Pragmatic Randomised Trials

Background Many clinical trials take place in

artificial conditions that do not represent NORMAL clinical practice.

Often trials are EXPLANATORY or MECHANISTIC in that their main aim is to identify biological, physiological mechanisms for how a treatment works.

Background (cont) Explanatory trials often measure

outcomes that are not relevant to the patient (e.g. changes in various blood markers).

They are also undertaken by ‘expert’ clinicians who carefully select patients.

Explanatory View How does it work? By what biological mechanism can

we explain the effects? Can be seen as a more robust

approach, than qualitative methods, of answering the how or why questions.

Pragmatic Attitude Does it work? For whom does it work? How much does it cost? Of secondary importance – how or

why does it or does not work?

Selection Criteria – Explanatory Trials

An Explanatory study will often select patients with very tight clinical characteristics – for instance the same gender, small age range, defined clinical characteristics.

This makes it possible to reduce response variation and allow inferences of effect from small sample sizes.

Comparators Explanatory trials often use the

‘wrong’ comparator (e.g., placebo). For most conditions there are

existing treatments, what we want to know is whether the new treatment is better than existing care NOT whether it is better than no treatment or placebo.

Generalisability Because explanatory studies are

undertaken in tightly defined clinical circumstances, and usually use a placebo, they are not very generalisable to routine clinical practice.

An alternative approach is to use the PRAGMATIC design.

Pragmatic Trials In the 1960s Schwarz and Llellouch

coined the phrase ‘pragmatic trial’. In a pragmatic trial the design

mimics as closely as possible ROUTINE clinical practice, with the exception that patients are randomly allocated to treatment.

Advantages of pragmatic trials An advantage of the pragmatic

approach is that because placebos are not used and EFFECTIVENESS is estimated.

Because conditions mimic routine clinical practice this makes the results more applicable to the ‘average’ patient.

Antibiotics for sore throats The Little trial was a 3 armed trial of:

immediate antibiotics; no antibiotics or delayed antibiotics. It was pragmatic BECAUSE: Set in primary care where most sore throats

are dealt with; Used ‘bog standard’ GPs; Did NOT use placebos; Outcome was clinical severity from patient

NOT microbial swabs.

Cranberry Juice for urinary tract infection Avorn et al randomised elderly

women to receive cranberrry juice or a placebo.

Outcomes were microbiological (I.e., bacterial counts in urine samples).

Result – Cranberry juice significantly reduced bacteria in the urine.

SO WHAT – what we need to know is whether it reduces symptoms.

Cranberry again. Kontiokari et al randomised a

group of young women (mainly students) to an ‘open’ trial of cranberry, lactobacillus (yakult type of drink) or open control.

Outcome was time to recurrence of urinary tract symptoms (e.,g., pain on passing urine, flank pain).

Infection confirmed with swabs.

Cranberry results

Cranberry conclusion First trial was suggestive in that it

showed an effect on a SURROGATE outcome measure of urinary tract infection.

The second trial was more definite – cranberry supplementation reduces symptoms of urinary tract infection in young women.

Fracture prevention Two trials of calcium and vitamin D. MRC RECORD trial allocating

participants with a recent fracture to placebos or active treatment using research nurses in fracture clinics.

York trial uses practice nurses to give treatment to patients in GP practices.

Differences York trial using practice nurses to give

calcium and D to patients with a range of risk factors who know what they are taking.

MRC trial allocating participants with recent fractures – not generalisable to other settings or groups of patients. Patients do not know what they are getting.

Generalisability York results will inform GPs as to

whether or not their practice nurses using calcium and D can prevent fractures and at what cost.

MRC results applicable to secondary care only a smaller population.

Other ‘bone’ trials Generally most research into

fracture prevention is explanatory with small numbers of patients being allocated to treatments and success being measured in changes in bone mass or bone turnover, which is distinctly uninteresting to the patient.

Explanatory vs Pragmatic Probably most trials are of the

explanatory nature and many consider pragmatic trials as being unscientific because of loss of control of a number of variables.

Pragmatic trials are best for questions of effectiveness.

Loss of control Randomisation does control for all

known and unknown confounds, covariates, etc. Eliminating some confounds (e.g, by taking only non-smokers) WILL increase precision but at the loss of much information.

Better to have a larger sample size.

Counter-arguments to pragmatic trials. It is argued that a pragmatic trial

may not be generalisable because of the wide inclusion criteria. In a pragmatic trial we will know the treatment works for the ‘average’ patient BUT most patients are not average and we cannot tell which patients in those recruited does the treatment work. In an explantory trial we can.

Against this Few treatments have a ‘qualitative’

interaction, that is for some subgroups the treatment has an opposite effect. The treatment MAY have a quantitative effect but usually it still is effective in all sub-groups. Whilst an explantory trial may truly be more generalisable among white, non-smoking, middle class men with high BP – what happens to everyone else?

Summary Explanatory trials follow the

tradition of very tight control of sample – difficult to generalise from results.

Pragmatic study much more generalisable interested in EFFECTIVENESS not too interested in how things work.