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Randomised Controlled Trials  (RCTs) Graeme MacLennan
James Lind <ul><li>Born Edinburgh 1716 </li></ul><ul><li>On HMS Salisbury in 1747 he allocated 12 men with scurvy </li></u...
Think about…  <ul><li>Consider how you would go about evaluating the following interventions </li></ul><ul><ul><li>Surgica...
The need to evaluate health care <ul><li>Variations in health care </li></ul><ul><li>Unproven treatments </li></ul><ul><li...
Evaluation process <ul><li>Define research question </li></ul><ul><li>What is already known? </li></ul><ul><li>Identify ap...
Define research question and what is already known <ul><li>Research question (PICOT) </li></ul><ul><ul><li>Population </li...
Definition of population,  intervention and “outcomes” <ul><li>Population </li></ul><ul><ul><li>Strict definition (explana...
Measuring “outcome” <ul><li>Questionnaires, interview, medical notes etc </li></ul><ul><li>Timing of questionnaires? </li>...
Sources of systematic errors <ul><li>Selection bias </li></ul><ul><ul><li>can be introduced by the way in which comparison...
What is a randomised controlled trial?  <ul><li>Simple Definition </li></ul><ul><li>A study in which people are allocated ...
Simple RCT model  RANDOMLY  allocated  to experimental  or  CONTROL  group CONTROL EXPERIMENT Trial participants
What is a  randomised  controlled trial? <ul><li>Random allocation  to intervention groups </li></ul><ul><li>all participa...
Terminology  <ul><li>Interventions  are comparative regimes within a trial  </li></ul><ul><li>Prophylactic, diagnostic, th...
What is a randomised  controlled  trial? <ul><li>One intervention is regarded as control treatment (the group of participa...
Terminology <ul><li>Control Group </li></ul><ul><li>can be  </li></ul><ul><ul><li>conventional practice </li></ul></ul><ul...
What is a  randomised controlled trial ? <ul><li>RCTs are </li></ul><ul><ul><li>Experiments:   investigators can influence...
What is a randomised controlled trial?  <ul><li>More Complex Definition </li></ul><ul><li>Quantitative, comparative, contr...
Inclusion/exclusion criteria <ul><li>Decision rules applied to potential trial participants to judge eligibility for inclu...
What is randomisation?  <ul><li>Randomisation is the process of random allocation </li></ul><ul><li>Allocation is not dete...
Pseudo-randomisation <ul><li>Other allocation methods include </li></ul><ul><ul><li>according to date of birth  </li></ul>...
Terminology <ul><li>Controlled  clinical trials (CCTs)   are not the same as randomised controlled trials </li></ul><ul><l...
Why use randomisation?  <ul><li>Characteristics similar across groups at baseline  </li></ul><ul><li>can isolate and quant...
Why do we need a control group? <ul><li>Don’t need a control group if completely predictable results </li></ul><ul><ul><li...
Regression to the mean <ul><li>Occurs when an intervention aimed at a group or characteristic that is very different from ...
DISTRIBUTION OF RESULTS threshold measurement 1 measurement 2
Hawthorne Effect <ul><li>Experimental effect in the direction expected but not for the reason expected  </li></ul><ul><li>...
Placebo Effect <ul><li>Effect (usually, but not always positive) attributed to the expectation that a therapy will have an...
EFFECT OF AN INTERVENTION Effect size Experimental group Control group Hawthorne E. R. mean Placebo E. Therapeutic E. Real...
Minimising bias in RCTs <ul><li>Blinding </li></ul><ul><ul><li>Single blind – participants are unaware of treatment alloca...
Concealment of random allocation list <ul><li>“ Trials with inadequate allocation concealment have been associated with la...
Blinding, placebos <ul><li>RCTs should use the maximum degree of blinding that is possible </li></ul><ul><li>Placebo is a ...
