Methodological Challenges in Post-Licensure Vaccine Safety Studies Using Large Routinely Collected Datasets

Methodological challenges in post-licensure vaccine safety studies using large routinely collected datasets by Julia Margaret Toffa-Stowe A thesis submitted in partial fulfilment of the requirements of the Manchester Metropolitan University for the degree of Doctor of Philosophy by Published Work (Route 2) Manchester Metropolitan University 2017 Table of Contents 1. Abstract 2. Acknowledgments 3. Introduction 3.1 Vaccine safety concerns past and present 3.2 Routinely collected health data 3.3 Pre-Licensure 3.4 Post-Licensure 3.4.1 Signal detection 3.4.2 Signal Strengthening 3.4.3 Individual Causality Assessment 3.4.4 Hypothesis Testing 3.4.5 Statistical Methods 3.5 Ethical and Legal framework 3.6 Summary 4. Critical account of Published Works 4.1 Study 1: Intussusception / Rotavirus vaccination 4.2 Study 2: Narcolepsy in adults / Pandemic Influenza vaccine 4.3 Study 3: Convulsions / Pandemic and Seasonal Influenza vaccine 4.4 Study 4: Bacterial and Viral Infections / Measles Mumps and Rubella vaccine 4.5 Study 5: Guillain-Barré syndrome / Seasonal Influenza vaccine 4.6 Study 6: Idiopathic Thrombocytopenic Purpura / second dose of Measles Mumps and Rubella Vaccine 4.7 Study 7: Bell’s Palsy / Seasonal Influenza vaccine 5. Methodological Challenges in Post-Licensure Vaccine Safety Studies 5.1 Setting up the study 5.2 Study design and dealing with confounding 5.3 Case identification 5.4 Defining index data 5.5 Cleaning Data 5.6 Media attention 5.7 Validation 5.8 Publication 5.9 The communication of risk 6. Conclusions 7. Published works 8. References 9. Tables 10. Appendix 1 List of abbreviations BMJ British Medical Journal CHIS Child Health Information System CTV Clinical Terms Version DTP Diphtheria, Tetanus, Pertussis Vaccine EHR Electronic Health Record EMA European Medicines Agency FDA Food and Drug Administration GBS Guillain-Barre syndrome GP General Practitioner GRPD General Practice Research Database HES Hospital Episode Statistics HPA Health Protection Agency HPV Human Papillomavirus HSCIC Health and Social Care Information Centre ICD International Classification of Diseases ICSD International Classification of Sleep Disorders ITP Idiopathic Thrombocytopenia Purpura MHRA Medicines and Healthcare Products Regulatory Agency MMR Measles, Mumps and Rubella Vaccine MSLT Multi Sleep Latency Test NHS National Health Service OPCS Classification of Intervention and Procedures PbR Payment by Results PHE Public Health England PRISM Post-Licensure Rapid Immunization Safety Monitoring Program QOF Quality Outcomes Framework SCCS Self-Controlled Case-Series VAERS The Vaccine Adverse Event Reporting System VSD Vaccine Safety Datalink WHO World Health Organisation 2 Glossary Reports which have been proactively sought. Registers and Active Reporting data linkage techniques can be used to identify adverse events. An event which follows the administration of a drug or a Adverse event vaccine but is not necessarily caused by that event Reports where no active measures have been taken to Passive reporting encourage the reporting of safety concerns Activities relating to the detection, assessment, understanding Pharmacovigilance and prevention of adverse effects Part of the healthcare system which is accessed through a patient’s general practice surgery which can be the first point Primary care of contact for patients. The GP coordinates day to day and ongoing care that a patient may need. Electronic data that is collected for purposes other than for Routinely collected data scientific research. An example of this is the hospital administration database which schedules appointments. Services that are based at hospital and patient access the Secondary care services either by Accident and Emergency departments or by referral from General Practice or other specialities. The suggestion of a relationship between a drug/vaccine and a condition which has not been documented previously. The Signal information should be from multiple sources and judged to be sufficient for further investigation 3 1. Abstract Robust and responsive epidemiological post-licensure vaccine safety studies are the backbone to having confidence in a vaccination programme. Consideration must be given to the unique methodological challenges inherent when assessing a potential causal association between a vaccine and the condition of interest; these can be present from setting up the study through to communicating the results. Public Health England (PHE) has addressed a number of vaccine safety concerns since the 1990’s using routinely collected healthcare data and methods specific to the disease and vaccine under scrutiny. This thesis comprises of seven published post-licensure vaccine safety studies which were carried out in response to a number of different pertinent safety concerns relevant to the UK’s immunisation schedule. As a background to these studies the history of routinely collected data is examined in the context of how we use the data today along with a description of the pre and post-licensure vaccine safety activities which often precede the epidemiological