Antiretroviral Drugs: Analysis of Ukrainian pharmaceutical market and Intellectual Property

 

Elena Vyacheslavna Litvinova^1*, Olga Viktorovna Posilkina²

¹Candidate of Biology (PhD), Associate Professor of the National University of Pharmacy, Kharkov, Ukraine

²Doctor of Pharmacy, Professor of the National Pharmaceutical University, Kharkov, Ukraine

 

ABSTRACT:

The aim of this study was to analyze Ukrainian pharmaceutical market and patent protection of antiretroviral drugs in Ukraine and abroad. It has established that in Ukraine most of medicines are foreign antiretroviral drugs under patent protection. Take into account the prevalence of HIV in Ukraine the introduction into clinical practice domestic generic antiretroviral drugs which included in clinical guidelines for the management of HIV and AIDS in adults and adoloscents and have obvious economic benefits is prospect and economically reasonable. It has found out that the most negative risks of commercialization antiretroviral drugs which influence on their access for patients with HIV are next risks: high cost of foreign antiretroviral drugs; lack of original domestic antiretroviral drugs; sharp rise in antiretroviral drug prices as a result of switch to second- and third line therapy; patent protection and monopolization of antiretroviral drugs; exclusivity data of clinical trials. It has proved that the use of the flexible mechanisms of the TRIPS Agreement in Ukraine, namely involving the grant of compulsory licenses, the implementation of parallel imports, the tightening of the criteria for patentability is necessary for increase of antiretroviral drugs access for patients with HIV infection.

 

 

 

 

 

INTRODUCTION:

Human immunodeficiency virus (HIV) continues to be a major global public health issue, having claimed more than 35 million lives so far. In 2015, 1.1 (940 000–1.3 million) million people died from HIV-related causes globally. There were approximately 36.7 (34.0–39.8) million people living with HIV at the end of 2015 with 2.1 (1.8–2.4) million people becoming newly infected with HIV in 2015 globally [1].

 

Ukraine has experienced one of the worst HIV epidemics in Eastern Europe and Central Asia. Of the total country population of 45.5 million, there were estimated 234 thousand people living with HIV by 2014. Of these, a total of 137970 people were registered and alive by end of 2014 (i.e. approximately 58.5% of the estimated HIV burden) with 19273 new people registered during 2014 alone [2].

 

At the present time there are three groups of antiretroviral drugs that can affect on HIV enzymes-reverse transcriptase and protease, as well as drugs blocking viral entry into human cells [3-4].

 

Antiretroviral drugs of the first group are nucleoside reverse transcriptase inhibitors. They are “defective” analogues of the naturally occurring nucleosides needed to synthesize the viral DNA and they compete with the natural nucleosides for incorporation into the growing viral DNA chain. Thus, when nucleoside reverse transcriptase inhibitors are incorporated, viral DNA synthesis is halted, a process known as chain termination. Drugs of this group can be divided into the following groups: thymidine analogues – zidovudine, stavudine; cytidine analogues – zalcitabine, lamivudine, emtricitabine; adenine analogues – didanosine; guanine analogs – abacavir; combination of drugs – zidovudine + lamivudine; zidovudine + lamivudine + abacavir.

 

Antiretroviral drugs of the first group also include nucleotide reverse transcriptase inhibitors: thymidine analogues – phosphaside; adenine analogues – tenofovir.

 

Antiretroviral drugs of the second group include non nucleoside reverse transcriptase inhibitors. These drugs are incorporated into the active site of virus enzyme and thus blocking further construction of HIV RNA. Physicians have the following antiretroviral drugs of this group: nevirapine, efavirenz, delaverdin etc.

 

Antiretroviral drugs of the third group are HIV protease inhibitors, which block the active site of the viral protease and disrupt the formation of viral proteins: saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, atazanavir, combination drug Kaletra (lopinavir and ritonavir) etc. This group includes also integrase inhibitors; fusion inhibitors; receptor inhibitors.

 

However, it will be noted that the cost of combination antiretroviral therapy remains high. Antiretroviral drugs of latest-generation are more expensive drugs because of patent protection.

 

The aim of this study was to analyze Ukrainian pharmaceutical market and patent protection of antiretroviral drugs in Ukraine and abroad.

