The Analysis of Organizational Approaches in Drug Registration in the EU, Ukraine, Tajikistan, Turkmenistan and Uzbekistan

 

Нanna Panfilova¹, Olesia Nemchenko², Liusine Simonian³, Oksana Tsurikova⁴

Organization and Economy of Pharmacy Department, National University of Pharmacy, Kharkiv, Ukraine

 

ABSTRACT:

The increase of the level of drug availability to the population is one of the most important tasks of the healthcare development in any country. As the international experience shows, one of the ways to increase the availability of medicines for the population is introduction of various mechanisms of drug registration. At the moment, Ukraine like other countries of the former USSR is in the process of development and introduction of modern organizational approaches to drug registration. Therefore, the aim of the study was the comparative analysis of organizational approaches implemented in drug registration in the European Union, as well as in some countries of the former USSR, namely Ukraine, Tajikistan, Turkmenistan and Uzbekistan. It has been found that there are many similar organizational approaches to drug registration in Tajikistan, Turkmenistan and Uzbekistan. However, the cost for considering the data of the Registration Dossier for drugs is significantly different in these countries. The cheapest drug registration is in Tajikistan. The presence of the differentiated approach to the registration of imported and domestic drugs in Uzbekistan allowed increasing the number of the registered products of the Uzbek production by 26.7 times within 1996-2017. Unlike the countries mentioned, since 2014 the legislative regulations are gradually introduced in Ukraine to register medicines, which meet the European requirements. At the same time, has been found that after introduction of the European standards in organization of drug registration in Ukraine a significant increase of drugs registered in the country was not observed. The results of the study can be used when developing the interstate program of the economic cooperation between the CIS countries in the field of pharmaceutical provision of the population. In future, implementation of this program should help the regional pharmaceutical markets in the reference countries to integrate into the world pharmaceutical market.

 

 

 

INTRODUCTION:

Ukraine belongs to the countries that have clearly outlined the European goals in its development. Despite the financial and socio-economic crisis that exists in Ukraine since 2014 the government develops and implements a complex of measures aimed at European integration. Building modern relationships is of particular importance in the process of effective promotion of  Ukraine to the European values^1,2.

 

As it is known, the pharmaceutical market is the most important component of the system of pharmaceutical provision of the population. There is a variety of interests at the pharmaceutical market, among them the issues of drug availability are the most important and socially significant³. The problem of increasing the level of physical availability of medicines is solved in the countries of the European Union (EU) by using different methods of direct and indirect government impact on various aspects of pharmaceutical activities.The regulation of the drug registration procedure takes a special place in improving the physical availability of medicines in the EU countries. In order to standardize the norms of the Ukrainian legislation according to the European standards in 2014 the new conditions for drug registration at the pharmaceutical market were introduced. The consequences of introduction of the European standards and requirements in the process of drug registration in Ukraine have not been considered in the scientific literature. Therefore, it is topical to conduct a comparative analysis of t the drug registration procedure in Ukraine and other countries that are members of the Commonwealth of Independent States (CIS) with the purpose of scientific assessment of the level of their compliance with the European practice of the state regulation of the drug turnover at the pharmaceutical market.

 

MATERIAL AND METHODS:

In the studies the data presented in the open information access on the websites of the Ministry of Health of Ukraine, the Ministry of Health and Social Protection of the Population of the Republic of Tajikistan, the Ministry of Health and Medical Industry of Turkmenistan and the Ministry of Health of the Republic of Uzbekistan were used⁴.

 

The choice of the countries was determined by the following factors. These countries have common historical features of development for more than seventy years. As it is known, they were part of the former USSR. Currently, all these countries are in the process of development and introduction of the new policy at the pharmaceutical market; the main purpose of this policy is to improve the physical and socio-economic availability of medicines. In all countries taken for analysis the problem of improving the availability of medicines is the most important in the system of pharmaceutical provision of the population. This group of countries in our study is called the reference group.

