The problem of over-volunteering in early phase clinical trials

This article discusses important problem of early phase clinical trials – over-volunteering. The overlapping or dual enrollment of healthy volunteers is a potential high risk not only to study subjects, but also to commercial sponsors because it could cause the delay in advancement of promising drug candidates. The problem of over-volunteering is payed special attention by clinical research professionals in foreign countries. Guidelines for early phase clinical trials recommend implementation of different control and prevention measures of multiple enrollment. The most effective instrument to prevent over-volunteering is considered to be a central internet-based registry of healthy volunteers. Such registries operate in various countries and differ in structure, scope of information collected, types of funding and management. The general operating principles of such registries are described on the example of TOPS data base. TOPS is а special system to prevent over-volunteering that is used by UK phase 1 units. In conclusion, authors urge regulatory authorities and pharmaceutical companies to approach this problem closely because over-volunteering is already a burning issue in our country. It is essential to improve relevant regulatory framework and launch central registries of healthy subjects with regard to international experience

Multivariate analysis of medication adherence among outpatients with stable coronary artery disease

Introduction. The results of local studies indicated that medication adherence of coronary outpatients is low (not more than 60 %). The search for significant predictors of adherence to recommended treatment might allow tailoring specific strategies to control adherence for further optimization of the pharmacotherapy of coronary artery disease (CAD) in routine primary care practice. Aim. To determine the factors associated with medication adherence in outpatients with stable CAD. Methods. This paper describes the results of the fragment of randomized controlled study of the effects of Pharmacy Care Program on medication adherence of coronary outpatients, that was conducted in 2019-2020 in one of the primary care clinics of Moscow. 123 subjects with stable CAD were included in line with the pre-specified criteria. Demography, social status, medical history, pharmacotherapy, healthcare burden data were registered. Medication adherence was measured by validated questionnaire MMAS-8 (8-item Morisky Medication Adherence Scale). The analysis of predictors of adherence was performed by linear regression. Results. Simple regression analysis revealed the list of parameters, that showed statistically significant (or as statistical trend) association with medication adherence of coronary patients in univariate models. The level of medication adherence was associated with patient’s having a partner or caregiver (p=0,002), higher education (p=0,009), additional medicinal maintenance (p=0,006). Medication adherence did not depend on medical history and pharmacotherapy characteristics, but the association of high values of low-density lipoproteins cholesterol (LDL-C) (p=0,001) with suboptimal adherence was demonstrated. Good medication adherence was associated with more frequent visits to general practitioner (p=0,036) and (as statistical trend) to cardiologist (p=0,093). The multivariate regression analysis revealed two positive independent predictors of medication adherence - patient’s having a partner or caregiver (р=0,015) and regular visits to cardiologist (р=0,025). Also, the negative association was confirmed for high LDL-C (р=0,002). Conclusion. Patient’s having a partner or caregiver and regular visits to cardiologist were revealed as independent predictors of good medication adherence of coronary outpatients. Subjects with suboptimal adherence had higher LDL-C

Medication adherence in patients with stable coronary artery disease in primary care

Medication non-adherence in coronary outpatients exceeded 50%. High adherence was associated with more frequent use of fixed dose combinations and fewer pills taken by patien

Effect of medication adherence on the risk of cardiovascular events in outpatients with stable coronary artery disease: results of two-year monitoring

Introduction. Incidence of inadequate medication adherence to secondary prevention medications among Russian coronary patients is around 50 %, but the question, how this might influence on the risk of unfavorable outcomes, still has no answer.Aim. To determine the effect of medication adherence on the risk of unfavorable clinical outcomes in outpatients with stable coronary artery disease (CAD). Methods. Prospective observational cohort study was conducted. 281 subjects with verified stable CAD were included in line with the pre-specified criteria. Medication adherence was measured by validated 8-item Morisky scale. Data on cardiovascular events were obtained over the 24-month monitoring period. Study endpoint was a composite cardiovascular event (all-cause mortality, acute myocardial infarction, unstable angina, revascularization surgery, acute heart failure, decompensation of chronic heart failure). Survival analysis by Kaplan — Meier method was performed.Results. 26.0 % of coronary outpatients had low medication adherence (below 6 points by Morisky scale). Groups of patients with satisfactory and low medication adherence were comparable by demography, medical history, and pharmacotherapy. Over the monitoring period composite cardiovascular event was registered in 115 patients (40.9 %). 46.6 % of patients from the low adherence group suffered from the composite event, 38.9 % — from the satisfactory adherence group. Time to the event was lower in the low adherence group — median 24.2 (IQR 7.5-29.2) vs. median 27.9 (IQR 17.4-34.5) months. Cumulative incidence of the composite cardiovascular event over the monitoring period was higher in the low adherence group compared to satisfactory adherence group (p=0.032; log-rank test), also when adjusted for history of cardiovascular events (p=0.033; log-rank test). Satisfactory medication adherence reduced risk of composite cardiovascular event by 37 % (HR 0.63; 95 % CI 0.42-0.94; р=0.025; Cox-regression adjusted for history of cardiovascular events).Conclusion. Coronary outpatients with satisfactory medication adherence had lower risk of cardiovascular events over the 24-month monitoring period

