Developing methodologies for use in observational studies of drug effects using computerised clinical data.

Lead Research Organisation: London Sch of Hygiene and Trop Medicine
Department Name: Epidemiology and Population Health

Abstract

The safety of medicines can be difficult to investigate and often the only possibility is to conduct observational studies to see whether people receiving a drug are more likely to experience a side effect than people who do not receive the drug. Recently more and more of these studies have been done and frequently their results have been of major public health importance (e.g. the lack of association between MMR vaccine and autism). It is important that the results of these studies are reliable, and yet their underpinning methodologies are subject to many possible biases. I plan to investigate some of these methodologies and explore their biases, with the objective of increasing the reliability of drug safety studies. This will be achieved through at least four studies using an electronic database of anonymised patient medical records. The studies will investigate possible links between SSRI antidepressants and cerebral haemorrhage, tiotropium (a treatment for chronic obstructive pulmonary disease) and stroke, ezetimibe (a lipid lowering agent) and cancer and glitazone antidiabetics and myocardial infarction. This programme of research will therefore answer questions directly related to the safety of four drugs/drug classes and will improve methodological approaches to drug safety studies in the future.

Technical Summary

The efficacy of a medicine is established by the time it becomes marketed. However, the possible harms associated with a drug are usually less well understood. Randomised controlled trials to assess side effects are often impractical as they may need to be unfeasibly large or could be unethical. Observational studies therefore offer an ideal practical method for investigating drug safety issues, and in recent years the number of such studies has increased. Much research in this area is done using anonymised patient information from large primary care databases such as the General Practice Research Database (GPRD). Over the last three years I have gained substantial experience in using the GPRD to answer questions about the safety of medicines. Recent advances in data quality and linkage offer even greater opportunities for research, but better methodologies are needed to take full advantage. I propose the following programme of research in order to improve approaches to using primary care data for drug safety studies:

AIMS:
Further develop strategies for using primary care data. In particular focusing on diagnostic validity, the impact of consultation frequency and distinguishing prevalent from incident diagnoses.
Explore the utility and limitations of the self-controlled case series method. Specifically I will investigate the impact of time varying confounders, situations where the occurrence of an outcome of interest affects the length of the observation period and instances where the likelihood of exposure is dependent on the presence or absence of the outcome of interest.

OBJECTIVES:
To improve on existing methods and establish optimal methodologies for conducting drug safety studies.

METHODOLOGY
I plan to achieve these aims by conducting four drug safety studies examining the associations between: SSRI antidepressants and cerebral haemorrhage; ezetimibe and cancer; tiotropium and stroke; and glitazones and myocardial infarction. I will use the self controlled case series method, comparing results with other study designs, such as case control and cohort methods and using external validatory data from randomised clinical trials. Collaborative input will be provided by the Medical Statistics Unit of LSHTM and the Department of Statistics at the Open University

SCIENTIFIC/MEDICAL OPPORTUNITIES
The current regulatory environment demands more observational studies of drug effects. Patients and prescribers rightly expect investigators to produce reliable answers to questions about the safety of a drug and robust methodologies are therefore needed to ensure confidence in the outcome of drug safety studies.

Publications

10 25 50
 
Description EMA Workshop
Geographic Reach Asia 
Policy Influence Type Participation in advisory committee
Impact Contributed to workshop for guidelines on drug effectiveness research using observational data
 
Description Euroepi Training
Geographic Reach Asia 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Hong Kong training
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
 
Description MHRA Training
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Tailor made training designed, and delivered for MHRA requiring expertise in understanding pharmacoepidemiology in order to assess drug licensing and safety issues
 
Description Membership of Pharmacovigilance Expert Advisory Group
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
Impact Improvement in the methods used to investigate adverse drug effects of public health importance. Improvements in the committments for post-marketing safety assessment made by pharmaceutical companies at the time of drug licensing.
 
