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Russian Pharmaceutical Market: Regulatory Affairs
| 작성자 | 임이슬 | 카테고리 | 전문가 인사이트 |
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| 작성일 | 2017-12-01 | 조회수 | 3,930 |
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Russian Pharmaceutical Market: Regulatory Affairs
- 글 Ravil Niyazov
- KHIDI 해외제약전문가 상임컨설턴트
경력사항
- 현재 Center of Scientific Advice Ltd. (Russia), Regulatory Affairs, Head
세부 전문분야
- Regulatory affairs: Appropriate rules governing medicinal products for human use in Russia, EAEU, and EU
- Clinical Trial: Scientific aspects of clinical development, medical writing
- R&D 기획: Development of generic and biosimilar medicinal products; new chemical entities/biologics
ABSTRACT
In this paper, 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, including accelerated approval, 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 will be provided.
INDRODUCTION
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 put 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. E.g. the legal definitions of bioequivalence studies or generics are not observed.
Human and veterinary provisions are combined in one law.
ELEMENTS NEEDED FOR SUBMITTING AN APPLICATION
Competent authorities for human pharmaceuticalsRussian 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 ФГБУ НЦЭСМП or merely ФГБУ (FGBU). 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 undertakings and GMP certification of manufacturing or distribution facilities both in Russia and abroad.
The next important regulatory player is Roszdravnadzor which is the 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.
GMP certification
To apply for granting a marketing authorization via the national procedure, the applicant shall have a valid GMP certificate 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 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 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.
Non-clinical studies/tests
In appropriate cases, non-clinical test data needs to be provided, e.g. 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: (1) general GLP regulations that are in line with the OECD GLP guidelines and (2) 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, subacute toxicity (2 to 4 weeks) 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.
Local clinical trials
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 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 Russian partners who may take part running at least one manufacturing step (e.g. 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, we recommend you discuss these issues with local consultants.
Clinical trial application
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 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.
MARKETING AUTHORIZATION AND RELATED TOPICS
Granting a marketing authorizationTo apply for a marketing authorization, either a valid GMP certificate issued by the Ministry of Industry and Trade should be in place or the decision on the certificate should be pending. Local clinical data should be included in the file unless exemptions or biowaivers apply.
The assessment is carried out by the institution under auspices of the Ministry of Health, i.e. FGBU which was mentioned earlier. The assessment procedure takes 110 business days which equals to 150 calendar days. Where observations arise during the assessment procedure, the applicant is furnished with the list of questions and the assessment is suspended. The applicant should satisfactorily respond to list of questions in 90 business days, i.e. approximately 130 calendar days.
During the assessment, verification of the finished product specification test methods is carried out by the laboratory department of the assessment institution. This topic will be further discussed later.
In case of placing on the Russian market of generic or biosimilar products, a reference product shall be authorized in Russia, and the appropriate studies, for example bioequivalence studies should be carried out using this Russian reference product. This needs to be considered in advance. Where this condition is not fulfilled and there is no applicable reference product on the Russian market, a generic, hybrid/IMD, or biosimilar product might be recognized as a stand-alone or new product necessitating submission of a full non-clinical and clinical data package. In certain cases, it is possible to persuade the regulators and assessors that full non-clinical and clinical data package is not needed, and the thorough bibliographic dossier will address all potential safety and efficacy issues.
Verification of the test methods included in the specification
Verification of the test methods included in the specification is mandatory during the assessment within granting a marketing authorization or variation the marketing authorization where proposed variations involve manufacturing or quality issues of the finished product.
In more than 99% cases, the verification is carried out at the assessment institution’s facilities and only in small amount of cases where the assessment institution doesn’t have appropriate equipment or methods, the on-site verification of test methods is possible. Vast amount of assessors’ observations is related to such method verification. As was mentioned previously, instead of using specification, test methods are verified against a normative document. The normative document generally resembles specification, but there are no formal rules of establishing a normative document, except the Russian State Pharmacopoeia. It is important to keep in mind that the State Pharmacopoeia is not harmonized with any other pharmacopoeia, neither the USP, nor European Pharmacopoeia, nor JP, nor International Pharmacopoeia.
Moreover, when establishing pharmacopoeial texts, no validation or meaningful laboratory testing takes place, so the wording, acceptance criteria, and method description might be unsubstantiated experimentally.
Also, when the assessment institution carries out verification of test methods, it doesn’t perform any validation or manufacturer’s method transfer, so the observations of the assessors might be related to such defects in analysis rather than to true issues discovered during the method verification.
Therefore, a local partner is needed to draw up the Normative Document which will satisfy Russian assessors.
Recognition of an MA granted in other countries
According to Russian regulations, recognition of foreign authorizations is possible in case of a valid agreement between the Russian Government and the Government of the country where an applicant is established.