Medication adherence in patients with cardiovascular disease: current view of the problem

In this article the authors address the problem of poor medication adherence in patients with cardiovascular disease. Poor medication adherence significantly reduces efficacy of pharmacotherapy thus increasing risk of cardiovascular complications and higher treatment costs in routine clinical practice. This problem was first raised by a few foreign scientists in the 90s and then officially recognized by the World Health Organization in 2003. The article presents review on the prevalence of low medication adherence in patients with cardiovascular disease and describes key factors associated with decreased adherence. An overview of widely used indirect methods to measure medication adherence is presented as well. On the way to solve this problem, the development and implementation of various measures and interventions to improve medication adherence is actively carried out in recent years. The results of the most significant studies on the effectiveness of such interventions are also presented in the article. Positive influence on patient adherence was demonstrated, however, only a number of studies reported reduction of the risk of unfavorable clinical outcomes of cardiovascular diseases. This confirms the need to further study the problem of medication adherence focusing on routine clinical practice in Russia

Critical aspects of the management of stable coronary artery disease in primary care practice or how to increase the efficacy of evidence-based pharmacological therapy?

The publication describes a fragment of the pharmacoepidemiologic study conducted to review the quality of management of patients with stable coronary artery disease (SCAD) in primary care over a 12-year period. The aim of the study was to justify the application of standard operating procedures (SOPs). Such determinants of pharmacotherapy as non-pharmacological modification of cardiovascular risk factors (RFs) and medication adherence were analyze

Potential barriers towards optimal medication adherence in out-patients with stable coronary artery disease

Introduction. The results from foreign and local studies demonstrate that more than a half of patients with cardiovascular diseases do not take medication in compliance with doctors’ recommendations. The search for significant barriers to optimal medication adherence might improve the development of adherence control measures in patients with stable coronary artery disease (SCAD) in routine clinical practice of primary care.Aim. To study the nature and incidence of potential barriers to optimal medication adherence and their association with social and demographic parameters in patients with SCAD.Methods. This publication describes the fragment of the study “PHARMCARE” in which 123 coronary patients were included. Data on demography, social status, medical history and pharmacotherapy were registered. The barriers to medication adherence were identified by means of validated scale (questionnaire) SEAMS (Self-Efficacy for Appropriate Medication Use Scale). Data analysis was conducted by descriptive statistics and regression modeling.Results. The analysis of incidence of barriers to medication adherence allowed to identify the list of most significant ones: “fear of side effects”, “intake of several different medicines each day”, “intake of medicines more than once a day”, “medicines look different than usual”, “normal routine gets messed up”, “busy day planned”, “no one reminds to take medicines” and “staying away from home”. More than a third of all the respondents reported at least one of barriers (37%), that was in major cases “fear of side effects” (22%). Linear one-factor modeling revealed association of number of significant barriers in patients with level of their education (р=0,009) and presence of partner or caregiver (р=0,001), that was also confirmed by the multivariate model. Less barriers were identified in coronary patients that had partner or caregiver (р=0,009) and higher education (р=0,045).Conclusion. The study results revealed that the significant barriers to optimal medication adherence in out-patients with SCAD were related either to patients’ behavior or to pharmacotherapy profile. Uncertainty in overcoming barriers was most typical for single patients without higher education. The obtained results should be taken into consideration when develop strategies for improvement of medication adherence in patients with SCAD in primary care practice

The role of reference intervals of laboratory tests in early phase clinical research in healthy volunteers

This article discusses one of the most disputable issues in national clinical research practice in healthy volunteers. Regulatory requirements forbid to assess even minor deviations of laboratory parameters from reference intervals as not clinically significant. Authors made analysis of such requirements from positions of foreign and national guidelines of early phase clinical research and with regard to their own experience in the field. As an important part of this work, retrospective analysis of the laboratory test results data of healthy volunteers taken from several clinical trials was conducted. The aim of this analysis was to establish the rate of not clinically significant deviations from reference intervals. The results of the analysis revealed rather high rate of not clinically significant deviations of some laboratory parameters from reference intervals in volunteers with confirmed status “healthy”. Authors noted that developers of clinical trial protocols have no unified approach to generate list of necessary laboratory tests and methods of assessment of the results. Ethical and financial aspects of the problem under discussion are also touched in this article. In conclusion, authors suggest the scale of clinical significance assessment of deviations of basic laboratory parameters from reference intervals as one of the possible options of optimizing current regulatory requirements

Implementation of the concept of standard operating procedures into primary care practice: utopia or urgent need?

