Phase I trials Flashcards
What is an issue with the short duration of phase I trials? (For secondary outcomes like efficacy)
Long term endpoints can’t be documented so surrogate markers of efficacy have to be used instead.
How many participants are there usually in a phase I trial? Why?
Few participants (Around 30) - first in man trial so it would be unethical to give lots of participants the drug without knowing the toxicity they will experience. Also it saves on costs.
What is the primary outcome of a phase I trial?
Dose limiting toxicity (DLT)
Why might an adverse event not be classified as a DLT?
If the subjects are already ill, some adverse events would be expected to occur naturally, so would not be counted as a DLT
What is the maximal tolerated dose?
A primary outcome measure for a phase I trial. It is the dose that has an acceptable number of side-effects and therefore can be used in further studies.
OR a dose at which a pre-specified number of individuals suffer a severe adverse event indicating that this dose may be too unsafe so the next lowest dose would be investigated further.
What are 4 secondary outcomes of phase I trials?
Drug uptake
Metabolism
Excretion
Surrogate markers
What are 5 examples of the series in which phase I trials are conducted
- Dose escalation
- Expansion cohort studies
- Interaction studies with food/ other drugs
- Multiple dose studies
- Pharmacokinetics/ Pharmacodynamics
What is pharmacodynamics referring to?
The physical or biological measures that show the effect of the new drug on the body (could include efficacy).
What is an example of pharmacodynamic effects to be looked at during a phase I study?
Does it make you drowsy - so you can’t take the drug when driving
What is pharmacokinetics referring to?
Physical or biological measures that show how the body deals with the new drug. Eg absorption, metabolism or elimination
What is Cmax?
The max concentration that a drug is found at in the plasma following administration.
What is AUC?
Area under the curve - the measure of the total plasma exposure to the drug over a given time period and is determined by the dose and clearance of the drug.
What are examples of preclinical information that could help determine the starting dose for first in human studies?
Toxicology data
Novelty of the agent
Biological potency
Mechanism of action
Degree of species-specificity of the agent
Dose response curves of biological effects in human and animal cells
Pharmacokinetic and pharmacodynamic modelling
What are the common starting doses compared to preclinical ones?
1/10th of the lethal dose in 10% of rodents
1/3 or 1/6th of lowest dose that results in any adverse event in other animals
What methods are used to decide what the subsequent dosage should be following the initial dose?
Fibonacci sequence
Evidence from other studies or previous experience
What is the 3+3 phase I trial design?
Give a dose to 3 patients. If 0 have a DLT go to the next, higher dose and give it to three new patients. If 1 patient in the original group had a DLT, treat a new set of 3 patients with the same dose. If any of them experience a DLT then the previous dose is the MTD. If in the original group 2 or 3 of the patients experienced a LTD then the previous dose is the MTD.
What are some advantages to the 3+3 trial design
Simple, easy to implement, it’s conservative in escalation so is safe, clear decision making for stopping or escalating.
What are some disadvantages of the 3+3 design?
Trial can take longer due to slow dose escalation, may require a large number of patients, several subjects may be treated without providing much information about the MTD (patients treated at subtherapeutic doses as a result), design has a high probability of recommending a dose below the MTD for phase II trials.
How does the 3+3 design variation differ to the original?
Dose escalation is only stopped if all three of the patients experience a LTD
What are more efficient methods of dose escalation?
Continuous reassessment method and Bayesian methods (both are based on statistical modelling - often a sigmoid curve)
What are key pharmacokinetic parameters of interest
AUC - area under the curve Cmax - maximum plasma concentration Tmax - Time to reach Cmax T1/2 - Terminal half life Clearance - removal of the drug from the body mediated by metabolism and excretion
How is the Fibonacci sequence used for dose escalation?
While the numbers appear to increase quickly, the relative increase is roughly constant. In practice, the doses are rounded down or up - this is modified Fibonacci
