Clinical Trials in Kazakhstan: Open For Business

You probably don’t think of Kazakhstan when you think of clinical trials? Maybe you should. This brief overview
will help you get acquainted with this emerging clinical trial location. 

At a glance

After Russia, Kazakhstan is the largest of the former Soviet republics and based on the 2016 census has a population of nearly 18 million people. The main population of Kazakhstan is Kazakhs, one of the Turkic peoples of Central Asia. According to Kazakhstan’s Statistics Committee, about 11 million Kazakhs currently reside in Kazakhstan [1].

The local government has made significant strides in promoting public health research in the country [2]. Moreover, a number of recent studies have allowed for a better understanding of both genetic and phenotypic makeup of Kazakhstani population and numerous genes responsible for Absorption, Distribution, Metabolism, and Excretion (ADME) of a large number of therapeutics have been identified for the local ethnic groups [3]. The most common diseases in Kazakhstan are respiratory infections, cardiovascular disorders, tuberculosis, and diabetes.

Obermann et al. concluded that “Kazakhstan has embarked on a large-scale reform of its healthcare system in order to achieve Universal Health Coverage. The health-related 2020 Strategic Development Goals reflect this political ambition” [4]. Continuing the trend, the Kazakhstan-2030 national strategy defines health of its citizens is as one of the main long-term priorities in Kazakhstan’s development [5].

Country overview

Kazakhstan is geographically diverse, comprised of extensive grassland, semi-desert, and mountainous areas

covering almost three million square kilometers. Kazakhstan lies above the rest of Central Asian republics and is bordered by Russia to the north, China to the east, Kyrgyzstan and Uzbekistan to the south, and the Caspian Sea
and part of Turkmenistan to the west. It has almost 1,894 km of coastline on the Caspian Sea.  The capital of Kazakhstan is Astana. Other principal cities are Almaty, Karaganda, Pavlodar, Aktobe, Atyrau, and Shymkent. Kazakh is the official language, and Russian is the language of international communication. Tenge (KZT) is the national currency. The country is part of Eurasian Economic Union (EAEU) that allows for simplified logistics with its neighboring Armenia, Belarus, Kyrgyzstan and Russia. EAEU member states have recently harmonized its rules and regulations as they pertain to the conduct of clinical trials and to drug registration process.

Healthcare system

The health care system of Kazakhstan was developed and implemented based on the Soviet model, which was focused on early transition to specialized care, while primary care sector and preventive services received less attention. For the last several years the Kazakhstani health care delivery system has been undergoing significant reorganization. The purpose of this reorganization is to bolster primary care through investments into that sector and by training more general practitioners [6]. Kazakhstan is home to six medical schools and the recently established Nazarbayev University School of Medicine has adapted a US-style curriculum that is being taught in English. Based on the 2016 government statistics report, Kazakhstan has 877 hospitals and around 100,000 hospital beds (Table 1). Please note the recent trend towards reduction of hospital stays and emphasis on outpatient and preventive care.

Table 1. Main characteristics of Kazakhstan’s public health sector

While all citizens are entitled to universal healthcare, the free health care system remains rather basic, which has led to the emergence of a private medical sector. While the private sector is still relatively small, it is growing quickly and is starting to fill the unmet need for higher quality healthcare.

On March 31, 2010 the Ministry of Healthcare (MoH) issued order #222 listing all clinical sites that are permitted to conduct clinical trials. Unfortunately, to date the list covers only large medical and scientific centers in major cities and excludes private medical sector.

Clinical trials

Kazakhstan is definitely a newcomer on the clinical trial arena with the first international clinical trials being initiated in 2009. However, in the last five years, the interest towards Kazakhstan and the number of completed and ongoing clinical trials has been growing exponentially. Currently, there are approximately 20 late stage clinical trials being conducted in the country by such companies as Abbvie, Bayer, Merck, St. Jude Medical, Terumo Europe NV, and Thoratec.