Empirical evidence of bias
‘ Explanatory’ and ‘Pragmatic’ questions <ul><li>Explanatory </li></ul><ul><li>Can  it work in an ideal setting …..? </li>...
Key differences between  explanatory and pragmatic trials (1) <ul><li>Explanatory Pragmatic </li></ul><ul><li>Question eff...
Key differences between  explanatory and pragmatic trials (2) <ul><li>Explanatory Pragmatic </li></ul><ul><li>Outcomes sho...
Example of selection bias for PP in an open trial Exp Ctrl None None White(2005) E E Worse prognosis
Terminology: explanatory versus pragmatic <ul><li>Explanatory trials </li></ul><ul><ul><li>estimates efficacy - that is th...
RCT as the Gold Standard <ul><li>The randomised controlled trial is widely regarded as the gold standard for evaluating he...
RCT strengths <ul><li>Confounding variables minimised </li></ul><ul><li>Only research design which can in principle yield ...
RCT limitations <ul><li>Contamination of intervention groups  </li></ul><ul><li>Comparable controls </li></ul><ul><li>Prob...
Other issues in RCTs (1) <ul><li>Ethics </li></ul><ul><li>Management issues </li></ul><ul><li>Interim analysis and ‘stoppi...
Other issues in RCTs (2) <ul><li>A power calculation is essential for the validity of a trial and will always be necessary...
Parallel group (simple) RCT design in practice Patient eligible for either treatment Patient gives informed consent Yes No...
Summary <ul><li>“ Gold standard” of research designs </li></ul><ul><li>Individual patients are  randomly allocated  to rec...
Good study design <ul><li>General considerations </li></ul><ul><li>maximise attribution </li></ul><ul><ul><li>Ensure no fa...
Minimise sources of error <ul><li>Systematic errors (bias) </li></ul><ul><li>“ inaccuracy which is different in its size o...
Study designs <ul><li>Experimental (Randomised controlled trial) </li></ul><ul><ul><li>A new intervention is deliberately ...
Evaluation of health care interventions <ul><li>Randomised controlled trials are considered as the “gold standard” </li></...
Useful/interesting links <ul><li>www.jameslindlibrary.org   (History) </li></ul><ul><li>www.consort-statement.org   (CONSO...
References <ul><li>Black.  Why we need observational studies to evaluate the effectiveness of health care.  BMJ 1996 : 312...
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Randomised Controlled Trials

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Randomised Controlled Trials

  1. 1. Randomised Controlled Trials (RCTs) Graeme MacLennan
  2. 2. James Lind <ul><li>Born Edinburgh 1716 </li></ul><ul><li>On HMS Salisbury in 1747 he allocated 12 men with scurvy </li></ul><ul><ul><li>Cider </li></ul></ul><ul><ul><li>Seawater </li></ul></ul><ul><ul><li>Horseradish, mustard, garlic </li></ul></ul><ul><ul><li>Nutmeg </li></ul></ul><ul><ul><li>Elixir Vitriol </li></ul></ul><ul><ul><li>Oranges and Limes </li></ul></ul>
  3. 3. Think about… <ul><li>Consider how you would go about evaluating the following interventions </li></ul><ul><ul><li>Surgical versus medical termination of pregnancy </li></ul></ul><ul><ul><li>Referral guidelines for radiographic examination </li></ul></ul><ul><ul><li>Paracetamol and/or ibuprofen for treating children with fever </li></ul></ul><ul><ul><li>Nurse counsellors as an alternative to clinical geneticists for genetic counselling </li></ul></ul><ul><ul><li>Single dose of chemotherapy versus radiotherapy treating testicular cancer http://news.bbc.co.uk/1/hi/health/7647007.stm </li></ul></ul><ul><ul><li>Cervical cancer vaccine http://news.bbc.co.uk/1/hi/health/6223000.stm </li></ul></ul>
