Tjeerd van Staa Professor of Health eresearch Centre for Health Informatics, University of Manchester

Transcription

1 Tjeerd van Staa Professor of Health eresearch Centre for Health Informatics, University of Manchester

2 Disclosure statement I have participated in expert meetings with GSK and Boehringer and provided methodological advice to Laser GSK has funded one of my research studies

3 Explanatory and pragmatic trials (Schwartz and Lellouch 1967) Explanatory (efficacy) trials: to verify a biological hypothesis Randomisation Blinding Placebo => Careful selection and monitoring in order to ensure compliance to protocol + adherence + no cross-over Pragmatic trials: to choose between different clinical strategies Randomisation No blinding No placebo => Representative of usual care: clinicians and patients; usual adherence with cross-over

4 Current system of drug development

5 Datafication: more digital data Routinely collected digital data and trials Fool s gold Unstructured I prefer paper case report form over messy electronic health record GCP inspector: no paper to inspect

6 Gold-standard research (??) = >

7 Temporal trends in reporting muscle problems in statin trials [Harsha V et al 2014].Most trials did not solicit muscle problems, use standard definitions

8 Number and percentage of records recorded in primary care (Clinical Practice Research Datalink), hospital care (Hospital Episode Statistics), and disease registry (Myocardial Ischaemia National Audit Project) for non-fatal myocardial infarction across the three sources (n= patients). Emily Herrett et al. BMJ 2013;346:bmj.f by British Medical Journal Publishing Group

9 Classic Trial Size Mostly small N Huge budgets Endpoints Mostly surrogate Clinical trials employ adjudication Setting Research enterprise parallel universe Focus on audit and monitoring 9 Califf RM et al. JAMA 2012;307:1838-

10 Clinical trials in crisis: Four simple methodologic fixes Andrew J Vickers There is growing consensus that the clinical trials system is broken, with trial costs and complexity increasing exponentially. 1. dramatically reducing eligibility criteria 2. clinical integration, investment in data infrastructure to bring routinely collected data up to research grade 3.cluster randomisation 4.simplified / early consent

11 Pragmatic trials integrated with routine care Tunis SR et al. JAMA 2003;290: van Staa et al, BMJ 2013

12 Medicines evidence in whose context: prescriber or patient? BEYOND THE PILL: DATA-INTENSIVE MEDICATION..we are so focused on a pill, and industry is only about patenting a molecule, that alone can not be

13 van Staa TP, Dyson L, McCann G, Padmanabhan S, Belatri R, Goldacre B, Cassell J, Pirmohamed M, Torgerson D, Ronaldson S, Adamson J, Taweel A, Delaney B, Mahmood S, Baracaia S, Round T, Fox R, Hunter T, Gulliford M, Smeeth L. The opportunities and challenges of pragmatic point-of-care randomised trials using routinely collected electronic records: evaluations of two exemplar trials. Health Technol Assess 2014.

14 Data flow in pragmatic trials [van Staa BMJ]

15 Pop-up boxes

16 Drop-out rates of practices at each step in the recruitment and approval procedure

17 EHR trials: feasible? Conclusion report: EHR point-of-care trials are feasible, although the recruitment of clinicians is a major challenge due to the complexity of trial approvals. These trials will provide substantial evidence on clinical effectiveness only if trial interventions and participating clinicians and patients are typical of usual clinical care and trials are simple to initiate and conduct

18 It Can Be Done [Slide M Lauer] N Engl J Med (posted online September 1, 2013)

19 Ongoing pre-licencing trial in suburb of Manchester (Salford) EHRs used to identify eligible patients and follow over time Integrated EHRs with hospital and GP data Local pharmacies used to dispense medication

20 We have had to overcome major challenges The majority of participating healthcare professionals had little experience of prelicence clinical research, and a change to a research culture has taken time. Extensive training in good clinical practice was delivered to more than 1000 nurses, pharmacists and GPs from 51 general practices in Salford Approximately 150 GlaxoSmithKline -funded healthcare workers are engaged in the study New et al Thorax 2014

21 Patient + Mobile = n-of-1 Frontier Reducing Relapse in Schizophrenia via Smartphone Drug + behaviour (information * psychological endotype) = outcome From J. Ainsworth & S. Lewis

22 An example of Data Quality analysis: Incidence rates of CVD by calendar year (cluster analysis)

23 E-Labs for transparency and reproducibility: Asthma e-lab: platform for uniform storage and interaction for UK birth cohorts data. Adnan Custovic et al. Thorax doi: /thoraxjnl Copyright BMJ Publishing Group Ltd & British Thoracic Society. All rights reserved.

24 Trials within Cohorts (TwiCs) Design [J Candish, A Pate et al in progress] Large observational cohort, O Subcohort of eligible patients, N M patients randomly selected to be offered the intervention N-M patients in the control arm followed in routine practice R1 number of patients are not offered the intervention by the onsite clinician M R1 patients are offered the intervention R2 number of patients refuse the offer of the intervention by the onsite clinician M R1 - R2 patients receive the intervention

25 Simulation Results

26 Current problems Anonymise the information collected during the course of your treatment and use it to support research and improve care for others

27 Discussion Healthcare priorities should be based on pragmatic trials, not explanatory trials Pragmatic trials are a disruptive technology! [Lauer et al] and evolving Pragmatic trials challenging to implement due to red tape [ Good Clinical Practice] Entering era of digital data Need for simple trials that compare different actual clinical decisions: Randomisation as a matter of routine: clinical practice as usual.