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Flashcards in 5 drug evaluation and regulation Deck (30):
1

APPROACHES IN DRUG DISCOVERY

1. Chemical modification
2. Random screening of the biological
products
3. Rational drug design
4. Biotechnology and cloning using gene

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The amount of animal testing required
before human studies begin is a function
of the proposed use and the urgency of
the application

PRECLINICAL SAFETY AND TESTING

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PRECLINICAL SAFETY AND TESTING

-Administration of single doses to the lethal doses in at least 2 species
-Determine the no-effect dose and maximum tolerated dose

1. ACUTE TOXICITY

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PRECLINICAL SAFETY AND TESTING

-2 weeks to 3 months of testing required
3 doses 2 species
-longer duration of expected clinical use, longer --- test
-determine biochemical, physiologic effects

2. SUBACUTE

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PRECLINICAL SAFETY AND TESTING
-6-24 months
-2 and 3 tests are conducted for at least
the length of time proposed for human

CHRONIC

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PRECLINICAL SAFETY AND TESTING
-Rodent and at least one nonrodent species for > 6 months
Required when drug is intended to be used in humans for prolonged periods
-Usually run concurrently with clinical trials
-Determine same end points as subacute toxicity tests

CHRONIC

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PRECLINAL SAFETY AND TESTING
-2 Species (usually one rodent and rabbits)
-Test effects on animal mating behavior, reproduction, parturition, progeny, birth defects, postnatal developmenr

EFFECT ON REPRODUCTIVE PERFORMANCE

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PRECLINAL SAFETY AND TESTING
-2 years, 2 species
-Required when drug is intended to be used in humans for prolonged periods
-Determine gross and histologic pathology

Carcinogenic Potential

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PRECLINAL SAFETY AND TESTING
-Test effects on genetic stability and mutations in bacteria (Ames Test) or mammalian cells in culture; dominant lethal test and clastogenicity in mice

Mutagenic Potential

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PRECLINICAL SAFETY AND TESTING

 Induction of developmental defects in
somatic tissues of the fetus

4. TERRATOGENICITY

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PRECLINICAL SAFETY AND TESTING

 Induction of changes in the genetic
material of animals of any age inducing
heritable abnormalities

5. MUTAGENICITY

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PRECLINICAL SAFETY AND TESTING

 Standard in vitro test for mutagenicity
 Uses a special strain of Salmonella
bacteria that naturally depends on
specific nutrients in the culture medium
 Loss of this dependence during exposure
to the test drug signals mutation

AMES TEST

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PRECLINICAL SAFETY AND TESTING

 Induction of malignant characteristics
in cells

6. CARCINOGENICITY

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EVALUATION IN HUMANS

 4-6 years
 Natural variable history of the diseases
 Cross-over design
2 groups of patients
One group is given the standard

CLINICAL TRIALS

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EVALUATION IN HUMANS

 Presence of other disease and risk factors
 Select the patients that conduct clinical
trials
 Subject and observer bias

CLINICAL TRIALS

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CLINICAL TRIALS

 Careful evaluation of the dose-response
relationship in a small number of normal
human volunteers (20-30)

A. PHASE I

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CLINICAL TRIALS

 Except for trials of chemotherapeutic
drugs and other highly toxic drugs
carried by administering to patients
with target disease

A. PHASE I

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CLINICAL TRIALS

 Evaluation of a drug in a moderate
number of patients (100-300) with
the target disease
 Placebo or positive control is included
in a single-blind or double-blind study

B. PHASE II

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CLINICAL TRIALS

 Carefully controlled conditions and very
closely monitored
 Determines if the drug has the
therapeutic effects

B. PHASE II

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CLINICAL TRIALS

 Placebo, double-blind crossover trial
 Explore the spectrum of beneficial
actions of the new drug, compare
with older therapies
 Discover toxicities

C. PHASE III

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LINICAL TRIALS

 Toxicities that occur very infrequently
will be detected and reported early
enough to prevent a major therapeutic
disasters

D. PHASE IV

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CLINICAL TRIALS

 Postmarketing surveillance
 Not rigidly regulated by the Bureau of
Food and Drugs (BFAD)

D. PHASE IV

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 Process of testing a drug candidate which involves a sequence of
experimentation and characterization to be able to define the pharmacologic
profile of the drug at the molecular, cellular, organ, system and organism levels

DRUG SCREENING

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o Leading candidate for a successful new drug

Lead compound

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Quantitative estimates
maximum dose at which a specific toxic effect is not seen

o No-effect-dose-

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Quantitative estimates
smallest dose that is observed to kill any experimental animal

o Minimum lethal dose-

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Quantitative estimates
if necessary only, dose that kills approximately 50% of the animals. This is usually estimated from the smallest number of animals possible

o Median lethal dose(LD50)-

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 Drug’s proprietary name and is usually registered, it is legally protected al
long as it is used

Trademark

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 Adverse drug event (ADE)
 Harmful or unintended response

ADVERSE DRUG REACTIONS (ADRs)

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 Drugs for rare diseases
 Difficult to research, develop and market

ORPHAN DRUGS

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