2.1. Russian Regulatory Framework: Pre-authorization Issues of Placing Pharmaceuticals on the Market

Welcome to PhED, Pharmaceutical Education and Development! I’m your host, Ravil Niyazov. This video has been prepared in order to provide you with a high-level description of the system for governing medicinal products for human use in the Russian Federation. Specifically, we focus on granting a marketing authorization. This is the second English video on our YouTube channel, and it is intended to inform those of you who are interested in the Russian pharmaceutical market. Within the video, we’re going to describe the main documents laying down the rules governing medicinal products for human use in Russia, regulatory aspects of applying for, or maintaining of, a marketing authorization for a medicinal product in Russia. We will also discuss clinical trial application issues and related topics. Please supports us by subscribing on our channel on YouTube or following me on Facebook and LinkedIn! In this video, we will provide a brief description of the Russian pharmaceutical market and regulatory pathway in Russia, discuss Russian competent authorities for human pharmaceuticals, GMP certification, non-clinical studies/tests, local clinical trials, clinical trial application process and procedure for granting a marketing authorization, verification of the test methods included in the specification, recognition of a marketing authorization granted in other countries, new labelling requirements as of 2019, approval of biosimilar products and incrementally modified drugs/hybrid applications, dealing with orphan products, communication with Russian regulators and assessors, official batch release testing issues, OTC products and OTC status and will wrap up with accelerated approval. The estimated size of the Russian pharmaceutical market is over 23 billion U.S. dollars. The growth rate in 2016 was 7%, and is expected to be 9% in 2017. The market share of foreign companies is around 71%, but the Russian government puts considerable efforts to support local manufacturers. Current legislation is stipulated by the Federal law on the circulation of medicinal products which was enacted in 2010. However, by the end of 2020 the national authorization procedure will cease to be effective. The statutory and regulatory provisions are quite scarce. Moreover, the regulatory provisions in the area of pharmaceuticals usually replicate the statutory provisions, but not develop them, so that such regulatory provisions can be viewed as redundant. It is worth mentioning that authorization periods are among shortest in the world. It is also important to know that Russian pharmaceutical legislation generally is not harmonized with international approaches. Moreover, pharmaceutical legislation is not in line with other healthcare products legislation, such as medical devices or cosmetics regulations. The legislation contains many controversial provisions which are not implemented or enforced. For example, the legal definitions of bioequivalence studies or generics are not observed. Human and veterinary provisions are combined in one law. Now let’s discuss particularly the main features of the Russian regulatory system for placing human pharmaceuticals on the market. Russian healthcare products regulatory system is rather fragmented in comparison with other countries and regions. Medicinal products for human use are regulated by at least four different competent authorities. One of the key players in regulation of human pharmaceuticals in Russia is the Ministry of Health. It is responsible for granting a marketing authorization, approval of clinical trial applications, and price control over certain medicinal products included in Russian Essential Medicines List. The Ministry of Health has in its disposal a government institution called the Federal State Budgetary Institution Scientific Center for Evaluation of Medical Application Products, briefly called in Russian FGBU НЦЭСМП or merely FGBU (ФГБУ) This institution carries out the assessment of marketing authorization application dossiers as well as other types of dossier such as clinical trial application dossiers, variation, or renewal dossiers. The second government agency important for the regulation of medicinal products for human use is the Ministry of Industry and Trade. The Ministry is responsible for issuing manufacturers’ authorizations for local establishments and GMP certification of manufacturing facilities both in Russia and abroad. The next important regulatory player is Roszdravnadzor which is the Russian abbreviation for the Federal Agency for Supervision in Healthcare and Social Development. It overseas pharmacovigilance of human pharmaceuticals and carries out GCP inspections. It conducts GLP inspections, but its remits in the area of GLP are limited to human pharmaceuticals. Roszdravnadzor is also responsible for official batch release testing of certain biological medicinal products. Federal Antitrust Service concludes the list of major human pharmaceuticals regulators in Russia. It overseas advertisement of medicinal products and also takes part in controlling prices of pharmaceuticals included in Russian Essential Medicines List. It also plays a big role in decision-making when drafting new pharmaceutical legislation. One of the main issues for foreign pharmaceutical companies is GMP certification, so let’s start with discussion of this topic. To apply for granting a marketing authorization via the national procedure, the applicant shall have a valid