BACHELOR OF SCIENCE IN PHARMACY

PHARMACEUTICAL DOSAGE FORMS, DRUG DELIVERY SYSTEMS AND MEDICAL DEVICES

CHAPTER 2: NEW DRUG DEVELOPMENT AND APPROVAL PROCESS

NEW DRUG DEVELOPMENT AND APPROVAL

1. After the discovery (e.g., synthesis) of a proposed new biologically characterized for pharmacologic and toxicologic
drug, the agent is effects and for potential therapeutic application.
2. initiated to defi ne the physical and chemical properties of
Pre-formulation studies
the agent.
3. to develop the initial features of the proposed
Formulation studies
pharmaceutical product or dosage form. T
a carefully designed and progressive sequence of
4. To obtain the required evidence demonstrating the drug’s
a. preclinical (e.g., cell culture, whole animal) and
safety and effectiveness for its proposed use, it undergoes…
b. clinical (human) studies is undertaken.
5. What will happen when the preclinical studies demonstrate
Drug’s sponsor file an IND application with the FDA for
adequate safety and the new agent shows promise as a
initial testing in humans.
useful drug?
6. If the drug demonstrates adequate safety in these initial
Phase 1
human studies is termed
Phases 2 and 3 are undertaken
7. progressive human trials
- to assess safety and efficacy.
8. At the completion of the carefully designed preclinical and the drug’s sponsor may file an NDA seeking approval to market
clinical studies… the new product.
the drug or the drug product is safe and effective for the
9. FDA’s approval of a NDA indicates the body of scientific proposed clinical indications, that there is adequate assurance
evidence submitted sufficiently of its proper manufacture and control, and that the final
demonstrates that… labeling accurately presents the necessary information for
its proper use

a. alosetron HCl (Lotrovec),

b. astemizole (Hismanal),
c. bromfenac sodium (Duract),
d. cerivastatin (Baycol),
e. cisapride (Propulsid),
f. dexfenfl uramine HCl (Redux),
g. fenfl uramine HCl Pondimin),
10. Some products, however, have been approved and later
h. grepafl oxacin HCl (Raxar),
removed from the market for safety reasons:
i. mibefradil (Posicor),
j. natalizumab (Tysabri),
k. pemoline (Cylert),
l. phenylpropanolamine (Propagest, Dexatrim),
m. rofecoxib (Vioxx),
n. terfenadine (Seldane), and
o. troglitazone (Rezulin).
11. summary of the entire drug development process because it
contains the essential chemistry, pharmacology, toxicology,
content of a product’s approved labeling,
indications and contraindications for use, adverse effects,
represented by the package insert
formulation composition, dosage, and storage requirements,
as ascertained during the research and development
12. if there are no satisfactory approved drugs or treatment protocol is termed a treatment IND
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PHARMACEUTICAL DOSAGE FORMS, DRUG DELIVERY SYSTEMS AND MEDICAL DEVICES
CHAPTER 2: NEW DRUG DEVELOPMENT AND APPROVAL PROCESS

alternatives for a serious medical condition, special

protocols may be issued permitting the use of an
investigational drug to treat some patients prior to approval
of the NDA.
13. often are sought for orphan drugs, which are targeted for
small numbers of patients who have rare conditions or
Investigational New Drug (IND)
diseases for which there are no satisfactory alternative
treatments
14. is used to gain approval to market a duplicate
(usually a competing generic product) of a product that is
abbreviated new drug application (ANDA)
already approved and being marketed by the pioneer, or the
original sponsor, of the drug
15. INADA investigational new animal drug application
16. NADA new animal drug application
supplemental new animal drug application
17. SNADA
DRUG DISCOVERY AND DRUG DESIGN
18. antibiotic that became commercially available in 1944, 15
years after its discovery in England by Sir Alexander penicillin
Fleming and 1 year before the end of the war.
a. exenatide [Byetta],
19. to treat diabetes
b. pramlinitide [Symlin])
20. growth failure mecasermin [Increlex]
21. HIV infections chronic tipranavir [Aptivirus]
22. hepatitis B infection entecavir [Baraclude
a. ibandronate [Boniva]
23. osteoporosis
b. raloxifene hydrochloride [Evista
24. sleep-onset insomnia ramelteon [Rozerem]
25. chronic angina ranola zine [Ranexa]
26. pulmonary arterial hypertension ambrisentan [Letairis
27. hypertension aliskiren [Tekturna]
28. fungal infections posaconazole [Noxafil
29. wet age-related macular degeneration ranibizumab [Lucentis]
30. nicotine addiction varenicline [Chantix]
31. breast cancer lapatinib [Tykerb]
32. seasonal and perennial allergic rhinitis and urticaria levocetirizine dihydrochloride [Xyzal]
SOURCES OF NEW DRUGS
a. natural sources or synthesized in the laboratory
33. New drugs may be discovered from b. may be discovered by accident, serendipity,
or as the result of many years of tireless pursuit.
34. known plants thus far have been investigated for
270,000
medicinal activity
35. a tranquilizer and a hypotensive agent, is an example of a
reserpine,
medicinal chemical
36. From what plant drug, reserpine, was isolated from? Rauwolfia serpentina
37. was first scientifically investigated as a result of its
reputation in folklore as an agent useful in the treatment of Periwinkle (Vinca rosea)
diabetes mellitus
38. Plant extracts from Vinca rosea yield two potent
drugs, which when screened for pharmacologic vinblastine and vincristine
activity surprisingly exhibited antitumor capabilities:
39. treatment of certain types of cancer, including
acute leukemia, Hodgkin disease, lymphocytic vinblastine and vincristine
lymphoma, and other malignancies.
40. • prepared from an extract of the Pacific yew tree
paclitaxel (Taxol),
• treatment of ovarian cancer
41. are rich in the chemical steroid structure from which
Dioscorea, popularly known as Mexican yams,
cortisone and estrogens are semisynthetically produced.
a. thyroid extract,
b. insulin, and
42. Hormonal substances c. pituitary hormone
- obtained from the endocrine glands of cattle, sheep, and
swine
43. rich source of estrogens urine of pregnant mares
44. Who worked with the smallpox vaccine in 1796.? Edward Jenner
45. prepared in cultures of renal monkey tissue, the mumps and poliomyelitis vaccine
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PHARMACEUTICAL DOSAGE FORMS, DRUG DELIVERY SYSTEMS AND MEDICAL DEVICES
CHAPTER 2: NEW DRUG DEVELOPMENT AND APPROVAL PROCESS

