Safety/Toxicology Flashcards
What must be considered during a risk assessment?
- Hazard identification
- Dose-response relationship
- Exposure assessment
- Risk characterization
When is a risk-assessment needed?
OEL/EXP ≤ 1
What is an uncertainty factor used for?
For extrapolation between intra-species and inter-species
Which studies are performed before the clinical studies?
Non-clinical safety studies
What are the objectives of phase 1 trials?
- Access tolerance/safety
- Define/describe pharmacokinetics and pharmacodynamic
- Explore drug metabolism and drug interactions
- Early measurement of drug activity
It involves less than 30 people.
What are the objectives of phase 2 trials?
- Explore use for the targeted indication
- Estimate dosage for subsequent studies
- Provide basis for confirmatory study design, endpoints, methodologies
It involves around 100 volunteers and some patients.
What are the objectives of phase 3 trials?
- Demonstrate / confirm efficacy
- Establish a safety profile
- Provide an adequate basis for assessing the benefit/risk relationship to support licensing
It involves around 1000 people.
What are the objectives of phase 4 trials?
- Refine understanding of benefit/risk relationship in general or special populations
- Identify less common adverse effects
What are exploratory clinical trials?
Clinical trials performed early in phase 1 prior to dose escalation, safety and tolerability trials.
What kind of exploratory clinical trials can be performed?
- Microdose trials
- Single-dose trials at sub-therapeutic range or the anticipated therapeutic range
- Multi-dose trials
Why and when is a repeated dose toxicity experiment performed?
It is performed to support the conduct of clinical trials, so it is a preclinical experiment.
When are genotoxicity trials performed?
Some genotoxicity studies are performed prior to phase 1, but all must be performed prior to phase 2.
What is an ames test?
A well characterized assay for gene mutations
For which drugs should carcinogenicity studies be performed?
It should be performed for pharmaceuticals whose expected clinical use is continuous for at least 6 months
When should the required carcinogenicity studies be completed?
It should be completed before the application for marketing approval
Are carcinogenicity studies always required?
They are generally not needed for endogenous substances given as replacement therapy
What are the problems with animal studies?
- Problems with extrapolation of data from animals to humans
- They are not sufficient to evaluate adverse drug reactions in humans
Why is testing in humans necessary?
It provides information about the most common occurring adverse drug reaction
What is the difference between an adverse event and an adverse drug reaction?
An adverse event is an untoward medical occurrence in a patient or clinical trial subject administered a medical product, which does not have a causal relationship with the treatment
Which safety measures are noted in phase 1?
Adverse drug reactions and tolerability
Which safety measures are noted in phase 2?
Adverse drug reactions and toxicity
Which safety measures are noted in phase 3?
Adverse drug reaction, benefit/risk, SUSAR
Who is phase 1 trials conducted on?
Healthy male volunteers
Who is phase 1 trials conducted on?
Healthy male volunteers
What is a clinical outcome / clinical endpoint?
Direct measure of whether people in the trial feel or function better or liver longer
What are surrogate endpoints?
Measure of effect of a specific treatment that may correlate with a clinical endpoint but does not necessarily have a guaranteed relationship.
An example is cholesterol lowering drugs.
When is benefit/risk performed?
During the clinical trial and post registration (Phase 4)