 

To conduct a comparative analysis of the registration procedures for medicines available in reference countries ten key research parameters were identified. In our opinion, these parameters can describe the drug registration procedures existing in the country from the qualitative point of view, primarily compliance with the European norms and requirements in the process of regulation of drug turnover at the pharmaceutical market. Effective implementation of the European regulations concerning drug registration as indicated previously can significantly improve the physical and socio-economic availability of medicines in countries. The following parameters for analysis were considered: the existence of a unified state authority that issues the registration certificate for a drug; the types of the drug registration procedure; the presence of the accelerated mechanism for drug registration; the possibility of using the simplified scheme for drug registration (re-registration); the existence of the procedure for mutual recognition of the data of registration documents for drugs registered in the EU, USA, Canada, Switzerland, Australia and Japan; the presence of the unified Register of Medicines registered in the country; free access to the data of the specified Register of Medicines; the need for registration of medicines prepared in pharmacies by prescription; the need for conformity of drug production to the GMP standards; the time for consideration of the data of the drug registration dossier; the term of registration of the drug in the country; the cost for consideration of the data of the drug registration dossier and its registration (re-registration). As the qualitative assessment of the procedures for drug registration was carried out compared with the European standards, the characterization of the existing procedures for drug registration in the EU countries was an important step in our research. In addition, the question of the impact of changes in the Ukrainian legislation on the dynamics of the registered drugs is of special consideration. In 2015, the procedure of the simplified drug registration and the mechanism for mutual recognition of the data of registration documents for drugs registered in the EU, USA, Canada, Australia and Switzerland was introduced in Ukraine. It was important for us to know how introduction of the European approaches in drug registration at the Ukrainian pharmaceutical market affected the dynamics of the registered drugs in Ukraine. The analysis of dynamics of drug registration indicators in Ukraine was carried out according to the data of the State Expert Centre (SEC) of the Ministry of Health of Ukraine”. The official website of this state organization presents the data of the State Register of Medicines registered in Ukraine⁵.

 

The necessary statistical data processing was carried out using a Microsoft Office Excel 2010 standard spreadsheet and standard methods of variation statistics. After a preliminary assessment of the data all indicators were imported into a Statistica 6.0 standard program for the applied statistical analysis (the license of a V.7. English – V.6 Russia K 892818 software product).

 

In the study such methods of scientific research as a historical, systematic, logical, comparative, graphical, mathematical-statistical and logical modeling were used.

 

RESULTS:

The analysis of organizational approaches in drug registration in the EU countries.

 

The fundamental documents of the EU countries in the sphere of drug registration are “Directive 2001/83/ EU” and “Regulation 726/2004” of the European Parliament and EC Council. These documents regulate such issues as acquisition of license when importing medicines into the country; acquisition of license for manufacture and import, wholesale and retail sale of drugs; control in the process of the drug turnover, including pharmacovigilance, etc.^1,6,7,8.

 

In the EU countries the following procedures for drug registration can be mentioned:

·        centralized (standard) procedure;

·        mutual recognition procedure;

·        decentralized procedure^8,9,10.

 

Registration (marketing approval) of medicines containing substances introduced to the pharmaceutical market for the first time is performed by the centralized procedure. In addition, the centralized procedure is used when registering drugs in chemotherapy of HIV/AIDS, cancer, neurodegenerative disorders or diabetes mellitus ^7,9,10. To obtain a marketing approval by the centralized procedure of drug registration an applicant must submit the documents to the European Medicines Agency (EMA). In case of obtaining the marketing approval by the centralized procedure the applicant can position the product in all national markets of the EU countries.

 

The mutual recognition procedure is applied to most of the so-called conventional medicinal products. This procedure is based on the principle of recognition of the existing national authorizations for marketing (registration) in individual EU countries^1,6,8,9.

 

At the European pharmaceutical market the decentralized procedure of drug registration was introduced only in 2004. This procedure of drug registration like the mutual recognition procedure is applied to the majority of traditional drugs that are widely used in medical practice. The essence of the decentralized procedure is as follows. The applicant must submit the documents to organizations registering drugs simultaneously in several EU countries. The decentralized procedure of drug registration involves the existence of the competent authority, which assess materials of the dossier and issues the appropriate permits for drug sale in each EU country. In the EU countries this centralized authority is EMA.

 

Based on the principles of publicity and transparency of information all necessary data concerning the specific drug name are in free information access. It is known that in the EU there is a consolidated data base for assessing the post-clinical efficiency of drug use. This base functions according to the standards described in the Directives 2001/83/EU and 2001/82/EU–Eudra GMDP.

 

On the official website of EMA the clinical reports are regularly published; on their basis the European regulatory authority makes a decision on giving the possibility of issuance or cancellation of the license for marketing of medicines at the EU market.

 

For the purpose of rapid provision of the population with high effective and qualitative medicines the EU legislation includes several procedures for accelerated registration of new drugs entering the pharmaceutical market by the centralized procedure of drug registration. Accelerated assessment of the registration material data for a drug considerably reduces the time for consideration and evaluation of the application for obtaining marketing approval for the drug from 220 to 150 days. This mechanism acts on drugs that are of special value for public healthcare and the system of pharmaceutical providing of the population. The mechanism of the accelerated consideration of the registration dossier data has great importance when introducing to the pharmaceutical market of innovative drugs^1,7,8,9.