  4. 4. The need to evaluate health care <ul><li>Variations in health care </li></ul><ul><li>Unproven treatments </li></ul><ul><li>Inadequacies in care </li></ul><ul><li>Inaccurate medical models </li></ul><ul><li>Limitation of resources </li></ul><ul><li>New innovations </li></ul><ul><li>… </li></ul><ul><ul><ul><ul><ul><li>Crombie (1996) </li></ul></ul></ul></ul></ul>
  5. 5. Evaluation process <ul><li>Define research question </li></ul><ul><li>What is already known? </li></ul><ul><li>Identify appropriate study design </li></ul><ul><li>Define population, intervention and criteria for evaluation </li></ul><ul><li>How large a study? </li></ul><ul><li>Consider measurement of evaluation criteria (“outcomes”) </li></ul><ul><ul><li>How often? </li></ul></ul><ul><ul><li>Timing? Length of follow up? </li></ul></ul><ul><ul><li>To whom? Who collects the data? What format? </li></ul></ul><ul><li>Analysis of data </li></ul><ul><li>Dissemination and implementation </li></ul>
  6. 6. Define research question and what is already known <ul><li>Research question (PICOT) </li></ul><ul><ul><li>Population </li></ul></ul><ul><ul><li>Intervention </li></ul></ul><ul><ul><li>Control/comparator </li></ul></ul><ul><ul><li>Outcome </li></ul></ul><ul><ul><li>Target </li></ul></ul><ul><li>Has the question already been answered? </li></ul><ul><ul><li>Conduct review to assess what is know about intervention </li></ul></ul>
  7. 7. Definition of population, intervention and “outcomes” <ul><li>Population </li></ul><ul><ul><li>Strict definition (explanatory) or flexible (pragmatic) </li></ul></ul><ul><li>Intervention </li></ul><ul><ul><li>Dose of drug, timing etc </li></ul></ul><ul><li>“ Outcomes” </li></ul><ul><ul><li>Health related Quality of Life </li></ul></ul><ul><ul><li>Biochemical outcomes </li></ul></ul><ul><ul><li>Symptoms </li></ul></ul><ul><ul><li>Physical assessment </li></ul></ul><ul><ul><li>Patient satisfaction </li></ul></ul><ul><ul><li>Acceptability </li></ul></ul><ul><ul><li>Cost-effectiveness </li></ul></ul>
  8. 8. Measuring “outcome” <ul><li>Questionnaires, interview, medical notes etc </li></ul><ul><li>Timing of questionnaires? </li></ul><ul><ul><li>Baseline (prior to treatment) </li></ul></ul><ul><ul><li>Short term outcomes </li></ul></ul><ul><ul><li>Long term outcomes </li></ul></ul><ul><li>Who collects the data? </li></ul>
  9. 9. Sources of systematic errors <ul><li>Selection bias </li></ul><ul><ul><li>can be introduced by the way in which comparison groups are assembled </li></ul></ul><ul><li>Attrition bias </li></ul><ul><ul><li>systematic differences in withdrawal/follow up </li></ul></ul><ul><li>Performance bias </li></ul><ul><ul><li>Systematic differences in care provided </li></ul></ul><ul><li>Observation/detection bias </li></ul><ul><ul><li>systematic differences in observation, measurement, assessment </li></ul></ul>
  10. 10. What is a randomised controlled trial? <ul><li>Simple Definition </li></ul><ul><li>A study in which people are allocated at random to receive one of several interventions </li></ul><ul><li>(simple but powerful research tool) </li></ul>
  11. 11. Simple RCT model RANDOMLY allocated to experimental or CONTROL group CONTROL EXPERIMENT Trial participants
  12. 12. What is a randomised controlled trial? <ul><li>Random allocation to intervention groups </li></ul><ul><li>all participants have equal chance of being allocated to each intervention group </li></ul><ul><li>why RCTs are referred to as randomised controlled trials </li></ul>
  13. 13. Terminology <ul><li>Interventions are comparative regimes within a trial </li></ul><ul><li>Prophylactic, diagnostic, therapeutic e.g. </li></ul><ul><ul><li>preventative strategies </li></ul></ul><ul><ul><li>screening programmes </li></ul></ul><ul><ul><li>diagnostic tests </li></ul></ul><ul><ul><li>drugs </li></ul></ul><ul><ul><li>surgical techniques </li></ul></ul>
