ФАРМАКОЭПИДЕМИОЛОГИЧЕСКОЕ ИССЛЕДОВАНИЕ ОСЛОЖНЕНИЙ ФАРМАКОТЕРАПИИ ПРИ НАЗНАЧЕНИИ ЛЕКАРСТВЕННЫХ СРЕДСТВ С НАРУШЕНИЕМ ПРЕДПИСАНИЙ ИНСТРУКЦИИ (OFF-LABEL) И РАЗРАБОТКА МЕР ИХ ПРОФИЛАКТИКИ тема диссертации и автореферата по ВАК РФ 14.03.06, кандидат медицинских наук Переверзев, Антон Павлович

• Переверзев, Антон Павлович
• кандидат медицинских наук
• 2013

Оглавление диссертации кандидат медицинских наук Переверзев, Антон Павлович

ОГЛАВЛЕНИЕ

СПИСОК СОКРАЩЕНИЙ

ВВЕДЕНИЕ

ГЛАВА I. ОБЗОР ЛИТЕРАТУРЫ

1.1. Общая часть

1.2. Возможные меры профилактики развития осложнений, вызванных использованием лекарственных средств с нарушением предписаний инструкции

1.2.1. Обучающие мероприятия

1.2.2. Структуризация и унификация сведений, содержащихся в утвержденной инструкции по медицинскому применению

1.2.3. Коммуникации

1.2.4. Нормативно - правовое регулирование назначений ЛС с нарушением предписаний инструкции в Российской Федерации

1.2.5. Нормативно - правовое регулирование распространения информационных материалов и рекламы ЛС с нарушением предписаний инструкции в Российской Федерации

1.2.6. Нормативно - правовое регулирование назначений ЛС с нарушением предписаний инструкции за рубежом

1.2.7. Зарубежная судебная практика

1.2.8. Отечественная судебная практика

ГЛАВА II. МАТЕРИАЛЫ И МЕТОДЫ ИССЛЕДОВАНИЯ

2.1. Дизайн исследования

2.2. Объект исследования

2.3. Статистическая обработка данных

ГЛАВА III. ОПИСАНИЕ РЕЗУЛЬТАТОВ

3.1. Систематизации JIC, вошедших в исследование, по фармакологическим группам и типам нарушения предписаний инструкции

3.2. Анализ случаев развития серьезных осложнений фармакотерапии

на фоне off-label применения ЛС

3.3. Типы организации медицинской помощи пациентам, при которых имело место назначение ЛС с нарушением предписаний инструкции

ГЛАВА IV. ОБСУЖДЕНИЕ РЕЗУЛЬТАТОВ

ВЫВОДЫ

ПРАКТИЧЕСКИЕ РЕКОМЕНДАЦИИ

СПИСОК ЛИТЕРАТУРЫ

ПРИЛОЖЕНИЕ

СПИСОК СОКРАЩЕНИЙ

БД база данных

ВОЗ Всемирная организация здравоохранения

ЖКТ желудочно - кишечный тракт

КИ клиническое исследование

ЛП лекарственный препарат

ЛС лекарственное средство

МНН международное непатентованное наименование

HP нежелательная реакция

НС нервная система

ПСС причинно - следственная связь

РУ регистрационное удостоверение

СС спонтанное сообщение

ТН торговое наименование

ТЭЛА тромбоэмболия легочной артерии

FDA U.S. Food And Drug Administration - Агентство по контролю

лекарственных средств и продуктов питания США

UMC Uppsala Monitoring Centre - Сотрудничающий центр ВОЗ по

мониторингу безопасности лекарственных средств

Введение диссертации (часть автореферата) на тему «ФАРМАКОЭПИДЕМИОЛОГИЧЕСКОЕ ИССЛЕДОВАНИЕ ОСЛОЖНЕНИЙ ФАРМАКОТЕРАПИИ ПРИ НАЗНАЧЕНИИ ЛЕКАРСТВЕННЫХ СРЕДСТВ С НАРУШЕНИЕМ ПРЕДПИСАНИЙ ИНСТРУКЦИИ (OFF-LABEL) И РАЗРАБОТКА МЕР ИХ ПРОФИЛАКТИКИ»

ВВЕДЕНИЕ

Актуальность исследования. Проблема контроля безопасности лекарственных средств является актуальной задачей во всем мире. Миллионы людей получают тяжелые, подчас необратимые осложнения при проведении лекарственной терапии 1 в связи с внедрением в широкую медицинскую практику большого числа фармакологических препаратов с высокой биологической активностью, сенсибилизацией населения к биологическим и химическим веществам, нерациональным использованием лекарств и рядом других причин, среди которых можно назвать применение ЛС с нарушением предписаний утвержденных инструкций по медицинскому применению. В зарубежной литературе такого рода применение ЛП обозначается термином «off - label use of drugs».