influenza vaccines in fluids of chick embryo

46. vaccine coming from duck embryo rubella (German measles) vaccine
47. vaccine from the skin of bovine calves inoculated with
the smallpox vaccine
vaccinia virus
48. being developed through the use of cell and tissue cultures. Vaccines for AIDS and cancer
a. recombinant DNA
49. two basic technologies that drive the genetic field of drug b. monoclonal antibody production
development - the ability to manipulate and produce proteins, the
building blocks of living matter.
50. • almost infinite source of drugs.
• Made up of long chains of amino acids, their sequence
proteins
and spatial configuration offer a staggering number of
possibilities
51. recombinant rDNA and monoclonal antibody production
produce proteins.
techniques influence cells’ ability to..
52. • more fundamental of the two techniques
recombinant DNA
• It has the potential to produce almost any protein
53. • Genetic material can be transplanted from higher species, gene splicing
such as humans, into a lowly bacterium. - Such drug products as human insulin, human
• can induce the lower organism to make proteins it would growth hormone, hepatitis B vaccine, epoetin-alpha,
not otherwise have made. and interferon are being produced in this manner
54. involve the manipulation of proteins within the
recombinant DNA techniques
cells of lower animals
55. conducted entirely within the cells of higher animals,
b. monoclonal antibody production
including the patient.
56. • are used in home pregnancy testing products.
monoclonal antibodies
• to stage and to localize malignant cells of cancer
57. highly sensitive to binding on one site on the human
monoclonal antibody
chorionic gonadotropin (HCG) molecule
58. • a specific marker to pregnancy because in healthy women
human chorionic gonadotropin (HCG) molecule
• synthesized exclusively by the placenta
59. used to prevent, treat, cure, diagnose, or mitigate human
diseases caused by genetic disorders, is another promising Human gene therapy
new technology
60. How many genes does the human body contain? 100,000 genes.
61. When a gene is expressed… a specifi c type of protein is produced
62. is a medical intervention based on the modification of the
Gene therapy
genetic material of living cells
63. Cells may be modified outside the body ex vivo
64. Cells may be modified within the body in vivo
65. entails the transfer of new genetic material to the cells of a
Gene therapy
patient with a genetic disease
66. What was the first use of human gene therapy? treat adenosine deaminase (ADA) deficiency
67. a condition that results in abnormal functioning of the
adenosine deaminase (ADA) deficiency
immune system
68. On what year did the FDA approves labeling change for
August 16, 2007
warfarin (Coumandin)?
A GOAL DRUG
69. would produce the specifically desired effect, be
administered by the most desired route (generally orally) at
minimal dosage and dosing frequency, have optimal onset
and duration of activity, exhibit no side effects, and a goal drug
following its desired effect would be eliminated from the
body efficiently, completely, and without
residual effect.
METHODS OF DRUG DISCOVERY
70. are used to differentiate the effect and potency (strength of
effect) of the test agent from those of controls of known bioassays
action and effect.
71. may be performed in vitro using cell cultures to test the new
initial bioassays
agent’s effect against enzyme systems or tumor cells
72. may be performed in vivo and may use more expensive and
subsequent bioassays
disease specific animal models.
73. are capable of examining 15,000 chemical compounds a
high-throughput screening
week using 10-20 biologic assays
74. a chemical alteration of a known and previously Molecular modification
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PHARMACEUTICAL DOSAGE FORMS, DRUG DELIVERY SYSTEMS AND MEDICAL DEVICES
CHAPTER 2: NEW DRUG DEVELOPMENT AND APPROVAL PROCESS