  14. 14. What is a randomised controlled trial? <ul><li>One intervention is regarded as control treatment (the group of participants who receive this are the control group) </li></ul><ul><li>NOTE: Contemporaneous (not historical controls) </li></ul><ul><li>why RCTs are referred to as randomised controlled trials </li></ul>
  15. 15. Terminology <ul><li>Control Group </li></ul><ul><li>can be </li></ul><ul><ul><li>conventional practice </li></ul></ul><ul><ul><li>no intervention (this may be conventional practice) </li></ul></ul><ul><ul><li>placebo </li></ul></ul><ul><li>Experimental Group </li></ul><ul><li>receive new intervention </li></ul><ul><li>(also called treatment group or intervention group interchangeably) </li></ul>
  16. 16. What is a randomised controlled trial ? <ul><li>RCTs are </li></ul><ul><ul><li>Experiments: investigators can influence number, type, regime of interventions </li></ul></ul><ul><ul><li>Quantitative: measure events rather than try to interpret them in their natural settings </li></ul></ul><ul><ul><li>Comparative: compare two or more interventions </li></ul></ul>
  17. 17. What is a randomised controlled trial? <ul><li>More Complex Definition </li></ul><ul><li>Quantitative, comparative, controlled experiments in which a group of investigators study two or more interventions in a series of participants who are allocated randomly to each intervention group </li></ul>
  18. 18. Inclusion/exclusion criteria <ul><li>Decision rules applied to potential trial participants to judge eligibility for inclusion in trial </li></ul><ul><li>See CONSORT statement </li></ul><ul><li>www.consort-statement.org </li></ul><ul><li>Important that they are applied identically to all groups in a trial! </li></ul>
  19. 19. What is randomisation? <ul><li>Randomisation is the process of random allocation </li></ul><ul><li>Allocation is not determined by investigators, clinicians or participants </li></ul><ul><li>Equal chance of being assigned to each intervention group </li></ul><ul><li>Individual people </li></ul><ul><ul><li>patients </li></ul></ul><ul><ul><li>caregivers (physicians, nurses etc) </li></ul></ul><ul><li>Groups of people, ‘cluster randomisation’ </li></ul><ul><li>(Covered in more depth in later lecture) </li></ul>
  20. 20. Pseudo-randomisation <ul><li>Other allocation methods include </li></ul><ul><ul><li>according to date of birth </li></ul></ul><ul><ul><li>the number on hospital records </li></ul></ul><ul><ul><li>date of invitation etc. </li></ul></ul><ul><li>These are NOT regarded as random </li></ul><ul><li>These are called pseudo- or quasi-random </li></ul>
  21. 21. Terminology <ul><li>Controlled clinical trials (CCTs) are not the same as randomised controlled trials </li></ul><ul><li>Controlled clinical trials include non-randomised controlled trials and randomised controlled trials </li></ul>
  22. 22. Why use randomisation? <ul><li>Characteristics similar across groups at baseline </li></ul><ul><li>can isolate and quantify impact of interventions with effects from other factors minimised </li></ul><ul><li>Risk of imbalance not abolished completely even if perfect randomisation </li></ul><ul><li>To combat selection bias </li></ul><ul><li>Unpredictability paradox: review of empirical comparisons of randomised and non-randomised clinical trials, Kunz and Oxman 1998 BMJ </li></ul><ul><li>http://www.bmj.com/cgi/content/abstract/317/7167/1185 </li></ul>
  23. 23. Why do we need a control group? <ul><li>Don’t need a control group if completely predictable results </li></ul><ul><ul><li>Parachutes when jumping from plane </li></ul></ul><ul><ul><li>New drug cures a few rabies cases </li></ul></ul><ul><li>But </li></ul><ul><ul><li>No intervention has 100% efficacy </li></ul></ul><ul><ul><li>Many diseases recover spontaneously </li></ul></ul>