Description Primary care data use workshop
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Short courses in pharmacoepidemiology
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact By bringing together experts in the field of pharmaoepidemiology from LSHTM, the GPRD, MHRA and other organisations I established a new advanced short course in pharmacoepidemiology at LSHTM. This ran for the first year in 2010, and is complimentary to the well establisehd pharmacoepidemiology and pharmacovigilance short course run by LSHTM. I am course organiser for both courses, and the student body this year was from Europe, North America, Africa and Asia. These courses are an important capacity building resource for people working in the area of drug safety in industry, regulatory authorities and increasingly academic institutions. I am now leading the development of a distance learning version of the LSHTM Cert in Pharmacoepidemiology and Pharmacovigilance
 
Description ADHD Treatments and Hospital Accident and emergency attendance aNalysis (ATHAN
Amount HK$357,632 (HKD)
Organisation Research Grants Council Hong Kong 
Sector Public
Country China
Start 06/2013 
End 07/2014
 
Description Data driven semi-automated approaches to comparative effectiveness research using electronic health record data
Amount £458,327 (GBP)
Funding ID MR/S01442X/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 02/2019 
End 01/2022
 
Description HOD2: Data driven semi-automated approaches to comparative effectiveness research using electronic health record data
Amount £465,792 (GBP)
Funding ID MR/S01442X/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 08/2019 
End 07/2022
 
Description Immediate Postdoctoral Basic Science Research Fellowship
Amount £258,700 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2019 
End 04/2023
 
Description Impact of EU label changes and pregnancy prevention programme for medicinal products containing valproate and related substances: rlsk awareness and adherence
Amount € 24,975 (EUR)
Organisation European Medicines Agency 
Sector Public
Country United Kingdom
Start 02/2020 
End 04/2021
 
Description Innovative Medicines Initiative
Amount £341,261 (GBP)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 11/2009 
End 11/2014
 
Description MRC population health scientist fellowship (supervisor)
Amount £238,859 (GBP)
Funding ID MR/M014649/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 08/2015 
End 07/2018
 
Description Methodology
Amount £495,446 (GBP)
Funding ID MR/M013278/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 08/2015 
End 07/2017
 
Description Michael J Fox Foundation Rapid Response Award
Amount $74,930 (USD)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 12/2013 
End 12/2014
 
Description PERsonalised Medicine for Intensification of Treatment (PERMIT) of T2DM,
Amount £547,572 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 02/2020 
End 02/2022
 
Description Pharmacoepidemiology Partnership
Amount £993,198 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 09/2018 
End 09/2023
 
Description Pharmacoepidemiology of oral anticoagulation agents - a comparison of dabigatran exilate, warfarin and dual-antiplatelet therapy in patients with atrial fibrillation
Amount HK$213,938 (HKD)
Organisation Research Grants Council Hong Kong 
Sector Public
Country China
Start 09/2014 
End 08/2015
 
Description RNIB Research Funding
Amount £56,144 (GBP)
Organisation Royal National Institute for Blind People 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2014 
End 07/2015
 
Description Sir Henry Wellcome Postdoctoral Fellowship (supervisor)
Amount £250,000 (GBP)
Funding ID 107340/Z/15/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2015 
End 09/2019
 
Title Linked data - GPRD + MINAP 
Description I have acquired a source of linked data containing the primary care records and highly accurate information on myocardial ischaemia events for patients receiving antiplatelet medication. Such linked data has only just been made available for research and will lead to vast improvements in the accuracy of outcome ascertainment and hence the validity of research findings. 
Type Of Material Database/Collection of Data/Biological Samples 
Provided To Others? No  
Impact This work has been presented at an international conference (ICPE, Chicago 2011), and submitted for publication 
 
Description COPD Treatment Effectiveness 
Organisation Harvard University
Department Harvard Medical School
Country United States 
Sector Academic/University 
PI Contribution I obtained funding from NIHR for a 3 year project to determine whether electronic health records can be used to determine the effectiveness of treatments for COPD
Collaborator Contribution Expertise in disease area and epidemiology.
Impact Recently accepted BMJ Open protocol for the study
Start Year 2017
 
Description COPD Treatment Effectiveness 
Organisation Imperial College School of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution I obtained funding from NIHR for a 3 year project to determine whether electronic health records can be used to determine the effectiveness of treatments for COPD
Collaborator Contribution Expertise in disease area and epidemiology.
Impact Recently accepted BMJ Open protocol for the study
Start Year 2017
 