a. could mean enhancing its specificity for a particular body

target site, increasing its potency,
characterized organic compound (frequently a lead
b. improving its rate and extent of absorption,
compound) for the purpose of enhancing its usefulness as a
c. modifying to advantage its time course in the body,
drug.
d. reducing its toxicity, or changing its physical or chemical
properties (e.g., solubility)
75. first commercial beta-blocker propranolol
76. • First compound with beta-adrenoreceptor action
Dichloroisoproterenol
• Had partial agonist (sympathomimetic) activity
77. • Beta-adrenoreceptor blocking agent
Pronethalol
• relatively free from sympathomimetic activity
78. • beta-adrenoreceptor blocking agent, free of
sympathomimetic activity Propranolol
• Lacking side effects of pronethalol in humans
79. • Frist histamine H2-receptor blocking agent
Burimamide
• poor oral bioavailability
80. • histamine H2-receptor blocking agent
Metiamide
• good oral bioavailability
81. • histamine H2-receptor blocking agent
• good oral bioavailability Cimetidine
• No agranulocytosis in man
82. first commercial histamine H2-receptor blocking agent cimetidine
83. molecular modification to design a drug that interferes
Mechanism-based drug design
specifically with the known or suspected biochemical
Ex. enalaprilat
pathway or mechanism of a disease process.
84. What the active metabolite of enalaprilat? enalapril (Vasotec)
85. What has compound has the active metabolite of enalapril
enalaprilat
(Vasotec)?
- inhibits the angiotensin-converting enzyme (ACE) that
catalyzes the conversion of angiotensin I to the vasoconstrictor
substance angiotensin II.
86. What is the MOA of enalapril?
- Inhibition of the enzyme results in decreased plasma
angiotensin II, leading to decreased vasopressor effects and
lower blood pressure.
ranitidine (Zantac)
87. an inhibitor of histamine at the histamine H2-receptors, - inhibits gastric acid secretion, making the drug effective in the
including receptors on the gastric cells. treatment of gastric ulcers and other gastrointestinal conditions
related to the production of gastric acid.
88. which inhibits the central nervous system’s neuronal uptake
of serotonin, making the drug useful in the treatment of sertraline (Zoloft)
depression.
lead compound
89. prototype chemical compound that has a fundamental - may not possess all of the features
desired biologic or pharmacologic activity. desired, such as potency, absorbability, solubility,
low toxicity, and so forth
90. additional H2-antagonists from the pioneer drug cimetidine, cephalosporin antibiotics
91. large series of antianxiety drugs derived from the benzodiazepine structure
__________ and the innovator drug ___________ chlordiazepoxide (Librium).
92. as originally developed and approved to treat benign
finasteride (Proscar)
prostatic hyperplasia.
93. Later, the same drug (as_______) was approved at a lower
Propecia
recommended dosage to treat male pattern baldness.
PRODRUGS
94. term used to describe a compound that requires metabolic
- . The conversion of an inactive prodrug to an active
biotransformation after administration to produce the
compound occurs primarily through enzymatic biochemical
desired pharmacologically active compound.
cleavage.
95. An example of a prodrug which after oral
administration, is bioactivated by hydrolysis to
enalapril maleate (Vasotec)
enalaprilat, an ACE inhibitor used in the treatment of
hypertension
a. solubility,
b. absorption,
96. Prodrugs may be designed preferentially for
c. biostability, and
d. prolonged release
Solubility
97. Example of soluble prodrug that could be prepared through hydrocortisone sodium succinate
the addition of a functional group that later would be
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PHARMACEUTICAL DOSAGE FORMS, DRUG DELIVERY SYSTEMS AND MEDICAL DEVICES
CHAPTER 2: NEW DRUG DEVELOPMENT AND APPROVAL PROCESS

detached by the metabolic process to yield, once again, the

active drug molecule
Absorption
98. A drug may be made more water or lipid soluble, as
desired….
99. for patients requiring prolonged antipsychotic
therapy, the addition of the ________ to
________the makes the molecule
less water soluble.
Biostability
100. If an active drug is prematurely destroyed by biochemical
or enzymatic processes…
101. is a prodrug of acyclovir. Normally, the bioavailability of
acyclovir is 10% to 20% after oral administration.
102. treatment of Parkinson disease that is unable to cross the
blood–brain barrier
103. What prodrug of dopamine that is able to cross the blood-
brain barrier and then is converted to dopamine to treat
Parkinson’s disease
Prolonged Release
104. Depending on a prodrug’s rate of metabolic conversion to
an active drug…
FDA’S DEFINITION OF A NEW DRUG
105. any drug that is not recognized as being safe and effective
in the conditions recommended for its use in the labeling
among experts who are qualified by scientific training and
experience
106. Considerations of New drug:
DRUG NOMENCLATURE
107. What represents an organic compound wen first synthesized
or identified from a natural source
108. Empirical formula of amoxicillin
109. What does a compound receives when the knowledge of the b. acid,
relative locations of these atoms increases?
110. What do you call the shortened name of the chemical?
111. SQ 14,225
112. W/here does a sponsor may formally proposed a
nonproprietary name, when the results of testing indicate
that a compound shows sufficient promise of becoming a
drug?
113. Who is tasked of designating appropriate nonproprietary
names for chemical agents rests primarily with?
114. This reference of drug names now includes more than
115. Proposals are expected to conform to the council’s
guidelines for coining nonproprietary names.
to facilitate absorption via the intended route of administration
decanoate ester to haloperidol molecule
- when it is administered by a deep intramuscular injection, the
molecule provides a sustained effect that lasts up to 4 weeks
the design of a prodrug may protect the drug during its
transport in the body.
Valacyclovir
- converted to acyclovir by liver esterases via the first pass
metabolism resulting in a 55% bioavailability.
dopamine
levodopa
It may provide prolonged drug release and extended
therapeutic activity
New drug
a. change in a previously approved drug product’s
formulation or method of manufacture constitutes newness
b. combination of two or more old drugs or a
change in the usual proportions of drugs in an
established combination product
c. proposed new use for an established drug, a new dosage
schedule or regimen, a new route of administration, or a
new dosage form makes a
drug or a drug product’s status
Its empirical formula
C16H19N3O5 S.3H2O
- indicates the number and relationship of the atoms in the
molecule.
compound receives a systematic chemical name
Ex.
a. 4-Thia-1-azabicylco [3.2.0]heptane-2-carboxylic
c. 6-[amino(4-hydroxyphenyl) acetyl]amino-3,
d. 3-dimethyl-7-oxo,
e. trihydrate 2S-[2[alpha],
f. [5[alpha], 6[beta](S∗)] ]
nonproprietary (or generic) name
the investigational code number for the drug captopril,
initially developed by Squibb)
a. U.S. Adopted Names (USAN) Council in association with
the USP Expert Committee on Nomenclature,
b. the FDA, and the U.S. Patent and Trademark Office (and
foreign agencies as well) for a proprietary or trademark
name
USAN Council
9,500 nonproprietary drug
The name should be
a. short and distinctive in sound and spelling and not be such
that it is easily confused with existing names,
b. indicate the general pharmacologic or therapeutic class
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PHARMACEUTICAL DOSAGE FORMS, DRUG DELIVERY SYSTEMS AND MEDICAL DEVICES
CHAPTER 2: NEW DRUG DEVELOPMENT AND APPROVAL PROCESS