 

There is also the procedure of conditional marketing authorization. This procedure allows obtaining marketing approval for the drug until all the necessary information about the use of this product becomes available. The procedure of compassionate use of medicines is also of special social significance. This procedure allows the use of unregistered names drugs for patients with the unsatisfactory treatment outcomes when using registered medicines. With the accelerated drug registration procedure the Committee for Medicinal Products for Human Use (CHMP) gives the appropriate conclusion. This conclusion indicates the evaluation criteria of the drug and the conditions under which the competent national agencies in different countries may include the drug in the Register of Medicines registered in the country^7,8,9.

 

ІІ. The comparative analysis of organizational approaches in drug registration in reference countries (Tajikistan, Turkmenistan, Uzbekistan, Ukraine)

 

Further the data of the legal and regulatory framework regulating the process of drug registration in Tajikistan, Turkmenistan, Uzbekistan and Ukraine were analyzed. The results of the comparative analysis of the legal and regulatory framework data in regulating the pharmaceutical activities in these countries are presented in Table 1. As can be seen, all countries have a unified state authority that issues permits for selling drugs in the country. In Ukraine such authority is the Ministry of Health, in Tajikistan it is the State Service for Surveillance of Pharmaceutical Activities, in Turkmenistan–the Ministry of Health and Medical Industry, in Uzbekistan–the Main Directorate for Quality Control of Medicines and Medical Equipment of the Ministry of Health. In all reference countries, except for Ukraine, drug registration is performed exclusively by the centralized registration procedure; its duration is on average 180 days.

 

In Ukraine drug registration is by both the centralized procedure and the procedure for mutual recognition of registration in the EU, USA, Canada, Switzerland and Australia. In addition, in Ukraine, unlike other reference countries, there is the accelerated mechanism for consideration of the data of the drug registration dossier. As a result, the period of drug registration in Ukraine varies within the broader range of values than in Tajikistan, Turkmenistan and Uzbekistan. For example, in Ukraine it takes 10-210 days from the moment of submission of documents to the competent body to authorize a drug in the country. In addition, only in Ukraine there is the possibility of unlimited re-registration of medicines. In Tajikistan, Turkmenistan and Uzbekistan all medicines are registered for a period of five years, and after this period the applicant must apply for re-registration of the drug in the manner prescribed by law.

 

 

Table 1: The study of organizational approaches in drug registration in Ukraine, Tajikistan, Turkmenistan and Uzbekistan

The parameters analyzed
Ukraine	Tajikistan	Turkmenistan		Uzbekistan
The existence of a unified state authority that issues the registration certificate for a drug
Yes	Yes	Yes		Yes
The types of the drug registration procedure
Centralized (standard); Accelerated standard; Accelerated procedure for mutual recognition (for state purchases of drugs)	Centralized (standard)	Centralized (standard))		Centralized (standard)
The presence of the accelerated mechanism for drug registration
Yes	No		No	No
The possibility of using the simplified scheme for drug registration (re-registration)
Yes	No		No	No
The existence of the procedure for mutual recognition of the data of registration documents for drugs registered in the EU, USA, Canada, Switzerland, Australia and Japan
Yes	No		No	No
The presence of the unified Register of Medicines registered in the country
Yes	Yes		Yes	Yes
Free access to the data of the Register of Medicines registered in the country
Yes	No		No	Yes
The need for registration of medicines prepared in pharmacies by prescription
No	No		No	No
The need for conformity of drug production to the GMP standards
Yes	No		No	No
The time for consideration of the data of the drug registration dossier
210 working days 45 working days 10 days	180 days		Up to 180 days	180 working days
The term of registration of the drug in the country
5 years, after re-registration – unlimited	5 years		5 years	5 years

 

The common feature for all reference countries is the existence of the State Registers of Medicines registered in the country. These Registers are constantly updated. However, in such countries as Turkmenistan and Tajikistan there is no free access for consumers to the data of the Register.

 

Another similar feature in organizing drug registration in reference countries is the fact that there is no need to register extemporaneously compounded medicines prepared in pharmacies according to prescriptions. As can be seen from the data in Table 1, Ukraine is the only reference country, in which when registering medicines documentation confirming that the drug is manufactured in accordance with the GMP requirements must be provided. This legislative norm in drug registration in the country was introduced in 2011.

 

In our opinion, it is interesting to analyze the cost of drug registration in the reference countries (Table 2).