Figure 1. Clinical trials in Kazakhstan by phases according to National Center for Expertise of Medicines, Medical Devices and Medical Equipment

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Figure 2. Сlinical trials in Kazakhstan by therapeutic areas: 2014-2016

Initial dossier for study approval

List of documents submitted to Regulatory Authorities (RA) for study approval is provided below:

· Apostilled Power of Attorney (PoA) with clearly specified rights if clinical trial applicant is not its sponsor

· Notarized translation of the PoA

· Cover letter according to a provided template

· Certificate of Product Origin

· Documents on quality, manufacture, and control of the Investigational Medicinal Product (IMP)

· Available safety information on the IMP

· Certificate of Analysis of the IMP from the Pharmacopoeia Center

· Clinical Trial Protocol (CTP) signed by both sponsor and investigator

· Investigator’s Brochure (IB) and IMP Information leaflets for providers

· Informed Consent Form (ICF)

· Patient information

· CRF (where applicable)

· Investigators’ current Curriculum Vitae and/or other documents, confirming their qualifications

· Proof of payment of administrative fee

· Advertisement materials to be used for recruitment of study participants (if applicable)

· Health insurance policy for study participants

Regulatory authorities and submission / approval processes (see also Table 2)

· The applicant submits the aforementioned documents to the National Center for Expertise of Medicines, Medical Devices and Medical Equipment (National Center)

· After positive outcome of pre-assessment phase, the applicant submits a Clinical Trial Application (CTA) to the Republican Center for Health Development - Central Commission for Ethics (CEC), which is mandatory for all clinical studies conducted in Kazakhstan. If a there exists a local ethics committee at the clinical trial site, then its approval is also mandatory

· The applicant submits the results of ethics evaluation to the National Center

· The National Center issues a positive opinion and transfers the file to the MoH

· The MoH is obligated to provide a final decision on the CTA within 10 days

· After receipt of positive decision from the MoH, the National Center approves the CTP and informs the applicant that the CTA has been approved

· Export/import license for medicinal products and clinical trial materials is granted as part of the approval process

Table 2. Average clinical trial start-up times in Kazakhstan

Specific features of study start-up in Kazakhstan

· For transnational clinical studies, the universal guidance for patient insurance is applicable

· The study protocol and investigator brochure should be submitted in both English and Russian and all the documents which are distributed to patients (informed consent forms, patient information sheets, questionnaires, etc.) should be provided in both Kazakh and Russian languages

Kazakhstan experiences

In our company’s experience, there is still significant variability in the approval times between the studies that range from 3 to 7 months.

Upon payment of administrative fees the National Center must respond with an approval or denial within 30 days. In some cases, the National Center may have additional questions. If such questions arise, the applicant has 90 days to submit a response. If the applicant cannot meet the 90-day deadline, then a request for extension must be submitted. In order to avoid these delays, it helps to establish an open line of communication with the National Center and to conduct pre-submission consultations.

Upon receipt of a positive feedback from the National Center, the MoH should issue final decision within 10 days. However, based on recent experience, this can take up to two months. Again, early discussions with the representatives of the MoH can be very useful and can help expedite this process.

Another caveat relates to sequential submission to the National Center first and then to the Central Ethics Committee. However, the National Center always asks for the CEC’s position. Thus, it makes sense to submit to the CEC in parallel with the submission to the National Center.

References:

[1] Ministry of National Economy of the Republic of Kazakhstan. Committee on Statistics. Available at: http://www.stat.gov.kz/ (2015). Accessed 19 June 2015.

[2] Mahendradhata Y, Nabieva J, Ahmad RA, et al. Promoting good health research practice in low- and middle-income countries. Global Health Action. 2016;9:10.3402/gha.v9.32474. doi:10.3402/gha.v9.32474.

[3] Iskakova AN, Romanova AA, Aitkulova AM, Sikhayeva NS, Zholdybayeva EV, Ramanculov EM. Polymorphisms in genes involved in the absorption, distribution, metabolism, and excretion of drugs in the Kazakhs of Kazakhstan. BMC Genetics. 2016;17:23. doi:10.1186/s12863-016-0329-x.

[4] Obermann K,  Chanturidze T, Richardson E, et al. Data for development in health: a case study and monitoring framework from Kazakhstan. BMJ Global Health 2016;1:e000003. doi:10.1136/bmjgh-2015-000003

[5] Kulzhanov M, Rechel B. Kazakhstan: Health system review. Health Systems in Transition, 2007; 9(7): 1–158.

[6] Kumar AB, Izekenova A, Abikulova A. Inpatient care in Kazakhstan: A comparative analysis. Journal of Research in Medical Sciences : The Official Journal of Isfahan University of Medical Sciences. 2013;18(7):549-553.

Vlad Bogin, MD, FACP is CEO of Cromos Pharma.