CC BY
11
Вестник КазНМУ, №2(2)- 2014
УДК 616 (075.8)
K.S. KHAZHIDINOV, A.A. AZEMBAYEV, A.B ABZHALELOV
Republic of Kazakhstan
REPUBLICAN STATE ENTERPRISE "SCIENTIFIC CENTRE FOR ANTI-INFECTIOUS DRUGS"
1. Conducting of clinical trials needs further improvements in the Republic of Kazakhstan to create favourable environment in the field.
2. Implementation of Good Clinical Practice in the Republic of Kazakhstan necessitates complex approach with respect to the national, Custom Union, and international standards.
Keywords: Development of new medical products; Good clinical practice ICH GCP; clinical site; central and local ethics committee, clinical research specialist.
Final milestone in the development of the pharmaceutical drug is clinical trials. The quality of clinical trials process depends on various factors such as regulatory framework, educated and experienced research staff, and clinical sites which are in compliance with international standards. In accordance with ICH E6R1 guideline "Good Clinical Practice" primary responsibility for conducting clinical trials remains with clinical trial Sponsor; other parties, such as Contract Research Organizations, investigators, clinical site's staff, monitors, auditors, regulatory authorities, local and central ethics committees, and trial subjects also bear some responsibilities during the trials. In the Republic of Kazakhstan GCP international standard was implemented and harmonized in 2006 as a result the State Standard of Republic of Kazakhstan CT PK "Good clinical practice. Main provisions" has been established [1]. Performance of the clinical trials in Kazakhstan becomes complicated due to several factors related to different parts along the process:
1. Staff The root of the problem with respect to national qualified and educated specialist on the field conducting and organizing clinical trials lies in the educational program of medical students; in other words we lack 'clinical research administration' speciality at our medical institutions. Educational program of medical specialists should not be limited to the fundamental of medical disciplines; in spite, it should be extended to the subjects as ethical issues in clinical researches, data management, clinical research documents arrangement, pharmaceutical drug development, and the role of the human, statistical aspects, controlling of clinical trial process, and others. Current graduates of the national medical universities are pure practical clinicians without research skills.
Clinicians participating in clinical trials bear special responsibilities that require presence of knowledge, experience, and skills; otherwise investigator becomes more dangerous to the trial subjects than testing drugs with respect to safety concerns. The requirements are stated in ICH GCP E6R1 [2], and investigators recruited for the trials should absolutely meet those requirements; unfortunately, such specialists are rare for Kazakhstan. Due to absence of experience, special qualifications, and weak legislation investigator could be dangerous for the trial subjects; and mistakes or GCP breaches made by them could be left unpunished. Regulatory frameworks of developed countries like United States of America Food and Drug Administration 21 CFR 312 include provisions concerning penalties to be applied for negligent harm made by investigators; moreover, the grey list practice helps drug developers to avoid employing investigators who were suspicious of malpractice or unethical behaviour. [3] Those penalties vary significantly and include, but not limited to, withdrawal from the trial and even recall of medical licence. Medical and Healthcare products Regulatory Agency in United Kingdom launched Guidance for the Notification of Serious Breaches of GCP or the Trial Protocol which also includes sanctions against GCP breaches and negligent harm [4]. Factors mentioned above concerning lack of the appropriately qualified specialists could lead to negligent or non-negligent behaviour due to unawareness of the latter; that is why regulatory authorities should pay more attention to this issue.
2. Clinical sites and Ethical committees Next problem, which is not less important, is the absence of clinical sites that could afford conduct of clinical trials starting from protocol development and ethical-regulatory submissions to the final report writing, which
would meet requirements of ICH E3 guideline "Clinical trial report". In such circumstances often national drug developers purchase costly services from near and far abroad specialists, or even conducting trials out of the republic. To ensure safety of clinical trial subjects the clinical sites should have sufficient staff and material resources to maintain continuous progress of the trials. The order # 222 released by Ministry of Healthcare in 31st March 2010 was the list of clinical sites permitted for conducting of clinical trials established [5]. This order raises some controversies because each medical organization, which had available staff and facilities resources could and should conduct, or at least participate, in multi-central clinical trials. Unfortunately, the above mentioned list covered only huge medical and scientific centers in big cities, automatically excluding rural medical centers and other medical organizations from the field of ordinal clinical practices. As a result rural population, representing significant part of commonwealth, can not participate in trials; and thus, they could not benefit from the development of new agents targeted for treatment of diseases inherent by them. Results of clinical trials conducted in urban conditions can not be successfully extrapolated to the rural population. Existence of the list of clinical sites permitted to participation in clinical trials implies the existence of some requirements for the sites and personnel, who conduct assessment of sites; unfortunately, such requirement still absent. Since the Republic of Kazakhstan is quite young developing country, it is preferable to use experience of developed regions such as EU and US and actualize and harmonize Euro commission's EudraLex Volume 10 regulations that cover all aspects and issues related to clinical trial [6].