 

EXPERIMENTAL:

Studies were conducted using a databases on the Internet: Ukrainian patent office, the European patent office, the US patent office, the Food and drug administration, European Medicines Agency (EMEA), State enterprise “The State Expert Center” of the Ministry of Health of Ukraine. It was studied the main sources of international patent law and Ukrainian law connecting with intellectual property. It has used retrospective, logical, systematic and analytical methods.

 

RESULTS AND DISCUSSION:

It has carried out the analysis of Ukrainian pharmaceutical market structure of generic and original antiretroviral drugs. It has established that 23% original foreign antiretroviral drugs have registered in Ukraine. Unfortunately, domestic original antiretroviral drugs are absent. The percentage of foreign generic antiretroviral drugs in Ukrainian market – 65%, and domestic generic antiretroviral drugs are 12%.

It has established, that 9 original foreign antiretroviral drugs of the first group (nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors) have registered in Ukraine; foreign generic antiretroviral drugs of the first group include 32 drugs; and domestic generic antiretroviral drugs  of the first group are 5 drugs (which include zidovudine – 3,  lamivudine – 2).

 

There are 2 original foreign antiretroviral drugs of the second group (non nucleoside reverse transcriptase inhibitors), 14 foreign generic antiretroviral drugs and 2 domestic generic antiretroviral drugs of the second group in Ukraine.

 

6 original foreign antiretroviral drugs of the third group (HIV protease inhibitors, integrase inhibitors; receptor inhibitors) are represented in Ukrainian pharmaceutical market. There are also 2 generic foreign antiretroviral drugs of the third group and 2 domestic generic antiretroviral drugs (Aluvia is prodused by Ukrainian pharmaceutical company “Indar” in partnership with Abbvie Deutschland GmbH & Co. KG, Germany).

 

Represented data suggests that domestic original antiretroviral drugs are absent in Ukrainian pharmaceutical market and domestic generic antiretroviral drugs are not enough and they mainly cover only 2 groups: nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors; non nucleoside reverse transcriptase inhibitors.

 

It has carried out the analysis and systematization of patenting of major groups of domestic and foreign antiretroviral drugs, which are registered in Ukraine (table 1). It should be noted that most of these antiretroviral drugs are included in clinical guidelines for the management of HIV and AIDS in adults and adolescents.

 

It has established that the implementation of international standards of intellectual property in Ukraine has facilitated registration of foreign original antiretroviral drugs, which occupy a significant share of Ukrainin pharmaceutical market and they are under patent protection, or have a period of exclusive rights. It should be noted that the price of foreign original antiretroviral drugs exceeds in value of domestic generic drugs in several times.

 

It has carried out expert survey to determine the risks of commercialization antiretroviral drugs which influence on their access for patients with HIV. Experts were researchers with practical experience in medicine and pharmacy (Figure 1).

 

Table 1. Antiretroviral drugs are registered in Ukraine

Active pharmaceutical ingredient	Proprietary name of original drug; dosage form; applicant holder full name	Countries of the foreign manu-facturers of generic drugs	National manufacturers of generic drugs	Patent data, patent expiration	Pediatric exclusivity data expiration
1	2	3	4	5	6
Nucleoside and nucleotide reverse transcriptase inhibitors
Zidovudine	Retrovir, syrup, tablet, injection, Viiv Healthcare co	India	„Pharmaceutical firm „Darnytsa”, PJSC “Technolog”, “Yuria-Pharm”	There are no unexpired patents for this product	There is no unexpired exclusivity for this product
Zidovudine + lamivudine	Combivir, tablet, Viiv Healthcare co.	India	„Pharmaceutical firm „Darnytsa”	There are no unexpired patents for this product	There is no unexpired exclusivity for this product
Abacavir+ lamivudine+ zidovudine	Trizivir, tablet, Viiv Healthcare co	–	–	US6294540 14.05.2018; UA56231 14.05.2023	14.11.2018
Lamivudine	Epivir, solution, Viiv Healthcare co	India, Canada	„Pharmaceutical firm „Darnytsa”, PJSC “Technolog”	UA60328 20.03.2023	There is no unexpired exclusivity for this product
Abacavir+ Lamivudine	Epzicom, (Kivexa) tablet, Viiv Healthcare co	–	–	US6294540 14.05.2018; UA56231 14.05.2023	14.11.2018
Abacavir+ dolutegravir+ lamivudine	Triumeq, tablet; Viiv Healthcare co	–	–	US6294540 14.05.2018; UA56231 14.05.2023	14.11.2018
Abacavir	Ziagen, solution, tablet, Viiv healthcare co	India	–	US6294540 14.05.2018; UA56231 14.05.2023	14.11.2018 04.08.2019
Stavudine	Zerit XR, capsule, extended release; Bristol Myers Squibb co (It has not registered in Ukraine)	India	–	There are no unexpired patents for this product	18.08.2023
Tenofovir	Viread, tablet, Gilead Sciences inc	India	–	WO2002008241 20.07.2021; UA75889 15.06.2031	25.01.2018

