Drug registration – legislative acts. The state structure that regulates registration issues – structure, interaction with applicants,...grls.rosminzdrav.ru portal.
The first step of launching drug to the market of the Russian Federation is its registration. The registration is a state procedure of drug quality, efficacy and safety evaluation to obtain an approval for medical use of a drug in the Russian Federation.
In 2010, the drug registration procedure was essentially modified due to the adoption of new Federal Law No. 61-ФЗ “On circulation of medicines” of April 12, 2010 which became effective on September 01, 2010. To date, 4 modifications of the law have been adopted: No. 192-ФЗ of July 27, 2010, No. 271-ФЗ of October 11, 2010, No. 313-ФЗ of November 29, 2010, No. 409-ФЗ of December 06, 2011.
The regulatory legal acts that regulate the medicinal product registration procedure:
- Federal Law No. 61-ФЗ “On circulation of medicines” of April 12, 2010 (became effective on September 01, 2010).
- Order N 1413н of the Ministry of Health and Social Development of the Russian Federation «On approval of the Guidelines for contents and execution of documents required for creation of the Registration Dossier for a pharmaceutical product for medical use for the purpose of its state registration» of November 23, 2011.
- Order N 750н «On approval of the rules of pharmaceutical product for medical use evaluation and the form of an expert committee opinion» of August 26, 2010.
The following pharmaceutical product (MP) categories are subject to state registration:
1) original pharmaceutical products;
2) generic pharmaceutical products;
3) new combinations of earlier registered pharmaceutical products;
4) pharmaceutical products registered earlier but manufactured in other pharmaceutical forms, new strengths.
1) original pharmaceutical products;
2) generic pharmaceutical products;
3) new combinations of earlier registered pharmaceutical products;
4) pharmaceutical products registered earlier but manufactured in other pharmaceutical forms, new strengths.
The following products are not subject to state registration:
1) medicinal products made by pharmacies, individual entrepreneurs licensed to conduct pharmaceutical business, made under drug prescriptions and on requests of medical institutions, veterinary institutions;
2) medicinal (herbal) plant raw materials;
3) medicinal products purchased by physical entities outside the territory of the Russian Federation and intended for personal use;
4) medicinal products intended for export;
5) radiopharmaceutical medicinal products made in medical institutions directly.
1) medicinal products made by pharmacies, individual entrepreneurs licensed to conduct pharmaceutical business, made under drug prescriptions and on requests of medical institutions, veterinary institutions;
2) medicinal (herbal) plant raw materials;
3) medicinal products purchased by physical entities outside the territory of the Russian Federation and intended for personal use;
4) medicinal products intended for export;
5) radiopharmaceutical medicinal products made in medical institutions directly.
The state registration is not allowed for:
1) different pharmaceutical products under the same trade name;
2) one pharmaceutical product made by one and the same manufacturer under different trade names.
1) different pharmaceutical products under the same trade name;
2) one pharmaceutical product made by one and the same manufacturer under different trade names.
The designated federal executive authority regulating drug registration issues is the Ministry of Health of the Russian Federation (http://www.rosminzdrav.ru)
The Ministry of Health of the Russian Federation has a separate department – the Department of state regulation of pharmaceutical product circulation which is responsible for registration of new medicines and circulation of already registered medicines.
The Department of state regulation of medicinal product circulation has several divisions: the Division of pharmaceutical product clinical studies, the Division of pharmaceutical product registration, the Division of regulation of registered pharmaceutical product circulation, the Division of price registration for vital and most important medicinal products.
The state structure that regulates registration issues* As of February 11, 2013.
The Ministry of Health of the Russian Federation makes a decision on a pharmaceutical product registration based on results of evaluations performed by the lower institution – the Federal State Budgetary Institution “Scientific Center for Evaluation of Medicinal Products" of the Ministry of Health of the Russian Federation (FSBI SCEMP (www.regmed.ru)). The FSBI SCEMP evaluates the proposed drug quality control methods and quality of submitted samples of a drug, and also evaluates the expected benefit to possible risk ratio which is done after the clinical study of a drug. To date, the FSBI SCEMP of the Ministry of Health of the Russian Federation has been prohibited to render services on pharmaceutical product evaluation directly to applicants in the course of the registration process. As a budgetary institution, the FSBI SCEMP only performs evaluations for the Ministry of Health of the Russian Federation upon receipt of their instructions.