The article emphasizes the need to develop and apply standard operating procedures (SOP) as an instrument of quality management system of rational pharmacotherapy in primary care practice. To justify the reasonability of SOP implementation into outpatient clinical practice pharmacoepidemiologic analysis of the quality of care provided to patients with stable coronary artery disease in the primary care setting of Moscow over two consecutive periods was used. tte key variables of interest were characteristics that reflected physician adherence to clinical practice guidelines

Фармакокинетика нового отечественного антитромбоцитарного препарата из группы ингибиторов гликопротеиновых IIb/IIIa-рецепторов

Relevance. As part of the conducted open non-randomized phase I clinical trial the pharmacokinetics (PK) of the first Russian novel antiplatelet agent Angipur (nonpeptide glycoprotein IIb/IIIa receptor inhibitor) was studied.Aim of the research was to evaluate PK parameters of Angipur in healthy volunteers after single dose ascending infusions.Methods. 20 male healthy volunteers were enrolled in this phase I trial. Angipur (0.02% concentrate solution for infusion) was administered to every subject in single doses 0.015, 0.05, 0.09 mg/kg for 3 consecutive days. PK parameters were evaluated.Results. After single intravenous administration of doses 0.015, 0.05, 0.09 mg/kg to healthy volunteers the peak plasma concentration of Angipur was reached at the end of the infusion, and then the plasma concentration rapidly decreased 15 minutes after the end of the infusion followed by slow decrease for 12 hours. Dose proportionality for key PK parameters was established. After single infusions of doses 0.015, 0.05, 0.09 mg/kg mean AUC0-t was 27.11, 92.04 and 180.39 ng× h/ml; mean AUC0-¥ – 37.03, 125.76 and 239.61 ng×h/ml; mean Сmax – 12.44, 46.1 and 92.48 ng/ml; mean Vd – 304.01, 299.67 and 252.96 l; mean Т1/2 – 6.72, 6.84 and 6.06 h; Сl – 32.19, 32.29 and 31.55 l/h; kel – 0.1073, 0.1109 and 0.1257 l/h; MRT – 8.94, 8.93 and 8.18 h.Conclusion. Pharmacokinetics of Angipur in studied doses demonstrated linearity, rapid reaching of Сmax immediately after the infusion and the high distribution of the drug in tissues and biological fluids of the human organism..Актуальность. В рамках проведённого открытого нерандомизированного клинического исследования I фазы изучена фармакокинетика (ФК) первого отечественного оригинального антитромбоцитарного препарата Ангипур из группы непептидных ингибиторов гликопротеиновых IIb/IIIa-рецепторов.Целью работы было определение ФК параметров препарата Ангипур при внутривенном введении здоровым добровольцам в однократных разовых дозах.Методы. В клиническое исследование I фазы было включено 20 здоровых добровольцев мужского пола. Препарат Ангипур (0,02 % концентрат для приготовления раствора для инфузий) вводился каждому добровольцу 3 дня подряд последовательно в разовых однократных дозах 0,015; 0,05 и 0,09 мг/кг. Далее оценивались основные ФК параметры исследуемого препарата.Результаты. Установлено, что после однократного внутривенного введения доз 0,015; 0,05 и 0,09 мг/кг здоровым добровольцам максимальная концентрация препарата Ангипур в плазме крови отмечалась после окончания введения, а через 15 минут она быстро снижалась с последующим медленным снижением в течение 12 ч. Выявлена прямая пропорциональная зависимость основных ФК параметров от величины дозы. После введения исследуемого препарата в дозах 0,015; 0,05 и 0,09 мг/кг AUC0-t составляла в среднем 27,11; 92,04 и 180,39 нг×ч/мл; AUC0-¥ — 37,03; 125,76 и 239,61 нг×ч/мл; Сmax — 12,44; 46,1 и 92,48 нг/мл; Vd — 304,01; 299,67 и 252,96 л. После введения указанных доз Т1/2 в среднем был равен 6,72; 6,84 и 6,06 ч; Сl — 32,19; 32,29 и 31,55 л/ч; kel — 0,1073; 0,1109 и 0,1257 1/ч; MRT — 8,94; 8,93 и 8,18 ч, соответственно.Заключение. ФК препарата Ангипур в изученных дозах показала свой линейный характер, быстрое достижение значения Сmax сразу после введения и способность препарата интенсивно распределяться в ткани и биологические жидкости организма