Registration of a new product is the first step of launching drug to the market of the Russian Federation. The registration is a state procedure of drug quality, efficiency and safety evaluation to obtain an approval for medical use of a drug in the Russian Federation. Registration of a new drug - the first step in the process of withdrawal of the pharmaceutical market of the Russian Federation. This procedure is essentially a state examination quality, efficiency and safety of the drug, which is held for the subsequent issuance of the permit on its medical use.
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.
Law of Russian Federation on December 22, 2014 N 429-FZ on "Amendments to the Federal Law" "On Circulation of Medicines ". Some of the introduced amendments will enter into force on 1 July 2015, another part - on 1 January 2016 and the last - more than a year, that is from January 1, 2017.
Foreign and Russian drugs undergo identical registration procedure.
The registration procedure consists of 4 sequential stages:
To apply for registration of a medicinal product, it is necessary to draw up a Registration dossier:
The Registration dossier consists of several parts:
All documents must be submitted in Russian or have a certified translation into Russian
The documents are certified as follows:
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:
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.
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.
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 portal http://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).
3.1. 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(225 000 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).
3.2. 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.
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.
According to Law No.61-Federal Law “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 active pharmaceutical ingredients (API) can be approved for use (registered) in the territory of the Russian Federation in the following two ways:
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.
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:
The period of registration of a active pharmaceutical ingredients (API) not used in drug manufacturing: 5-7 months.