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:
    • 1/10^th LD10 in rodents
    • 1/5^th TDL in rodents
    • 1/3^rd 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…

	G1				G2				G3
Block	Patient ID	Allocation	Block	Patient ID	Allocation	Block	Patient ID	Allocation
1	1234	A	1	7890	B	1	5567	A
1	2345	B	1	8901	B	1	6678	B
1	3456	B	1	9012	B	1	7789	A
1	4567	B	1	2234	A	1	8890	A
2	5678	A	2	3345	A	2	9901	B
2	6789	A	2	4456	A	2	0012	B
…	…	…	…	…	…	…	…	…

• 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

Ethics

• 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