1.1- 2: Intro + Principles Flashcards
Phase I trials:
Focus upon the pharmacodynamics…
- Absorption
- Distribution
- Metabolism
- Excretion
- Toxicity -> Maximum tolerated dose (MTD)
Phase II trials:
Initial clinical investigation into doses and dose schedules (‘dose-finding’) and early indication of efficacy
Phase III trials:
Aimed at full scale evaluation, efficacy, of a new experimental treatment compared to a standard therapy or placebo, acting as a control.
Phase IV trials:
- Measuring effectiveness
- Post-marketing surveillance
- -> information regarding uncommon side-effects, long term effects
Effect, efficacy and effectiveness:
- Effect: Impact of treatment with vs without
- Efficacy: True biological effect (does it work under idealised conditions?)
- Effectiveness: Effect of treatment when widely used in general practice
Trial design objectives and 7 key considerations:
- Minimising bias and maximising efficiency
Considerations…
- Replication
- Control
- Randomisation
- Blocking
- Treatment blinding / masking
- Ethics
- Choice of analysis set
Gold standard in clinical trial design:
- Concurrent (not historical)
- Randomised, double-blind, controlled
Purpose of randomisation (x2):
- Avoid bias due to differences in clinical and demographic characteristics
- Support the independence assumption underlying many statistical procedures
Simple randomisation scheme: Description and application
- Most simple scheme; independent random treatment allocation with a fixed probability
- Can be carried out using tables in books, random number generators [0,1), computer based services (typical of multi-centre trials)
- Typically, sealed envelopes are prepared in advance to aid blinding
Simple randomisation: 2 advantages, 3 disadvantages
Positives:
- Easy to implement
- Analysis via standard statistical methods
Negatives:
- Likely to get unequal numbers in treatment groups (particularly in small sample sizes)
- Doesn’t ensure balance over confounders
- Lack of adaptability could lead to ethical issues
Block randomisation: Purpose and procedure (a.k.a restricted randomisation)
- Balancing numbers of participants in each group
- Choose blocks at random, assign patients accordingly
- Block size is a multiple of the number of treatments
- -> can be fixed or randomly varying, but must be kept relatively short to prevent incomplete blocks
Block randomisation: 1 advantage, 1 disadvantage
- Achieving balance; maximum difference is b/2 for blocks of size ‘b’ and two treatments
- Assignment may become known if blocking factor is revealed
Stratified randomisation: Principle and procedure
- In small sample sizes, simple or block randomisation may lead to imbalance with regard to an important factor. Stratification aims to aid group comparability over important characteristics
- Procedure: use block randomisation in each stratum defined by factors to be balanced over
Stratified randomisation: 2 advantages, 3 disadvantages
Positives:
- Increased efficiency
- Reduces potential bias
Negatives:
- Number of strata may limit usefulness
- Procedure to assign treatment is more complicated
- Standard statistical methods not strictly valid
Adaptive randomisation (minimisation): Principles/purpose and procedure, typical application
- Non-random treatment allocation; allocation probabilities adjusted sequentially according to patient imbalance
- Yields balance between treatment groups with regard to important prognostic factors
- Simple randomisation is used when the groups are balanced. When imbalanced, allocate next patient to treatment so that imbalance is minimised (via minimisation score)
- e.g. weighted randomisation