GMP certificateFederation issued by the Ministry of Industry and Trade of the Russian Federation. Foreign GMP certificates are not recognized for the purposes of granting a marketing authorization in Russia, even if the manufacturer is established in ICH or PIC/S Member States. However, GMP certificates issued by other Eurasian Economic Union Member States, i.e. Belarus, Kazakhstan, Armenia, or Kyrgyzstan are accepted as a proof that a manufacturer is compliant with Russian GMP standards. The GMP Inspectorate operates under auspices of the Ministry of Industry and Trade; it is a separate government institution called Federal Budgetary Institution responsible State Institute of Medicinal Products and Good Practices. It is also responsible for carrying out GDP inspections. It is worth mentioning that the procedure of applying for an inspection is not directly linked to granting a marketing authorization. Generally, two procedures are not connected. However, where a GMP certificate issued by the Ministry of Industry and Trade does not exist, a marketing authorization application still might be submitted if the company provides a confirmation issued by the Pharmaceutical Inspectorate that the inspection will be carried out in the future. In this case, the marketing authorization will be pending until the applicant provides a valid GMP certificate issued by the Russian Ministry of Industry and Trade based on the inspection conducted by the Russian GMP Inspectorate. Russian GMP Order is based on Good Manufacturing Practice guidelines of the European Union provided in the EudraLex – Volume 4. Namely, the Glossary, Parts from I to III, as well as Annexes to Part I were translated. However, several amendments were introduced making Russian rules somewhat different from the EU guidelines. It is worth noting that when drafting Russian version of GMP, the government paid attention mostly to technical aspects of good manufacturing practices while procedural aspects were largely ignored. This created procedural vagueness and needs to be addressed. For instance, GMP Order lacks provisions similar to those laid down in Titles IV and XI of Directive 2001/83/EC, Directive 1572/2017 of the European Union, as well as national provisions of EU Member States, such as contained in the UK Human Medicines Regulations of 2012. Since GMP regulations became effective relatively recently, the number of applications for GMP certificates exceeds the operational capacities of the Inspectorate, so a waiting list has emerged. The estimated waiting time as of the date of publishing this video is 6 to 12 months. Therefore, it is important to consider GMP certification sufficiently in advance of submitting a marketing authorization application. The certificate shall be renewed at least once in 3 years, and the renewal inspection is mandatory. However, the scope of inspection might depend on issues determined in accordance with the risk-based approach. Where the appropriate manufacturing facilities have not been inspected for GMP compliance, a marketing authorization application will be rejected by the Ministry of Health. To get the certificate issued, an applicant needs to negotiate and approve inspection date with the Ministry of Industry and Trade and GMP Inspectorate and before applying for marketing authorization. Sometimes foreign manufacturers of finished products may experience problems during product-specific inspections since the main quality control document in Russia is a normative document which usually differs from the specification drawn up by the manufacturer. The normative document is based on the Russian State Pharmacopoeia which is not harmonized with other pharmacopoeias, and also the assessors usually give recommendations to improve analytical methods included in the normative document. These recommendations are based on the testing results obtained in the official laboratory which does not conduct any validation or method transfer when verifying test methods proposed by the applicant. To minimize these and other potential issues when obtaining a GMP certificate from the Russian GMP Inspectorate, it is strongly recommended to find a local partner which is familiar with those issues and can facilitate this process. The cost of GMP certification is approximately fifty thousand U.S. dollars. In appropriate cases, non-clinical test data needs to be provided, for instance when applying for a clinical trial authorization, marketing authorization, or extending the use of a medicinal product. Foreign non-clinical data are generally accepted, but the tests shall be conducted in accordance with GLP. No local non-clinical data are needed. Nevertheless, there are several specific issues. According to the federal regulations, all non-clinical tests shall be conducted in accordance with GLP. This means that even non-clinical PD and PK testing should comply with GLP requirements; this is generally impossible to fulfill. This compliance, however, is usually not checked by the regulator, so no problems have arisen due to this issue so far. However, this needs to be taken into account and appropriately explained to the regulators or assessors if such observations are made. It is important to say that Russia has two GLP systems that do not agree with each other: the first, general GLP regulations that are in line with the OECD GLP guidelines and the second, the pharmaceutical-specific GLP Order which is a substantially abbreviated version of the OECD GLP guidelines. Since OECD GLP guidelines cover Russian pharmaceutical-specific