Toxicology Regulation and Risk Assessment

phase I clinical trial

drug is studied in a small number of healthy participants to test safety

phase II clinical trial

drug is studied in a small number of people with the disease that the drug is meant to treat to measure effectiveness and safety

phase III clinical trial

drug is studied in a larger number of people (more heterogeneous group) with the disease that the drug is meant to treat to measure effectiveness and safety

preclinical toxicology studies

FDA does not have specific requirements for _____ (including not necessarily requiring animal studies), but most organizations follow methods that have previously been used

ICH (International Council for Harmonization)

organization that combines the regulatory bodies of the US, EU, and Japan to reduce the need for repeat testing by standardizing the safety and efficacy requirements for studies

goals of preclinical toxicity studies

-identify target organs that may be affected by drug

-determine relationship between effects and drug exposure

-determine on-target and off-target effects

-assess potential relevance of data to humans

-identify safety biomarkers that should be monitored in the clinic

acute testing phase

small groups of animals tested with at least 3 doses over a wide range to encompass the anticipated therapeutic dose and multiples higher to determine potential toxicity; look for changes in weight, behavior, mortality, etc., drug plasma levels over time, and eventually look for changes in specific organs as a result of toxicity

repeated-dosing phase

drug is administered for about 2-4 weeks (time can be adjusted based on anticipated clinical use) in order to establish MTD and NOAEL for phase I clinical trials and look for potential toxicity using measures of liver, kidney, heart, respiratory, immune, or behavioral functioning

metabolic cages

used in preclinical toxicology studies to simultaneously measure food/water intake and collect urine/feces to measure and be examined

whole-body plethysmography

technique used in preclinical toxicology studies to measure respiratory rate and volume exchange using CO2 and pressure sensors

ECG (electrocardiogram)

used in preclinical toxicology studies to measure heart rate and rhythm to detect potential arrhythmias or QT prolongation

behavioral tests

used in preclinical toxicology studies to determine CNS effects; ex: open-field test, grip strength, rotarod tests

Ames test

a genotoxicity procedure used to determine if a drug readily causes mutagenesis by treating mutated salmonella strains that are incapable of forming colonies incubated either with or without rat liver enzymes (to metabolize drug) → if no colonies form then the drug does not easily cause mutations

chromosomal damage

can be looked at after adding a drug to whole mammalian cells to determine potential genotoxicity

DART (developmental and reproductive toxicology) studies

studies that test for potential developmental or reproductive damage caused by drug; includes FEED, EFD, and PPND studies

FEED (fertility and early embryonic development)

mated rodent pairs are administered drug for 2 weeks while sperm counts, estrous cycle, and unsuccessful breeding are tracked

EFD (embryo-fetal development)

pregnant females are administered drug and pups are examined for organogenesis

PPND (pre- and postnatal development)

examining whether drug can be passed through placenta or breast milk of treated female

subchronic dosing phase

drug is administered to rodents and non-rodents for about 13 weeks with a large enough sample (at least 20 per sex for rodents and 4-5 per sex for other species) to subdivide groups if necessary

FIH (first-in-human) studies

phase I clinical trials typically involving healthy subjects (6-10 receiving drug in ascending dose order) to ensure safety/validate preclinical safety testing as well as human drug pharmacokinetics, although can be done using patients if the drug is known to have some risk (ex: chemotherapeutics)

chronic toxicity studies

drug is administered to rodents for 6-9 months and to non-rodents for 9 months with similar structure and endpoints being measured as subchronic studies

rasH2 mice

a strain of mice that is susceptible to carcinogenic compounds that can be used to test drugs that are anticipated to be used for lifetime for a shorter period of time (6 months)

post-market surveillance (phase IV)

FDA continues to collect data after drug approval to ensure safety when given to a larger, more heterogeneous population