Drug Discovery, Clinical Development Flashcards
what is the general process of development and testing required to bring a drug to market in the US
- in vitro studies: drug discovery
- animal testing: efficacy, selectivity, mechanism
- clinical testing: phase 1, 2, 3
- marketing: surveillance
what is the goal of phase 1, 2, and 3 clinical trials?
phase 1: safety and pharmacokinetics (20-100 subjects)
phase 2: efficacy in patients (100-200 patients)
phase 3: double blind trial (gold standard) (1000-6000 patients)
IND vs NDA
IND = investigational new drug
NDA = new drug application
when does drug patent expire?
20 years after filing of application
what is being looked for during posmarketing surveillance?
basically taking the drug from limited patient population in study to the entire world
so looking for adverse reactions, side effects, etc that were not seen before - possibly due to differing patient populations or lifestyles, etc, that were not accounted for in clinical trials
what is being tested in the animal testing phase of drug discovery to market? (preclinical studies/trials)
efficacy, selectivity, mechanism
high-throughput drug screening
screen biological activity of large numbers of natural products, banks of previously discovered chemicals, small molecules, large libraries of peptides, nucleic acids, etc
can screen up to millions of compounds - looking for a hit via something that binds
fluorescent marking
me-too approach of drug discovery
chemical modification of a known active molecule, creating analog - able to patent it as separate
modify the compound slightly (remove a molecule, for example) to make it more efficacious or specific for a certain disease, more safe, longer half-life, etc
rational drug design drug discovery approach
aka computer-aided drug design (CADD) - computational methods
identity or elucidate new drug target, followed by rational design of new molecule based on understanding of drug-receptor structure
solve crystal/MMR/other structure of target protein
calculate binding affinities (score)
what is the key purpose of clinical trials
control for variables (pharmacodynamics/kinetics, dose amount/frequency, drug interactions, social environment of patient, clinical state of patient, etc)
[some biases will still remain]
this phase of clinical trials, known as the human micro-dosing studies, includes administration of the drug at a lower dose than would be therapeutically active
phase 0: 10-15 health subjects, gathering preliminary data on pharmacokinetics (not commonly used)
may be done in cancer trials with patients who ran out of options
greatest number of drug failures occurs in phase ___
phase 2 - first time focus is on whether drug works in human patients (proof of concept)
finalize doses
only 25% move on to phase 3
this phase of clinical trials tests side effects, max tolerated dose, dose-limiting toxicity, and drug formulation
phase 1: pharmacokinetics/dynamics, 20-100 usually healthy patients but can also be patients with target disease or subpopulations
assessing tolerability (maximum tolerated dose (MTD) - give higher and higher doses
this phase of clinical trials is for confirmatory or pivotal studies
phase 3: confirm efficacy and safety in target population - controls are necessary (no treatment, placebo, or exiting therapy)
comparing IND to existing therapy requires rejecting the null hypothesis (IND group must do better)
post-authorization safety studies and real world studies make up stage ___ of clinical trials
stage 4: AFTER FDA approval, aka post-market surveillance
asses if there are other rare toxicities not observed prior (can be withdrawn from market if there are many adverse effects)
opportunities to assess if drug can be used for other uses beyond what it was approved for
