Clinical Trials/Ethics

Clinical Trials

  • Interventional/experimental trials
    • Usually include randomisation
    • They are prospective (individuals are followed forward from some point in time)
    • Causal analysis – test causal relationship between exposure of interest & outcome

Phases of clinical trials

  • Translational pathway of clinical trials: 
  • Pre-clinical trials:
    • Before testing in humans
    • Helps decide whether the drug is ready for clinical trials (from ‘bench to bedside’)
    • Look at toxicity, pharmacokinetic and safety information
    • Typically testing in vivo (laboratory animals) or in vitro (test tubes and cell cultures)
  • Phase 0
    • First in-human trials
    • Microdosing studies at subtherapeutic levels
    • Very small studies 
    • Look at pharmacokinetics & pharmacodynamics – not establishing response
    • All active interventions 
    • Not randomised/blinded
  • Phase 1
    • Aims:
      • Establishing dose limiting toxicity
      • Identify recommended phase II dose
      • Also: toxicity profile, pharmacokinetics/pharmacodynamics
    • All active interventions
    • Not randomised/blinded
    • Phase 1 starting dose options:
      • 1/10th LD10 in rodents
      • 1/5th TDL in rodents
      • 1/3rd TLD in larger animals
    • LD10: lethal dose in 10% animals
    • TLD: toxic low dose – lowest dose to cause animal toxicity
    • MTD: maximum tolerated dose – dose with DLT in pre-determined proportion of pts (33%)
    • Recommended phase II starting dose is 1 level lower than MTD
  • Phase 2
    • Establishing potential biological effect
    • To aim to exclude inactive drugs from further development – although phase 2 is NOT a definitive test of clinical efficacy
    • Uses larger sample sizes with more inclusion/exclusion criteria
    • Classical phase 2 trials have a single arm with no in-built controls
  • Phase 3 (usually randomised controlled trial)
    • Establishing efficacy (and safety)
    • Larger sample sizes
    • Longer follow up 
    • Usually blinded
    • Regulatory approval (MHRA) based on these trials
  • Phase 4
    • Post marketing studies once drug is already in use
    • Focus is to assess safety (and efficacy & cost effectiveness) in a more generalised population
    • Largest sample sizes and longest follow up
    • Usually observational 

Design elements of clinical trials

  • Trial designs
    • Classic/parallel design
      • ≥2 groups with follow up –> compare response between patients
      • Participants receive 1 intervention each 
      • Most common design 
  • Crossover design
    • Each participant receives both interventions —> compare response within patients
    • Advantages – participants are their own control so influence of confounding variables is reduced, can have smaller sample sizes
    • Disadvantages – crossover effect (unclear what to do if carry-over effect are found), order effect (could order of drugs affect outcome)
  • Factorial design
    • Multiple interventions e.g. A, B, A&B, nothing
    • Allows simultaneous analysis of a number of factors of interest e.g. adherence trial
    • An efficient method of evaluating more than one intervention providing the absence of interactions
  • Basket trial – targeted therapy in diseases with common pathway – MULTIPLE DISEASES 1 TREATMENT
  • Umbrella trial – disease with multiple targeted therapies – MULTIPLE TREATMENTS 1 DISEASE SITE
  • Platform trial – multiarm multistage
  • Randomisation
    • Randomisation is the process of dividing participants into groups randomly with no predetermined factors influencing this apart from chance
    • Allocation ratio is usually 1:1, which usually has the most power (not always)
    • Types:
      • Simple
        • Examples – random numbers or computer generated randomisation
        • Each allocation is independent of the others
        • This does risk imbalanced groups
      • Block
        • Relatively small block sizes are chosen, then patients are allocated to each block
        • Ensures roughly equal sized treatment groups
        • Fixed block size = constant block size – needs to be hidden from team (otherwise this method can be manipulated by the researcher who knows which block the patient may be allocated) 
        • Random block sizes = varied block sizes
      • Cluster
        • Randomisation of ‘clusters’ of patients rather than randomisation of individuals 
        • Example – Randomisation of hospital sites
      • Stratified
        • If there are factors which may alter outcome – these could be used to form stratum to control for these effect of these factors
        • Used with cluster or block randomisation
        • Example – block randomisation which has been stratified for grade of breast cancer…



BlockPatient IDAllocationBlockPatient IDAllocationBlockPatient IDAllocation
  • Stratified randomisation vs minimisation
    • Both achieve the same thing in balancing factors between groups
    • Stratified randomisation is fixed into stratum
    • Minimisation is based on statistical algorithm which can vary during course of recruitment depending on which patient is recruited into which group
  • Blinding
    • Blinding/masking is when patients/clinicians/researchers are unaware of treatment allocation
    • Reduces assessment bias
    • Can be before (allocation concealment) & after intervention (blinding)
    • Single = participant
    • Double = participant, research team
    • Triple (rarely) = participant, research team, statistician


  • GCP – trial protocols & ethics
  • Trial protocol
    • Defines how the clinic trial will be run (contents can vary as it is not officially regulated)
    • Produced before trial is commenced 
    • Usually contains:
      • Title & registration number
      • Chief investigator details & trial team
      • Version of protocol & date (to know whether it has been updated or not)
      • Funding
      • Roles & responsibilities of those involved in trial
      • Background, objectives of the trial, patient selection criteria & methods
      • Trial design, treatment & clinical evaluation
      • Ethics & ethics approval
  • Ethics
    • Prior to 1947 there were no ethical principles to guide undertaking of clinical research
    • Nuremburg code – introduced to avoid unnecessary or harmful trials without patient consent
    • Followed by Declaration of Helsinki (1964) – which outlines moral principles – the responsible investigator should ensure that the study is conducted in agreement with the Declaration of Helsinki
    • Led to International Council for Harmonisation Good Clinical Practice Guideline
  • Informed consent
    • Patients need to be informed of the details of the study including: aims; procedures; possible adverse effects & mechanism of treatment allocations
    • Patients can decline further participation at any point in the trial
    • The informed consent procedure must conform with GCP

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