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Design and analysis of clinical trials

  • Primary research includes:
    • Animal or volunteer experiments
    • Clinical trials
    • Surveys
  • Secondary research includes:
    • Systematic review and meta-analyses
    • Guidelines
    • Decision analyses
    • Economic analyses

Hierarchy of evidence

  • The strength of a study depends on its design
  • A hierarchy of evidence exists with decreasing strength as follows:
    • Systematic review and meta-analysis
    • Randomised controlled trials with definitive results
    • Randomised controlled trials with non-definitive results
    • Cohort studies
    • Case-control studies
    • Cross sectional surveys
    • Case reports
  • Questions regarding:
    • Drug treatment or medical interventions require a double-blind randomised controlled trial
    • Prognosis require longitudinal cohort studies
    • Causation require cohort or case-control studies

Levels of Evidence

Level Description
Ia Evidence from a meta-analysis of randomised controlled trials
Ib Evidence from at least one randomised controlled trial
IIa Evidence from at least one well designed controlled study without randomisation
IIb Evidence from at least one well designed quasi-experimental study
III Evidence from well-designed non-experimental descriptive studies such as comparative studies, correlation studies or case studies
IV Evidence from expert committee reports or opinions or clinical experiences of respected authorities

Purpose of clinical trials

  • Clinical trials conduct ‘human experiments’
  • Three fundamental principles apply:
    • The trial must address a legitimate question
    • The patient must be informed and willing to participate
    • The patient may decline entry or withdraw at any stage
  • There are 4 clinical trial structures

Phase 1 study

  • Provides basic pharmacological and toxicology information
  • Not a test of therapeutic efficacy
  • Performed on either
    • Healthy volunteers
    • Patients whose disease has progressed on all available treatments

Phase 2 study

  • Used to identify dose range of a particular drug
  • Sample size is usually about 20 patients
  • Patients usually have end-stage disease
  • Not usually randomised and drug combinations may be tested

Phase 3 study

  • Randomised trial designed to compare effects of different treatments
  • One treatment option should be the best currently available
  • Outcome measures usually include survival, disease-free survival, response and toxicity
  • Usually involve large numbers of patients
  • May involve different institutions in several countries

Phase 4 study

  • Less commonly used
  • Aimed to evaluate the long-term outcome of established therapies
  • Often regarded as a post-marketing study

Randomised controlled trials

  • In RCT participants are randomly allocated to one intervention or another
  • Both groups are followed up for a specified period
  • Groups analysed in terms of outcome defined at the outset
  • If groups similar at outset any difference should be due to intervention

Advantages of RCTs

  • Allows rigorous evaluation of a single variable in a defined patient group
  • Potentially eradicates bias by comparing two (or more) identical groups
  • Allows for meta-analysis

Disadvantages of RCTs

  • Expensive and time consuming
  • Often have too few patients or too short a follow-up period
  • Surrogate endpoints are often used in preference to clinical outcome measures
  • Often imperfect randomisation
  • Often not all eligible patients are randomised
  • Failure to blind assessors to randomisation status of patients

Cohort studies

  • Cohort studies compare groups exposed to different factors
  • Followed up to see whether there is a difference in outcome
  • Usually used to study disease aetiology
  • Also used to assess disease prognosis

Case-control studies

  • Case-control studies match patients with a disease to controls
  • Data then collected retrospectively to find a difference between the groups

Why are papers rejected for publication?

  • The study does not address an important scientific issue
  • The study was not original - it had been done before
  • The study did not address the authors hypothesis
  • A different type of study should have been done
  • The sample size was too small
  • The study was uncontrolled
  • The statistical analysis was inappropriate or incorrect
  • The authors drew unjustified conclusions from their data
  • The papers was poorly written and incomprehensible


Greenhalgh T. How to read a paper: getting you bearings (deciding what the paper is about). Br Med J 1997; 315: 243-246.

Lilford R,  Braumholtz D,  Harris J,  Gill T.  Trials in Surgery.  Br J Surg 2004;  91:  6-16.



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