Pharmacoepidemiology and Drug Safety

: Examining Clinical Drug Trials Via Technology

Abstract

This thesis provides a succinct analysis on the use of Information Technology (IT) in the fields of clinical research and pharmacoepidemiology. The primary research project explores a means of identifying a cost effective, and robust mechanism for conducting large scale clinical study using IT. The thesis was devised after examining the findings of the Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares (MAPEC) study, which identified a 64% relative risk reduction in participants who took one or more of their antihypertensive medications in the evening, as opposed to taking them all in the morning. The significance of the MAPEC findings have been met with scepticism by the research community, but the potential advancement to the treatment and prevention of cardiovascular disease suggested that additional studies be conducted to refute or substantiate these findings.

Due to the large number of participants required to power a study capable of successfully answering the research question, it became clear that conventional study methodologies would not be practical, and so therefore were unsuitable. IT allows for a more streamline approach to efficiently collect and collaboratively share research data. Therefore, it was conceived that the project would be conducted using all electronic advantages that IT has to offer.

Literature review
Before proceeding with the research project, I conducted a systematic literature review (chapter 3) examining the prevalence of electronic data capture (EDC) and electronic case report forms (eCRF) in clinical research and pharmacoepidemiology. The review indicated that these fields have yet to fully embrace IT. The reasons are varied; cost of installation and deployment, ethical fears regarding patient confidentiality and security, and resources to maintain the technology and infrastructure. The findings of the review revealed that adoption of technology is in its infancy in these areas. There is a need for clearer legislation and frameworks governing electronic health records and guidelines are necessary on best practices for researchers on the use of IT. The subject area would also benefit from a standard method of evaluating technical journals.

Treatment in morning versus evening study
Once I had expanded my understanding of how IT is currently utilised in clinical trials and pharmacoepidemiology, I began working with my thesis supervisor on the protocol for the main research project. The Treatment In Morning versus Evening (TIME) study will provide additional evidence to whether morning or evening dosing of hypertensive medication is more cardio-protective, and could potentially be a very cost effective means of lowering cardiovascular outcomes. Chapter 4 documents in detail the TIME study protocol. Furthermore, conducting the TIME study has provided me opportunities to do further research; determining the most effective recruitment strategy for the study, analysis of EDC, creating a dynamic EDC system, researching an electronic means of evaluating the TIME website, and assessing where further research would be most productive. These questions are examined throughout the thesis.

Poster advertising
Chapter 5 of the thesis discusses a poster advertising campaign that attempted to bring the TIME study to the attention of potential participants. I created a poster and sent it to all General Practitioner (GP) practices and prescribing cost centres in the UK. The response rate from practices and cost centres was low and the instance of posters displayed was disappointing. It became evident early on in the pilot study for TIME that poster advertising was ineffective when only 40 participants were randomised as a result of the posters. However, this led us to concentrate on alternative recruitment strategies. Further strategies were adopted in the formal TIME study that allowed the study recruitment target to be fulfilled.

TIME pilot study
Due to the uncertainty of the novel online methodology used in the TIME study, there were doubts as to the sustainability and the ability to recruit the necessary number of participants to power the study. Therefore, it was necessary to prove the viability of the TIME by conducting a pilot study. Chapter 6 reviews the feasibility of the TIME study. The TIME pilot successfully recruited and randomising 402 participants. GP recruitment from primary and secondary care was identified as being the most successful and cost effective means of highlighting the study to potential participants. Based on the data from the pilot, the British Heart Foundation has funded the formal study, which has now recruited over 21,000 participants. The withdrawal rate and follow-up rate remain acceptable and add weight to the hypothesis that the online methodology can productively be used to conduct a randomised trial.

Dynamic electronic data capture system
Whilst the pilot study for TIME was ongoing and continuing with recruitment, it became evident that protocol amendments would often involve substantial changes to the software of the TIME study website. In an effort to minimise the work involved for myself as a software developer, and to curtail disruption to the study I investigated a dynamic EDC system. A system was successfully developed that dynamically creates eCRFs and allows data to be submitted to a study database. The software, discussed in chapter 7, does require formal validation and needs to be externally audited before it can be used within a live study of an investigational medical product. However, the prototype system is a sound basis on which to build and improve upon.

Electronic questionnaire
Chapter 8 discusses an electronic questionnaire as a means of validating clinical trial technology. The questionnaire identifies participants perceptions of the study website, the online methodology, and their views on TIME using their clinical data for research. The relevant literature was reviewed, and several iterations of questions were sent to participants before a final version was found to be sufficient. The survey found that participants do have concerns on how their confidential data could potentially be used but many participants agreed to take part in the study, despite these concerns, due to having altruistic motives and wishing to assist in research. The questionnaire provides a good foundation for future questionnaires looking to assess similar trial technology.

Analysis of the TIME study methodology
Chapter 9 summarises and compares the TIME study recruitment, follow-up and retention rates against similar clinical studies using more conventional methodologies. A review of the literature was conducted. During my analysis it was clear that the online recruitment was extremely successful at meeting the recruitment target, and that recruitment via GP letter was the most efficient method. The follow-up and retention rates were similar to conventional paper based studies and I recommend various recruitment strategies are utilised to ensure recruitment targets are met. Additionally, all viable options should be encouraged to maintain participant engagement throughout the life of a study.

Conclusion
This thesis provides a concise analysis of how IT is currently used within clinical studies and pharmacoepidemiology. IT has been identified as beneficial and can assist in recruitment and data capture. The innovative dynamic EDC system I developed and discuss in chapter 7, will allow for future research studies to be conducted more efficiently, and with far fewer software changes. This thesis concludes that there remain areas within clinical research and pharmacoepidemiology that would undoubtedly benefit from closer integration of IT and recommends where integration should be expedited.

Date of Award	2018
Original language	English
Awarding Institution	University of Dundee
Sponsors	British Heart Foundation
Supervisor	Thomas MacDonald (Supervisor) & Isla Mackenzie (Supervisor)