 

1	2	3	4	5	6
Emtricitabine+ tenofovir	Truvada, tablet, Gilead Sciences inc	India	–	US5914331 02.02.2017 US6642245 04.05.2021 US6703396 09.09.2021 UA81797 30.01.2033	02.11.2017 04.11.2021 09.03.2022
Non Nucleoside Reverse Transcriptase Inhibitor
Nevirapine	Viramune, suspension,  Boehringer Ingelheim Pharmaceuti-cals inc (It has not registered in Ukraine)	India	„Pharmaceutical firm „Darnytsa”	WO2008154234 04.06.2028; UA44370 11.08.2023 UA97971 04.06.2023	There is no unexpired exclusivity for this product
Zidovudine + lamivudine + nevirapine	Zidolam-N, tablet, Hetero drugs limited, India (It has not registered in Ukraine)	India	–	WO2008154234 04.06.2028 UA44370 11.08.2023 UA97971 04.06.2023	There is no unexpired exclusivity for this product
Efavirenz	Sustiva, tablet, Bristol myers squibb co (it has not registered in Ukraine)	India	Pharmaceutical company “Zdorovie”	UA42699 06.05.2018	14.08.2018 20.07.2018
Efavirenz+ emtricitabine+ tenofovir	Atripla, tablet, Gilead sciences inc	–	–	WO200613593 13.06.2026	02.01. 2018 25.01.2018 14.08.2018 04.05.2021 09.09.2021 09.09.2021
Etravirine	Intelence, tablet, Janssen research and development llc	–	–	US7887845 25.03.2019 US7037917 13.12.2020 UA74797 31.08.2020	There is no unexpired exclusivity for this product
HIV protease inhibitor, integrase inhibitor, receptor inhibitor
Ritonavir	Norvir,  capsule; Abbvie inc	India	–	US7432294 22.11.2020 WO200000401630.03, 2020	07.05.2018 22.11.2020 22.11.2020
Lopinavir+ ritonavir	Kaletra, oral solution, Abbvie inc	Germany	Abbvie inc + PrJSC “Indar”	US7432294 22.11.2020 UA85564 10.02.2024	28.05.2022
Fosamprenavir	Lexiva (Telzir), oral suspension, Viiv healthcare co	–	–	US6436989 24.06.2018 UA72733 15.04.2023	24.06.2018 15.01.2020
Darunavir	Prezista, oral suspension; Janssen products lp	–	–	US8518987 16.02.2024 UA100835 11.02.2025	23.12.2019 26.06. 2027 23.12. 2019
Raltegravir	Isentress, tablet, Merck sharp and dohme corp	–	Lumier Pharma LLC	US7169780 03.10.2023 UA77454 15.12.2024 UA87884 25.08.2029	There is no unexpired exclusivity for this product
Lamivudine+ raltegravir	Dutrebis, tablet; Merck sharp and dohme corp (it has not registered in Ukraine)	–	–	US7169780 03.10.2023 UA77454 15.12.2024 UA87884 25.08.2029	There is no unexpired exclusivity for this product
Maraviroc	Selzentry, tablet, Viiv healthcare co	–	–	US6586430 01.12.2019 US7576097 25.05.2021 UA72750 15.04.2025	There is no unexpired exclusivity for this product

Note: US – Patent US, UA – Ukrainian Patent, WO – International Application

 

Figure 1. Risks of commercialization  antiretroviral drugs which influence on their access for patients with HIV

 

Z6 – high cost of foreign antiretroviral drugs; Z8 - lack of original domestic antiretroviral drugs; Z4 –sharp rise in antiretroviral drug prices as a result of switch to second- and third line therapy; Z2 – patent protection and monopolization of antiretroviral drugs; Z1 – exclusivity data of clinical trials; Z7 - extension of patent term; Z10 - HIV drug resistance; Z9 – search of sponsor for investigations; Z3 - pharmaceutical market research; Z5 - technology transfer.

