Title and code of the project
Advancements in the DESIGN, conduct and analysis of randomised trials on drug effects
Principle People/(co)promotores
Prof. D.E. Grobbee, MD, PhD, Clinical Epidemiology, Julius Center, UMC Utrecht (chair)
C.B. Roes, PhD, Clinical Information & Biometrics, Organon, Oss (co-chair) Other team members
Prof. A. de Boer , MD, PhD, Pharmaco Epidemiology, UU Utrecht
Prof. A.W. Hoes, MD, PhD, Clinical Epidemiology, Julius Center, UMC Utrecht
M.J. Knol, Clinical Epidemiology, Julius Center, UMC Utrecht
D. Dobre, MD, MPH, PhD, Department of Clinical Pharmacology, UMC Groningen
Statistician TBD
Location of PhD fellow
Julius Center of the University Medical Center Utrecht
Qualifications
The candidate should have an MD, PharmD or degree in biomedical sciences or related field. Experience in research and training in epidemiology are appreciated. Motivated to work in cutting edge drug development research is a prerequisite
Application
Candidates can apply by sending their CV and application letter to Mirjam Knol (m.j.knol@umcutrecht.nl).
Please indicate in your application letter how you heard of this vacancy.
Employment terms
The candidate will have an appointment at the Julius Center of the University Medical Center Utrecht (www.juliuscenter.nl) and will closely collaborate with people from other institutions. We offer a temporary full time appointment as a PhD student for one year with the perspective of prolongation with another three years.
Contact People for information on project/application
M.J. Knol, University Medical Center Utrecht,
+31 (0)88 755 9380,
P.A. van Meurs, Project leader Escher programme
+31 (0)88 755 5196 or mobile +31 (0)621 512631, p.a.vanmeurs@umcutrecht.nl
Introduction of the Research topic/ background
(300 words)
In the past decades the RCT has been viewed as the paradigm study design to determine the intended effects of drug interventions. In addition RCTs are important to assess type A (i.e. more common, predictable) unintended effects of drugs. Typically these RCTs are executed in three phases during a period of 10 years prior to drug registration.
Currently, trials are not designed, conducted and analysed in the most efficient and expeditious manner and several improvements in the design, conduct and analysis phase could lead to increased efficiency. For example, prevention of losses to follow-up and incomplete data, and sophisticated methods to impute missing values if they occur can increase the effective sample size. Sophisticated methods to indicate when there is enough information to stop the trial can shorten the duration of the trial and decrease the number of patients to be included. By using information of earlier trials when analysing a new trial, evidence of efficacy of a drug might be available earlier and less trials have to be performed.
Research Questions
(200 words)
How can the design, conduct and analysis of randomized controlled trials on drug effects be improved?
Improvements of design phase:
selection of patient populations sample size estimation randomization and blinding primary, secondary and composite outcomes Improvements in conduct phase: recruitment and compliance of study participants follow-up of study population stopping trials early Improvements in analysis phase: imputation methods for 'lost-to-follow-up' and incomplete data pooling of studies
Methods
(300 words)
Improvements in design phase:
Review of the literature summarizing different strategies to select patient populations, to perform sample size estimations and to conduct randomisation and blinding, and analysing which of these different strategies are most effective. This review can then be used to formulate a recommendation on designing RCTs.
Comparison of existing and development of new statistical methods to analyze composite endpoints using empirical data.
Improvements in conduct phase:
Review of the literature on different strategies to recruit and follow-up study participants and summarizing different strategies to improve and monitor compliance. This information is used to analyse which strategies are most effective and to formulate a recommendation on improving conduct of RCTs.
Comparison of different methods and strategies, for example conventional and Bayesian analyses, to stop trials early, using empirical data of already performed trials. Improvements in analysis phase:
Comparison of different imputation methods of increasing complexity for random and non-random missing values due to 'lost-to-follow-up' and incomplete collection of data. Empirical data of trials will be used to compare these different methods.
Comparison and application of different meta-analytical (Bayesian) techniques to analyse data of a trial using data from previously performed trials. Comparison and application of different meta-analytical (Bayesian) techniques to pool phase III and IV studies.
Deliverables
(300 words)
Recommendation to improve design phase of RCTs in terms of selection of patient populations, sample size estimation, randomisation and blinding, and composite outcomes.
Recommendation to improve conduct phase of RCTs in terms of recruitment, compliance and follow-up of study participants, and stopping trials early.
Recommendation to improve analysis phase of RCTs in terms of missing data and pooling of studies.
5 Papers in international scientific journals PhD Thesis
Presentations at (inter) national scientific meetings
Timelines and Milestones
(per 6 month episodes)
(200 words)
0-12 months: Reading relevant literature and research training in Epidemiology
12-18 months: Review and analysis of different strategies in design phase and recommendation of improvements
18-24 months: Review and analysis of different strategies in conduct phase and recommendation of improvements
24-30 months: Comparison of methods of stopping trials early
30-36 months: Comparison of imputation methods for missing data
36-42 months: Comparison of meta-analytical techniques to pool studies
42-48 months: Finalization of publications and PhD thesis. Most of the aforementioned periods will be finalized by a manuscript
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Best Regards,
Grace Wangge