  24. 24. Regression to the mean <ul><li>Occurs when an intervention aimed at a group or characteristic that is very different from average </li></ul><ul><li>For example selecting people because they have high blood pressure then measuring them in future will see the blood pressure measurements closer to the mean of the population </li></ul><ul><li>Morton and Torgerson BMJ 2003 326:1083-4 </li></ul><ul><li>Bland and Altman BMJ 1994 308:1499 and 309:780 </li></ul>
  25. 25. DISTRIBUTION OF RESULTS threshold measurement 1 measurement 2
  26. 26. Hawthorne Effect <ul><li>Experimental effect in the direction expected but not for the reason expected </li></ul><ul><li>Essentially studying/measuring something can change what you studying/measuring </li></ul>
  27. 27. Placebo Effect <ul><li>Effect (usually, but not always positive) attributed to the expectation that a therapy will have an effect </li></ul><ul><li>The effect is due to the power of suggestion </li></ul><ul><li>A placebo is an inert medication or procedure </li></ul><ul><li>Waber et al 2008 JAMA Commercial Features of Placebo and Therapeutic Efficacy </li></ul><ul><li>http://jama.ama-assn.org/cgi/content/full/299/9/1016 </li></ul>
  28. 28. EFFECT OF AN INTERVENTION Effect size Experimental group Control group Hawthorne E. R. mean Placebo E. Therapeutic E. Real difference Noise Signal
  29. 29. Minimising bias in RCTs <ul><li>Blinding </li></ul><ul><ul><li>Single blind – participants are unaware of treatment allocation </li></ul></ul><ul><ul><li>Double blind – both participants and investigators are unaware of treatment allocation </li></ul></ul><ul><ul><li>Requires use of placebos in drug trials Schulz and Grimes (2002) </li></ul></ul>
  30. 30. Concealment of random allocation list <ul><li>“ Trials with inadequate allocation concealment have been associated with larger treatment effects compared with trials in which authors reported adequate allocation concealment” </li></ul><ul><li>Schulz KF (1995). Subverting randomisation in controlled trials. JAMA, 274, 1456-8 </li></ul>
  31. 31. Blinding, placebos <ul><li>RCTs should use the maximum degree of blinding that is possible </li></ul><ul><li>Placebo is a ‘dummy’ treatment given when there is no obvious standard treatment </li></ul><ul><ul><li>needed as the act of taking a treatment may have some effect -need to attribute </li></ul></ul><ul><ul><li>double blind treatments must be indistinguishable to those affected </li></ul></ul>
  32. 32. Empirical evidence of bias
  33. 33. ‘ Explanatory’ and ‘Pragmatic’ questions <ul><li>Explanatory </li></ul><ul><li>Can it work in an ideal setting …..? </li></ul><ul><li>Efficacy </li></ul><ul><li>Hypothesis testing </li></ul><ul><li>Placebo controlled </li></ul><ul><li>Double blind </li></ul><ul><li>Pragmatic </li></ul><ul><li>Does it work in the real world …..? </li></ul><ul><li>Effectiveness </li></ul><ul><li>Choice between alternative approaches to health care </li></ul><ul><li>Standard care </li></ul><ul><li>Open </li></ul>
  34. 34. Key differences between explanatory and pragmatic trials (1) <ul><li>Explanatory Pragmatic </li></ul><ul><li>Question efficacy effectiveness </li></ul><ul><li>Setting ‘laboratory’ normal practice </li></ul><ul><li>Participants strictly defined broader, clinically indicated (uncertainty) </li></ul><ul><li>Interventions strictly defined as clinical practice </li></ul>