into which the substance falls or the general chemical

nature of the substance if the latter is associated with the
specific pharmacologic activity, and
c. embody the syllable or syllables characteristic of a related
group of compounds
BIOLOGIC CHARACTERIZATION
116. must undergo pre-clinical testing for biologic activity to
Prospective drug substances
assess their potential as useful therapeutic agents. T
a. information must be gained on how it is absorbed,
b. distributed throughout the body,
c. stored,
117. To judge whether a drug is safe and effective d. metabolized,
e. excreted
f. how it affects the action of the body’s cells, tissues, and
organs.
118. are being used increasingly to screen for toxicity before
Cell cultures
progressing to whole-animal testing
PHARMACOLOGY
119. • is the science concerned with drugs, their sources,
appearance, chemistry, actions, and uses
• the term can be expanded to include properties, Pharmacology
biochemical and physiologic effects, mechanisms of action,
absorption, distribution, biotransformation, and excretion
120. • the study of the biochemical and physiologic effects of
pharmacodynamics
drugs and their mechanisms of action
121. • deals with the absorption, distribution, metabolism or
pharmacokinetics
biotransformation, and excretion (ADME) of drug
122. which applies pharmacologic principles to the study of the
clinical pharmacology
effects and actions of drugs in humans
123. biochemical processes in the body’s cells involve what
intricate enzymatic reactions
reactions?
124. The selectivity and specificity of drugs for a certain body receptive only to chemicals of a particular chemical structure
tissue are related to specific sites on or within the cells, and configuration.
a. carboxyl, amino,
b. sulfhydryl, phosphate, and
125. What are the active centers of enzymes c. similar reactive groups oriented on or in the cell in a
pattern complementary to that of the drugs with which
they react.
a. ionic,
126. The binding of a drug to the receptor is thought to be
b. covalent,
accomplished mainly by what bonds?
c. other relatively weak reversible bonds
127. What occasionally is the bond between a drug to the firm covalent bonding
receptor? - drug effect is then slowly reversible

128. When the receptors are saturated
129. Two drugs in a biologic system may compete for the same
binding sites…
130. Certain cells within the body are capable of binding drugs
the effects of the specific interaction are maximized
with the drug having the stronger bonding
attraction for the site generally prevailing.
- Already bound molecules of the more weakly
bound drug may be displaced from the binding
site and left free in the circulation.
act as carriers and may be important to a drug’s transport to
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PHARMACEUTICAL DOSAGE FORMS, DRUG DELIVERY SYSTEMS AND MEDICAL DEVICES
CHAPTER 2: NEW DRUG DEVELOPMENT AND APPROVAL PROCESS
without eliciting a drug effect.
131. What are used to define a chemical’s pharmacologic
profile?
132. pharmacologists progress stepwise through increasingly
sophisticated levels of evaluation, based on the test
compound’s success in prior studies
133. What studies are used to evaluate the pharmacologic effects
of the agent on specific organ systems.
134. What studies are undertaken for which the compound is
considered a drug candidate?
135. in final pharmacologic and toxicologic studies, what animal
species are used as required by FDA?
136. primary objective of the animal studies
137. Animal models used in hypertension to mimic certain
human diseases
138. Animal models used in respiratory effects,
139. diuretic activity
140. blood coagulation
141. central nervous system studies
DRUG METABOLISM
142. A series of animal studies of a proposed drug’s
ADME are undertaken to determine the ff.:
143. biochemical transformation or metabolism of drug
substances is the body’s means of what?
144. What term is transit through the liver and exposure to the
hepatic enzyme system?
145. If the fi rst-pass effect is to be avoided
146. Drug metabolism or..
147. frequently results in the production of one or more
metabolites of the administered drug, some of which may
be pharmacologically active compounds, while others may
not
148. drug metabolism may be essential…
149. What is important to determine about the drugs metabolic
products?
150. When metabolites are found,..
151. metabolic byproducts, or
152. Some new drugs are discovered as metabolic byproducts, or
metabolites of what?
153. are performed through the timely collection and analysis of
urine, blood, and fecal samples and through a careful
examination of animal tissues and organs upon autopsy.
TOXICOLOGY
154. deals with the adverse or undesired effects of drugs
155. The direct extrapolation of preclinical animal safety data to
humans is difficult because…
156. preclinical drug safety evaluation or toxicity studies are
undertaken to determine
active sites or to sites of the drug’s biotransformation and
elimination.
a. In vitro cultures of cells and enzymes systems
b. in vivo animal models
pharmacologic profile
whole-animal studies
animal models of human disease
rodent and an animal from another order
to obtain basic information on the drug’s effects
that may be used to predict safe and effective use
in humans.
dogs and rats
dogs and guinea pigs
dogs
rabbits
mice and rats
a. the extent and rate of drug absorption from various routes
of administration, including the one intended for human
use;
b. the rate of distribution of the drug through the body and
the site or sites and duration of the drug’s residence;
c. the rate, primary and secondary sites, the mechanism of
the drug’s metabolism in the body, and the chemistry and
pharmacology of any metabolites;
d. the proportion of administered dose eliminated from the
body and its rate and route of elimination.
transforming nonpolar drug molecules into polar
compounds, which are more readily eliminated.
First-pass effect
other routes of administration (buccal, rectal) may be used
- allow the drug to be absorbed into the systemic circulation
through blood vessels other than hepatic
biotransformation
Drug metabolism or biotransformation
to convert prodrugs to active compounds
whether a drug’s metabolic products are toxic or nontoxic to
the animal and later to the human.
they are chemically and biologically characterized for activity
and toxicity
metabolites
parent compounds.
ADME studies
toxicology
a. species variation,
b. different dose-response relationships,
c. immunologic differences,
d. subjective reactions that are not deducible in
animals (such as headache),
a. the substance’s potential for toxicity with short-term
(acute effects) or long-term use (chronic effects);
b. the substance’s potential for specific organ toxicity;
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PHARMACEUTICAL DOSAGE FORMS, DRUG DELIVERY SYSTEMS AND MEDICAL DEVICES
CHAPTER 2: NEW DRUG DEVELOPMENT AND APPROVAL PROCESS

