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

2.  Introduce explanatory and pragmatic designs  The concept of a continuum rather than dichotomy  Use of the PRECIS wheel in BLISTER  Clinical implications of internal versus external validity

3.  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.  Treatment already known to work, but can it work in real world clinical practice? - effectiveness  Wider group of participants – co morbidity, less compliant  Maybe primary care setting  Flexible dosing, switching and rescue therapy compatible with daily practice – “policy” of a treatment pathway rather than one drug  Cost effectiveness key

5. ExplanatoryPragmatic  Homogenous patients  Tightly defined intervention  Clearly defined control group – often placebo  Objective/surrogate outcomes  Real life patients  Flexible intervention with changes  Active comparator  Clinically important outcomes

6.  Still have to fiercely minimise bias 1. Selection - Randomisation and allocation concealment 2. Performance – similar conditions both groups 3. Detection bias – blinded outcome 4. Attrition bias – collecting data on dropout and intention to treat analysis

7. 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.

8.  The Pragmatic-Explanatory Continuum Indicator Summary  Typically used as a tool when designing study  Requires a judgement on key aspects of trial design  Illustrated by a PRECIS wheel

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

10. PRECIS summary of a randomized trial of low-dose aspirin for the prevention and treatment of pre-eclampsia (Collaborative Low dose Aspirin Study in Pregnancy [CLASP])

11. PRECIS summary of a randomized trial of low-dose aspirin for the prevention of pre-eclampsia in women at high risk

12.  Sent to six TMG members  Two pemphigoid experts  One clinician interested in clinical trials  Two trial statisticians

13. Eligibility Criteria Flexibility of the Experimental Intervention Primary Analysis Practitioner Adherence Participant Compliance Outcomes Follow-up Intensity Practitioner Expertise (Comparison) Flexibility of the Comparison Intervention Practitioner Expertise (Experimental)

18.  Described explanatory and pragmatic trials  A continuum not a dichotomy  Applied PRECIS wheel to BLISTER  Pragmatic studies not an excuse for bias  Most clinical trials that change NHS practice need to be pragmatic