  35. 35. Key differences between explanatory and pragmatic trials (2) <ul><li>Explanatory Pragmatic </li></ul><ul><li>Outcomes short-term long-term, patient- surrogates centered and resource orientated </li></ul><ul><li>Size small (usually larger </li></ul><ul><li>single centre) (often multi-centre) </li></ul><ul><li>Analysis treatment received intention to treat </li></ul><ul><li>Relevance indirect direct </li></ul><ul><li>to practice </li></ul>
  36. 36. Example of selection bias for PP in an open trial Exp Ctrl None None White(2005) E E Worse prognosis
  37. 37. Terminology: explanatory versus pragmatic <ul><li>Explanatory trials </li></ul><ul><ul><li>estimates efficacy - that is the benefit the treatment produces under ideal conditions </li></ul></ul><ul><li>Pragmatic trials </li></ul><ul><ul><li>estimates effectiveness - that is the benefit the treatment produces under routine clinical practice </li></ul></ul><ul><ul><li>Roland M, Torgerson D. What are pragmatic trials? BMJ 1998;316:285 </li></ul></ul>
  38. 38. RCT as the Gold Standard <ul><li>The randomised controlled trial is widely regarded as the gold standard for evaluating health care technologies because it allows us to be confident that a difference in outcome can be directly attributed to a difference in the treatments and not due to some other factor </li></ul>
  39. 39. RCT strengths <ul><li>Confounding variables minimised </li></ul><ul><li>Only research design which can in principle yield causal relationships </li></ul><ul><ul><li>can clarify the direction of cause and effect </li></ul></ul><ul><li>Accepted by EBM school </li></ul><ul><li>Don’t have to know everything about the participants </li></ul>
  40. 40. RCT limitations <ul><li>Contamination of intervention groups </li></ul><ul><li>Comparable controls </li></ul><ul><li>Problems with blinding </li></ul><ul><li>What to do about attrition? </li></ul><ul><li>Are patients/professionals willing to be in trial different from ‘refusers’?- external validity </li></ul><ul><li>Cost! </li></ul>
  41. 41. Other issues in RCTs (1) <ul><li>Ethics </li></ul><ul><li>Management issues </li></ul><ul><li>Interim analysis and ‘stopping rules’ </li></ul><ul><ul><li>part of ethical concern </li></ul></ul><ul><ul><li>mechanisms to avoid patient harm </li></ul></ul><ul><ul><li>Data Monitoring and Safety Committee required for trials </li></ul></ul><ul><li>Clemens F et al Data monitoring in randomised controlled trials: surveys of recent practice and policies. Clin Trials 2005;2(1):22-33. </li></ul>
  42. 42. Other issues in RCTs (2) <ul><li>A power calculation is essential for the validity of a trial and will always be necessary for grant applications and in publications of the trial (later lecture) </li></ul><ul><li>The methods of randomisation should always be reported. It is not enough to say that the patients were randomly allocated to the treatments. (see CONSORT) </li></ul>
  43. 43. Parallel group (simple) RCT design in practice Patient eligible for either treatment Patient gives informed consent Yes No Randomise Exclude from trial Experimental treatment Standard treatment Standard treatment
  44. 44. Summary <ul><li>“ Gold standard” of research designs </li></ul><ul><li>Individual patients are randomly allocated to receive the experimental treatment (intervention group) or the standard treatment (control group) </li></ul><ul><li>Maximises the potential for attribution </li></ul><ul><li>Randomisation guards against selection bias between the two treatment groups </li></ul><ul><li>Standard statistical analysis </li></ul><ul><li>Good internal validity </li></ul><ul><li>May lack generalisability due to highly selected participants </li></ul><ul><li>Can be costly to set up and conduct, ethical issues </li></ul>
