New Drug Development and Approval Process

Chapter 2
New Drug Development

and
Approval Process
NEW CHEMICAL ENTITY

SOURCES:
Organic Synthesis
Molecular Modification
Isolation from plants
Genetic Engineering
2016 UST: NTT Chapter 2
Pharmacy 3
PRECLINICAL STUDIES
Including:
Chemistry
Physical Properties
Biological
Pharmacology
ADME
Toxicology
Preformulation
Pharmacy 3
INVESTIGATIONAL NEW
DRUG APPLICATION (IND)
Submission
FDA Review
CLINICAL TRIALS
Phase I
Phase II
Phase III
PRECLINICAL STUDIES (Continued)

long term animal toxicity
product formulation
Manufacturing and controls
Package and label design
Pharmacy 3
NEW DRUG
APPLICATION (NDA)
Submission
FDA Review
Pre-approval Plant inspection
FDA action
Pharmacy 3
POST MARKETING TRIALS

Phase IV Clinical Trials
clinical pharmacology/Toxicology
additional indications
Adverse Reaction Reporting

Product Defect Reposting
Product Line Extension
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DRUG PRODUCT FLOW

Discovery
Lead
Finding
IND
Track
Development
P
H
A I
Phase
S
E
I
Phase
II
Phase
III
Registration
Pharmacy 3
4 Phases Of Clinical Studies In Man

PHASE 1 (Clinical Pharmacology)
design to determine that the drug is
safe and the side effects
might be
provide basic information about how
drug works in the body
(Pharmacokinetic activity)
Pharmacy 3
PHASE 1
Duration: 1 to 3 years
Sample size: less than 100 patients
Test on: Healthy volunteers
If passed this Phase, chances of the product
reaching to the market will be 30%
Begins to analysis and develop the drugs
safety profile
How the drug is absorbed, distributed,
metabolized and excreted
Pharmacy 3
CONCLUSION: Phase I
Studies
How well does Phase I measure?
!
!
!
Tolerability and toxicity

Desired pharmacologic effect
(efficacy)
Pharmacokinetics
How well does Phase I prepare

the investigator for Phase II?
!
!
Selection of doses
Safety monitoring strategy
Pharmacy 3
DRUG PRODUCT FLOW

Discovery
Lead
Finding
IND
Track
Development
Phase
I
P
H
A
Phase
II S
E
2
Phase
III
Registration
Pharmacy 3
PHASE II (Clinical
Investigation)
Duration: 2 years
Sample size: 100 300 patients

Test on volunteers who suffer from the
disease
Upon passing this Phase, chances of the
product reaching to the market will be
60%
To evaluate the drug's safety and assess
side effects
Establishes the
optimal dosage of the Pharmacy

drug 3
PHASE II (Clinical
Controlled clinical trials (randomized, blinded,
Investigation)
etc.)
Typically 100-500 patients with disorder

Biggest goal is proof of concept
Second biggest goal is dose determination
Critical are the categorization of the adverse
effects
Also: dosing schedule
Pharmacy 3
PHASE II (Clinical Investigation)

evaluate dosage needed
detail how and why drug works in
the body and side effect it
causes
the drug must be effective and
safe
Pharmacy 3
DRUG PRODUCT FLOW

Discovery
Lead
Finding
IND
Track
Development
Phase
I
Phase
II
P
H
A
Phase
III S
E
3
Registration
Pharmacy 3
PHASE III (Clinical Trials)
Duration: 3-4 years

Sample size: 1000 - 3000 patients
Test on volunteers who suffer from the
disease
If passed this phase, chances of the
product reaching to the market will be
70%
Verifies the drugs effectiveness in its
intended use
Assessment of long term effects
Pharmacy 3
PHASE III (Clinical Trials)

compare the drug with the
existing drugs
provide statistics on adverse
reaction
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Parallel to Phase III
Ongoing toxicity tests

Dosage forms
Production scale-up
Package design
Begin preparation for NDA
Pharmacy 3
PHASE IV (Post Marketing

Clinical Trials)
postmarketing surveillance may be required
unexpected reactions are detected, reported,
and evaluated
new indications for using the drug, problems
of people who take the drug
Pharmacy 3
NDA
New Drug Application (FDA)

Analysis of all data is complete
Drug is safe and effective
All data submitted to the FDA (or other
foreign agency)
(May require a big truck)
Wait for questions
Pharmacy 3
NDA Filing
Upon desirable results from Phase III, New Drug

Application (NDA) will be submitted
NDA contains data supporting the efficacy and safety
of the drug
Approval can take 2 month to several years, but on
average, it takes around 18 to 24 months
Drugs are subject to ongoing review, making sure no
adverse side effects appear from the drug.
After FDAs approval, the drug can be marketed and
distributed
Pharmacy 3
NDA Review/Approval
FDA scientists review all the data

May require an Advisory Panel review
Cleared for Marketing means it is
now available
--FDA took an average of 16.9 months
--Rejected applications stable at 1015%
Pharmacy 3
Drug Discovery Process
Pharmacy 3
The Long Road to a New Medicine