Description CPRD - EMIS data 
Organisation Medicines and Healthcare Regulatory Agency
Department Clinical Practice Research Datalink (CPRD)
Country United Kingdom 
Sector Public 
PI Contribution I am supervising a CPRD staff member to do a PhD looking at how best to combine EMIS and Vision data for research
Collaborator Contribution Provision of EMIS data and expertise
Impact None yet
Start Year 2017
 
Description DSRU 
Organisation Drug Safety Research Unit
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Expertise in the use of electronic health records to measure the effects of drugs, specifically use of the self-controlled case series
Collaborator Contribution Primary research question, obtaining data, data analysis, drafting reports
Impact None to date: Disciplines represented, Medicine, epidemiology, medical statistics
Start Year 2011
 
Description Farr Pharmacoepi 
Organisation University of Glasgow
Country United Kingdom 
Sector Academic/University 
PI Contribution I am leading a collaborative bid for funding across three of the recently established Farr Institutes, to develop better methodology to define drug exposures using electronic healthcare records, and to apply this to currently relevant clinical research
Collaborator Contribution All partners are engaged with definining aims, objectives and deliverables for the project
Impact None yet
Start Year 2014
 
Description Farr Pharmacoepi 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution I am leading a collaborative bid for funding across three of the recently established Farr Institutes, to develop better methodology to define drug exposures using electronic healthcare records, and to apply this to currently relevant clinical research
Collaborator Contribution All partners are engaged with definining aims, objectives and deliverables for the project
Impact None yet
Start Year 2014
 
Description GSK 
Organisation GlaxoSmithKline (GSK)
Department Epidemiology
Country United Kingdom 
Sector Private 
PI Contribution Expertise in the use of the self-controlled case series study. We are developing research projects involving both PhD students and a research fellow to pursue methodological advances in the study of drug effects using real world data. We have now appointed 2 PhD studnets to look at different aspects of methodological pharmacoepidemiology.
Collaborator Contribution Obtaining data, data analysis, co-supervision of students and research fellow
Impact None to date. Expertise in epidemiology and medical statistics
Start Year 2012
 
Description Glitazones 
Organisation Imperial College London
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Led the planning of the study and application for funding. The study will investigate whether the glitazone antidiabetics prevent the development of Parkinson's disease
Collaborator Contribution Assistance with drafting the protocol, from expertise in diabetes and pre-clinical Parkinson's disease
Impact Study completed and submitted for publication; results presented at ICPE Taipei, 2014. Expertise in epidemiology, general practice, statistics, diabetes, Parkinson's disease
Start Year 2012
 
Description Glitazones 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Led the planning of the study and application for funding. The study will investigate whether the glitazone antidiabetics prevent the development of Parkinson's disease
Collaborator Contribution Assistance with drafting the protocol, from expertise in diabetes and pre-clinical Parkinson's disease
Impact Study completed and submitted for publication; results presented at ICPE Taipei, 2014. Expertise in epidemiology, general practice, statistics, diabetes, Parkinson's disease
Start Year 2012
 
Description Hong Kong Uni 
Organisation University of Hong Kong
Department Department of Pharmacology and Pharmacy
Country Hong Kong 
Sector Academic/University 
PI Contribution Input to study design and analysis plan for two planned studies. One has secured funding, another is pending. Hosted 3 visitors from Hong Kong in 2014 to learn about UK primary care data and to conduct a series of pharmacoepi studies supervised by me
Collaborator Contribution Leading study planning for Hong Kong studies, obtaining data, data analysis
Impact Ongoing. Multidisciplinary team with statistics, pharmacy, pharmacology and pharmacoepidemiology expertise. Resulted in 1 publication (in press; journal Paediatrics), and 2 successful funding applications
Start Year 2012
 
Description Huntington's 
Organisation Columbia University
Country United States 
Sector Academic/University 
PI Contribution Led the design and analysis of one aspect of the project. Obtained data for all aspects. Input to planning, design, analysis, interpretation and manuscript drafting for all elements
Collaborator Contribution Input to planning, design, analysis, interpretation and manuscript drafting for all elements
Impact Publications: 23482661, 23558730. Multidisciplinary team with public health, statistics, epidemiology, Huntington's disease, primary care expertise
Start Year 2012
 
