5 drug evaluation and regulation

Question 1

APPROACHES IN DRUG DISCOVERY

Answer 1

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

Question 2

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

Answer 2

PRECLINICAL SAFETY AND TESTING

Question 3

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

Answer 3

1. ACUTE TOXICITY

Question 4

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

Answer 4

2. SUBACUTE

Question 5

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

Answer 5

CHRONIC

Question 6

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

Answer 6

CHRONIC

Question 7

PRECLINAL SAFETY AND TESTING

• 2 Species (usually one rodent and rabbits)
• Test effects on animal mating behavior, reproduction, parturition, progeny, birth defects, postnatal developmenr

Answer 7

EFFECT ON REPRODUCTIVE PERFORMANCE

Question 8

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

Answer 8

Carcinogenic Potential

Question 9

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

Answer 9

Mutagenic Potential

Question 10

PRECLINICAL SAFETY AND TESTING

 Induction of developmental defects in
somatic tissues of the fetus

Answer 10

4. TERRATOGENICITY

Question 11

PRECLINICAL SAFETY AND TESTING

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

Answer 11

5. MUTAGENICITY

Question 12

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

Answer 12

AMES TEST

Question 13

PRECLINICAL SAFETY AND TESTING

 Induction of malignant characteristics
in cells

Answer 13

6. CARCINOGENICITY

Question 14

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

Answer 14

CLINICAL TRIALS

Question 15

EVALUATION IN HUMANS

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

Answer 15

CLINICAL TRIALS

Question 16

CLINICAL TRIALS

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

Answer 16

A. PHASE I

Question 17

CLINICAL TRIALS

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

Answer 17

A. PHASE I

Question 18

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

Answer 18

B. PHASE II

Question 19

CLINICAL TRIALS

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

Answer 19

B. PHASE II

Question 20

CLINICAL TRIALS

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

Answer 20

C. PHASE III

Question 21

LINICAL TRIALS

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

Answer 21

D. PHASE IV

Question 22

CLINICAL TRIALS

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

Answer 22

D. PHASE IV

Question 23

 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

Answer 23

DRUG SCREENING

Question 24

o Leading candidate for a successful new drug

Answer 24

Lead compound

Question 25

Quantitative estimates

maximum dose at which a specific toxic effect is not seen

Answer 25

o No-effect-dose-

Question 26

Quantitative estimates

smallest dose that is observed to kill any experimental animal

Answer 26

o Minimum lethal dose-

Question 27

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

Answer 27

o Median lethal dose(LD50)-

Question 28

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

Answer 28

Trademark

Question 29

 Adverse drug event (ADE)

 Harmful or unintended response

Answer 29

ADVERSE DRUG REACTIONS (ADRs)

Question 30

 Drugs for rare diseases

 Difficult to research, develop and market

Answer 30

ORPHAN DRUGS