Today clinical site should have group of specialists to conduct successful clinical trials that includes but not limits to: experienced investigators, who could act as Principal Investigator, experienced pharmacist, who could dispense testing drugs without breach of blinding and keeping allocation concealment, managers, who would be able to organize the whole process, IT supportive staff, data entering staff, and others. Thus, for high quality clinical trial the clinical site requires group of specialist, which is not currently presented. Nevertheless, pharmaceutical organizations conducting trials in the Kazakhstan are investing into staff in order to obtain valuable results.
Weak chain in the clinical trial process as in other developed countries is low quality laboratory assays due to absence of educated specialists or good facilities and equipment. Although theoretically state laboratories are following ISO 15189 standards in their work, often on practice state of things is controversial; therefore, Sponsors are additionally investing in laboratories. Clinical sites should have minimal hardware equipment to meet nowadays requirements since the part of the work relates to the data entry lies on the shoulders of investigators. Clinical site should have Independent Ethics Committee acting in sake of subjects' rights protection by reviewing clinical trial documents. Central ethics committee to ensure proper work performance should control activities of such committees. With respect to ICH E6R1 GCP these committees should consist of qualified, experienced specialists from the field; however, due to the recent emergence of the drug development activities such specialists are still absent in our republic. The order # 425 released by Ministry of Healthcare in 30th of July 2008 concerning central and
BecmuK Ka3HMY, №2(2)- 2014
local ethics committees reflects common terms, structure and procedures, and lacks of particular requirements for members' experience, qualification, education and conventional methods of ethical assessment [7]. Due to the absence of methods for risk assessment used by ethics committees, procedures for protocol analysis should be standardized and implemented on the regulatory level to exclude the possibility of subjective assessment by IEC members. Weak awareness of actual functions of IEC members could lead to overlap of regulatory authorities and ethical IEC functions, which might result in prolonging of regulatory approval process that could take at least 6 months. Differentiating of functions would let to accelerate approval process, by delegating functions of risk assessment to ethical committees and methodological assessments to regulatory authorities. 3. Regulatory framework One of the main issues in good quality clinical trials is carefully following regulatory requirements. Legislation in clinical trials in the Republic of Kazakhstan is still quite weak and it requires further efforts and investments. Currently, there are two regulatory documents: first is CT PK 1616-2006 mentioned above, and the other is Order # 744 released by Ministry of Healthcare in 19th of November in 2009 "Regulations concerning researches and/or trials of drugs, medical equipment and medically oriented goods" [8]. These documents are the first step, which should be followed by complete implementation of all guidelines recommended by International Conference on Harmonization. ICH GCP E6R1 states "...Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy.". Since clinical trial involves human investigators it should be assured that such trial is innovative | and does not place subject under the risk, by conducting_ replication of previous trials, by the other word research experiments should be based on previous experience of scientific society. It could be realized by examining international study databases, such as Clinicaltrials.gov or others;that each investigator has scientific | responsibility for registration of trials in international databases to contribute to the world knowledge and in sake of protection of the subjects' rights. Unfortunately, presently there are no obligations placed behind investigators to register their trials and report results of the trials by publishing them in scientific journals. As it was mentioned before, regulations lack penalties for the negligent or other harms made to the subject in the course of participation in clinical trials. In order to control breach of GCP, regulatory authority should establish guidelines or standards, which cover different types of malfunctions. Such standards should be implemented in order to prevent biased subjective inspections. Since we are developing country and we have modern independent history of only 20 years, the presence of regulations is a matter of time; nevertheless, actions toward resolution should be taken today. As support and example, Kazakhstan could base its regulations in the field of quality control and inspection on directives released by European Union such as «RECOMMENDATIONS ON THE QUALIFICATIONS OF INSPECTORS VERIFYING COMPLIANCE IN CLINICAL TRIALS WITH THE PROVISIONS OF GOOD CLINICAL PRACTICE» [9].
