Toxicology and the role of safety evaluation in drug discovery and development Flashcards
Definition of efficacy
Max response achievable from an applied or dosed agent
Definition of toxicity
Refers to how poisonous/harmful a substance can be
Drug toxicity occurs when a person has accumulated too much drug in the bloodstream leading to adverse effects on the body
Definition of adverse drug event (ADE)
Injury resulting from medical intervention related to a drug
Definition of Food and Drug Administration (FDA)
US government agency that protects public health by ensuring the safety, efficacy and security of drugs and medical devices
Definition of the Ministry of Health, Labour and Welfare (MHLW)
Japanese group that protects public health by ensuring safety, efficacy and security of drugs and medical devices
Definition of ICH S7A safety pharmacology studies
Document providing definitions, general principles and recommendations for safety pharmacology studies
Definition of max tolerated dose (MTD)
Highest dose that will produce the desired effect without unacceptable toxicity
Definition of no observed adverse effect level (NOAEL)
Level of exposure of an organism where there is no biological/statistically significant increase in frequency/severity of adverse effects
What is safe
What is the probability of an adverse event
There is no such thing as safe
All drugs have benefits and risks
Probability of an adverse event = total exposure x likelihood
What does the benefit:risk ratio depend on
- Efficacy
- Toxicity
- Disease
How is drug safety achieved
Hazard identification (what needs to be controlled)
Risk assessment (why is it a risk, who will this affect)
Risk management (how to reduce the risk)
Hazard monitoring (has the hazard happened again even when managed, are there any new hazards)
Who is involved in drug safety management
Researchers Clinicians Patients Regulators (watch process carefully) Experts (help with process)
How can you manage risks
Identify the risk
Find ways of reducing the risk, doesnt have to be a hug change
If benefit:risk ratio is too low, drug can be removed from the market
Patient groups can get drugs back on the market if the benefits still outweigh the risks but are monitored more closely to reduce ADE
How are drugs regulated
Legal contract based on benefit:risk ratio
Between Health Authorities and the pharmaceutical company
Who are the Health Authorities and what do they do
FA, EMFA, MHLW
- Represent society
- Protects public health, safety from the investigation of a new drug (IND) => new drug application (NDA) and marketing authorization application (MAA)
- Monitors non compliance
How are the pharmaceutical companies involved in drug regulation
- Applies for permission to market drugs in a specific indication
- Owns documentation used in assessment
- Collects, compiles and evaluates safety and quality data
How and where does safety evaluation occur in drug discovery and development
All stages
Design, select, develop best compounds as new drugs
Understand exposure, response relationships for effects that may be predictive of adverse events in humans
Protect clinical trial population and patients from potential AE
Understand AE mechanisms in trials and throughout the lifecycle of the drug
How is safety designed into the drug in early stage safety evaluations
Target info from knock out, mutational and SNP studies
Chemotype info: structure, activity relationship, toxicity flags and selectivity
Test compounds: selectivity and specificity
Rational design of selective, specific molecules
Knowledge of likely liabilities but limited exposure in vivo
What happens in late discovery stage safety evaluations in clinical trials
Assessment of
- Tolerability: wide range doses, chronic dosing, disease models
- Cardiac Integrated Risk Assessment (hERG, Purkinje, Lagendorff)
- Genotoxicity risk in vitro
Tests and uses
- Broader, more speculative selectivity in vitro
- ICH S7A safety pharmacology studies
- 7-28 day toxicity in 2 species to define MTD and NOAEL
What is needed before Phase I can start
Clinical trial application (CTA), Investigative Brochure (IB)
Approval from ethics committee
-NOAEL, MABEL calculations: first dose based on safety window
What is the purpose of Phase I regarding safety
Find out
- Frequency and severity of treatment, AEs
- Work out dose range in normal subjects
- Human drug metabolism pharmacokinetic (DMPK) and proof of mechanism (POM)
What is the purpose of Phase II regarding safety
Longer duration, larger groups for efficacy determination
Supported by longer term detailed toxicity studies
Potential to identify biomarkers of efficacy, toxicity
Determine commercial profile for further investment
ADR monitoring starts
Pharmacovigilance starts here
How do you calculate the probability of detecting an ADE
Probability of detecting event = total exposure x likelihood
Describe the probability of a drug having efficacy
On target pharmacology generally has high likelihood on effect
Describe the probability of safety pharamcology
On target and off target pharmacology have high likelihoods of effect
However, this may need greater exposure
Describe the probability of a drugs toxicology
Idiosyncratic, lower likelihood events need high exposure and larger group sizes
Describe the probabilities related to pharmacovigilance
Some ADR may only be detectable by the post marketing surveillance
The longer a drug is around, more likely to detect ADR
What happens if an ADR does happen
Report them via Yellow Card Scheme
What is always found in the package insert leaflet
1 side effect is always about allergies
