TREATMENT 2 Evaluation of interventions Types of RCT Blinding

OBJECTIVES (Treatment lecture 1) Describe structure of RCT Define, calculate and interpret main measures of effect for RCTs Compare RCT design with observational study designs Treatment lecture 2 Explain differences between efficacy and effectiveness Distinguish between explanatory and management trials)

What will be covered Experimental design RCT architecture RCT analysis (measures of effect) Calculation examples Types of RCT Compliance E.g. NTD trials Blinding

Types of RCT Compliance explain differences between efficacy and effectiveness distinguish between explanatory and management trials NTD trials used below to illustrate these concepts.

Folate and neural tube defects (NTD) Neural tube defects (NTD) = failure of closure of neural tube (at days gestation) Cause(s) of NTDs? Step 1 Map occurrence of NTDs by time, place and person (descriptive epidemiology) Step 2 Why this pattern observed? (analytic epidemiology)

Occurrence of NTDs by time, place and person Declining secular trend Geographic differences N vs S Europe Higher in Scotland, Ireland NTD rates higher in Low SES Poorer diet Winter births Low fruit/vegetable intake in spring coincides with approx. 4 weeks gestation Dietary link with NTDs???

Neural tube defects (NTD) and folate? NTD rates higher in Women treated with anti-epileptic drugs Epilepsy drug = folate antagonist Women with gastric bypass Nutritional deficiencies including B12 and folate NTD mothers: Dietary differences Low serum folate & low red blood cell folate Folate link with NTDs?? RCT to test this hypothesis

RCT architecture RANDOMISATION Informed consent

RCT architecture RANDOMISATION

RCT analyses Relative risk (RR) = incidence in treated group incidence in control group Odds ratio = Outcome/ no outcome in treated group Outcome/ no outcome in control group Risk difference / Attributable risk (RD) = (incid. in treated group) - (incid. in control group) (Absolute) Risk reduction (RRed) = (incid. in control group) - (incid. in treated group) Relative risk reduction (RRR) (%) = risk reduction (x100) incidence in control group = 1 - RR (x 100) Number needed to treat (NNT) = 1/ risk reduction

Relative risk reduction (RRR): = Risk reduction x100 Incidence in controls = (Incidence in cntrls - Incid. in Rx group) x100 Incidence in controls = 1 - Incidence in Rx group X 100 Incidence in controls = 1 - RR (x 100) If confidence limits include 0, then NOT statistically significant reduction in risk

Laurence et al. (BMJ 9 May 1981, ) Original analysis

What to do with non compliers? Should they be reassigned as in the previous table? Should they be dropped from the analysis? Should they be retained in their original group irrespective of whether they adhered to the treatment/control regimen?

Hampton RCT chart - NTD study RANDOMISATION No. of NTD(%) 'As treated'

Coronary Drug Project Trial

Laurence et al. “Pure” analysis

Hampton RCT chart - NTD study RANDOMISATION 2 NTD (3.3%)4 NTD (7.8%) EFFICACY EFFECTIVENESS (1+2 vs 3+4)

Hampton RCT chart - NTD study RANDOMISATION No. of NTD(%) EFFICACY (1 vs 3) EFFECTIVENESS

Explanatory trial Efficacy: Compare outcome in compliers in treatment group with outcome in compliers in control group Non compliers omitted from analysis What if large number of non compliers?! Management /intention to treat/pragmatic trial Effectiveness: Compare outcome according to group to which assigned (irrespective of compliance) What if large number of non compliers?!

Intention-to-treat vs explanatory trials Both types of trial have their place, depending on the trial objectives. Explanatory trials show whether an intervention can work preferred by drug companies as it’s easier to show an effect of a drug etc. Management trials show whether an intervention does work more realistic, more likely to show what is likely to happen in real life clinical situations Use results from management trials to make your clinical decisions!!

Fletcher & Fletcher 4 th edn Clinical Epidemiology, Chapter 8,Treatment, p Explanation of explanatory trials misleading Figs 8.7 & 8.8 not helpful

Characteristics of explanatory and management trials EXPLANATORY Can it work? Intention mechanisms efficacy Restricted recruitment Idealised application Restricted eligibility of events Type I (  )error MANAGEMENT Does it work? Intention all consequences effectiveness All comers recruited Pragmatic All events eligible Type II (  )error

Error types associated with management & explanatory trials Conclusion from RCT The Truth A betterA no better A better than B  ** A no better than B **  * Error associated with management trials (effectiveness) ** Error associated with explanatory trials (efficacy)

BLINDING Students often confused about this so some explanatory notes provided in the next sides. Definitions Single blind Patient not aware of whether on treatment on not. Double blind Neither patient nor doctor knows who is on treatment on not. Treble blind Neither patient nor doctor nor laboratory know who is on treatment on not. vs open treatment allocation (not blind, patient and doctor aware of whether in treatment group or not)

‘Double’ blinding Requires making the actual treatment and the control indistinguishable – hence use of placebo Dummy (inert) substance or intervention which is indistinguishable in appearance from the treatment (drug or other intervention) Required to counteract the placebo effect Feel better because believing something will work See example in next 2 slides Helps ensure similar behaviour by patients and similar treatment of patients in both treatment and control groups Avoids assessment bias observer and patient

Participants’ guesses regarding whether they received nicotine or placebo, assessed at the 6-month follow-up survey Assigned versus perceived placebo effects in nicotine replacement therapy for smoking reduction in Swiss smokers. R. Dar, F. Stronguin & J-F Etter, J Consult & Clin Psychol. 2005, 73, ResponseReceived nicotine N=247 Received placebo N=244 % guessed nicotine % guessed placebo % did not know

Mean reduction in cigarettes smoked per day as a function of actual and perceived treatment ResponseReceived nicotine, n=247 Received placebo, n=244 Total n=491 Guessed nicotine CI Guessed placebo 8.1 CI Did not know CI Total CI = 95% confidence intervals for group means J Consult & Clin Psychol. 2005, 73, 350-3