An applicant pays a state duty (MoH fees) to the account of the Ministry of Health of the Russian Federation for state registration or introduction of changes (amount of the state duty; banking details for payment of the state duty)
For interaction with applicants, a new state portal grls.rosminzdrav.ru was created. The portal contains public (accessed without a password) and restricted information (accessed via a personal account protected by a password assigned). The public information is the State Register of pharmaceutical products and the State Register of selling price limits.
The state portal of the Ministry of Health of the Russian Federation for on-line submission of documents ...grls.rosminzdrav.ru
Public information: the State Register of medicinal products, the State Register of selling price limits.
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The state portal of the Ministry of Health of the Russian Federation for on-line submission of documents http://grls.rosminzdrav.ru/
Restricted information (it is necessary to get a password to access the information)
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To freely navigate the whole website, it is necessary to complete an access application on behalf of an applicant who is a drug developer, manufacturer or an authorized legal entity. The completed application together with a power of attorney attached is submitted to the registry office of the Ministry of Health of the Russian Federation, and in 5 days a login and password are sent to the e-mail address mentioned in the registration application.
The portal structure is simple enough: a tab of various registers and applications (related to pharmaceutical product registration, conduct of clinical studies, price registration, importing of samples), topical forum (log), service, and website information search. All information on drug registration process is reflected on the website. The portal contains regulatory documents (the federal law and dependent regulations), instructions on completion of applications, of the Registration Dossier, documents for clinical studies.
It is possible to submit a question in the forum section.
Author: © Alyona Chorich, «PharmaReg», February 2013
Stages of drug registration, time-frames and costs. The Registration dossier – a list of documents. Requirements to document execution. Clinical studies at the stage of medicinal product registration. The sample import procedure.
Foreign and Russian drugs undergo the same registration procedure.
The registration procedure consists of 4 sequential stages:
1. Creation of a Registration dossier including documents necessary for clinical study initiation, and submission of the Registration dossier to the Ministry of Health of the Russian Federation.
2. Obtaining a permission for the conduct of a clinical study in the Russian Federation.
3. Drug quality evaluation and evaluation of the expected benefit to possible risk ratio which is done after the clinical study of a drug:
The third stage may be divided into 2 sub-stages for convenience:
3a. Drug quality control at the FSBI SCEMP’s laboratory and approval of a Normative document (specification and analytical procedures);
3b. Evaluation of the expected benefit to possible risk ratio and approval of Instruction for medical use of a drug.
4. Decision by the Ministry of Health of the Russian Federation on registration of the pharmaceutical product, it’s entering in the State Register of pharmaceutical products and marketing authorization issuance.
1. Creation of a Registration dossier including documents necessary for clinical study initiation, and submission of the Registration dossier to the Ministry of Health of the Russian Federation.
2. Obtaining a permission for the conduct of a clinical study in the Russian Federation.
3. Drug quality evaluation and evaluation of the expected benefit to possible risk ratio which is done after the clinical study of a drug:
The third stage may be divided into 2 sub-stages for convenience:
3a. Drug quality control at the FSBI SCEMP’s laboratory and approval of a Normative document (specification and analytical procedures);
3b. Evaluation of the expected benefit to possible risk ratio and approval of Instruction for medical use of a drug.
4. Decision by the Ministry of Health of the Russian Federation on registration of the pharmaceutical product, it’s entering in the State Register of pharmaceutical products and marketing authorization issuance.