Согласно определению, термин «off - label» означает назначение препаратов по показаниям в возрастных группах, в дозировках, в путях введения и т.д., которые отличаются от рекомендованных инструкцией по медицинскому применению2.

Следует отметить, что в медицинской практике возникают ситуации при которых применение препаратов с нарушением предписаний неизбежно. Существует целый ряд редких заболеваний, эффективная фармакотерапия которых не разработана, но имеющиеся научные данные дают основание предположить возможность достижения куративного или паллиативного эффекта при применении определенного ЛП. Другими причинами назначений ЛС с нарушением предписаний инструкции являются отсутствие по этическим соображениям клинических исследований на беременных женщинах и детях, а также медицинские ошибки вызванные не знанием

1 Астахова А.В., Лепахин В.К. Лекарства. Неблагоприятные побочные реакции и контроль безопасности, - 2-е изд., испр. и доп. - М.: Эксмо, 2008 - 256 с

2 Christopher M. Wittich,a, Christopher M. Burkle,b and William L. Lanierb. Ten Common Questions (and Their Answers) About Off-label Drug Use. Mayo Clin Proc. 2012 October; 87(10): 982-990.

информации, содержащейся в инструкции по медицинскому применению или халатностью3.

Выявлено, что off - label применение JIC ассоциировано с более высоким риском развития HP, чем при использовании препаратов в соответствии с инструкцией.4'5'6

В России полноценных фармакоэпидемиологических исследований нежелательных реакций, связанных с использованием препаратов с нарушением инструкции на основании анализа спонтанных сообщений, зарегистрированных в специализированных БД, до настоящего времени не проводилось. Это предопределило выбор темы, формулировку основной цели и задач диссертационного исследования.

Цель исследования.

Целью работы является изучение осложнений фармакотерапии вследствие off - label применения JIC и разработка мер их профилактики.

Для достижения поставленной цели необходимо было решить следующие задачи:

1. Определить масштаб проблемы осложнений фармакотерапии при off - label применении JIC путем анализа СС, зарегистрированных в отечественной и международной БД HP за 2009-2011 годы.

2. Оценить частоту развития серьезных осложнений фармакотерапии, связанных с использованием JIC с нарушением предписаний инструкции и зарегистрированных в БД HP.

3 Gijsen R et al. Frequency of ill-founded off-label prescribing in Dutch general practice. Pharmacoepidemiol Drug Saf. 2009 Jan;18(l):84-91.

4 Santos DB, Clavenna A, Bonatti M, Coelho HLL. Off-Label and Unlicensed Drug Utilization in Hospitalized Children in Fortaleza, Brazil. Eur J Clin Pharmacol. 2008;64:1111-8.

5 Ditsch N, Kiimper C, Summerer-Moustaki M, Riickert S, Toth B, Lenhard M, Strauss MA. Off-label use in Germany - a current appraisal of gynaecologic university departments. Eur J Med Res. 2011 Jan 27;16(1):7-12.

6 Radley DC, Finkelstein SN, Safford RS. Off- label prescribing among office- based physicians. Arch Intern Med. 2006;166:1021-6

3. На основании анализа СС, зарегистрированных в БД HP определить группы ЛС, наиболее часто вызывающих осложнения при использовании с нарушением предписаний инструкции.

4. Выделить группы пациентов, у которых отмечается наибольшее число осложнений фармакотерапии при off - label применении ЛС.

5. На основании полученных результатов подготовить рекомендации по профилактике осложнений, возникающих на фоне off -label применении ЛС.

Научная новизна

Впервые проведен сравнительный анализ спонтанных сообщений об осложнениях фармакотерапии, зарегистрированных в отечественной и международной базах данных HP, возникших вследствие использования ЛС с нарушением предписаний инструкции.

