ministry of Health of Russia no earlier than 180 days before the expiration of the validity of the registration certificate of the medicinal product for medical use.

The following must be attached to the application for confirmation of state registration:

• documents containing the results of monitoring the efficacy and safety of the medicinal product;
• information on the date of issuance and the registration number of the license for the production of medicines or information on the date of issuance of the conclusion on the manufacturer's compliance with the requirements of the rules of Good Manufacturing Practice (GMP);
• a copy of the manufacturing license for the medicinal product issued by the authorized body of the manufacturer's country and its translation into Russian, as well as a copy of the conclusion on the manufacturer's compliance with the rules of Good Manufacturing Practice (GMP) in cases where the production of the medicinal product for medical use is carried out outside of Russia.

Within 10 working days from the date of acceptance of the application for confirmation of state registration, the Ministry of Health performs the following actions:

• verifies the completeness of the information contained in the documents submitted by the applicant;
• decides whether to conduct or refuse to conduct an expertise of the benefit-risk ratio of the medicinal product based on the results of monitoring its efficacy and safety conducted by the holder or owner of the registration certificate;
• notifies the applicant and the expert institution of the decision made in electronic or written form, or, in the case of a decision to refuse the expertise, specifies the reasons for such refusal.

If inaccuracies and (or) insufficiency of information are identified in the submitted application and attached documents, an additional request for such information is sent to the applicant, who must provide it within 90 working days from the date of receipt of the request. Also, if during the subsequent expertise the expert determines the insufficiency of the submitted information, they send a corresponding notification to the Ministry of Health of Russia, which in turn sends a request to the applicant. The applicant's response period to the request is 60 working days.

After the expertise is conducted, the expert institution sends a conclusion, based on the results of which the Ministry of Health makes a decision to confirm the registration or to refuse such confirmation.

The ground for refusal to confirm state registration is a conclusion stating that the risk of harm to human or animal health due to taking the medicinal product exceeds its efficacy.

It should be noted that during the procedure for confirming the state registration of medicines, their circulation is not suspended.

The judicial practice regarding the challenge of the cancellation of a medicinal product's state registration during the consideration of an application for confirmation of such registration deserves attention. For instance, a court established that following the consideration of an application for confirmation of a drug's state registration, the Ministry of Health of Russia decided to cancel the state registration of the medicinal product and exclude it from the state register of medicines. The specified decision was motivated by a conclusion from a commission of experts from the FSBI "Scientific Center for Expertise of Medical Products" based on the results of an expertise of the medicine's quality and an expertise of its benefit-risk ratio. In declaring such a decision illegal, the courts concluded that the challenged decision and conclusion were unlawful and violated the rights and legitimate interests of the applicant. This was due to the fact that it did not follow from the challenged expert conclusion that the institution had evaluated the monitoring data presented by the applicant during the study. On the contrary, the institution referred to international practice for the use of drugs, while the sources of foreign legislation used by the institution are not provided for by federal legislation or international treaties.

Furthermore, according to Part 4 of Article 29 of the Law on the Circulation of Medicines, after the submission of an application for confirmation of registration, a decision is made to conduct or refuse to conduct an expertise of the benefit-risk ratio of the medicinal product, of which the applicant is notified in writing. However, the ministry did not make a decision to refuse the expertise due to the applicant's failure to provide the documents necessary for its conduct. At the same time, in the submitted "Periodic Safety Update Report for the medicinal product," the applicant reported the absence of reports regarding adverse reactions associated with the use of the medicinal product from medical specialists, consumers, or other persons not employed in the healthcare sector.

It is important to note that according to the limited judicial practice on challenging the decisions of the Ministry of Health of Russia to refuse state registration or confirmation of state registration, it is vital that the registering body provides a full and comprehensive evaluation of the documents and materials submitted by the applicants.

Next, let us consider the features of state registration of medicines under the new EAEU rules.

Registration of Medicines Under EAEU Rules

According to the EAEU Registration and Expertise Rules, their requirements apply to developers and manufacturers of medicines, holders of registration certificates for medicinal products, and their authorized persons.

As with Russian rules, under the EAEU Registration and Expertise Rules, it is prohibited to register medicinal products with different qualitative compositions of active substances under a single trade name.

