1. Research Techniques Made Simple: Pragmatic or Explanatory Trial? The BLISTER Study The Bullous Pemphigoid Steroids and Tetracyclines Study Hywel Williams University of Nottingham with help from Daniel Bratton and Andrew Nunn MRC Clinical Trials Unit HTA reference 06/403/51 ISRCTN13704604

2. Pragmatic study – does it work in my clinic? Treatment already known to work, but can it work in real-world clinical practice? - effectiveness Wider group of participants – more comorbidities, less compliant Maybe in a primary care setting Flexible dosing, switching, and rescue therapy compatible with daily practice – “policy” of a treatment pathway rather than one drug Cost-effectiveness is key

3. Explanatory trials - can it work? Conducted under “ideal” conditions Highly selected and homogeneous participants Usually tertiary care Good compliance Likely to remain in study Only one medical condition Strict dosing schedules Monitored closely To “explain” if a treatment works - efficacy

4. PICOT comparison Pragmatic Homogenous patients Tightly defined intervention Clearly defined control group – often placebo Objective/surrogate outcomes Short-term follow-up time, e.g., 6 weeks Real-life patients Flexible intervention with changes Active comparator Clinically important outcomes Longer-term follow-up times, e.g., 6 months

5. Pragmatic does not mean “anything goes” Still have to fiercely minimize bias 1.Selection - Randomization and allocation concealment 2.Performance – similar conditions for both groups 3.Detection bias – blinded outcome 4.Attrition bias – collecting data on dropout and intention-to-treat analysis

6. Back to BLISTER..... Is it explanatory or pragmatic? X wrong question To what extent is it explanatory or pragmatic? √ right question Thorpe KE et al: A pragmatic–explanatory continuum indicator summary (PRECIS): a tool to help trial designers. Journal of Clinical Epidemiology 2009, 62:464-475.

7. More about PRECIS The Pragmatic-Explanatory Continuum Indicator Summary Typically used as a tool when designing study Requires a judgment on key aspects of trial design Illustrated by a PRECIS wheel

8. A blank pragmatic - explanatory continuum indicator summary (PRECIS) ‘‘wheel.’’

9. Applied PRECIS to BLISTER Sent to six TMG members Two pemphigoid experts One clinician interested in clinical trials Two trial statisticians

11. Summary points Described explanatory and pragmatic trials A continuum, not a dichotomy Applied PRECIS wheel to BLISTER Pragmatic studies are not an excuse for bias Most clinical trials that change clinical practice need to be pragmatic