 

 

 

 

 

 

 

 

Table 2: The analysis of the cost for consideration of the data of the drug registration dossier and its registration in Ukraine, Tajikistan, Turkmenistan and Uzbekistan

The cost for consideration of the data of the drug registration dossier and its registration
Ukraine	Tajikistan	Turkmenistan	Uzbekistan
Centralized (standard) procedure: - original drug – 4500 $; - generic drug – 2700 $. Accelerated procedure – 1490 $	Imported drug – 1000 $, additionally for each dose, dosage form and packing – 500$. Domestic drug –150$, additionally for each dose, dosage form and packing – 50$	One trade name of the drug – 1400 $, additionally for each dose, dosage form and packing – 560$	Imported drug – 5000$, changes in the registration dossier – from 500 to 2500$, re-registration of the drug – 2500$. Domestic drug – 250$, changes in the registration dossier – 125 $, re-registration of the drug – 125 $

 

 

Figure 1: The dynamics of changes in the number of drugs registered in the Republic of Uzbekistan since 1996

 

 

Figure 2: The analysis of the dynamics of the number of drugs registered in Ukraine:

 

As a result of the studies it has been determined that the cost of drug registration in all reference countries depends on some factors. For example, in Ukraine this indicator depends on the type of the drug registration procedure and the type of a drug (original drug or generic drug). Thus, to register an original drug (4500 US dollars) by the centralized (standard) procedure in Ukraine is 1.7 times more expensive than a generic drug (2700 US dollars).

 

In Tajikistan and Uzbekistan the cost of registration depends on the origin of the drug, i.e. the drug of domestic or imported companies is registered. For example, the cost of registration for an imported drug in Tajikistan is 1000 US dollars, and for a domestic drug it is 6.7 times less, i.e. 150 US dollars.

 

In Uzbekistan the cost of registration for an imported drug is 5000 US dollars. When registering a domestic drug the applicant must pay to the state budget only 250 US dollars. Therefore, the cost of registering drugs of the Uzbek production is 20 times less than for imported products. Moreover, in Uzbekistan the cost of any change in the data of the registration dossier for a drug differs significantly. Thus, the cost of any change in the dossier for an imported drug varies in the range from 250 to 5000 US dollars, while for a domestic drug the cost of this service is only 125 US dollars. Figure 1 presents the results of the dynamics of changes in the number of drugs registered in Uzbekistan.

Since 1996 in Uzbekistan the number of imported drugs registered in the country increased by 2.2 times compared to the data of 2017 (as of 01.07.2017), drugs manufactured in the CIS countries by 5.1 times, while domestic medicines–by 26.6 times.

 

In Turkmenistan the cost of drug registration does not depend on any factors. The data of Table 2 show that the lowest cost of drug registration is observed in Tajikistan. Thus, to register a drug of domestic production the applicant must pay only 150 US dollars to the state budget of the country.

 

Consequences of introduction of the accelerated drug registration in Ukraine in 2016 on the state of the Ukrainian pharmaceutical market development have not been studied yet in detail. Therefore, it was interesting to analyze the dynamics of changes of the data of drug registration in Ukraine as of 01.07.2017, and as of the corresponding date in the period from 2009 to 2016. Figure 2 presents the analysis of the dynamics of drugs registered in Ukraine within 2009-2017.

 

From 2009 to 2011 there was a systematic increase in the number of drugs registered in Ukraine. It should also be noted that the greatest number of drugs registered in Ukraine for the period from 2009 to 2017 (as of 01.07.2017) was observed in 2014. Thus, in the State Register of Medicines of Ukraine there were 14035 names of drugs in 2014, and it was 32.5% more than in 2009. In the period from 2012 to 2015 the downward trend in the number of drugs presented at the pharmaceutical market of Ukraine was observed. For example, in Ukraine 13244 names of drugs were registered in 2012, while in 2015 there were 12413 drugs. Therefore, the decrease in the number of the names of drugs registered was 6.28%. A positive trend to increase the number of drugs registered in Ukraine was observed since 2016. Furthermore, according to the data of this year the number of registered products amounted 12654 names, it was 1.94% more than according to the data of the previous 2015. An insignificant increase in the number of registered drugs was also observed in 2017. As of 01.07.2017 there were 12898 drugs at the pharmaceutical market, it was 1.93% more than according to the data of 2016. In general, in 2017 there were 485 registered drugs more compared to the data of 2015, it was only 3.91% of the indicators in 2015.