Description Huntington's 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Led the design and analysis of one aspect of the project. Obtained data for all aspects. Input to planning, design, analysis, interpretation and manuscript drafting for all elements
Collaborator Contribution Input to planning, design, analysis, interpretation and manuscript drafting for all elements
Impact Publications: 23482661, 23558730. Multidisciplinary team with public health, statistics, epidemiology, Huntington's disease, primary care expertise
Start Year 2012
 
Description IMI BIFAP 
Organisation Database for Pharmacoepidemiological Research in Primary Care
Country Spain 
Sector Public 
PI Contribution Hosting a visitor to learn how to use the self-controlled case series, contributing expertise to study design, analysis, and interpretation.
Collaborator Contribution Data provision, analysis
Impact Ongoing.
Start Year 2012
 
Description IMI Protect funded PhD studentships (GPRD) 
Organisation European Commission
Department Innovative Medicines Initiative (IMI)
Country Belgium 
Sector Public 
PI Contribution I am directly supervising two PhD students carrying out research directly aligned with the aims of my fellowship to improve methodologies for obervational studies of drug effects
Collaborator Contribution GPRD partners contribute both data and expertise
Impact Both students continuing research projects. Output presented at conferences : EuropEpi, Aarus 2013, ICPE Montreal 2013, ICPE Barcelona 2012. Disciplines: statistics, epidemiology, general practice. Publications; first author Wing, 2014
Start Year 2011
 
Description IMI Protect funded PhD studentships (GPRD) 
Organisation Medicines and Healthcare Regulatory Agency
Department General Practice Research Database (GPRD)
Country United Kingdom 
Sector Academic/University 
PI Contribution I am directly supervising two PhD students carrying out research directly aligned with the aims of my fellowship to improve methodologies for obervational studies of drug effects
Collaborator Contribution GPRD partners contribute both data and expertise
Impact Both students continuing research projects. Output presented at conferences : EuropEpi, Aarus 2013, ICPE Montreal 2013, ICPE Barcelona 2012. Disciplines: statistics, epidemiology, general practice. Publications; first author Wing, 2014
Start Year 2011
 
Description IMI funded PhD studentship (Amgen) 
Organisation Amgen Inc
Department Pharmacovigilance and Traceability
Country United Kingdom 
Sector Private 
PI Contribution I am primary supervisor for this PhD studentship which is directly aligned with my own research priorities
Collaborator Contribution Data and expertise provided
Impact Publication (first author Brauer 2014); Publication (first author Brauer, 2011); conference presentation at ICPE Chicago 2011, ICPE Barcelona 2012, ICPE Montreal 2013. Disciplines represented - statistics, epidemiology, general practice
Start Year 2009
 
Description IMI funded PhD studentship (Amgen) 
Organisation European Commission
Department Innovative Medicines Initiative (IMI)
Country Belgium 
Sector Public 
PI Contribution I am primary supervisor for this PhD studentship which is directly aligned with my own research priorities
Collaborator Contribution Data and expertise provided
Impact Publication (first author Brauer 2014); Publication (first author Brauer, 2011); conference presentation at ICPE Chicago 2011, ICPE Barcelona 2012, ICPE Montreal 2013. Disciplines represented - statistics, epidemiology, general practice
Start Year 2009
 
Description Obesity 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Study design, obtaining data, analysis, intepretation and drafting manuscripts, applying for further research funding
Collaborator Contribution Input to study design, analysis plan, interpretation and drafting
Impact Ongoing: expertise includes epidemiology, statistics, primary care, bariatrics. Results presented at Euroepi Aarhus 2013; ICPE Montreal 2013, ICPE Taipei 2014. PLoS Medicine paper, Int J Obesity paper, BJCP paper.
Start Year 2012
 