So far, the Ministry of Health and the Ministry of Industry and Trade do not recognize foreign marketing authorizations, GMP certificates etc.
Non-clinical and clinical data is accepted where those studies have been conducted based on generally accepted guidelines, i.e. GCP, GLP. However, at least one clinical study should be conducted in Russia unless exemptions apply.
Obtaining marketing authorization in the European Union (including European Union Member States), United States, Japan, Canada, Australia is taken into account, but is not directly recognized. Where a medicinal product was granted an authorization in the above regions, it is a great support for justification that the applied product is eligible for entering the Russian market. One of the reasons is that these regions’ competent authorities have English language pharmaceutical web-portals, so that marketing authorization is easily verifiable.
Where granting a marketing authorization is expected in those regions, it is advisable to provide information on the outcome of this procedure before applying in Russia. A detailed explanation of regulatory strategy taken by the applicant is of a high value and allows to prevent potential problems due to inappropriate development approaches. Moreover, data provided should satisfy generally accepted scientific principles, for example as outlined in the ICH, FDA, or EMA scientific guidelines.
New labelling requirements as of 2019
In 2019 new labelling regulations will become effective in Russia. These regulations are intended to ensure full traceability of any medicinal product placed on the Russian pharmaceutical market, from its manufacturer across the whole supply chain to the final user. The movement of each pack will be traceable in each dealing between any supplier and purchaser. The equivalent measures will be taken at the Eurasian Economic Union level.
This is different from the European Union requirements since Russian labelling regulations will apply to all categories of medicinal products, not only prescription only medicines, and traceability should be assured at each step of supply chain till the end-user. At the same time, no legally binding technical specifications were established to date, and all supply chain members need to be prepared to invest in facilities to comply with the new labelling regulations.
Approval of biosimilar products
Approaches to authorization of biosimilars for marketing are close to the European Medicines Agency rules. In particular, the Russian Assessment Institution has published a guide which contains translated EMA general and product-specific guidelines on biosimilar development. In line with the European rules, the guide suggests a step-by-step approach to the development of biosimilar products. At the same time, general provisions of Russian pharmaceutical legislation apply, for instance at least one local clinical trial is still mandatory (unless the product is orphan), safety/tolerability testing in healthy volunteers within Phase 1 studies are not accepted. Also at least one multiple dose toxicity study is generally needed.
Moreover, within granting a marketing authorization for a biosimilar product, an interchangeability analysis is carried out by the assessors. The same analysis is conducted for generic products. The approaches to establishing the interchangeability favor generic or biosimilar manufacturers and intended to squeeze out foreign innovative manufacturers from the market.
It is worth mentioning that the EMA/EU or U.S authorization might not be a sufficient justification for acceptable safety or efficacy of a biosimilar product. For instance, in the situation with a certain biosimilar monoclonal antibody product, the initial application was refused since several additional cases of tuberculosis on the biosimilar product have occurred. Tuberculosis is a disease of concern for the Ministry of Health, therefore such unexplained increase was considered unacceptable and the application was rejected. The new application with a detailed justification of clinical irrelevance of those cases was accepted, and the marketing authorization was granted. This case underlines the importance of the communications with the regulators. Hence, rigorous Regulatory Affairs support is crucial in dealing with the Russian government agencies.
Incrementally modified drugs/hybrid applications
Incrementally modified drugs (IMD) or hybrid applications or sec. 505(b)(2) applications are not specified in Russian pharmaceutical legislation.
Any product is considered either innovative (reference), generic, combination, biological, biosimilar, herbal, or homeopathic. This list is restrictive. The product category should be declared in advance in the application form.
IMD products may be considered either generic or innovative or a combination, where appropriate. The requirements for the data package depend on the ability of an applicant to justify that the product is closer to generic, not the reference in order to minimize the extent of data needed. Regulatory affairs support might be of great value to achieve this goal. The situation is different within the Eurasian Economic Union legal framework where hybrid applications are considered an appropriate legal basis for authorization for marketing.
Dealing with orphan products
The product is considered to be orphan in Russia if it is solely intended to treat an orphan disease or make a medical diagnosis of the orphan disease. The disease or condition is considered orphan if its prevalence is less than 10 per 100,000 people (i.e. 1 per 10,000 people of Russian population). This is five times less than in the European Union or other EAEU countries. The Russian government maintains a list of orphan diseases which comply with the legal definition of an orphan disease. Although it is in Russian, the list contains ICD-10 codes, so English equivalents of orphan diseases can be found.
In order to designate a medicinal product as orphan, the condition/disease to be treated or diagnosed needs to be recognized as such. The designation procedure for a medicinal product is carried out within granting a marketing authorization.
Where orphan status for a disease or condition is recognized, the requirement on local trials is waived. Early consultation with local Regulatory Affairs agencies is encouraged to clarify the regulatory strategy. Sometimes it is possible to put a disease or condition into the list of orphan diseases. This procedure is not related to marketing authorization or clinical trial application procedures and processed by the different department of the Ministry of Health.