 

The result is that the most negative risks of commercialization  antiretroviral drugs which influence on their access for patients with HIV are next risks: Z6 – high cost of foreign antiretroviral drugs; Z8 - lack of original domestic antiretroviral drugs; Z4 – sharp rise in antiretroviral drug prices as a result of switch to second- and third line therapy; Z2 – patent protection and monopolization of antiretroviral drugs; Z1 – exclusivity data of clinical trials.

 

Take into account the limited availability of antiretroviral drugs for patients, the social importance, the high prevalence of HIV infection it has established prospect is the introduction into medical practice of effective domestic generic antiretroviral drugs. This is necessary to implement flexible mechanisms of international Agreement on trade-related aspects of intellectual property rights (TRIPS) in Ukraine. TRIPS allows countries to apply the flexible approach to the protection of intellectual property rights, including granting of compulsory licenses [5, 6].

 

Added to this is the fact that TRIPS encourages tighten control over patent grant on medicines, to exclude the possibility of patenting of inventions that do not meet the criteria of novelty, inventive step (for example, minor changes in the composition, dosage) [7].

 

Аccording to Article 39 of TRIPS, countries that have ratified it, protect clinical trial data against unfair commercial use. Thus, in addition to a 20-year patent for drugs, there is a regime of “data exclusivity”, which should be determined by the date of first marketing authorization for the implementation of the drug. If the term of data exclusivity within 20 patent protection, it does not affect the time of generic drug launch. If, however, the first marketing authorization has obtained for implementation at the end of the 20 year term of the patent, the term of drug protection lasts for the duration of “data exclusivity”. Thus, patent protection and data exclusivity independent of each other and cannot coincide in time. Comparing of exclusivity regimes in the United States and the European Union are given in Table 2 [8-10].

 

Table 2. Comparing of exclusivity regimes in the United States and the European Union

United States

European Union

ü  new chemical entity exclusivity – 5 years; ü  orphan drug exclusivity – 7 years; ü  other exclusivity (new dosage, mode of administration and indications) – 3 years; ü  pediatric exclusivity – 6 month; ü  180-day exclusivity – provides an incentive of 180 days of market exclusivity to the “first” generic applicant.

The “new rules” follow an “8 + 2 + 1” year approach: ü  During the first 8 years from the grant of the innovator company's marketing authorisation, data exclusivity applies. ü  After the 8 years have expired a generic company can make use of the pre-clinical and clinical trial data of the originator in their regulatory applications, but still cannot market their product. ü  After a period of 10 years from the grant of the innovator company's marketing authorisation, the generic company can also market their product, unless the innovator product qualifies for a further one year of exclusivity.  ü  This additional 1 year may be obtained in a number of circumstances, such as where the innovator company is granted a marketing authorisation for a significant new indication for the relevant medicinal product. In such a situation the generic company can only market their product after 11 years from the grant of the innovator company's marketing authorisation. ü   pediatric exclusivity – 6 month; ü  orphan drug exclusivity – an additional 2 years of market exclusivity can be granted to pediatric orphan drugs (for a total of 12 years).

 

Provisions of TRIPS connecting with exclusivity regime is provided for in article 9 of Ukrainine law “On medicines”. If the medicinal product has been registered in Ukraine it is prohibited to use the registration information for submission of the application for state registration of another medicinal product during five years of the day of such registration (regardless of the validity period of any patent related to the medicinal product). This term may be prolonged up to six years if within the first three years after state registration of the reference/original medicinal product the central executive body, which implements state policy for health care, allowed its use for one or more of its indications which are considered as having significant advantages over existing ones. The central executive body, which ensures development of state policy for health care, shall establish rules and criteria for specifying indications having significant advantages over existing ones. It should be noted that the current exclusivity regime in Ukraine ignores characteristics of drugs (eg drugs to treat rare diseases, pediatric drugs etc).

 

It will be remarked that Ukrainian national policy connecting with the treatment and prevention of HIV has to consider condition of TRIPS – parallel imports, giving significant benefits in terms of public health and individual health.

It has established recommendations for reducing risks of commercialization  antiretroviral drugs which influence on their access for patients with HIV (Table 3).

