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drug evaluation & regulation

herni suprapti

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safety & efficacy

animal testing
acute & subacute toxicity testing
therapeutic action (from the pharmacologic
profile in animals)

human testing

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ANIMAL TESTING

amount of animal testing

nonsystemic
chronic systemic
anticancer drugs
AIDS drugs

ANIMAL TESTING

A. acute toxicity

B. subacute & chronic toxicity

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ACUTE TOXICITY

required for all drugs

administration of single doses of the agent
up to the lethal level
at least 2 species (1 rodent & 1 nonrodent)

SUBACUTE & CHRONIC TOXICITY

required for most agents, especially for

chronic use
for at least the length of time proposed for
human application :
2-4 weeks (subacute)
6-24 months (chronic)
at least 2 species

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TYPES OF ANIMAL TESTS

pharmacologic effects
hepatic & renal function monitoring
blood & urine tests
gross & histopathologic examination of
tissues
tests of reproductive effects
carcinogenicity

TYPES OF ANIMAL TESTS

A. PHARMACOLOGIC PROFILE

B. REPRODUCTIVE TOXICITY
C. CARCINOGENESIS

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A. PHARMACOLOGIC PROFILE

all the pharmacologic effects of a drug

effects on blood pressure
gastrointestinal activity
respiration
renal function
endocrine function
CNS

B. REPRODUCTIVE TOXICITY

fertility effects

teratogenic & mutagenic effects

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Teratogenesis

induction of developmental defects in the somatic

tissues of the fetus (eg, by exposure of the fetus to a
chemical, infection, radiation).
pregnant female animals
at least 2 species
selected times during early pregnancy
examining the fetuses or neonates for abnormalities
Ex : thalidomide, isotretinoin, valproic acid, ethanol,
glucocorticoids, warfarin, lithium & androgens.

mutagenesis
is induction of changes in the genetic material of
animals of any age  induction of heritable
abnormalities
The Ames test
 standard in vitro test for mutagenicity
 salmonella bacteria
mice
male animals are exposed to the test substance before
mating
carcinogens (eg, aflatoxin, cancer chemotherapeutic
drugs & other agents that bind to DNA) have mutagenic
effects.

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C. CARCINOGENESIS
 is the induction of malignant characteristics in cells
 difficult & expensive to study
 Ames test is often used
 correlation : mutagenicity -- carcinogenicity
 carcinogenic effects :
 coal tar
 aflatoxin
 dimethylnitrosamine & other nitrosamines
 urethane
 vinyl chloride
 the polycyclic aromatic hydrocarbons in tobacco smoke (eg,
benzo[a]pyrene).

CLINICAL TRIALS

A. PHASE I

B. PHASE II

C. PHASE III

D. PHASE IV

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A. PHASE I
 evaluation of the dose-response relationship
 a small number (20-30) of normal human volunteers
 an exception :
 cancer chemotherapeutic agents
 highly toxic drugs
 administering the agents to patients with the target disease
 acute effects of the agent
 broad range of dosages
 starting with one that produces no detectable effect
 progressing to one that produces either a significant
physiologic response or a very minor toxic effect

B. PHASE II
 evaluation of a drug in a moderate number of
patients (eg, 100-300)
 the target disease
 a placebo or positive control drug
 single-blind or double-blind design
 very carefully controlled conditions
 patients are very closely monitored
 in a hospital research ward
 the goal  to determine whether the agent has
the desired therapeutic effects at doses that are
tolerated by sick patients

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C. PHASE III
 large design involving many patients (eg, 1000-
5000 or more)
 many clinicians
 placebo and positive controls
 double-blind crossover design
 the goal 
to explore further the spectrum of beneficial actions of
the new drug
to compare it with older therapies
to discover toxicities
to be undetectable in phase II studies

D. PHASE IV

the postmarketing surveillance phase of

evaluation
is hoped that toxicities that occur very
infrequently will be detected and reported
early enough to prevent major therapeutic
disasters
phase IV is not rigidly regulated by the
FDA

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