Показана высокая частота развития серьезных осложнений фармакотерапии и выявлены группы риска развития HP, возникающих на фоне приме-нения ЛС off - label.

Выявлено, что наиболее подвержены риску развития осложнений при off - label использовании ЛП лица средних лет.

Выявлено отсутствие в России четкой законодательной базы, регулирующей вопросы применения ЛС off - label.

Показано значительное влияние специализированных научных периодических изданий на частоту назначений ЛС с нарушением предписаний, а также отсутствие рекомендаций по подготовке и распространению информации об off - label применении ЛС.

Практическая значимость и внедрение результатов в практику

Проведенное исследование подтвердило высокую значимость проблемы применения лекарственных препаратов off - label для безопасности

больных и наличие определенного «пробела» в регламентации применения препаратов с нарушением предписаний инструкции нормативно-правовой базой Российской Федерации.

Полученные данные позволяют научно обоснованно подойти к подготовке новых административных мер по оптимизации лечебного процесса как в стационарном, так и в амбулаторном звене здравоохранения.

Разработаны и внедрены в практику кафедры общей и клинической фармакологии ФГБОУ ВПО РУДН «Рекомендации по профилактике развития негативных последствий, связанных с применением препаратов с нарушением предписаний инструкции (off - label)». Данные рекомендации позволяют улучшить качество готовящихся научных статей и учебных материалов, что повысит информированность врачей и пациентов в отношении возможных последствий off-label применения ЛП, и уменьшит риски развития HP.

Материалы диссертации используются при чтении лекций на проводимых в ФГБУ «НЦЭСМП» Минздрава России образовательных семинарах для всех субъектов обращения лекарственных средств в Российской Федерации.

Основные положения, выносимые на защиту

1. Назначение JIC с нарушением предписаний инструкции ассоциировано с высоким риском развития серьезных осложнений фармакотерапии.

2. Наибольшее количество случаев развития HP при использовании ЛП с нарушением предписаний инструкции отмечается у лиц среднего возраста.

3. У женщин регистрируется большее число HP, возникших вследствие offlabel фармакотерапии, чем у мужчин.

4. Наибольшее число случаев развития HP при использовании ЛП с нарушением предписаний инструкции связано с нейротропными, противоопухолевыми и противомикробными ЛС.

Личное участие диссертанта

Все использованные в работе данные получены при непосредственном участии автора, как на этапе постановки цели и задач, разработки методических подходов и их выполнения, так и при сборе первичных данных, обработке, анализе и обобщении полученных результатов для написания и оформления рукописи.

Апробация работы проведена на расширенном заседании кафедры общей и клинической фармакологии и кафедры общей врачебной практики ФГБОУ ВПО РУДН 17 апреля 2013 года.

Основные положения диссертации были доложены:

- на конкурсе инновационных проектов молодых ученых и специалистов «Инновационные технологии в клинической фармакологии» (Санкт -Петербург, 2012). Получен диплом победителя II степени.

- на первой научно-практической конференции молодых ученых «Медико-социальные аспекты проведения экспертизы качества, безопасности и эффективности лекарственных средств в условиях реформирования здравоохранения России» (Москва, 2012). Получено благодарственное письмо за активное участие.

- на XVII Российском национальном конгрессе «Человек и лекарство» (Москва, 2010).

Публикации по теме диссертации

По теме диссертации опубликовано 9 печатных работ, в том числе 3 работа в журналах, рекомендованных ВАК. Принято участие в подготовке Федерального руководства по использованию лекарственных средств, выпуск XII за 2011 год.

Содержание работы

В соответствии с поставленной целью и задачами диссертационного исследования работа изложена на 108 страницах машинописного текста, состоит из введения, четырех глав, основных выводов, практических рекомендаций и библиографического списка (352 источника). Работа иллюстрирована 14 таблицами и 4 рисунками.

Заключение диссертации по теме «Фармакология, клиническая фармакология», Переверзев, Антон Павлович

выводы

1. В общей структуре СС, зарегистрированных в специализированных базах данных, более 6% являются сообщениями о развитии HP при применении препаратов с нарушением предписаний инструкции.

2. Более чем в половине случаев (64,4%) применение препаратов off - label приводит к развитию серьезных HP.