  45. 45. Good study design <ul><li>General considerations </li></ul><ul><li>maximise attribution </li></ul><ul><ul><li>Ensure no factor other than the intervention differs between the intervention and control group </li></ul></ul><ul><ul><li>Random allocation, if adequately carried out, will in the long run ensure comparable groups with respect to all factors </li></ul></ul><ul><li>minimise all sources of error </li></ul><ul><ul><li>systematic error (bias) </li></ul></ul><ul><ul><li>random error (chance) </li></ul></ul><ul><li>be practical and ethical </li></ul>
  46. 46. Minimise sources of error <ul><li>Systematic errors (bias) </li></ul><ul><li>“ inaccuracy which is different in its size or direction in one of the groups under study than the others ” </li></ul><ul><li>Minimise bias by ensuring that the methods used are applied in the same manner to all subjects irrespective of which group they belong to. </li></ul><ul><li>Random errors (chance) </li></ul><ul><li>“ Inaccuracy which is similar in the different groups of subjects being compared” </li></ul><ul><li>Adequate sample size, accurate methods of measurement </li></ul><ul><ul><ul><ul><ul><li>Elwood (1998) </li></ul></ul></ul></ul></ul>
  47. 47. Study designs <ul><li>Experimental (Randomised controlled trial) </li></ul><ul><ul><li>A new intervention is deliberately introduced and compared with standard care </li></ul></ul><ul><li>Quasi-experimental (non-randomised, controlled before and after) </li></ul><ul><ul><li>Researchers do not have full control over the implementation of the intervention (“opportunistic research”) </li></ul></ul><ul><li>Observational (Cohort, case-control, cross-sectional) </li></ul><ul><ul><li>describes current practice </li></ul></ul><ul><ul><li>observed differences cannot be attributed solely to a “treatment” effect </li></ul></ul>
  48. 48. Evaluation of health care interventions <ul><li>Randomised controlled trials are considered as the “gold standard” </li></ul><ul><li>However, some debate over the advantages and disadvantages of different research designs for assessing the effectiveness of healthcare interventions </li></ul><ul><li>Polarised views </li></ul><ul><ul><li>“ observational methods provide no useful means of assessing the value of a therapy” (Doll, 1993) </li></ul></ul><ul><ul><li>RCTs may be unnecessary, inappropriate, impossible or inadequate (Black, 1996) </li></ul></ul><ul><li>Approaches should be seen as complementary and not as alternatives (Black, 1996) </li></ul><ul><ul><li>Interpretation of RCTs in terms of generalisability </li></ul></ul>
  49. 49. Useful/interesting links <ul><li>www.jameslindlibrary.org (History) </li></ul><ul><li>www.consort-statement.org (CONSORT) </li></ul><ul><li>www-users.york.ac.uk/~mb55/pubs/pbstnote.htm (All the stats notes from BMJ) </li></ul><ul><li>www.ctu.mrc.ac.uk (MRC CTU) </li></ul><ul><li>www.rcrt.ox.ac.uk (under construction) </li></ul><ul><li>Doll R. Clinical Trials the 1948 watershe BMJ 1998;317:1217-1220 </li></ul><ul><li>The unpredictability paradox: review of empirical comparisons of randomised and non-randomised clinical trials Regina Kunz and Andrew D Oxman BMJ 1998 317: 1185-1190 </li></ul>
  50. 50. References <ul><li>Black. Why we need observational studies to evaluate the effectiveness of health care. BMJ 1996 : 312;1215-8 </li></ul><ul><li>Crombie. Research in Health Care. 1996 </li></ul><ul><li>Doll. Doing more good than harm: the evaluation of health care interventions. Ann NY Acad Sci 1993:703;310-13 </li></ul><ul><li>Elwood M. Critical appraisal of epidemiological studies and clinical trials. 1998 OUP; Oxford. </li></ul><ul><li>Greenhalgh T. How to read a paper. 2001 BMJ; London </li></ul><ul><li>Schulz and Grimes. Lancet Epidemiology series. 2002 </li></ul>

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