Good Pharma Practice

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Good Pharmacovigilance Practice Guide

Good Pharmacovigilance Practice GuideCompiled by the Medicines and Healthcare products Regulatory Agency

London Chicago

Published by the Pharmaceutical Press An imprint of RPS Publishing 1 Lambeth High Street, London SE1 7JN, UK 100 South Atkinson Road, Suite 200, Grayslake, IL 600307820, USA Crown Copyright 2009 Medicines and Healthcare products Regulatory Agency Market Towers 1 Nine Elms Lane London SW8 5NQ Information on re-use of crown copyright information can be found on the MHRA website: www.mhra.gov.uk Published by the Pharmaceutical Press on behalf of the Medicines and Healthcare products Regulatory Agency (MHRA) is a trade mark of RPS Publishing RPS Publishing is the publishing organisation of the Royal Pharmaceutical Society of Great Britain First published 2009 Reprinted 2009 Typeset by J&L Composition Ltd, Filey, North Yorkshire Printed in Great Britain by Cambridge University Press, Cambridge ISBN 978 0 85369 834 0

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, without the prior written permission of the copyright holder. The publisher makes no representation, express or implied, with regard to the accuracy of the information contained in this book and cannot accept any legal responsibility or liability for any errors or omissions that may be made. Website listings published in this guide other than www.mhra.gov.uk are not under MHRA control, therefore we are not responsible for the availability or content of any site. Listings should not be taken as an endorsement of any kind and we accept no liability in respect of these sites. A catalogue record for this book is available from the British Library.

Contents

Foreword Acknowledgements Feedback Introduction Abbreviations

xii xiii xiv xv xvii

1 Qualified Person Responsible for Pharmacovigilance in the European Economic Area1.1 1.2 1.2.1 1.3 1.4 1.4.1 1.4.2 1.4.3 1.4.4 1.5 1.5.1 1.6 Appointment of the Qualified Person for Pharmacovigilance Notification of details of the Qualified Person for Pharmacovigilance Checklist for the detailed description of the pharmacovigilance system Who can be a Qualified Person for Pharmacovigilance? What are the responsibilities of the Qualified Person for Pharmacovigilance? Overview of the pharmacovigilance system Preparation of reports Requests from Competent Authorities Ongoing safety monitoring What other tasks might the Qualified Person for Pharmacovigilance perform? Points to consider Examples of inspection findings

11 3 3 5 6 6 9 10 11 13 14 14

2 Management of Pharmacovigilance Data2.1 2.2 2.2.1 2.2.2 Terminology Information collection and collation Reconciliation Duplicate reports

1717 20 20 22

v

vi

CONTENTS

2.3 2.4 2.5 2.6 2.6.1 2.7 2.8

Access to pharmacovigilance data Preparation of reports Requests from Competent Authorities Use of computer systems Checklist of requirements for computer systems Use of paper based systems Examples of inspection findings

22 23 23 23 24 25 26

3 Spontaneous Case Processing3.1 3.1.1 3.1.2 3.1.3 3.1.4 3.1.5 3.1.6 3.1.7 3.2 3.2.1 3.2.2 3.2.3 3.3 3.3.1 3.3.2 3.3.3 3.3.4 3.3.5 3.4 3.4.1 3.4.2 3.4.3 3.4.4 3.4.5 3.5 3.5.1 3.5.2 3.5.3 3.5.4 3.5.5 3.6 3.7 3.8 Sources of suspected adverse reactions Medical information enquiries Contact us emails and website enquiry forms Product technical complaints Medical representatives Published literature Reports from Competent Authorities Contractual partners Recording Individual Case Safety Report information Date of receipt Methods of recording information Coding Follow-up of adverse events Information to validate a case Information relevant for case evaluation Reports of drug exposure during pregnancy Reports of overdose, abuse and misuse Additional considerations regarding follow-up attempts Case assessment Seriousness assessment Causality assessment Expectedness assessment Upgrading and downgrading of cases Deletion/deactivation of cases Expedited reporting What to expedite Additional information to expedite What not to report When to expedite How to expedite Compliance monitoring UK requirements for specials Examples of inspection findings

2929 30 30 30 31 32 32 32 33 33 33 33 34 34 35 35 36 36 37 38 39 39 40 41 41 41 44 45 45 46 46 46 47

CONTENTS

vii

4 Literature Searching4.1 4.2 4.3 4.4 4.5 4.6 4.6.1 4.6.2 4.6.3 4.6.4 4.6.5 4.7 4.7.1 4.7.2 4.7.3 4.7.4 4.7.5 4.7.6 4.7.7 4.7.8 4.8 4.9 Identification of Individual Case Safety Reports Requirements relating to Periodic Safety Update Reports Riskbenefit assessment When to start and stop Where to look Database searches Precision and recall Search construction Selection of product terms Selection of search terms Limits Handling search results Record keeping Outputs Review and selection of articles Follow-up Day zero Translations Reporting Duplicates Contracting out literature search services Examples of inspection findings