However, it is permitted to register medicines with different trade names in different EAEU member states in the following cases:

• the use of the proposed trade name may contradict legal and moral norms or otherwise fails to account for national cultural and (or) linguistic features;
• intellectual property rights to the trade name in the form of a trademark belong to a person other than the person who submitted the registration application, and the applicant cannot provide a corresponding license agreement granting the right to use the trademark;
• the medicinal product was registered under different trade names in accordance with the legislation of EAEU member states prior to December 31, 2020.

Similar to Russian legislation, a five-year term is established for medicinal products registered for the first time, followed by the issuance of an indefinite certificate upon confirmation of registration. However, in cases related to pharmacovigilance issues, a registration certificate with a validity of 5 years may be reissued following the results of the confirmation of registration (re-registration).

The EAEU Rules introduce concepts such as "reference state" and "member state of recognition." A reference state is a member state that prepares an expert report on the assessment of the safety, efficacy, and quality of a medicinal product based on an expertise of the medicinal product in accordance with these Rules. A member state of recognition is a member state in which a medicinal product is registered (is being registered) based on an expertise that includes an assessment of the expert report on the safety, efficacy, and quality of the medicinal product prepared by the reference state.

In effect, the new rules establish 3 main registration procedures:

• mutual recognition procedure;
• decentralized procedure;
• procedure for bringing the registration dossier into compliance with EAEU requirements.

Let us examine the features of each in more detail.

The mutual recognition procedure is carried out:

• by the reference state for the purpose of circulating the medicinal product on the market of that state only (national registration procedure);
• in the member states of recognition – at the applicant's request after the registration of the medicinal product in the reference state under the mutual recognition procedure.

Simultaneous initiation of the mutual recognition procedure in several member states of recognition is permitted.

Thus, the specified procedure implies a mutual recognition procedure in the reference state or in the member state of recognition.

The period for conducting registration and expertise of a medicinal product in the reference state must not exceed 140 working days from the date of submission of the application.

For the purpose of registering a medicinal product, the applicant submits: an application and documents confirming the payment of the fee (duty), the registration dossier, and samples of the medicinal products.

The authorized body (expert organization) of the reference state, within 10 working days from the date of submission of the registration application, assesses the fullness, completeness, and correctness of the registration dossier documents. The applicant is granted no more than 90 working days, which are not included in the registration and expertise period, to submit materials missing from the registration dossier. If the missing materials are not provided, the application is rejected.

After the application and a full set of documents are submitted, the expertise is conducted within a period not exceeding 105 working days from the day the assessment of the fullness, completeness, and correctness of the documents is completed. During the expertise process, additional documents and clarifications may also be requested within a 90-working-day period. This period can be extended up to 180 days.

Furthermore, a procedure for unscheduled pharmaceutical inspection has been introduced. it is scheduled no later than 70 working days from the date of submission of the registration application. A request regarding the necessity of organizing the inspection is sent to the applicant.

Based on the results of the medicinal product expertise, the expert organization of the reference state prepares a final expert report. If a positive registration decision is made following the expertise, a registration certificate is issued to the applicant, and information about the medicinal product and its active pharmaceutical substances is placed in the unified register of registered medicines of the EAEU. Currently, this register is maintained on the official website of the Eurasian Economic Union.

Next, after registering the medicine in the reference state, the applicant can initiate registration in other member states chosen by the applicant as member states of recognition under the mutual recognition procedure. To do this, the following are submitted to the authorized bodies (expert organization) of such member states: a registration application under the mutual recognition procedure, documents confirming payment of the fee (duty) for registration and expertise, and Module 1 of the registration dossier.

We draw attention to the fact that Appendix No. 5 to the EAEU Registration and Expertise Rules establishes that the registration dossier consists of 5 modules. Module 1 is specific to the member states. Modules 2–5 are common to all member states. Compliance with this document must ensure the submission of these 4 modules in a format acceptable to the authorized bodies of the member states. Module 1 contains administrative information and information on the indication; Module 2 contains summaries of the certificate; Module 3 provides information on quality in a structured format; Module 4 contains preclinical study reports; and Module 5 contains clinical study reports.

If there are corresponding requirements in the legislation of the member state, a Summary of Product Characteristics (SmPC) is submitted—a document approved by the authorized body of the member state in accordance with EAEU acts, containing information for medical workers on the safe and effective use of the medicinal product—as well as the patient information leaflet and packaging mock-ups of the medicinal product in the state language of the member state of recognition.