GLP provisions, no problems are expected in this area if an applicant conducted their non-clinical tests in accordance with the OECD GLP guidelines. The next possible issue is a requirement to provide non-clinical test data for generic or hybrid applications. (Hybrid applications sometimes are called IMD or incrementally modified drugs.) Although this requirement is obsolete and in certain cases might be replaced by thorough bibliographic data, such observations keep emerging and might be addressed via detailed explanation and bibliographic literature data. In majority of cases, 2 to 4 weeks subacute toxicity and local tolerance studies are requested. We suggest finding an appropriate local consultancy which could help to address these issues without conducting any additional in vivo testing. According to Russian regulations, at least one clinical trial needs to be carried out on Russian clinical site or sites. In case of multi-site trials, one Russian site may be included, and this will satisfy legal requirement for local clinical trials. The legislation does not envisage replication or implementation of the entire clinical development program in Russia. Also, there is no such a requirement that whole phase (i.e. several CTs) of a clinical development program needs to be conducted. A bioequivalence study credits as a clinical trial. In case of generic products, since it is not usually appropriate to split a bioequivalence study among several clinical sites, a whole study needs to be conducted or replicated in Russia. In other cases, the most feasible option is an international multi-center clinical trial. At the same time, phase 1 safety/tolerability studies using clinical trial material manufactured abroad in healthy volunteers are not allowed. These provisions are to protect healthy individuals from investigation of previously untested substances on Russian healthy human subjects. However, such studies are allowed in case of patient subjects. Where Phase 1 study in healthy volunteers is desirable, it is better to seek for a Russian partner who may take part running at least one manufacturing step (for example, packaging). Clinical trials shall be carried out in accordance with the Russian GCP Order which is based on ICH GCP(R1), but not fully replicates it, being less stringent. For the Ministry of Health and the assessors, compliance with GCP is not of utmost importance, so mere declaration of compliance might be enough. There are several instances where applicants are exempt from providing local clinical trial data. Those instances are described in the Article 18 of the Federal law. First of all, orphan medicinal products are exempt from local clinical trials, so if a drug product is recognized in Russia as orphan, then no local clinical data is needed. Certain generic products are exempt from providing any clinical trial data whether local or not if they satisfy specified biowaiver criteria. For example, oral or parenteral solutions or medicinal gases might be authorized based on pharmaceutical equivalence data only. Additional strengths might also be authorized without any clinical data though this type of biowaiver is not provided in federal regulations. Formal criteria for additional strength biowaiver are not provided in the legislation, so the assessors evaluate applicability of this type of biowaiver individually. For certain combination products, no additional clinical data is needed as provided in the legislation. In these cases the bibliographic data might be sufficient. Local clinical trials also are not necessary where new uses or indications are added for an authorized medicinal product. At last, where a clinical trial was conducted in Belarus, such a trial counts for a local clinical trial because Russia has close connection with this Republic. To determine and justify applicability of these exemptions and waivers,local consultants we recommend you discuss these issues with local consultants. The requirements for clinical trial applications are quite loose. For instance, investigational medicinal product dossier is not needed. Only main clinical documents need to be provided within the clinical trial application dossier: the protocol, Investigator’s Brochure, Informed Consent Form, Case Report Form, Insurance policy etc. Quality conformance certificate for the investigational product is sufficient in a CTA dossier. That is no Investigational Medicinal Products Dossier or other documents sufficiently detailing quality aspects of the investigational product is needed. Generally, scientific standards for design and conduct of clinical studies are in line with internationally-accepted approaches as outlined in ICH, EMA, WHO, or FDA guidelines and guidance documents. The duration of the CTA procedure is 30 business days which corresponds to 40 calendar days. During the procedure, at least one request for additional information and/or data may be sent to the applicant. The applicant shall respond within a maximum of 90 business days. If the applicant fails to respond, the Ministry of Health concludes the procedure based on the application data submitted initially. Occasionally, Russian GMP might be needed for initiating a clinical trial. Fee for the assessment of a clinical trial application is around fifteen hundred U.S. dollars.

2 comments

  1. Dear Ravil, do you have any reference to law where possibility to submit to RU MoH results of clinical trial, performed in Belarus, is described? Im talking about 16:24 of the movie .

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