Pragmatic%20Randomised%20Trials

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Pragmatic Randomised Trials

• David Torgerson
• Director, York Trials Unit
• djt6_at_york.ac.uk
• www.rcts.org

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Placebo trials

• These are usually seen as the gold-standard
  method of evaluating drug treatments. Because
  the control patients receive identical looking
  treatment the effect of being in a trial and the
  psychological effects (placebo effect) of being
  in a trial are neutralised.
• This allows us to estimate the true value of a
  treatment within a patient population.

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Placebos are not pragmatic

• A problem with placebo trials is that they are
  not pragmatic.
• We do not use placebos in routine clincial
  practice. If there is a true placebo effect it
  is worth paying for and having. Using a placebo
  removes this potentially worthwhile effect.

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Explanatory trials

• 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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Explanatory trial outcomes

• Explanatory trials often measure outcomes that
  are not relevant to the patient (e.g. changes in
  various blood markers).
• Surrogate outcomes may be wrong sodium floride
  increases bone density but also INCREASES
  fracture.
• 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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Removing malaria - Rome

• Romans noted an association between outbreaks of
  malaria and smell from swamps near to Rome.
  Decided to drain swamp to remove smell and remove
  malaria. The treatment worked outbreaks of
  malaria were reduced as was the smell. The
  theory of how it works was wrong but the
  treatment was correct.

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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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Prevalence of Sore Throat
Antibiotics 37 None 35 Delayed 30
Proportion of patients better by day 3 (P0.28)
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Antibiotics

• Little et al showed that immediate use of
  antibiotics for a sore throat had NO significant
  effect on the resolution of symptoms
• A placebo trial would demonstrate this BUT this
  trial also showed that those who did not get
  antibiotics were less likely to visit their GP
  again

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Re-attendance within 12 months
Odds Ratio 1.39 (1.03 to 1.89) Antibiotics
38 None 27
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Pragmatic information

• GPs prescribing antibiotics for uncomplicated
  sore throats has very little, if any, effect
• Patients prescribed antibiotics are more likely
  to re-attend when they next have a sore throat
  compared with giving no antibiotics

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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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Pragmatic with explanatory features

• Many, if not most, pragmatic trials will also
  include features of explanatory studies. We
  might measure blood pressure, cholesterol or bone
  mass, to elucidate mechanisms to explain why or
  why something did not work. A RCT of vitamin D
  injection measured a PTH levels to check the
  treatment was being absorbed. This information
  can be collected cheaply from pragmatic trials to
  enhance their scientific value.

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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.
• Economic evaluations are best conducted using
  pragmatic studies.

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References

• Avorn et al. Reduction of bacteriuria and pyuria
  after ingestion of cranberry juice. JAMA
  1994271751-4.
• Godwin et al. Pragmatic controlled clinical
  trials in primary care the struggle between
  external and internal validity. BMC Medical
  Research Methodology 2003328.
• Helms PJ. Real world pragmatic clinical trials
  what are they and what do they tell us? Pediatr
  Allergy Immunol 2002134-9.
• Kontiokari et al. Randomised trial of
  cranberry-lingonberry juice and Lactobacillus GG
  drink for the prevention of urinary tract
  infections in women. BMJ 20013221571.

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References

• Little et al. Reattendance and complications in a
  randomised trial of prescribing strategies for
  sore throat the medicalising effect of
  prescribing antibiotics. BMJ 1997315350-2 (and
  BMJ314722-7).
• MacPherson H. Pragmatic clinical trials. Comp
  Ther Med 200412136-40.
• MacRae KD. Pragmatic versus explanatory trials.
  Int J Technol Assess Health Care 19895333-9.
• Medical Research Council. A framework for
  development and evaluation of RCTs for complex
  interventions to improve health. April 2000.
  http//www.mrc.ac.uk/index/publications/publicatio
  ns-ethics_and_best_practice/publications-clinical_
  trials_guidelines.htm

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References

• Pocock SJ (1983). The Justification for
  Randomized Controlled Trials. In Clinical Trials
  - a practical approach. John Wiley Sons,
  Chichester. p.182
• Riggs et al. Effect of fluoride treatment on the
  fracture error rate in post-menopausal women with
  osteoporosis. N Engl J Med 1990322802-9.
• Roland M, Torgerson DT. Understanding controlled
  trials What are pragmatic trials? BMJ
  1998316285.
• Schwartz D, Lellouch J. Explanatory and pragmatic
  attitudes in therapeutic trials. J Chron Dis
  196720637-648.
• Thompson SG, Barber JA. How should cost data in
  pragmatic randomised trials be analysed? BMJ
  20003201197-1200.