1. Creation of a Registration dossier
To apply for registration of a medicinal product, it is necessary to draw up a Registration dossier (list of documents for pharmaceutical product registration 2012 in English, in Russian)
The Registration dossier consists of several parts:
I. Administrative documents
II. Data on active pharmaceutical ingredients used for the pharmaceutical product manufacturing
III. Description of pharmaceutical properties of the finished pharmaceutical product
IV. Data on the pharmaceutical product manufacturing
V. Data on the pharmaceutical product quality control
VI. Data on the pharmaceutical product pre-clinical pharmacological and toxicological studies
VII. Data on the pharmaceutical product clinical studies
I. Administrative documents
II. Data on active pharmaceutical ingredients used for the pharmaceutical product manufacturing
III. Description of pharmaceutical properties of the finished pharmaceutical product
IV. Data on the pharmaceutical product manufacturing
V. Data on the pharmaceutical product quality control
VI. Data on the pharmaceutical product pre-clinical pharmacological and toxicological studies
VII. Data on the pharmaceutical product clinical studies
Document execution requirements:
All documents must be submitted in Russian or have a certified translation into Russian.
The documents are certified as follows:
A) The documents issued by official designated authorities of a foreign state (CoPP, GMP, manufacturing license, power of attorney, contracts) must be always legalized – by means of consular certification or apostille.
B) The documents prepared by the manufacturer (certificates of analysis, stability study reports) – original documents or their copies signed by the manufacturer’s authorized person and sealed.
C) Pre-clinical and clinical study reports – original documents or their copies are submitted which must be sewn and numbered and then signed and sealed on the last page by an authorized person.
D) Such documents as validation reports, description of manufacturing process, specifications and analytical procedures – copies of these documents are submitted.
2. Obtaining a permission for the conduct of a clinical study in the Russian Federation.
One of the main modifications introduced on September 01, 2010 in the registration procedure is that all pharmaceutical products must always undergo clinical studies during the registration process in Russia. The only exclusion that exempts from the obligation to perform a clinical study in the Russian Federation is when there is an analogous drug registered in Russia more than 20 years ago and it is impossible to conduct a bioequivalence (BE) study for this drug (e.g. metronidazole solution for infusions 5 mg/ml – the original drug was first registered in Russia in 1982, i.e. more than 20 years ago, and no BE study is possible for this drug as it is intended for parenteral use; pancreatine tablets – the drug was first registered more than 20 years ago, and no BE study is possible for this drug as it is not absorbed in the systemic circulation and is active in the GI tract). Such pharmaceutical products skip registration stage 2 (clinical/BE/therapeutic equivalence study) and after the Registration dossier is submitted to the Ministry of Health of the Russian Federation, the pharmaceutical product skips directly to the third stage of registration.
The clinical study scope and costs depend on the following factors:
A) The pharmaceutical product type, pharmaceutical form and route of administration – original or generic drug, for oral or parenteral administration.
If the drug is a generic one and intended for oral administration (capsules, tablets, syrups, oral solutions, etc.), a bioequivalence study is conducted in 18-24 healthy volunteers(See the Guidelines). For a generic drug for parenteral administration (solution for injections, for infusions), a therapeutic equivalence comparative study versus the original drug must be conducted for primary indication in 60-100 patients on the average.
B) The pharmacotherapeutic group and indications for use of the pharmaceutical product.
C) The scope of clinical studies conducted abroad.
The clinical studies conducted abroad are accepted in the Russian Federation meaning that if the studies have already been performed, there is no need to repeat the same in Russia. Availability of foreign clinical studies does not exempt the manufacturer from his obligation to conduct a clinical study in the Russian Federation but influences the scope (number of patients, specific indications, etc.) of the studies to be conducted in the Russian Federation.
D) The conduct of international multicenter clinical studies including a part of them performed in the Russian Federation. If Russia was included in one of international studies, such study is taken into account during the registration process and does not require additional studies to be performed.
The conduct of pre-clinical studies is not necessary in the Russian Federation. Provision of own reports (not a literature review) of studies conducted outside the territory of the Russian Federation is sufficient.