studies. By bringing together the methodological issues of these seven studies and demonstrating the different ways in which these issues have been handled it has created a blueprint for addressing vaccine safety concerns in the future. The seven studies are i) Intussusception and Rotavirus vaccination ii) Narcolepsy in adults and Pandemic Influenza vaccine iii) Convulsions and Pandemic and Seasonal Influenza vaccine iv) Bacterial and Viral Infections and Measles Mumps and Rubella vaccine v) Guillain-Barré syndrome and Seasonal Influenza vaccine vi) Idiopathic Thrombocytopenic Purpura and the second dose of Measles Mumps and Rubella vaccine vii) Bell’s Palsy and Seasonal Influenza vaccine. In conclusion the methodological approaches employed in these studies can be used in the future to assess potential adverse events and the access to routinely collected health data is an essential element of this. 4 2. Acknowledgements First and foremost I would like to thank Professor Liz Miller and Professor Nick Andrews who have been wonderful mentors and roles models for me over the years. Both are immensely knowledgeable, kind and patient and have always given me the opportunity to be involved in the great many challenging and exciting studies on vaccine safety which has allowed me to develop in my work. I would also like to thank Professor Brent Taylor for my first experiences in this field and for his humour, expertise and support throughout the years. I will be forever thankful to Angela Bridge for introducing me to the wonders of hospital data and for teaching me so much. I would like to especially acknowledge my co-authors from the seven papers that make this thesis, for all their individual expertise and their contributions to these studies. My grateful thanks go to Dr Kath Whitehead and Professor Ray Borrow from MMU who have steered me in the right direction during my time with the university. Profound gratitude goes to my husband Dr Samuel Toffa who has always encouraged me to pursue my career and has made it possible for me to complete this work over the past ten years. Finally special thanks go to my parents for their unfailing support in whatever I do in my life. I would also like to thank Florence and William who everyday inspire me to strive towards my goal. 5 3. Introduction The safety of vaccines attracts great interest from both public and scientific communities through media stories and scientific debate. Established methods are in place to assess the safety of vaccines from the development stage through to the pharmacovigilance activities after licensure. These post-licensure activities range from the passive reporting of adverse events to full epidemiological studies to quantify a risk. Key to the post-licensure epidemiological safety study is the ability to identify and use the appropriate data and methods. This thesis will present seven epidemiological studies that were carried out by Public Health England from 2006 to 2016 and use a number of different data sources and methods which all address pertinent vaccine safety concerns. Chapter 3 briefly describes the history of vaccine safety and its relevance today, the data sources and statistical methods used in the studies and their development and also discuss the ethical and legal frame work which is so critical in the ability to carry out this work. Chapter 4 summarises the seven published studies which this thesis is based on and presents a systematic review of the published evidence on each adverse event under study at the time the research was carried out. Chapter 5 discusses the methodical challenges from setting up a study to communicating the results. This includes a discussion on the many sources of potential bias that are possible when studying such complex conditions in challenging settings and the statistical methods developed to address specific issues in vaccine safety. 3.1 Vaccine safety concerns past and present There is no doubt that vaccination is one of the most significant health interventions ever developed, successfully controlling many serious diseases and saving countless lives globally. However, as with any medical treatment or drug, vaccination can never be risk-free in terms of unwanted side-effects. Another important factor unique to vaccination is that 6 unlike therapeutic drugs, vaccines are given prophylactically to healthy individuals, often young children. From the patient’s or parent’s perspective this changes the benefit to harm balance as the possibility and consequences of a certain serious adverse event occurring outweighs the benefits of being protected by the vaccine from a disease which they know little about. For example, a patient would accept a high incidence of drug-related morbidity in the treatment of cancer but would not tolerate anywhere near this level of distress from a vaccination for a disease which they think will never affect them. The assessment of the risk from an event occurring shortly after vaccination may be incorrect as there may be events that occur in time shortly after vaccination, which would have happened by chance without vaccination.

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