 

DISCUSSION:

For all reference countries the common organizational approach to registration is the existence of a unified state authority that issues the registration certificate for a drug. The absence of the state registration for medicines of pharmacy production is the result of a high degree of confidence of the state and the population to the quality of the drugs prepared under conditions of pharmacies. It should be noted that during the years of the Soviet Union existence the public authorities paid much attention to the organization of production of extemporaneously compounded medicines in pharmacies. In pharmacy production only time-proven magistral formulas were used. It should be noted that when preparing medicines in pharmacies in the former Soviet Union the whole complex of actions, which allowed effectively preventing the production of substandard pharmaceutical products, was used.

 

Analyzing the data of Table 1 it can be argued that Tajikistan, Turkmenistan and Uzbekistan have many common features in organization of registration and re-registration of drugs entering the pharmaceutical market. Primarily, the presence of only one type of the registration procedure, namely the centralized (standard) procedure, can be referred to these common features. In addition, in these countries when registering medicines there is no need to provide documents confirming that the drug is manufactured in accordance with the GMP requirements. The fact that the period of registration for a drug is 5 years is also common for Tajikistan, Turkmenistan and Uzbekistan. In these countries there is no legislative provision on unlimited drug registration. Moreover, it should be noted that among three countries mentioned above Uzbekistan demonstrates significant progress towards the implementation of the European norms and requirements for drug registration. For example, in Uzbekistan there is free consumer access to the data of the State Register of Medicines registered in the country. Special attention should be paid to the state policy of support of the domestic manufacturer of medicines in Uzbekistan. One of the aspects of the state policy of support of domestic drug production is a relatively low cost for registering drugs of the Uzbek production compared to registration of imported medicines. As a result of implementation of this policy in the pharmaceutical sector the number of drugs at the market in general, and in particular domestic products, has been significantly increased. Since 1996 compared to the data of 2017 the number of drugs of the Uzbek production at the pharmaceutical market increased by 26.7 times, while imported products increased only by 2.2 times¹¹.

 

In Ukraine, unlike other reference countries, organizational approaches to drug registration to a greater extent meet the European requirements and standards. Since 2014 there is fundamental change of the norms and requirements for the procedure for drug registration in Ukraine. The legislative norms to simplify the procedure for registration of drugs purchased using state funds for targeted programs of children vaccination were introduced. The requirements for registration of drugs used in the treatment of tuberculosis, HIV infection, AIDS, orphan diseases, viral hepatitis and cancers, as well as medicines for the treatment of wounds in soldiers were simplified significantly. Since 2016 in Ukraine the procedure for accelerated registration of drugs registered in the EU, USA, Switzerland, Australia, Japan was introduced by the centralized procedure. However, it was found that these measures had no significant impact on the dynamics of changes in the number of medicines presented at the Ukrainian pharmaceutical market. The positive dynamics of growth in the number of drugs at the Ukrainian pharmaceutical market observed since 2015 is associated, in our opinion, with stabilization of the situation in the country on the background of stabilization of the national currency. This fact once again emphasizes that the situation at the pharmaceutical market can not be settled only by administrative measures. To stimulate the Ukrainian pharmaceutical market development the introduction of the European standards, which allow accelerating and simplifying the process of drug registration proved to be insufficient.

 

CONCLUSION:

To improve the drug availability at the pharmaceutical market is a complex and multifaceted problem. The pharmaceutical market as a complex and multifunctional structure requires an integrated approach. It is especially important when solving questions of increasing the level of the physical and socio-economic availability of medicines for the population of countries at the stage of reforming their healthcare systems.

 

A number of issues on creation of favorable conditions for development of foreign economic relations between the CIS countries requires special consideration. Thus, the issues of cooperation between operators in the pharmaceutical industry within the CIS market have not yet been fully harmonized and settled. The results of our research will help to assess the level of development of systems of the drug turnover regulation in the reference countries. This will help to form common approaches and principles for the beneficial economic development among countries in the field of import and export of pharmaceutical products. Despite the European integration plans of Ukraine for development, the pharmaceutical market of CIS countries is of strategic importance for the Ukrainian manufacturers of medicines and medical products. Therefore, it seems logical to develop the interstate program for harmonization of requirements for drug registration in the CIS countries. When developing this program it is necessary to use not only the European experience of functioning the systems of the drug turnover regulation, but the existing approaches in functioning the mechanisms for drug registration in the CIS countries. In our opinion, implementation of this program will serve as a specific intermediate link to the integration of the common pharmaceutical market of the CIS countries into the world drug market.

 

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Accepted on 07.03.2018          © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(5):1894-1900.