Clinical trials Flashcards
What are clinical trials and what is their purpose?
Trials which are systematically designed to develop a new drug/medical intervention, designed to investigate:
1 - how a drug works (pharmacodyamics)
2 - what happens to the drug (pharmacokinetics)
3 - efficacy of the drug
4 - safety profiles of the drug
What are the different routes/mechanisms by which new drugs are discovered?
- empirically (e.g. the old way, aspirin comes from salycilic acid from willow bark/chemotherapy caused leukopenia)
- now it is a more targeted approach where ‘target
identification’ occurs to create a drug with the best chance of being efficacious (pharmacogenetics often used to dine SNP’s/DNA changes to use as targets)
Once a drug is discovered, the condition which it is best to use on is not always known:
PAPER: Hyman et al 2015, BRAF mutation (non melanoma) cancer trial to test Vemurafenib, best results seen in NSCLC
Describe the basis of the drug development process
TASHPAPA:
- target identification
- assays
- screening -> hits
- hits -> leads (lead development)
- Pre-clinical trials (toxicology testing and ADME)
- determine ADME (absorption, distribution, metabolism and elimination)
- phase 1-3 trials (clinical development)
- application for drug
(then phase 4 trials)
Describe features of phase 1 trials
- 20-50 healthy volunteers/desperate refractory pts
- to determine SAFETY PROFILE OF THE DRUG
- > MTD (maximum tolerated dose)
- > MEC (minimum effective concentration)
- > TI (therapeutic index)
- > ADME
Used to determine the early pharmacology and the most suitable doses to test in phase 2 studies.
Advantages are that recruitment is rapid, volunteers are normally readily available and there are no confounders (co-morbidities) in the subjects
Describe features of phase 2 trials
- 50-500 patients with the actual disease
- to determine preliminary EFFICACY
(Phase 2a) - test the preliminary efficacy i.e. proof of exposure, mechanism, benefit vs risk
(Phase 2b) - dose ranging -> used in a factorial trial design to create a dose-concentration curve, to work out which doses are the most efficacious
Describe features of phase 3 trials
250-1000+ diseased individuals
- often multi-centre and multi-national
- comprehensive assessment of efficacy and safety
- important to have control group, and an active control group is becoming increasingly common (e.g. Mease et al 2017 in psoriatic arthritis trial where Tofacitinib was tested against Adalimumab and also placebo)
3a - conducted before new drug application has been submitted
3b - conducted after new drug application has been submitted
Describe features of phase 4 trials
2000-10,000 individuals -> already taking drug for therapeutic use
- drug is now licensed for use
- long term surveillance is carried out to confirm efficacy in DIFFERENT GROUPS of people (ages, genders)
- pharmaco-economic evaluation carried out
What are the 4 principles of a first time in human study?
- uses healthy volunteers
- performed in clinical trial ‘units’ which have close monitoring
- dose escalation carried out very cautiously in small cohorts
- stringent stopping criteria is in place in the protocol
What are the two possible starting doses of a new drug?
Either a small fraction NOAEL or a small fraction of MABEL (both doses are determined from animal studies)
What is the definition of a ‘healthy volunteer’ for a phase 1 study?
Someone in good health with no mental/physical disorder requiring regular medication, and who can give valid consent
Describe how to determine the appropriate starting dose for a new drug in humans (based on NOAEL and MABEL):
Used in animal studies and then worked up using maths to determine human equivalent dose
The starting dose is either a fraction of NOAEL or MABEL
NOAEL = no observed adverse effect level
- this is the maximum dose of a drug which is given in animal studies and showed no significant adverse effects compared to control (usually HIGHER than mabel)
MABEL = minimal active biological effect level = i.e. the minimum dose of a drug which can be given to cause a biological effect, based on the minimum dose which causes effects in animal studies
- this is normally lower than NOAEL
Calculation: NOAEL is taken and multiplied up using a multiplication factor to create HED (human equivalent dose)
A safety factor is then applied to HED, giving the MRSD (max. recommended starting dose)
This is the MRSD for a phase 1 trial
What are the Bradford Hill criteria?
They are the criteria for causality -> assess these features of study results to determine if a drug is having a causal effect
T - temporal relationship present?
B - biological plausibility (if a biological mechanism is known it makes causality more likely)
D - dose-response relationship seen?
S - specificity?
S - Strength
C - consistency (have similar results been seen in other studies?)
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