Some controversies persist between two regulatory documents such as Standard 1616-2006 and Order # 744. Particularly, the insurance and indemnity issue seems to be controversial. Due to the
expensiveness of the drug development for government, some countries' regulatory authorities do not require costly commercial insurance to be purchased by governmental and non-profit organizations by limiting the requirements on legal and financial indemnities [10]. This is not a breach of GCP because it includes both options. While harmonization of ICH E6R1 GCP guideline in the form of state standard 1616-2006 both insurance and indemnities were left as an option;however, Order # 744 requires only insurance without differentiating, commercial and governmental organization. Spending great amount of money on insurance services for trials, which are financed by government, is quite undesirable due to its high cost. Moreover, money could have been granted for new drug development in rare disease, which is out of interest of the pharmaceutical industry.
Republic of Kazakhstan is struggling with dangerous societal diseases such as tuberculosis and HIV-infection. For this reason, Kazakhstan, based on the experience of developed countries, should give impetus and incentives for drug developers to invest in R&D and accelerate marketing of new promising drugs, and as an incentive the government could decrease amount of time necessary for approvals and some tax or other exemptions. Currently, by taking into account low workload in the field the minimal period for obtaining approval for investigational new drugs varies from 6 months and longer. Additional provisions could be made for trials conducted in the field of surgery and diagnostics, as there are no regulations covering those issues either.
Developing countries are in more favourable conditions than developed ones due to the persistence of ready model for creating own legislation framework in the field of drug development. By implementing and harmonization of ICH guidelines developing countries could save dozens of years that took developed countries to reach present condition. Both regulatory authorities' orders and standards should be developed in harmonized fashion to ensure consistency with international requirements and movement in one direction.
4. Society perception on clinical trials
Low social awareness of clinical trials importance in the healthcare system of Kazakhstan and of whole world could lead to the negative perception of society and reluctance of participation inthe medical researches; as a result, it could lead to the low recruitment rates and premature termination of the important clinical trials. Governmental and non-profit organizations should advocate participation in trials for new drugs development. Development of pharmaceutical industry is impossible without participation of society, and as previously mentioned we can adopt experience of developing countries. For instance, we can create organization as 'The Centre for Information and Study on Clinical Research Participation (CISCRP)', which actively works in the USA to increase society's interest in clinical trials. Everyone should remember that practically each drug in drugstores created with the contribution of volunteer participants in sake of altruism and humanity. Conclusion:Following the factors could positively influence on harmonization of international requirements for drug development and clinical trials, and create favourable conditions for clinical trials and drug development:
1. Improvement of regulatory framework by adopting experience of developed countries;
2. Invest in education of specialist on universities and hospital levels;
3. Adopting and improving clinical sites of Healthcare Ministry for clinical trials.
Вестник КазНМУ, №2(2)- 2014
REFERENCES
1 Государственный стандарт СТ РК 1616-2006 «Надлежащая клиническая практика. Основные положения», утвержденный приказом Комитета по техническому регулированию и метрологии Министерства индустрии и торговли РК от 29 декабря 2006 г. № 575 «Об утверждении государственных стандартов»;
2 'Good Clinical Practice' Guideline E6R1 International Conference on Harmonization (1996) http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html;