3. Наиболее часто HP развиваются при off - label применении противомикробных, противоопухолевых и нейротропных J1C, особенно у лиц среднего возраста и женщин.

4. При применении ЛС с нарушением предписаний инструкции осложнения фармакотерапии зарегистрированы при стационарном лечении в 48,8% случаев; при амбулаторном лечении - в 40,4% случаев.

ПРАКТИЧЕСКИЕ РЕКОМЕНДАЦИИ

1. Для профилактики осложнений, связанных с применением ЛП с нарушением предписаний инструкции, необходима принятие комплекса мер, направленных на обеспечение безопасности больных при фармакотерапии.

К таким мерам могут быть отнесены:

- внедрение в программу обучения медицинских и фармацевтических работников вопросов безопасности больных и рациональной фармакотерапии;

- представление работникам здравоохранения более широкой и объективной информации о безопасности ЛС;

- внедрение в практику работы редколлегии медицинских изданий методических рекомендаций по профилактике развития НР, связанных с применение ЛС с нарушением предписаний инструкции;

- разработка методов определения соотношения польза/риск при оценке результатов использования ЛП с нарушением предписаний инструкции.

2. В связи с высокой частотой использования ЛС с нарушением предписаний инструкции, Федеральный закон «Об обращении лекарственных средств» необходимо дополнить разделом «применение лекарственных средств»

3. При необходимости использования ЛС с нарушением предписаний инструкции специалистам практического здравоохранения следует обращать особое внимание на переносимость ЛП, а при развитии осложнений фармакотерапии в соответствии с установленным порядком сообщать о них в ответственный орган фармаконадзора.

4. Необходима разработка методов управления рисками при использовании JIC с нарушением предписаний инструкции.

5. Необходимы модификации существующих карт - извещений о HP, а также базы данных спонтанных сообщений, позволяющие выявлять и систематизировать информацию об осложнениях, связанных с off-label применением J1C.

Список литературы диссертационного исследования кандидат медицинских наук Переверзев, Антон Павлович, 2013 год

СПИСОК ЛИТЕРАТУРЫ Нормативно-правовая база

1. Основы законодательства об охране здоровья граждан от 22.07.1993 N 5487-1;

2. Федеральный закон от 13.03.2006 N 38-Ф3 «О рекламе»;

3. Федеральный закон от 12.04.2010 N 61-ФЗ "Об обращении лекарственных средств";

4. Федеральный закон от 21.11.11 N 323-ф3 «Об основах охраны здоровья граждан в Российской Федерации».

5. Приказ Минздравсоцразвития России №757н от 26 августа 2010 г.

6. Об утверждении Порядка осуществления мониторинга безопасности лекарственных препаратов для медицинского применения, регистрации побочных действий, серьезных нежелательных реакций, непредвиденных нежелательных реакций при применении лекарственных препаратов для медицинского применения.

Книги и монографии

7. Астахова A.B., Лепахин В.К. Лекарства. Неблагоприятные побочные реакции и контроль безопасности, - 2-е изд., испр. и доп. - М.: Эксмо, 2008-256 с;

8. Клиническая фармакология. Национальное руководство/ [Лепахин В.К. и др.]; под ред. Белоусова Ю.Б., Кукеса В.Г., Лепахина В.К., Петрова.В.И. - М.: «ГЭОТАР-Медиа», 2009. - 976 с.

9. Неблагоприятные побочные реакции лекарственных средств. Пособие для врачей/ [А.Т.Бурбелло и др.]; под ред. А.Т.Бурбелло. - Санкт-Петербург, 2008. http://www.labclinpharm.ru/490.html

Ю.Нисевич Н. И., Учайкин В. Ф. Инфекционные болезни у детей. — 1-е изд. — М.: Медицина, 1990.— 624 с.

П.Стриженок Е.А. Фармакоэпидемиология лекарственных средств у беременных, Смоленск, 2005

12.Стуров Н.В. Сравнительный анализ эффективности методов выявления неблагоприятных побочных реакций на лекарственные средства в Российской Федерации в современных условиях, Москва, 2009

Статьи и публикации

13.Белоусов Ю.Б., Моисеев B.C., Лепахин В.К., Клиническая фармакология и фармакотерапия, 1997;

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