Clinical studies are only conducted after the Ministry of Health of the Russian Federation grants a specific permission to conduct such clinical study. To obtain a permission for the clinical study, it is necessary to prepare a complete Registration dossier in a paper and electronic form (on the portal http://grls.rosminzdrav.ru), complete an application on state registration of pharmaceutical product, pay a state duty (75000,00 rubles) and submit a paper Registration dossier to the Ministry of Health of the Russian Federation, the Department of state regulation of medicinal product circulation (Moscow City, Rakhmanovsky lane, 3).
Upon submission, the Registration dossier must contain a protocol of clinical studies to be performed in the Russian Federation, Investigator’s Brochure, Patient Information Sheet, and a preliminary patient medical insurance agreement.
The Ministry of Health of the Russian Federation checks if the submitted dossier contains all necessary documents and then sends the registration dossier for two parallel evaluations: ethical evaluation (performed by an Ethics Committee) and evaluation of documents for the purpose of granting a clinical study permission (performed by the FSBI SCEMP of the Ministry of Health of the Russian Federation). In case of positive results of the both evaluations, the Ministry of Health of the Russian Federation makes a decision to grant a permission to conduct the clinical study. This decision appears in the applicant’s personal account on the portal http://grls.rosminzdrav.ru. After this decision appears, it is necessary to prepare the second package of clinical study documents, to complete an application on the portal and submit paper versions of the documents to the Ministry of Health of the Russian Federation which then issues a permission to conduct the clinical study of the pharmaceutical product in the Russian Federation. All approved clinical studies are included in the Register of permitted clinical studies and available on the portalhttp://grls.rosminzdrav.ru
Roszdravnadzor (the Federal Service on Surveillance in Healthcare and Social Development of Russian Federation www.roszdravnadzor.ru) is responsible for the control of clinical studies.
A clinical study may only be performed in accredited study centers. There exists a list of accredited study centers.
The registration procedure is suspended for a clinical study period which is not included in the legally established registration period.
The clinical study period depends on the study type, duration of treatment, etc. and lasts at least 6 months (10-18 months on the average).
3. Drug quality evaluation and evaluation of the expected benefit to possible risk ratio which is done after the clinical study of a drug.
3a. Drug quality control at the FSBI SCEMP’s laboratory and approval of a Normative document (specification and analytical procedures).
After the clinical study is terminated, the applicant submits a report on the clinical study results together with a state duty payment receipt (225000 rubles) and an application for renewal of the state registration procedure to the Ministry of Health of the Russian Federation. The registration procedure is renewed and the Registration dossier is forwarded to the evaluation institution of the Ministry of Health of the Russian Federation – FSBI SCEMP (www.regmed.ru) to perform drug quality evaluation and evaluation of the expected benefit to possible risk ratio of a drug.
The second important modification introduced in the registration procedure on September 01, 2010 refers to prohibition of communication between the manufacturer’s representatives and experts of the FSBI SCEMP. The registration process stages are reflected in the applicant’s personal account accessed on-line on the website of the Ministry of Health of the Russian Federation (grls.rosminzdrav.ru). All inquiries are answered via the on-line personal account with provision of a paper version through the forwarding department of the Ministry of Health of the Russian Federation.
This sub-stage involves evaluation of the proposed pharmaceutical product quality control methods (Normative document) and evaluation of submitted samples of the pharmaceutical product using such methods in the Laboratory of the Scientific Center. The manufacturer submits drug samples (as well as reference materials, columns) to the FSBI SCEMP of the Ministry of Health of the Russian Federation (Moscow, Shchukinskaya str., 6) within 15 working days following the receipt of the registration procedure renewal decision or decision on sending a drug for quality evaluation. As the sample submission period is very limited (15 working days), the sample import activities must be arranged 1-2 months before the start of the 3rd stage of drug registration procedure.
The amount of drug samples, reference materials and chromatographic columns necessary for testing could be seen on the site of Scientific Center (www.regmed.ru) after submission to this Scientific Center of the Power of Attorney.
To import drug samples and reference materials, it is necessary to obtain an Import License for an unregistered drug which is issued by the Ministry of Health of the Russian Federation. Such Permission is issued free of charge.