3 Title 21--Food and Drugs chapter I--Food and Drug Administration department of health and human services subchapter D--Drugs for human use Part 312 Investigational new drug application http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312;
4 'Guidance for the Notification of Serious Breaches of GCP or the Trial Protocol Medicines and Healthcare products Regulatory Agency' MHRA http://www.mhra.gov.uk/home/groups/is-insp/documents/websiteresources/con060111.pdf;
5 Приказа Министра здравоохранения Республики Казахстан от 31 марта 2010 года № 222 «Об утверждении Перечня доклинических и клинических баз, имеющих право проведения доклинических и клинических исследований в здравоохранении»
6 EudraLex - Volume 10 Clinical trials guidelines http://ec.europa.eu/health/documents/eudralex/vol-10/
7 Приказ Министра здравоохранения Республики Казахстан от 30 июля 2008 года № 425 'О создании Центральной комиссии по вопросам этики'
8 Приказ Министра здравоохранения Республики Казахстан от 19 ноября 2009 года № 744 «Об утверждении Правил проведения клинических исследований и (или) испытаний фармакологических и лекарственных средств, изделий медицинского назначения и медицинской техники»;
9 'Recommendations on the qualifications of inspectors verifying compliance in clinical trials with the provisions of Good Clinical Practice' EudraLex Vol. 10 Guideline http://ec.europa.eu/health/files/eudralex/vol-10/v10 chap4 en.pdf;
10 'Indemnity/insurance arrangements for Trust-sponsored clinical research trials' National Health Service United Kingdom http://www.hullhistorycentre.org.uk/discover/consortium/guidance resource directory/gcp forms/indemnity insurance.aspx
К.С. ХАЖИДИНОВ, А.А. АЗЕМБАЕВ, А.Б. АБЖАЛЕЛОВ
РМК «Инфекцияга нарсы препараттар гылыми орталыгы»
ДЭР1Л1К ЖАБДЫКТАРДЫ (ЗАТТАРДЫ ) 9ИДЕУДЕП КЛИНИКАЛЫК СЫНАКТАР 0ТК1ЗУДЕ КАЗАКСТАНДАГЫ
ЬЩПАЛ ЕТЕТ1Н ФАКТОРЛАР
Туйш: 1.^аза^стан Республикасында клиникалы^ сына^тар етшзуге жа^сьдолайлы жагдай жасалып, ец жогары децгейге жетшз^ керек. 2.1^аза1^станда GCP -стандартарын енпзу - ултты^, улт уст (Кеден одагы) жэне халы^аралы^ талаптарды есепке алудыц уйлеспру жолдарымен журпз^ керек.
ТYйшдi свздер: жаца дэрЫк жабды^тарды (заттарды)ецдеу; ICH GCP - тиiмдi клиникалы^ практика; клиникалы^ база; орталы^ жэне жергЫкт комиссия; клиникалы^ сына^ маманы
К.С. ХАЖИДИНОВ, А.А. АЗЕМБАЕВ, А.Б. АБЖАЛЕЛОВ
РГП «Научный центр противоинфекционных препаратов»
ФАКТОРЫ, ВЛИЯЮЩИЕ НА ПРОВЕДЕНИЕ КЛИНИЧЕСКИХ ИСПЫТАНИЙ ПРИ РАЗРАБОТКЕ ЛЕКАРСТВЕННЫХ СРЕДСТВ В КАЗАХСТАНЕ
Резюме: 1. В Республике Казахстан необходимо довести до усовершенствования и создать благоприятные условия для проведения клинических испытании.
2. При внедрении стандартов GCP в Казахстане необходимо следовать гармонизированному подходу с учетом требовании национальных, наднациональных (Таможенного союза) и международных требовании.
Ключевые слова: Разработка новых лекарственных средств; надлежащая клиническая практика ICH GCP; клиническая база; центральная и локальная комиссия по вопросам этики; специалист клинических испытаний.
УДК 628.012.011.56
А.Е.КУСНИЕВА, А.А. АЗЕМБАЕВ
РГП «Научный центр противоинфекционных препаратов»
СОЗДАНИЕ СИСТЕМЫ ДОКУМЕНТАЦИИ ПРЕДПРИЯТИЯ ПО ТРЕБОВАНИЯМ ЙМР КАК ЭЛЕМЕНТ ОБЕСПЕЧЕНИЯ КАЧЕСТВОМ
ЛЕКАРСТВЕННЫХ СРЕДСТВ
Введение стандарта GMP является необходимым шагом в разработке целого ряда взаимосвязанных документов, которые необходимы для проведения контроля качества лекарственных средств на производстве.
Ключевые слова: фармацевтическое предприятие, система управления качеством, правила GMP, качество лекарств.
Лекарственные средства являются особым видом продукции. К ним предъявляются высокие требования по безопасности и эффективности, обеспечиваемые на всех этапах разработки, испытаний, производства и реализации. Обеспечение качества является комплексной задачей, в которую входят: • использование материалов, отвечающих заданным требованиям;
производство продукции в помещениях и на оборудовании, гарантирующих выпуск продукции в соответствии с заданными требованиями;
• введение требований международных стандартов GMP на производстве;
• соответствие персонала требованиям к профессиональной подготовке, личной гигиене, исполнительности и добросовестности.