Registration of medicines in the member state of recognition, in the absence of disagreements between the authorized bodies of that member state and the reference state and given a conclusion on the possibility of recognizing the expert assessment report, is carried out no later than 60 working days from the date the expert organization receives access to all versions (sequences) of the electronic registration dossier. The expertise of medicines under the mutual recognition procedure in the member states of recognition is conducted within a period not exceeding 40 working days from the date of obtaining access to the expert assessment report, by reviewing the application and documents submitted in the registration dossier and reviewing the expert assessment report prepared by the expert organization of the reference state.

The authorized body of the member state of recognition refuses to register the medicinal product if, based on the results of the medicinal product expertise and after conducting the disagreement resolution procedure in the Expert Committee, it decides that the data presented in the expert assessment report cannot be recognized as sufficient to confirm the quality and (or) efficacy, and (or) a favorable "benefit-risk" ratio of the medicinal product.

If there are disagreements between the authorized bodies regarding the recognition of the expert assessment report and their consideration by the Expert Committee, the authorized body of the member state of recognition that made a positive decision to recognize the expert assessment report prepared by the expert organization of the reference state issues a registration certificate prior to the Expert Committee's decision. At the applicant's request, the issuance of the registration certificate by the authorized body of such a member state of recognition may be suspended until the disagreements between the authorized bodies of other member states of recognition and the reference state are resolved.

To register a medicinal product under the decentralized procedure, the applicant selects a reference state and member states of recognition.

The duration of the decentralized registration and expertise procedure is up to 140 working days from the date of submission of the application.

The decentralized procedure includes the following stages:

• registration and expertise of the medicinal product in the reference state;
• review of the expert assessment report prepared by the expert organization of the reference state in the member states of recognition.

To register under this procedure, the following are submitted to the reference state:

• registration application;
• documents confirming payment of the fee (duty) for the registration and expertise of the medicinal product;
• registration dossier;
• samples of the medicinal products.

Within a period of no more than 14 working days from the date of submission of documents to the authorized body of the reference state, the applicant also submits the following to the authorized bodies (expert organizations) of the member states of recognition:

• application;
• Module 1 of the registration dossier;
• documents confirming payment of the fee (duty) for registration and expertise.

The expertise of a medicinal product in the member states of recognition under the decentralized registration procedure is conducted by reviewing the application, documents, and registration dossier data, as well as the expert assessment report prepared by the reference state.

If there are unresolved disagreements within mutual consultations, the authorized body (expert organization) of the member state of recognition, within a period not exceeding 10 working days from the date of receipt of the final expert assessment report of the reference state, sends a conclusion on the impossibility of recognizing the expert assessment report prepared by the expert organization of the reference state, justifying the reasons for the negative decision to (1) the authorized body (expert organization) of the reference state and member states of recognition, as well as to (2) the Expert Committee, including in paper form.

In this case, the Expert Committee conducts a disagreement resolution procedure in accordance with the procedure established by the Commission within 60 calendar days from the date the member states of recognition send the conclusion on the impossibility of recognizing the positive expert assessment report prepared by the expert organization of the reference state.

Additionally, the EAEU Registration and Expertise Rules establish a special procedure for medicines that are already registered. Thus, registration dossiers of medicinal products registered in member states must be brought into compliance with EAEU requirements by December 31, 2025.

Upon initiating the procedure for bringing dossiers into compliance with EAEU requirements, the applicant submits to the authorized body (expert organization) of the reference state a written confirmation that the documents and data contained in the updated registration dossier submitted in the common technical document format correspond in their content to the data of the registered medicinal product's registration dossier and do not contain changes to the registration dossier that affect the quality, efficacy, safety, or the "benefit-risk" ratio of the medicinal product.

The duration of the procedure for bringing the registration dossier into compliance must not exceed 70 working days from the date of submission of the relevant application.

To bring a registration dossier into compliance with the EAEU Registration and Expertise Rules, the applicant submits:

• application;
• documents confirming the payment of the fee (duty) for bringing it into compliance;
• Modules 1–3 of the registration dossier.