c. the mode, site, and degree of toxicity; (d) dose–response

relationships for low, high, and intermediate doses over a
specified time;
d. gender, reproductive, or teratogenic toxicities; and
e. the substance’s carcinogenic and genotoxic potential.
157. What must be developed after successful initial testing, and
develop the FDA-required two-order
why another animal, usually a dog, is added to the testing
toxicology profile
program?
a. acute or short-term toxicity
b. subacute or sub-chronic toxicity
158. The toxicology profile includes, , , , and c. chronic toxicity
d. carcinogenicity testing,
e. reproduction studies
f. mutagenicity screening
Acute or Short-Term Toxicity Studies
159. These studies are designed to determine the
toxic effects of a test compound when administered in a
single dose and/or in multiple doses over a short period, Acute or Short-Term Toxicity Studies
usually a single day
- used such as lavage dosing via gastric tube
160. What are collected and clinical laboratory tests performed
to detect changes in clinical chemistry and other changes Feces and urine specimens
that could indicate toxicity?
Subacute or Subchronic Studies
161. animal toxicity studies of a minimum of 2 weeks of daily
drug administration at three or more dosage levels to two
subacute or subchronic
animal species are required to support the initial
administration of a single dose in human clinical testing
162. What is the term for drugs intended to be given to humans
for a week or more, animal studies of __________days chronic toxicity studies
must demonstrate safety.
163. For drugs intended to be given to humans for a week or
more, how many days must this animal studies must 90 to 180 days
demonstrate safety?
164. How many year/s must be undertaken of animal studies to
support human use if the drug is to be used for a chronic 1 year or longer
human illness?
165. Some animal toxicity studies last _______or longer and
may be used to corroborate findings obtained during the 2 years
course of the human clinical trials
Carcinogenicity Studies
166. • What type of testing or study is usually a component of
chronic testing and is undertaken when the compound has
shown sufficient promise as a drug to enter human clinical
trials? Carcinogenicity Studies
• usually carried out in a limited number of rat and mouse
strains for which there is reasonable information on
spontaneous tumor incidence
167. What type of studies are done with female and male
animals using high, intermediate, and low doses over a 90- Dose-ranging studies
day period.
168. • the high dose should be only high enough (the
maximum tolerated dose) to elicit signs of minimal
toxicity without significantly altering the animal’s normal
lifespan by effects other than carcinogenicity
• are long term (18 to 24 months), with surviving animals Carcinogenicity Studies
killed and studied at defined weeks during the test period.
- Data on the causes of animal death (other than killing),
tumor incidence, type and site, and
necropsy findings are collected and evaluated
Reproduction Studies
169. What studies are undertaken to reveal any effect of an
active ingredient on mammalian Reproduction studies
Reproduction?
170. What are included in Reproduction Studies? a. fertility and mating behavior;
b. early embryonic,
c. prenatal, and postnatal development;
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d. multigenerational effects; and