Registration
Clinical Data
Analysis
Full
Development
Studies in 100-300
Patients (Phase II)
Candidate Medicine Tested in

3-10,000 Patients (Phase III)
Studies in Healthy
Volunteers Phase I
Large Amounts of
Candidate Medicine
Synthesized
Extensive
Safety
Studies
ExploratoryDevelopment
Project Team
and Plans
Candidate
Formulations
Developed
Early
Safety
Studies
Synthesis
of Compounds
Screening
Discovery
Pharmacy 3
~100
~100 Discovery
Discovery Approaches
Approaches
High Risk Process:
11-15 Years, $800MM+

Millions of
Compounds Screened
Preclinical
Pharmacology
Preclinical Safety
1-2
Products
Clinical Pharmacology
& Safety
Discovery
Exploratory Development
Phase I
Phase II
Phase III
15
10
Idea
Full Development
Drug
11 - 15 Years
Pharmacy 3
Some products, however, have been

approved and later removed from the
market for safety reasons, including the
following:
Grepafloxacin HCL (Raxar)
Brofenac sodium (Duract)
Cisapride (Propulsid)
Alosetron HCL (Lotrovec)
Fenfluramine HCL (Pondimin)
Rofecoxib (Vioxx)
Terfenadine (Seldane)
Troglitazone (Rezulin)
Pharmacy 3
Some products, however, have been

approved and later removed from the
market for safety reasons, including the
following:
Dexfenfluramine HCL (Redux)

Cerivastatin (Baycol)
Mibefradil (Posicor)
Astemizole (Hismanal)
Pharmacy 3
Preclinical
Clinical
Research and
Research and Development
Surveillance Development
Initial synthesis
and
characterization
NDA Review
Post Marketing
Adverse
reaction
Phase 1
Phase 2
Surveys/sampling
testing
Phase 3
Animal testing
Short term
Long term
Average 61/2
years
Average 7 years
FDA 30-day safety review
Inspection
Average 1 1/2
years
NDA submitted
Average of approx. 15 years from initial synthesis to approval of NDA
NDA approval
ManyISTs Involved in Pharma

R&D
Chemists
Organic
Physical
Analytical
Combinatorial
Synthesis
Pharmacy 3

R&D
Chemists
Biologists
Organic
Physical
Analytical
Combinatorial
Synthesis
Pharmacologists
Cellular
Molecular
Bacteriologists
Virologists
Pharmacy 3

R&D
Chemists
Biologists
Organic
Physical
Analytical
Combinatorial
Synthesis
Pharmacists
Formulations
Clinical Supply
Product Stability
Analytical
Pharmacologists
Cellular
Molecular
Bacteriologists
Virologists
Pharmacy 3

R&D
Chemists
Biologists
Organic
Physical
Analytical
Combinatorial
Synthesis
Clinical Specialists
Medical Monitors
Clinical Scientists
Medical Writers
Biostatisticians
Data Management
Specialists
Pharmacists
Formulations
Clinical Supply
Product Stability
Analytical
Pharmacologists
Cellular
Molecular
Bacteriologists
Virologists

R&D
Chemists
Biologists
Organic
Physical
Analytical
Combinatorial
Synthesis
Clinical Specialists
Medical Monitors
Clinical Scientists
Medical Writers
Biostatisticians
Data Management
Specialists
Pharmacologists
Cellular
Molecular
Bacteriologists
Virologists
Pharmacists
Formulations
Clinical Supply
Product Stability
Analytical
Specialists
Toxicologists
Drug Metabolism
Project Managers
Human Relations
Regulatory
Legal
Safety Surveillance
Communications
Discovery
Screening
Specific Tests to
Aid in Selection
(e.g. Bioassay or
in vitro
Functionality)
Candidate
Nomination for
Development
General
Pharmacology
Profiles and Special
Models
Investigate SideEffect Issues and

Other Therapeutic
Indications
Phase IV
Monitoring
GENERAL
PHARMACOLOGY
IND
Mechanistic Followup Studies and Other
Therapeutic
Indications
Investigate
Side-Effect
Issues
NDA
Investigate SideEffect Issues and

Other
Therapeutic
Indications
(Figure 1. Flow Diagram Illustrating Where General Pharmacology Studies Can

Impact During the Typical Drug Discovery and Development Process. IND,
Investigational New Drug; NDA, New Drug Application
(From Fossa and Bucholtz, 1994)
Clinical
Trials
Supercompression of Drug
Discovery
Cell & Molecular
Sciences
Biotechnology
R
Robotics
Genetics
Combinatorial
Chemistry
Computer &
Inform. Technology
Informatics &
Databases
Drug Discovery and Drug Design
R and D activities on new Rx drugs for human
OTC drugs, generic drugs, biotechnology

products, animal health care drugs,
diagnostic products, and medical devices
development of new agents, such as
vaccines to protect against poliomyelitis,
measles, and influenza
Pharmacy 3
new pharmacologic categories of drugs

including oral hypoglycemic drugs effective against
certain types of diabetes mellitus
antineoplastic or anticancer drugs,
immunosuppressive agents to assist the bodys
acceptance of organ transplant
contraceptives to prevent pregnancy
tranquilizers and antidepressant drugs to treat
the emotionally distressed
Pharmacy 3
New and Important Innovative

