Теоретичні та науково-прикладні засади управління клінічними дослідженнями лікарських засобів на місці проведення випробувань

Abstract

Вперше обґрунтовано і розроблено загальну модель інтегрованої системи управління якістю КД ЛЗ і введено в науковий обіг поняття «інтегрована сис- тема управління КД ЛЗ». Сформовано підходи до реалізації СУЯ та стратегічні шляхи управління ризиками КД у роботі МПВ. Розроблено практичні підходи до ідентифікації ризиків для якості КД ЛЗ у МПВ, науково обґрунтовано сис- тему індикаторів і методику управління ризиками при організації дослідження. Розроблено алгоритми врахування ПР/ПЯ та впливу супутньої терапії у КД ЛЗ. Вперше розроблено модель еІРФ та методику її валідації у дослідженнях БЕ, а також запропоновано схему функціонального розподілу виконавців процедури менеджменту даних при роботі з еІРФ. Розроблена узагальнена структурна мо- дель зв’язку між ключовими аспектами захисту досліджуваних та факторами, що забезпечують їх реалізацію при управлінні КВ ЛЗ. За результатами анкету- вання досліджуваних запропоновані загальні методичні підходи до залучення та захисту досліджуваних на МПВ.

Впервые обосновано и разработано общую модель интегрированной си- стемы управления качеством КИ ЛС и введено понятие «интегрированная си- стема управления КИ ЛС». Сформированы подходы к внедрению такой систе- мы на МПИ и стратегические пути управления рисками КИ. Разработаны прак- тические подходы к идентификации рисков для качества КИ ЛС, научно обос- новано систему индикаторов и методику управления рисками для организации исследования биоэквивалентности (БЭ) на МПИ. Разработано алгоритм учета ПР/ ПЯ и влияния сопутствующей терапии в КИ ЛС. Впервые разработана мо- дель эИРФ и методика ее валидации в исследованиях БЭ, а также было предло- жено схему функционального распределения исполнителей процедур менедж- мента данных при работе с эИРФ. Разработана обобщенная структурная модель, связывающая ключевые аспекты защиты испытуемых и факторами управ- ления КИ ЛС. По результатам анкетирования испытуемых предложены общие методические подходы к их привлечению и защите на МПИ.

Under the conditions of financial resource shortage in public and/or insurance financing of health care, the high price of original drugs make for a high demand of generic drugs. The issue of the generic and original medication action identity on the human body is the main one for doctors and patients. One of the requirements imposed to generic drugs is the proof of their bioequivalence (pharmacokinetic equivalence) to the original ones. Clinical and Diagnostics Center of the National University of Pharmacy is the first Ukrainian University hospital which specializes in running clinical trials with the participation of healthy volunteers. By the beginning of 2016 the above mentioned establishment has already gained wide experience and conducted more than 40 trials on studying bioequivalence. All the clinical trials mentioned in the given thesis were held in Clinical and Diagnostics Center of the National University of Pharmacy. Nowadays, bioequivalence study of drugs is considered to be a complex and multistage process where groups of professionals from different branches of pharmacy, medicine, and biostatistics are involved. It is a long way from the trial design and the enrollment of the first study object to the point the first results are entered into the corresponding documents. For that matter, even in case of planning the study accurately there may be issues that can emerge during the study and that require mobilizing all the parties / participants of clinical trial of a given drug to discuss, approve and solve possible problems. The need of ensuring the implementation of planned objectives concerning quality, costs and timing of clinical trial in the complex and changing environment determines the systemic approach to clinical trial quality management. In addition, designing the quality management system according to the requirements of ISO 9001:2015 is a prerequisite for an integrated clinical trial quality management system which combines and allows to consider industry guidelines ICH on a single basis. This determined the relevance of implementing of the common model of integrated system of quality management which has been scientifically proved and developed for the very first time in Ukraine. And the scientific statement «integrated system of quality management» has been introduced into scientific use. By conducting sound analysis of the views of the competent local experts - experts in the field of clinical trials of drugs it has been obtained the results which formed the approaches to the implementation of quality management system and strategic ways of clinical trial risk management at trial site. The concept of clinical trial risk management at trial site has been justified, and in its terms the «target risks of clinical trials of drugs» have been identified, justified and put into scientific circulation the basic concept. The common risk management model of clinical trials of drugs has been proposed, and its role as well as the level structure of risk identification have been introduced in the given work. For the first time the practical approaches to the identification of risks for the quality of clinical trials of drugs have been developed. There have been offered the science-based risk indicators system for the implementation of risk-based monitoring at trial site and the methodology of risk management for the organization of bioequivalence study at trial site. There have been introduced the main identified risks which included the process of assessing abnormal ranges, registering and processing data entry, verifying source data, interpreting study data concerning adverse events/reactions (AE/AR) as well as the issues with concomitant therapy which is very essential for the contemporary clinical trials. Consequently, we have decided to carry out the assessment of the above mentioned risks with the help of FMEA methodology that functions as a modern tool of risk assessment, helping to identify potential errors of any clinical trial. As a result, it has been found out that the risk «AE/AR data missing due to incorrect conclusions about its significance» has been found among the highest values. Based on the held analysis of the risks for the quality of clinical trials of drugs at trial site the methodical foundations of development and implementation of electronic case report form (eCRF) have been scientifically justified and processed for the further successful management of bioequivalence study at trial site. Thus, eCRF is considered to be an effective tool for the monitoring and minimization of tof the possible errors and risks that can emerge during bioequivalence study. Thanks to that fact the first eCRF as well as its further validation procedure in BE studies have been introduced and tested during the bioequivalence study of the lipid-lowering agent. Selecting healthy volunteers carefully is one of the most important factors affecting the result of the study. From our point of view, it is not enough to merely assess volunteers’ health status at their screening visit. Thus, it is also extremely important to assess level of quality of life of healthy volunteers who take place in BE studies. At the same time, the factors to protect the volunteers participating in clinical trials, which include procedures such as the signing of informed consent, screening procedures (i.e. testing of HIV / AIDS, health status examination) proved to be essential for the study subjects’ safety and well-being. And it is obligatory that the trial site administration should also perform an additional control and monitoring of the given procedures.