At the same time, all available data from preclinical and clinical studies are submitted in Modules 4–5 of the registration dossier in the form of corresponding reports without the mandatory requirement to bring them into compliance with EAEU requirements for the formatting of preclinical and clinical study reports.

If a medicinal product is registered in one member state and is intended for circulation only on its territory, the applicant is entitled to submit only Modules 1–3 of the registration dossier in the state language of that member state without translation into Russian (if Russian is not a state language in that member state).

Based on the results of the registration dossier expertise, the authorized body (expert organization) of the reference state prepares and approves an expert assessment report.

The authorized body of the reference state refuses to bring the medicinal product's registration dossier into compliance with EAEU requirements if the registration dossier expertise determines that its quality is not confirmed or an unfavorable "benefit-risk" ratio is identified.

Following the procedure for bringing the registration certificate into compliance with EAEU requirements, the applicant is issued an indefinite registration certificate if the medicinal product has been registered in 3 member states for 5 years or more. If the medicine has been registered in 3 member states for less than 5 years, a registration certificate with a validity of 5 years is issued, with the requirement to confirm registration (re-registration) at the end of this period.

The above are the general rules for registering medicines in the EAEU. Because the EAEU Registration and Expertise Rules are being implemented in stages across EAEU territory, law enforcement practice regarding disputed issues arising during registration under the new rules is currently absent. Nevertheless, within the framework of national legislation, measures are being taken to regulate issues of simplifying the registration of medicines in certain cases. Next, let us consider the features of the simplifications being introduced into the medicine registration procedure.

Simplified Registration of Medicinal Products

Due to the current economic and socio-political situation and for the purpose of ensuring the pharmaceutical market is supplied with necessary medicines, the following measures have been implemented.

The Resolution of the Government of Russia dated April 3, 2020, No. 441 "On the specifics of the circulation of medicinal products for medical use intended for use in the event of a threat of an emergency, the occurrence and elimination of an emergency, and for organizing medical assistance to persons affected by emergencies, preventing emergencies, and preventing and treating diseases posing a danger to others, diseases and injuries resulting from exposure to unfavorable chemical, biological, or radiation factors" established that in an emergency mode, a temporary permit for the registration of medicinal products for medical use can be issued for a term until the beginning of 2023. Grounds for refusing to issue a temporary circulation permit include the identification of incomplete or inaccurate documents and information during registration, or the issuance of a conclusion by an expert commission or an ethics council on the impossibility of issuing a temporary circulation permit.

The Resolution of the Government of the Russian Federation dated April 5, 2022, No. 593 "On the specifics of the circulation of medicines for medical use in the event of a shortage or risk of a shortage of medicinal products in connection with the introduction of restrictive economic measures against the Russian Federation" established that the procedure for state registration of certain medicinal products has been simplified. Additionally, by decision of an interdepartmental commission, newly registered foreign drugs will be allowed to be sold in Russia in foreign packaging with a label in Russian. The list of medicines registered in a simplified manner is approved by the Ministry of Health of Russia. The document is valid until the end of 2023.

In addition to the legal acts adopted in Russia, the Decision of the Council of the EEC dated June 10, 2022, No. 96 "On temporary measures for establishing the specifics of the circulation of medicines for medical use" introduces the right for EAEU member states to extend until the end of 2023 the validity of registration certificates issued in accordance with EAEU Rules if their validity expires starting January 1, 2022. The right for EAEU member states to establish a temporary procedure for the circulation of medicines, valid until December 31, 2023, while maintaining the possibility of registering medicines in accordance with EAEU Rules, has also been introduced.

Thus, the aforementioned measures are exceptional in nature and are aimed at preventing disruptions in medicine supplies to the Russian pharmaceutical market and the EAEU market.

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References

• [1] Decision of the Council of the Eurasian Economic Commission dated November 3, 2016, No. 78 "On the Rules for Registration and Expertise of Medicines for Medical Use" as amended by the Decision of the Council of the Eurasian Economic Commission dated December 23, 2020, No. 128 "On Amending the Decision of the Council of the Eurasian Economic Commission dated November 3, 2016, No. 78".
• [2] Ruling of the Supreme Court of the Russian Federation dated April 9, 2018, No. 305-KG18-2392 in case No. A40-11957/2016.
• [3] Unified Register of Registered Medicines of the Eurasian Economic Union.