e. teratology
171. In these studies, the maternal parent, fetus, neonates, and
anatomic abnormalities, growth, and development.
weaning offspring are evaluated for
Genotoxicity or Mutagenicity Studies
172. are performed to determine whether the test compound can
Genotoxicity or Mutagenicity Studies
affect gene mutation or cause chromosome or DNA damage
173. What strains are routinely used in assays to detect
Salmonella typhimurium
mutations?
EARLY FORMULATION STUDIES
174. CMC
chemistry, manufacturing, and controls
- essential part of all drug applications fi led with the FDA
PREFORMULATION STUDIES
a. drug’s solubility,
175. What are the intrinsic chemical and physical characteristics b. partition coefficient,
that must be considered before the development of a c. dissolution rate,
pharmaceutical formulation each drug substance? d. physical form, and
e. stability.
Drug Solubility
176. What does a drug substance administered by any route must
aqueous solubility
possess?
177. For what purpose why a drug must possess aqueous
systemic absorption and therapeutic response.
solubility?
178. What compounds may exhibit incomplete, erratic, and/or
Poorly soluble compounds (e.g., less than 10 mg/mL
slow absorption and thus produce a minimal response at
aqueous solubility)
desired dosage?
179. What type of solubility may be achieved by preparing more
soluble derivatives of the parent compound, such as salts or
Enhanced aqueous solubility
esters, by chemical complexation, or by reducing the
drug’s particle size.?
Partition Coefficient
180. To produce a pharmacologic response, what does a drug first cross a biologic membrane of protein and lipid,
molecule must first pass? - which acts as a lipophilic barrier to many drugs
181. The ability of a drug molecule to penetrate this barrier is preference for lipids (lipophilic) versus its
based in part on its …. preference for an aqueous phase (hydrophilic)
182. A measure of its distribution in a lipophilic-hydrophilic
phase system and indicates its ability to penetrate biologic drug’s partition coefficient
multiphase systems.
Dissolution Rate
183. The speed at which a drug substance dissolves in
dissolution rate
a medium
184. What can dissolution rate data, when considered along with
data on a drug’s solubility, dissolution constant, and an indication of the drug’s absorption potential
partition coefficient provide?
185. For a chemical entity, its acid, base, or salt forms, as well as
substantial differences in the dissolution rate.
its physical form (e.g., particle size) may result in…
Physical Form
186. What does the crystal or amorphous forms and/or the dissolution rate, thus the rate and extent of absorption, for a
particle size of a powdered drug can affect? number of drugs.
a. by reducing the particle size and
187. How can the surface area of a poorly soluble drug be b. increasing the powder fineness
enhanced? - its dissolution rate in the gut is enhanced (through
greater exposure of the drug to gastrointestinal fl uid)
and its biologic absorption increased.
188. The smaller the particle, the deeper is the penetration into the alveoli.
Stability
189. How can drugs susceptible to oxidative be protected the
addition of antioxidant stabilizing agents to the formulation
potency decomposition?
in formulation, processing, and packaging may be required
190. How can drugs destroyed by hydrolysis be protected to prevent decomposition.
against moisture? - putting desiccants (silica gel)

INITIAL PRODUCT FORMULATION AND CLINICAL TRIAL MATERIALS

191. An initial product is formulated using the information a. dose or doses,
gained during the pre-formulation studies and with the b. dosage form, and
consideration of the… c. route of administration desired for the clinical studies and
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for the proposed marketed product

192. What type of phase is for orally administered drugs,
capsules are employed containing
Phase 1 studies
the active ingredient alone, without pharmaceutical
excipient?
193. Excipients are included in the formulation for what phase
Phase 2 trials.
trial?
194. During what trial do studies of the drug’s ADME are
undertaken to obtain a profile of the drug’s human
During human trials
pharmacokinetics and biologic availability from the
formulation administered?
195. • the final dosage form is selected and developed for Phase
3 trials;
During Phase 2
• this is the formulation that is submitted to the FDA for
marketing approval
196. are controlled studies in which at least one of the parties
(e.g., patient, physician) does not know which product is Blinded studies
being administered
197. In all clinical study programs, the package label of the
“Caution: new drug—limited by federal [or United States] law
investigational drug must bear the
to investigational use.”
Statement:
Blister Packaging
a. clinical study or protocol number,
198. is commonly used in clinical studies, with immediate labels b. patient identification number,
containing the… c. sponsor number,
d. directions for use,
e. code number to distinguish between investigational drug,
f. placebo, and/or comparator product,
THE INVESTIGATIONAL NEW DRUG APPLICATION
sponsor of a new drug
199. Under the Food, Drug, and Cosmetic Act as amended - takes responsibility for and initiates a clinical investigation
required to file with the FDA an IND before the drug may - The sponsor may be an individual (a sponsor–investigator), a
be given to human subjects. pharmaceutical company, governmental agency, academic
institution, or some other private or public organization.
must delay the use of the drug in human subjects
200. After submission of the IND, what will the sponsor do? for not less than 30 days from the date the FDA
acknowledges the receipt of the application.
201. an order issued by the FDA to delay the start of a clinical
investigation or to suspend an ongoing study
During this time, the investigational drug may not be
A clinical hold
administered to human subjects (unless specifically
permitted by the FDA for individual patients in an ongoing
study).
CONTENT OF THE IND
202.
THE CLINICAL PROTOCOL
203. a sponsor must submit an amendment for approval of any
proposed changes…
• This may involve changes of dosing levels,
Once an IND is in effect
• testing procedures,
• the addition of new investigators,
• additional sites for the study,
204. Who were excluded from early drug tests out of fear that
the subject would become pregnant during the investigation Women of childbearing age
with possible harm to the fetus?
205. When was FDA Guideline for the Study and Evaluation of 1993
Gender Differences in the Clinical Evaluation of Drugs - states the agency’s gender inclusion policy
because of altered body functions such as
a. diminished liver and kidney function,
206. Why older people handle a drug differently?
b. reduced circulation, and
c. changes in drug ADME.
207. body of professional and public members that has the
responsibility for reviewing and approving any study
IRB
involving human subjects in
the institution they serve.
208. The purpose of the IRB a. to protect the safety of human subjects by assessing a
proposed clinical protocol,
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b. evaluating the benefits against risks, and

c. ensuring that the plan includes all needed measures for
subject protection.
PRE-IND MEETINGS
a sponsor on scientific, technical, or formatting concerns
include:
a. advice on the adequacy of data to support an
209. What will the FDA advise relating to the preparation and investigational plan,
submission of an IND b. the design of a clinical trial, or whether the proposed
investigation is likely to produce the data needed to meet
the requirements of the next step− the filing of an NDA to
gain approval for marketing.
FDA REVIEW OF AN IND APPLICATION
a. to protect the safety and rights of the human subjects and
210. FDA’s objectives in reviewing an IND b. to help ensure that the study allows the evaluation of the
drug’s safety and effectiveness.
211. Within CDER, applications are forwarded to the appropriate office of drug evaluation and then to one of its divisions for
review as follows:

FDA DRUG CLASSIFICATION SYSTEM

212. Upon receipt and examination of an IND or NDA, what
will FDA do?
PHASES OF A CLINICAL INVESTIGATION
213. An IND may be submitted for one or more phases of a
clinical investigation, namely
214. In this phase, it includes the initial introduction of an
investigational drug into humans and is primarily for the
purpose of assessing safety.
215. Why Phase 1 studies are designed?
216. are used for orally administered drugs in Phase 1 studies
217. What phase is controlled clinical studies to evaluate the
effectiveness of a drug in patients with the condition for
which the drug is intended and to assess side effects and
risks that may be revealed?
218. used as investigators during Phase 2 studies
FDA classifies the drug by chemical type and
therapeutic potential
Phase 1, Phase 2, or Phase 3
Phase 1
- human subjects are usually healthy volunteers, although, in
certain protocols, they may be patients.
a. determine the human pharmacology of the drug,
b. structure– activity relationships,
c. side effects associated with increasing doses, and,
d. if possible, early evidence of effectiveness.
capsules without excipients
Phase 2 trials
- uses patients as subjects, side effects or toxicity symptoms
that were not shown in the preclinical animal studies or in
Phase 1 studies with healthy volunteers may be revealed for the
fi rst time.
clinicians expert in the disease
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219. What phase where it gets additional data are collected on

the drug’s pharmacokinetics and studies undertaken to Phase 2a studies
determine dose–response and dose ranging?
220. What phase is fairly common to be continued after an NDA
Phase 3 studies
is fi led but prior to approval?
221. What phase studies are considered sufficient for the NDA? Phase 3a studies
222. What Phase studies serve as additional studies which are
used
a. to gather supplemental information that may support
certain labeling requests,
b. provide information on patients’ quality of life issues,
c. reveal product advantages over already marketed Phase 3b studies
competing drugs,
d. provide evidence in support of possible additional drug
indications,
e. provide other clues for prospective postmarketing
studies
223. What phase studies where dose determination studies result
in the specific doses and the dose range to be used in Phase Phase 2b studies
3 studies?
224. During this phase, the drug product is refined, with the final
formulation developed for use during late Phase 2 and Phase 2 trials
Phase 3 trials.
225. What phase studies may include several hundred to several
Phase 3 studies
thousand patients in controlled and uncontrolled trials?
CLINICAL STUDY CONTROLS AND DESIGN
226. What phases are controlled, i.e., the effects of the
Phase 2 and some Phase 3 studies
investigational drug are compared with another agent?
placebo (placebo control) or an active drug (positive control)
227. What can be a standard or comparator drug product? - Both a placebo and an active drug may be used as controls in
the same study
studies that are blinded
228. What studies that the identities of the investigational drug
- all of the agents administered, investigational drug, placebo,
and the control or controls are not revealed to certain
and/or comparator drug, must be indistinguishable to the
participants to decrease bias?
blinded individuals.
229. the patient is unaware of the agent administered. single blind studies
230. neither the patient nor the clinician is aware of the agent
double blind studies,
administered.
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231.

232. useful in comparing different treatments within

individuals since following one treatment, a Crossover designs
patient is crossed over to a different treatment.
DRUG DOSAGE AND TERMINOLOGY
233. major part of any clinical drug study determination of a drug’s safe and effective dose
234. conducted during Phase 2 and concluded
dose and dose-ranging studies
during Phase 3 clinical trials
a. including characteristics of the drug substance,
b. the dosage form and its route of administration,
c. variety of patient factors including age,
235. safe and effective dose of a drug depends on… d. body weight,
e. general health status,
f. any pathologic conditions, and
g. concomitant drug therapy
236. most products are formulated to contain a drug’s usual
dose within a single unit (e.g., capsule) or within a
convenience of dosage administration,
specified volume (e.g., 5 mL or a teaspoonful) of a liquid
dosage form.
237. The effective dose of a drug may be __________ for
different
different patients.
238.
239.

a drug’s dose will provide what might be called an average

effect in most individuals.
- However, in a portion of the population, the drug will
produce little effect, and in another portion, the drug will
produce an effect greater than average

240. low dose of a barbiturate produces sedation

241. larger dose of a barbiturate produces hypnotic effects
242. What do you call that is determined during the clinical schedule of dosage, or the dosage regimen
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investigation and is based largely on a drug’s inherent

duration of action, its pharmacokinetic profile, and the
characteristics of the dosage form (e.g., immediate release
or modified release
243. What is certain biologic products?
244. What are the two usual doses of tetanus immune globulin?
245. What doses of vaccines and other biologic products?
246. What must be done for a drug to provide systemic effects?
247. What is one measure of a drug’s absorption characteristics?
tetanus immune globulin
a. A prophylactic dose,
- or the amount administered to protect the patient from
contracting the illness
b. therapeutic dose,
- which is administered to a patient after exposure or
contraction of the illness.
sometimes are expressed in units of activity rather than in
specific quantitative amounts of the drug.
a. a drug must be absorbed from its route of administration at
a suitable rate,
b. be distributed in adequate concentration to the receptor
sites, and
c. remain there for a sufficient period.
is its blood serum concentration at various intervals after
administration.