 

 

Table 3. Recommendations for reducing risks of commercialization  antiretroviral drugs which influence on their access for patients with HIV

Risks	Recommendations
Z6 – high cost of foreign antiretroviral drugs	The implementation of Ukrainian National AIDS programme The implementation of flexible mechanisms of international Agreement TRIPS
Z8 - lack of original domestic antiretroviral drugs	The innovation activity diversification of national pharmaceutical companies, universities, research institutions
Z4 – sharp rise in antiretroviral drug prices as a result of switch to second- and third line therapy	The implementation of domestic generic domestic antiretroviral drugs
Z2 – patent protection and monopolization of antiretroviral drugs	With the purpose to protect the health of population, ecological safety and other public interests, the Cabinet of Ministers of Ukraine may permit the use of the patented invention Eliminate the possibility of patenting minor changes dosage form, dose regimen of antiretroviral drugs
Z1 – exclusivity data of clinical trials	The use of compulsory licensing practices
Z7 – extension of patent term	Using the practice of parallel imports
Z10 – HIV drug resistance	Adhere to clinical guidelines for the management of HIV and AIDS in adults and adoloscents
Z9 – search of sponsor for investigations	Government funding of research, consortium of pharmaceutical companies
Z3 – pharmaceutical market research	Assignment of risk to technology transfer offices
Z5 – technology transfer	Fair and reasonable contract negotiation

 

Taking into consideration the above the analysis of patent protection of antiretroviral drugs and patent law connecting with availability of antiretroviral drugs in Ukraine and abroad suggests untapped resources and opportunities for domestic pharmaceutical companies to provide public antiretroviral drug supply.

 

CONCLUSION:

1. Analysis of the Ukrainian pharmaceutical market structure of antiretroviral drugs has established that most of medicines are foreign antiretroviral drugs under patent protection. Take into account the prevalence of HIV in Ukraine the introduction into clinical practice domestic generic antiretroviral drugs which included in clinical guidelines for the management of HIV and AIDS in adults and adolescents and have obvious economic benefits is prospect and economically reasonable.

 

2. It has found out that the most negative risks of commercialization antiretroviral drugs which influence on their access for patients with HIV are next risks: high cost of foreign antiretroviral drugs; lack of original domestic antiretroviral drugs; sharp rise in antiretroviral drug prices as a result of switch to second- and third line therapy; patent protection and monopolization of antiretroviral drugs; exclusivity data of clinical trials.

 

3. In the field of intellectual property it has proved that the use of the flexible mechanisms of the TRIPS Agreement in Ukraine, namely involving the grant of compulsory licenses, the implementation of parallel imports, the tightening of the criteria for patentability is necessary for increase of antiretroviral drugs access for patients with HIV infection.

 

REFERENCES:

1.       HIV/AIDS News-bulletin, N 360, 2016. Available from: URL: http://www.who.int/mediacentre/factsheets/fs360/en/

2.       Overview: antiretroviral therapy in Ukraine. Available from: URL: http://ecuo.org/media/filer_public/2016/03/29/8_ukraine_art_mapping_rus.pdf

3.       Kalapila AG, Marrazzo J. Antiretroviral Therapy for Prevention of Human Immunodeficiency Virus Infection. Med Clin North Am. 100(4); 2016: 927-950. doi: 10.1016/j.mcna.2016.03.013.

4.       Bartlett JG, Gallant JE. Medical management of HIV-infection. Johns Hopkins University, 2012.

5.       Agreement on trade-related aspects of intellectual property rights. Available from:  URL: https://www.wto.org/english/docs_e/legal_e/27-trips.pdf.

6.       Pascual F. Intellectual property rights, market competition and access to affordable antiretrovirals. Antivir Ther. 19 Suppl 3; 2014: 57-67. doi: 10.3851/IMP2901.

7.       Amin T, Kesselheim AS. Secondary patenting of branded pharmaceuticals: a case study of how patents on two HIV drugs could be extended for decades. Health Aff (Millwood). 31(10); 2012: 2286-2294. doi: 10.1377/hlthaff.2012.0107.

8.       Patents and Exclusivity. Available from: URL: http://www.fda.gov/downloads/drugs/developmentapprovalprocess/smallbusinessassistance/ucm447307.pdf

9.       EMA Procedural advice for users of the centralised  procedure for generic/hybrid applications. Available from: URL: http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004018.pdf

10.     Ravi HM, Dilip G. Maheshwari regulatory exclusivity strategies: further protection for pharmaceuticals in US, Europe and Japan. World journal of pharmacy and pharmaceutical sciences Vol 4, Issue 02; 2015:  971-992.

 

 

 

Accepted on 05.02.2017          © RJPT All right reserved