PCL102H1 Study Guide - Midterm Guide: Therapeutic Index, Indigestion, Induced Pluripotent Stem Cell
8 Jun 2018
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PCL102H 2013
PCL102H1 Spring 2013 THE ART OF DRUG DISCOVERY
Lecture 16: Clinical Trials and the Food and Drug Administration (F.D.A.)
FDA sets the regulations
drug approved for intended use
obstacles of change → agents of change
CASE 1: Thalidomide
drug for morning sickness
non-teratogenic in mice, but teratogenic in primates
Frances Kelley (Canadian working in FDA) refused to approve thalidomide in USA →
tighter safety amendments; proof of efficacy now required
today, this drug is used for leprosy and AIDS
CASE 2: AIDS drugs
1980s: first years of HIV, no drugs to treat it
ACT UP (AIDS Coalition To Unleash Power) closes FDA
activists, protests, international press coverage, among them Vito Russo
8 days later, new regulations were made
New models for clinical trials
I-SPY 2
breast cancer clinical trial
public-private consortium
screen multiple drugs from multiple companies (up to 12 drugs)
master umbrella Investigational New Drug (IND) approval from FDA
neoadjuvant treatment: giving chemotherapy treatment before surgery
investigational drug: a drug not yet approved by the FDA
biomarkers
adaptive randomization: use early data from one set of patients to guide decisions about
which treatments might be more useful for patients later in the trial
multiple corporate input
trial design initiated by breast cancer patients
open-source
women for whom an improvement over standard treatment could dramatically change the
odds of survival
Phase 0
tests pharmacokinetics and pharmacodynamics
lower doses, fewer patients → no direct benefit for participants (harder to recruit
volunteers?)
quickly weed out drugs that don't produce desired effects
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PCL102H 2013
less toxicity testing required, faster process
phase 0 is performed for drugs that use biomarkers, have a wide therapeutic
window, or have existing data
Lecture 17: Toxicology in Drug Development
Reading: Terence Young, Author of "Death By Prescription"
Terence Young's 15-year old daughter Vanessa suddenly collapsed and died
after taking Prepulsid for bloating
died of heart arrhythmia
drug taken off the market 4 months later
pharmaceutical companies "bribe" doctors and politicians
Lecture
Failure of Drugs
60% of drugs fail in late-clinical trials due to adverse and unpredicted side effects
undesired effects
include: o
idiosyncratic
reactions
o reversible vs. irreversible
reactions o local vs. systemic
reactions
dose-limiting toxicity: when toxic dose < efficacy dose
exaggerate dose and exposure during testing,
look for: o cell endpoints (cell death)
o physiological endpoints (changes in organ
function) o morphology
also look at gene expression and protein arrays
Toxicology: the study of adverse effects of chemicals on living organisms
mechanisms of action and function (biochemical and
immunological/neurobehavioral)
acute vs. chronic effects (first exposure vs. long-term)
"toxicology is part of the solution" : toxicologists study how to use chemicals
and drugs safely
mechanism of toxicity: binding of drug to receptor; activation of drug to
metabolite that
binds/damages protein
Risk Assessment and Biomarkers
hazard and exposure combined
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Pcl102h1 spring 2013 the art of drug discovery. Lecture 16: clinical trials and the food and drug administration (f. d. a. ) Obstacles of change agents of change. Non-teratogenic in mice, but teratogenic in primates. Frances kelley (canadian working in fda) refused to approve thalidomide in usa tighter safety amendments; proof of efficacy now required. Today, this drug is used for leprosy and aids. 1980s: first years of hiv, no drugs to treat it. Act up (aids coalition to unleash power) closes fda. Activists, protests, international press coverage, among them vito russo. 8 days later, new regulations were made. Screen multiple drugs from multiple companies (up to 12 drugs) Master umbrella investigational new drug (ind) approval from fda. Neoadjuvant treatment: giving chemotherapy treatment before surgery. Investigational drug: a drug not yet approved by the fda biomarkers adaptive randomization: use early data from one set of patients to guide decisions about which treatments might be more useful for patients later in the trial.