«The Import License» is a document authorizing the import of an unregistered batch of a pharmaceutical product to evaluate its quality for the purpose of registration or clinical studies. This License does not exempt the shipper from customs clearance of the imported product. A customs broker’s assistance is required for the customs clearance. The period during which the samples may be imported is 1-2 months (taking into account the period of obtaining the Import License).
3b. Evaluation of the expected benefit to possible risk ratio and approval of Instructions for medical use of a drug.
Based on Registration dossier, data of the drug clinical study conducted in the Russian Federation and on experience of medical use of the drug, the FSBI SCEMP experts evaluate and correct the draft Instructions for medical use of a drug, and give their opinion on drug efficacy and safety.
4. Decision by the Ministry of Health of the Russian Federation on registration of the pharmaceutical product, it’s entering in the State Register of pharmaceutical products and marketing authorization issuance.
The evaluation institution (FSBI SCEMP) forwards the expert opinion with results of evaluations performed (3a and 3b) to the Ministry of Health of the Russian Federation. In case of the positive opinion, the experts of the Ministry of Health of the Russian Federation enter a drug in the State Register of medicinal products and issue a Marketing Authorization. If the drug quality or efficacy/safety cannot be confirmed by results of the evaluation performed, a decision to refuse the state registration of a drug is issued.
The Marketing Authorization is issued for 5 years for a pharmaceutical product first registered in Russia. Upon expiration of this period, the manufacturer applies for confirmation of drug registration, thereafter the Marketing Authorization is issued for an unlimited period of time.
Registration time-frames
According to Law No.61-ФЗ “On circulation of medicines”, the period of the registration procedure is 210 working days. This period does not include the time required for conduction of a clinical study.
The total registration period* for a medicinal product that requires a clinical study in the Russian Federation is at least 18 months:
The total registration period* for a medicinal product that does not require a clinical study in the Russian Federation is at least 9 months:
* This is an estimated period.
Costs of registration
The cost of registration of one medicinal product that requires a clinical study in the Russian Federation is made up of several sums:
The cost of registration of one medicinal product that does not require clinical studies in the Russian Federation due to the existence of an analogous drug registered in the Russian Federation for more than 20 years and impossibility to perform its bioequivalence study:
Author: © Alyona Chorich, «PharmaReg», February 2013
Stages of active pharmaceutical ingredient (API) registration, time-frames and costs.
The active pharmaceutical ingredients (API) can be approved for use (registered) in the territory of the Russian Federation in the following two ways:
1) As part of registration of a finished pharmaceutical product for which this API will be used.
If the manufacturer intends to supply the API to a specific plant only, then information is provided and API quality evaluation is performed as part of the finished pharmaceutical product registration procedure. In this case, the API may only be used for the pharmaceutical product so evaluated.
2) Registration of an active pharmaceutical ingredients (API) not used in drug manufacturing.
If the manufacturer has no decision to which plants he will supply his product and is going to expand the scope of his market, he is entitled to apply for registration of a API not used in drug manufacturing.
The API will be included in the State Register of registered medicinal products under a separate number.
Stages of registration of an active pharmaceutical ingredients (API) not used in drug manufacturing
Registration of a active pharmaceutical ingredient (API) consists of 2 stages:
1. API evaluation (quality control and approval of a Normative document (specification and analytical procedures));
2. Entering an API in the State Register of medicinal products.
1. API evaluation (quality control and approval of a Normative document (specification and analytical procedures));
2. Entering an API in the State Register of medicinal products.
The cost of registration of one active pharmaceutical ingredient (API) is made up of 2 sums:
State duty (MoH fee) (100,000 rubles) + Creation of a DMF in Russian and registration process support (services rendered by “PharmaReg” 300,000 rubles).
State duty (MoH fee) (100,000 rubles) + Creation of a DMF in Russian and registration process support (services rendered by “PharmaReg” 300,000 rubles).
The period of registration of a active pharmaceutical ingredients (API) not used in drug manufacturing: 5-7 months.
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