248. is the amount that will produce the desired intensity of

The median effective dose of a drug
effect in 50% of the individuals tested.
249. is the amount that will produce a defined toxic effect in
The median toxic dose
50% of the individuals tested.
250. The relationship between the desired and undesired effects a. therapeutic index
of a drug is commonly expressed as the (a)________and is b. ratio between a drug’s median toxic dose and its median
defined as the (b)_________ effective dose, TD50/ED50.
251. Thus, a drug with a therapeutic index of 15 would be
expected to have a _______than a drug with a therapeutic greater margin of safety in its use
index of 5.
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AGE
252. • may be a consideration in the determination of drug
dosage.
Age
• particularly important in the treatment of neonatal,
pediatric, and geriatric patients
have immature hepatic and renal function,
253. Infants, especially newborns and those born prematurely - the means by which drugs are normally inactivated and
eliminated from the body.
254. A reduced capacity to detoxify and eliminate
can result in drug accumulation in the tissues to toxic levels
drugs
255. These doses are based on body weight or body surface area
pediatric doses
(BSA)
Pharmacogenetics
256. multiple forms of enzymes governing drug metabolism,
affect the clearance from the blood of many therapeutically Common genetic polymorphisms
important drugs used in large patient populations.
257. What is the usual doses for drugs are considered generally
70-kg (150 lb)
suitable for individuals?
body weight and are expressed on a milligram (drug) per
258. The doses for certain drugs are based on…
kilogram (body weight) basis (e.g., 1 mg/kg)
259. is considered more dependable than age as determinant of
body weight
drug dosage for youngsters,
260. the dose is based on… milligrams per kilogram
261. pediatric dose is based on combination of age and weight
Body Surface Area
262. is determined at the intersect of a straight line BSA
drawn to connect an individual’s height and Ex. an adult measuring 67 in height and weighing 132 lb would
weight have a BSA of approximately 1.7 m2
Sex
a. include the effects of the menstrual cycle and
b. menopausal status on a drug’s
263. Other important studies on women..
c. pharmacokinetics and
d. the drug interaction potential of concomitant estrogen or
oral contraceptive use
Pathologic State
264. The effects of certain drugs may be modified by the… pathologic condition of the patient.
Tolerance
265. ability to endure the influence of a drug, particularly during
drug tolerance
continued use
266. developed to a specific drug and to its chemical congeners;
Cross-tolerance
in the latter instance
267. Tolerance is common with the what type of drugs? antihistamines and narcotic analgesics
Concomitant Drug Therapy
268. may be due to a chemical or physical interaction between
the drugs or to an alteration of the absorption, distribution, drug–drug interaction
metabolism, or excretion patterns of one of the drugs
269. Example of “social” agents, which affect the
pharmacokinetics of a number of drugs and require an such as tobacco and alcohol
alteration in a drug’s usual dose−drug-to-drug interaction
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Time and Conditions of Administration

270. This is true especially for oral therapy in relation to meals. Time and Conditions of Administration
the stomach and the upper portions of the intestinal tract are
271. Absorption proceeds more rapidly if…
empty of food.
when taken before a meal may be less effective if administered
272. A dose of a drug that is effective
during or after eating
273. can affect a drug’s usual absorption pattern. Drug–food interactions
Dosage Form and Route of Administration
274. Type of route of administration enter the blood stream
Drugs administered intravenously
directly and completely
275. Type of route of administration absorbed into the blood
stream because of the various physical, chemical, and drugs administered orally are rarely
biologic barriers to their absorption
276. What type of route of administration is required than the
oral dose to achieve the same blood levels or clinical a lower parenteral (injectable) dose
effects?
TREATMENT IND
277. permits the use of an investigational drug in the
treatment of patients not enrolled in the clinical
study but who have a serious or immediately life- treatment IND or a treatment protocol
threatening disease for which there is no satisfactory
alternative therapy
“a stage of a disease in which there is a reasonable likelihood
278. “immediately life-threatening” means that death will occur within a matter of months or in which
premature death is likely without early treatment”
IND FOR AN ORPHAN DRUG
279. defined as a rare disease or condition that affects fewer than
200,000 people in the United States and for which there is orphan disease
no reasonable expectation that costs of research and - chronic lymphocytic leukemia, Gaucher disease, cystic
development for the indication can be recovered by sales of fibrosis, and conditions related to AIDS.
the product in the United States
WITHDRAWAL OR TERMINATION OF AN IND
 If an IND is withdrawn for safety reasons, the FDA, IRB, and all investigators must be so advised.
 FDA may terminate an IND and end related clinical investigations for reasons of safety, efficacy, or regulatory compliance
THE NEW DRUG APPLICATION
DRUG PRODUCT LABELING
280. According to federal regulations, _______includes not only
the labels placed on an immediate container but also the
drug labeling
information on the packaging, in package inserts, and in
company literature, advertising, and promotional materials.
281. is a summary of all of the preclinical and clinical studies
conducted over the period from drug discovery through Labeling for prescription drugs
product development to FDA approval.
a. Description of the product
b. Clinical pharmacology
c. Indications and usage
d. Contraindications
e. Warnings
282. The package insert is required to contain the following
f. Precautions
summary information in the order listed
g. Adverse reactions
h. Drug abuse and dependence
i. Overdosage,
j. Dosage and administration
k. How supplied