Description Pfizer self controlled case series 
Organisation Pfizer Ltd
Country United Kingdom 
Sector Private 
PI Contribution Initial discussions for a collaboration on the use of the self-controlled case series for signal identification using electornic health records. I have contributed to the design of a study and will comment further as the study progresses
Collaborator Contribution Pfizer had the idea for the study, obtained the data and will do the analyses
Impact Signal Detection for Recently Approved Products: Adapting and Evaluating Self-Controlled Case Series Method Using a US Claims and UK Electronic Medical Records Database. Zhou X, Douglas IJ, Shen R, Bate A. Drug Saf. 2018 Jan 11. doi: 10.1007/s40264-017-0626-y. [Epub ahead of print]
Start Year 2014
 
Description SSRI and stroke 
Organisation Medicines and Healthcare Regulatory Agency
Department Vigilance & Risk Management
Country United Kingdom 
Sector Public 
PI Contribution I was involved with the study design, carried out all analysis and wrote the manuscript for this study
Collaborator Contribution Data provision and collaboration for a study now completed
Impact Br J Clin Pharmacol. 2011 Jan;71(1):116-20. doi: 10.1111/j.1365-2125.2010.03797.x. The use of antidepressants and the risk of haemorrhagic stroke: a nested case control study. Douglas I, Smeeth L, Irvine D.
Start Year 2009
 
Description Self controlled case series 
Organisation Open University
Department Department of Mathematics and Statistics
Country United Kingdom 
Sector Academic/University 
PI Contribution I directly contributed to the development of a modified verion of the self-controlled case series by providing real world data from my own work (antipsychotics and stroke), thus allowing the method to be extended beyond simulation stage
Collaborator Contribution Through this collaboration I am able to drawn on the statistical expertise of the department in applying novel methodology to my own research
Impact Farrington et al paper (2011). Petersen et al, 2016; Whitaker et al 2018, Collaboration involves statisticians, epidemiologists and a general practitioner.
Start Year 2009
 
Description Takeda 
Organisation Takeda Pharmaceutical Company
Country Japan 
Sector Private 
PI Contribution Led application for an MRC Case Studentship
Collaborator Contribution Contributed to application for MRC Case Studentship
Impact Not funded. Expertise includes statistics, epidemiology, drug regulation, primary care
Start Year 2012
 
Description Utrecht EMA Sponsored Studies 
Organisation Utrecht University
Country Netherlands 
Sector Academic/University 
PI Contribution Collaborative partner in a consortium bidding for funding to conduct drug safety studies on behalf of the European Medicines Agency
Collaborator Contribution Contributing to study proposals, protocols, analysis plans. Analysis and interpretation of data.
Impact None to date
Start Year 2019
 
Description clopidogrel 
Organisation University College Hospital
Department Pharmacy
Country United Kingdom 
Sector Academic/University 
PI Contribution I led and conducted an observational study to assess the clinical implications of a theoretical interaction between clopidogrel and proton pump inhibitors
Collaborator Contribution Providing specific clinical expertisePharmacy expertise
Impact BMJ. 2012 Jul 10;345:e4388. doi: 10.1136/bmj.e4388. Clopidogrel and interaction with proton pump inhibitors: comparison between cohort and within person study designs. Douglas IJ, Evans SJ, Hingorani AD, Grosso AM, Timmis A, Hemingway H, Smeeth L. Disciplines represented: cardiology, epidemiology, general practice, pharmacy
Start Year 2009
 
Description clopidogrel 
Organisation University College London
Department Institute of Epidemiology and Health Care
Country United Kingdom 
Sector Academic/University 
PI Contribution I led and conducted an observational study to assess the clinical implications of a theoretical interaction between clopidogrel and proton pump inhibitors
Collaborator Contribution Providing specific clinical expertisePharmacy expertise
Impact BMJ. 2012 Jul 10;345:e4388. doi: 10.1136/bmj.e4388. Clopidogrel and interaction with proton pump inhibitors: comparison between cohort and within person study designs. Douglas IJ, Evans SJ, Hingorani AD, Grosso AM, Timmis A, Hemingway H, Smeeth L. Disciplines represented: cardiology, epidemiology, general practice, pharmacy
Start Year 2009
 
Description GSK talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact ~30 drug industry epidemiologists in a single company were keen to hear more about techniques I have used (propensity scores and the self controlled case series) as they are considering these methods for their research activities.

Stronger ties with industrial contacts who are keen to take advice from me going forward.
Year(s) Of Engagement Activity 2009,2010