For orphan drugs accelerated assessment is envisaged, although it is of relatively little value for applicants.
Orphan products are reimbursed by the Federal or State government.
It is also worth mentioning that unlike the EU or U.S. pediatric development is not mandatory in Russia as well as in the Eurasian Economic Union, although this issue is not directly related to the orphan products.
Communication with Russian regulators and Scientific Advice
Regulatory communications are crucial for successful outcome of any regulatory procedure. However, miscommunication between Russian regulators and foreign companies’ headquarters occurs frequently which might delay entering the market or even abandon the attempts for placing the product on the Russian market.
In Russia, communications with the competent authority or assessors are possible only within the marketing authorization application or clinical trial application procedure. It takes Q↦A format: assessors or the MoH officials send their written observations and accept only written response prepared by the applicant. Oral explanations are extremely rare and take place in exceptional circumstances determined by the MoH officials on a case-by-case basis. No written protocols exist for such communications.
Scientific Advice delivered by the assessors is also not envisaged by the Russian legislation, i.e. pre-IND, IND, pre-NDA meetings, protocol assistance, etc. are not possible. Moreover, although many people call it scientific advice, companies generally seek for procedural rather than scientific advice because it is recognized that scientific advice capacities of the Russian assessment institution are limited and not on a par with such agencies like the U.S. FDA or EMA.
However, petitioning to the Ministry of Health is allowed, but answers will be rather unspecific, and the petitioning procedure is not connected with the processing of the application, so the decision on the application might be made before the petition is duly considered. The best approach when petitioning is to propose one or more strategies and seek a nod from the Ministry of Health; a petitioner should not expect that the officials prepare a robust strategy from scratch.
If an inappropriate local regulatory affairs consultant is chosen, indirect communication between the Ministry of Health or assessors and foreign company’s headquarter might be misleading due to misunderstanding between the parties. We recommend thoroughly select an appropriate local regulatory affairs consultant. It shall have at least minimal regulatory experience. Moreover, due to small and slow feedback from the MoH, the best approach is to prequalify a marketing authorization application dossier with at least one regulatory affairs company.
Questions/observations sent by assessors or MoH officials to the applicant may be vague or ambiguous. Therefore, deciphering techniques are essential in understanding what is being asked and how to deal with the issues raised by assessors. For instance, sometimes when the assessors ask for additional studies, it may mean that the justification of absence thereof might also be accepted. When clarifying or explaining outstanding issues, comprehensive knowledge of Russian regulatory environment is essential because any scientific explanation needs to be in line with the current legal framework.
Official batch release testing
Official batch release is carried out by the laboratories designated by the Roszdravnadzor for these purposes. The list of products for which official release is mandatory differs from the European Union approach. Almost any biological product might be subject to official batch release. For instance, unlike the European Union where only plasma-derived medicinal products and immunological products should be officially released, in Russia recombinant DNA technology-derived products also need to be released officially. No official guidelines on tests to be carried out within the official batch release so far. The EDQM’s OCABR guidelines are not applicable.
The tests are determined individually within granting a marketing authorization when approving the normative document. The test list usually considerably shorter than in the ICH Member States. Moreover, outdated test methods might be used, e.g. abnormal toxicity testing, and this might be challenging for some marketing authorization holders.
OTC products and OTC status
The supply category is determined individually within granting a marketing authorization. Two categories are possible: a prescription only medicine or OTC product. No such categories as a pharmacy medicine or hospital medicine are envisaged.
Russian legislation does not provide any specific rules for determining the supply category. However, an abbreviated version of the European Commission guideline is used unofficially, but it is not legally binding. Since the European Commission document is available in English, it is possible to find all criteria for changing the supply category which are outlined in detail. Any product claiming the OTC category should comply with those criteria.
Accelerated approval
Russian pharmaceutical legislation allows accelerated approval for certain groups of medicinal products. Where the accelerated procedure is approved, granting a marketing authorization should be completed within 90 days which is 60 days shorter than the normal procedure. It is one of the shortest accelerated procedure in the world!
The following product classes are eligible for accelerated approval: orphan products, first three generic products and pediatric use only medicines. The product is considered pediatric use only where such a product is indicated for children use only.
Some products are specifically ineligible for accelerated approval, including biological products and combinations of previously authorized substances.
CONCLUSION
This concludes our introduction to the Russian pharmaceutical legislation. The requirements both for issuing a marketing authorization and approving a clinical trial are quite loose, but it is expected that they will be replaced by the Eurasian Economic Union standards by the end of 2020. Currently, great efforts are being made to establish the EAEU legal framework and put it into operation. The dossier might be submitted according to new rules as of 2017.
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