DRUG EVALUATION

AND REGULATION

FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS
The development and testing process required to bring a drug to market in the USA. Some of the requirements may be different for drugs used in life-
threatening diseases (see text).

Source: Introduction: The Nature of Drugs & Drug Development & Regulation, Basic & Clinical Pharmacology, 13e
Citation: Katzung BG, Trevor AJ. Basic & Clinical Pharmacology, 13e; 2015 Available at:
http://accesspharmacy.mhmedical.com/content.aspx?bookid=1193&sectionid=69103583 Accessed: January 24, 2017
Copyright 2017 McGraw-Hill Education. All rights reserved
 DRUG EVALUATION AND
REGULATION

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

DRUG SCREENING
---- Biologic products
---- Chemical synthesis
---- Lead compound
 DRUG EVALUATION AND
REGULATION

PRECLINICAL SAFETY AND

TESTING
The amount of animal testing required
before human studies begin is a function
of the proposed use and the urgency of the
application
 DRUG EVALUATION AND
REGULATION

PRECLINICAL SAFETY AND TESTING

1. ACUTE TOXICITY
Administration of single doses to the
lethal doses in at least 2 species

2. SUBACUTE
2-4 weeks
 DRUG EVALUATION AND
REGULATION
PRECLINICAL SAFETY AND TESTING
3. CHRONIC TOXICITY
6-24 months
2 and 3 tests are conducted for at least the
length of time proposed for human

4. TERRATOGENICITY
Induction of developmental defects in somatic
tissues of the fetus
 DRUG EVALUATION AND
REGULATION
PRECLINICAL SAFETY AND TESTING
5. MUTAGENICITY
Induction of changes in the genetic
material of animals of any age inducing
heritable abnormalities
 DRUG EVALUATION AND
REGULATION

PRECLINICAL SAFETY AND TESTING

AMES TEST
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
 DRUG EVALUATION AND
REGULATION
PRECLINICAL SAFETY AND TESTING
6. CARCINOGENICITY
Induction of malignant characteristics
in cells
 DRUG EVALUATION AND
REGULATION
EVALUATION IN HUMANS
CLINICAL TRIALS
4-6 years
Natural variable history of the diseases
Cross-over design
2 groups of patients

One group is given the standard Presence of other

disease and risk factors
Select the patients that conduct clinical
trials
 DRUG EVALUATION AND
REGULATION
EVALUATION IN HUMANS
CLINICAL TRIALS
Presence of other disease and risk factors
Select the patients that conduct clinical
trials
Subject and observer bias
 DRUG EVALUATION AND
REGULATION
CLINICAL TRIALS
A. PHASE I
Careful evaluation of the dose-response
relationship in a small number of
normal
human volunteers (20-30)
Except for trials of chemotherapeutic
drugs and other highly toxic drugs
carried by administering to patients
with target disease
 DRUG EVALUATION AND
REGULATION
CLINICAL TRIALS
B. PHASE II
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
 DRUG EVALUATION AND
REGULATION
CLINICAL TRIALS
B. PHASE II
Carefully controlled conditions and very
closely monitored
Determines if the drug has the
therapeutic effects
 DRUG EVALUATION AND
REGULATION
CLINICAL TRIALS
C. PHASE III
Large design involving many patients
(1000-5000) or more in many centers
and many clinicians who are using the
drug in the manner proposed for its
general use
 DRUG EVALUATION AND
REGULATION
CLINICAL TRIALS
C. PHASE III
Placebo, double-blind crossover trial
Explore the spectrum of beneficial
actions of the new drug, compare
with older therapies
Discover toxicities
 DRUG EVALUATION AND
REGULATION
CLINICAL TRIALS
D. PHASE IV
Toxicities that occur very infrequently
will be detected and reported early
enough to prevent a major therapeutic
disasters
 DRUG EVALUATION AND
REGULATION

CLINICAL TRIALS
D. PHASE IV
Postmarketing surveillance
Not rigidly regulated by the Bureau of
Food and Drugs (BFAD)