V - Drug Regulation Flashcards
Required before human studies begin
Animal Testing
Demonstrates the function of the proposed use and the urgency of the application
Animal Testing
Required for all new drugs
Acute Toxicity
Involve administration of single doses of the agent up to the lethal level in at least 2 species
Acute Toxicity
Required for most agents especially those intended for chronic use, tested in at least 2 species
Subacute and Chronic Toxicity
Duration: Subacute Toxicity
2-4 weeks
Duration: Chronic Toxicity
6-24 months
Description of all the pharmacologic effects of a drug
Pharmacologic Profile
Pharmacologic profiles require _____ data.
graded and quantal dose-response
Involves the study of the fertility effects of the candidate drug and its teratogenic and mutagenic toxicity
Reproductive Toxicity
FDA Drug Categories: fail to demonstrate a risk to human fetus in the first trimester, no evidence of risk in later trimesters, possibility of harm is remote
A
FDA Drug Categories: animal studies have not demonstrated fetal risk and no controlled human studies, animal studies showed adverse effect not confirmed in humans
B
FDA Drug Categories: adverse effect in animal fetus and no controlled human studies, studies in humans and animals are not available
C
FDA Drug Categories: positive evidence of human and animal fetal risk, some benefits
D
FDA Drug Categories: fetal abnormalities and risk, risk outweighs benefit
X
Induction of developmental defects in the somatic tissues of the fetus
Teratogenesis
Teratogenesis is studied by
treating pregnant female animals of at least 2 species at selected times during early pregnancy when organogenesis takes place
Teratogens: ACE Inhibitors
fetal renal damage
Teratogens: Anti-epileptic Drugs
neural tube defects
Teratogens: Phenytoin
fetal hydantoin syndrome
Teratogens: Oral Hypoglycemic agents
neonatal hypoglycemia
Teratogens: Barbiturates
neonatal dependence
Teratogens: Diethylstilbestrol (DES)
vaginal clear cell adenoCA
Teratogens: Ethanol
fetal alcohol syndrome
Teratogens: Lithium
Ebstein’s anomaly
Teratogens: Isotretinoin
craniofacial malformations
Teratogens: Iodide
congenital hypothyroidism
Teratogens: Misoprostol
Mobius sequence
Teratogens: Penicillamine
cutis laxa
Teratogens: Thalidomide
phocomelia
Teratogens: Smoking
IUGR
Teratogens: Tetracycline
tooth discoloration
Teratogens: Streptomycin
ototoxicity
Teratogens: Methimazole
aplasia cutis congenita
Teratogens: Sulfonamides
kernicterus
Teratogens: Fluoroquinolones
cartilage damage
Teratogens: Warfarin in the 1st Trimester
chondrodysplasia
Teratogens: Warfarin in the 2nd Trimester
CNS malformations
Teratogens: Warfarin in the 3rd Trimester
bleeding diatheses
Induction of changes in the genetic material of animals of any age and therefore induction of heritable abnormalities
Mutagenesis
Standard in vitro test for mutagenicity
Ames Test
Uses a special strain of Salmonella that naturally depends on specific nutrients, loss of this dependence signals a mutation
Ames Test
In vivo mutagenicity test carried out in mice
Dominant Lethal Test
Male animals are exposed to the test substance before mating, abnormalities in the results of subsequent mating signal a mutation in the male’s germ cells
Dominant Lethal Test
Induction of malignant characteristics in cells and expensive to study, high degree of correlation with mutagenicity in Ames Test
Carcinogenesis
Requires approval by institutional committees that monitor the ethical and scientific aspects of the proposed test
Clinical Trial
Includes all pre-clinical data collected up to the time of submission and the detailed proposal for clinical trials
Investigational New Drug
Constitutes the request for approval of general marketing of the new agent for prescription use and includes all the results of pre-clinical and clinical testing
New Drug Application
Clinical Trial Phases: careful evaluation of the dose-response relationship and pharmacokinetics among normal human volunteers (25-50), acute effects of the agent are studied over a broad range of dosages
Phase I Trial
Clinical Trial Phases: Is it safe?
Phase 1 Trial
Clinical Trial Phases: evaluation of a drug in a moderate number of patients with the target disease (100-300), placebo and control (single/double blind), controlled conditions and close monitoring (hospital ward), tests if desired efficacy is achieved and if drug istolerated by sick patients
Phase 2 Trial
Clinical Trial Phases: Is it effective?
Phase 2 Trial
Clinical Trial Phases: large design involving many patients (1000-5000) and many clinicians, placebo and control (double-blind/crossover), explores the spectrum of beneficial actions, compares new drug to old treatment, discovers toxicities, large amount of data, very expensive
Phase 3 Trial
Clinical Trial Phases: post-marketing surveillance phase, detects toxicites that occur infrequently, findings reported early enough to prevent major therapeutic disasters
Phase 4 Trial
Submitted when a new drug enters animal testing, right to market the drug without competition from other firms for a period of 20 years, after expiration, any company may apply to the FDA for permission to market a generic version of the same drug
Drug Patent
A new version of a patented drug must be
bioequivalent
Two related drugs are _____ if they show comparable bioavailability and similar times to achieve peak blood concentrations.
bioequivalent
Used in determining safety and efficacy of generic drugs
Bioequivalence
Drug for a rare disease (< 20,000 people)
Orpan Drug