4949 50 51 51 52 52 53 53 53 54 54 55 55 56 56 57 57 57 58 58 58 59

5 Periodic Safety Update Reports5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 5.10 5.11 Who is responsible for producing Periodic Safety Update Reports? When should Periodic Safety Update Reports be submitted? Submission dates for Periodic Safety Update Reports Renewals and Periodic Safety Update Reports Data selection and inclusion Combination products and differing formulations of the same active substance Special patient populations Reference Safety Information Review of cumulative data Quality control Examples of inspection findings

6161 62 63 64 64 67 67 69 69 70 70

viii

CONTENTS

6 Evaluation of Safety Data6.1 6.2 6.2.1 6.2.2 6.2.3 6.2.4 6.3 6.4 6.5 6.5.1 6.6 6.7 General considerations for signal detection Methods of signal detection Individual case review Systematic review of multiple case reports Periodic Safety Update Reports Other sources of information Investigation of potential signals Follow-up of potential signals Communication of potential signals Direct Healthcare Professional Communications Counterfeit medicines Examples of inspection findings

7373 74 74 75 77 77 78 79 80 81 82 83

7 Risk Management Plans7.1 7.2 7.2.1 7.2.2 7.2.3 7.3 7.3.1 7.3.2 7.3.3 7.3.4 7.4 Purpose Content of the European Union Risk Management Plan Safety specification Pharmacovigilance plan Risk minimisation Key assessment issues Safety specification Pharmacovigilance plan Risk minimisation Other information Examples of issues

8585 86 86 86 86 87 87 88 88 88 88

8 Reference Safety Information8.1 8.2 8.3 8.4 8.5 8.5.1 8.5.2 8.5.3 8.6 8.6.1 8.6.2 Types of Reference Safety Information Uses of Reference Safety Information Availability of Reference Safety Information Consistency between different types of Reference Safety Information Updates to Reference Safety Information Triggers for updates Labelling committees Points to consider Timelines Timelines for periodic review Timelines for updates

9191 91 92 92 93 93 93 93 94 94 94

CONTENTS

ix

8.7 8.8 8.9

Introduction of new labels and patient information leaflets following approval of changes Considerations for herbal products Examples of inspection findings

95 95 96

9 Quality Management System9.1 9.2 9.3 9.4 9.5 Written procedures Training Quality assurance Record retention Examples of inspection findings

9999 101 103 105 105

10 Interactions between Pharmacovigilance and Other Functions10.1 10.2 10.3 10.4 10.4.1 10.4.2 10.4.3 10.4.4 10.4.5 10.4.6 10.4.7 10.5 10.6 10.7 10.8 10.9 10.10 All personnel Medical information Sales and marketing Regulatory affairs Safety variations and urgent safety restrictions Responses to requests for information from regulatory authorities Post-marketing commitments Periodic Safety Update Reports Product labelling Worldwide marketing authorisation status Preparation for marketing authorisation submission Non-clinical staff Product quality Legal department Human resource department or those responsible for training Senior management Information technology

107107 109 110 111 112 112 112 113 113 113 114 114 115 115 116 116 117

11 Contracts and Agreements11.1 11.1.1 11.2 11.2.1 11.3 General considerations for contracts and agreements Points to consider for contracts and agreements Outsourcing of pharmacovigilance activities Points to consider for outsourcing agreements Third party distributors and manufacturers

119119 120 121 122 123

x

CONTENTS

11.4 11.4.1 11.5 11.5.1 11.5.2 11.6

Co-licensing/co-marketing and co-promotion of products Points to consider in co-licensing/co-marketing/ co-promotion agreements Other types of contracts and agreements Agreements with local affiliates Transfer of a marketing authorisation Examples of inspection findings

123 124 124 124 125 125

12 Requirements for Solicited Reports12.1 12.1.1 12.1.2 Relevant terminology Trial/study definitions Other definitions that may clarify safety reporting requirements 12.1.3 Summary of study categorisation 12.2 Safety reporting for non-interventional studies 12.2.1 Expedited reporting of adverse reactions 12.2.2 Ongoing safety evaluation 12.2.3 Periodic Safety Update Reports 12.2.4 Annual Safety Reports 12.2.5 Final study reports 12.3 Interventional clinical trials 12.3.1 Causality assessments 12.3.2 Investigators brochure 12.3.3 What is a SUSAR? 12.3.4 Reporting requirements for investigational medicinal products 12.3.5 Reporting requirements for non-investigational medicinal products 12.3.6 Electronic reporting 12.3.7 Considerations for blinded trials 12.3.8 Annual Safety Reports 12.3.9 Safety monitoring boards 12.3.10 Safety reporting to ethics committees 12.4 Post-author