Pragmatic Randomised Trials

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Pragmatic Randomised Trials
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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.

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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.

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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.

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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?

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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Cranberry results
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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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?

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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.