Therapeutic Agents Approved by FDA
1. Efavirenz - Sustiva - to treat AIDS
2. Didanosine - Videx EC - to treat AIDS
3. Tenofovir - Viread - to treat AIDS
4. Leuprolide acetate - Eligard prostate cancer
5. Triptorelin pamoate - Trelstar - prostate cancer
6. Lovastatin - Mevacor - hyperlipidemic
7. Treprostinil sodium - Remodulin - pulmonary
arterial hypertensive
Pharmacy 3
8. Moxifloxacin HCl - Avelox - infectious disease

9. Montelukast sodium - Singulair - chronic
asthma
10. Tegaserod maleate - Zelnorm - irritable bowel
syndrome in women
11. Sodium oxybate -Xyrem - cataplexy in patient
with narcolepsy
12. Galantamine HCl - Reminyl - dementia with
Alzheimers disease
13. Fondaparinux sodium - Arixtra - deep vein
thrombosis
14. Voriconazole - Vfend - infectious disease
Pharmacy 3
SOURCES Of DRUGS
1. Pure organic compound
2. Natural or Synthetic
3. Organometallic
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These remedial have their origin in

essentially 3 ways
1. Naturally occurring materials in both
plants and animals
Examples: Ergot, opium, curare,
cinchona
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These remedial have their origin

in essentially 3 ways
2. Synthesis of organic compounds

whose structure are closely related to
those naturally occurring compounds
Example: morphine, atropine,
cortisone, cocaine
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3. Pure synthesis in which no attempt

has been made to pattern after a
known naturally occurring
compounds exhibiting some
activity
Examples: antihistamine,
barbiturates, diuretics, antiseptic, etc.
Pharmacy 3
Sources of New Drugs

1. Reserpine - tranquilizers and hypotensive agent
- isolated from Rauwolfia serpentina
2. Periwinkle or Vinca rosea - use as treatment of
diabetes mellitus
3. Vinblastine and Vincristine - Vinca rosea cancer, including acute leukemia, Hodgkins
disease and lymphocytic lymphoma and
other
malignancies
Pharmacy 3
4. Paclitaxel (Taxol)- Pacific yew tree - ovarian

cancer
5. Dioscorea - Mexican yams - chemical steroid
structure - cortisone and estrogen are
semisynthetically produced
6. Endocrine glands of cattle, sheep, and swine hormonal substances like thyroid, insulin, and
pituitary hormone replacement therapy in the
human body
Pharmacy 3
7. Urine of pregnant mares - rich source

of estrogen
8. Animals - serum, vaccines, toxins
9. Renal monkey tissue - poliomyelitis
vaccines
10. Fluid of chick embryo - mumps and
influenza vaccines
Pharmacy 3
11. Duck embryo rubella (German

measles)
12. Skin of Bovine calves inoculated
with vaccinia virus- smallpox
vaccines
13. Cell and Tissue cultures - new vaccines
for diseases AIDS and cancer
Pharmacy 3
14. Genetic engineering - manipulation

of the helix, the spiral DNA chain of
life.
2 basic technologies that drive the
genetic field
1. Recombinant DNA
2. Monoclonal antibody production
(mAb)
Pharmacy 3
15. Gene splicing - can be transplanted from

higher species, such as human, into lower
bacterium
- to produce proteins
- human insulin, human growth hormone,
hepatitis B vaccine, epoetin-alpha, and
interferon are being produced in this
manner.
Pharmacy 3
16. Monoclonal antibodies - the ability

of the cells with potential to produce a
desired antibody and stimulates
an unending stream of pure antibody
production.
Example: Pregnancy testing products
Pharmacy 3
In these test, the monoclonal

antibody is highly sensitive to binding
on one site on the human chorionic
gonadotropin (HCG) molecule, a
specific marker to pregnancy
because in healthy women. HCG is
synthesized exclusively by the
placenta
Pharmacy 3
In medicine: MA are being used to

stage and to localize malignant cells
of cancer, and it is anticipated that
they will be used in the future to
combat disease such as lupus
erythematosus, juvenile-onset
diabetes, and myasthenia gravis
Pharmacy 3
17. Human Gene Therapy - used to

prevent, treat, cure, diagnose, or mitigate
human disease caused by genetic disorders
Human body contains up to 100,000
genes
adenine and thymine (A and T,
respectively), cytosine and guanine (C and G,
respectively) constitute the instructions on a
gene.
Pharmacy 3
genetic diseases, gene expression may be

altered, gene sequences may be mismatched,
partly missing, repeated too many times,
causing cellular malfunction and disease
modification of the genetic material of living
cells may be modified outside the body (ex
vivo) for subsequent administration or modified
within the body ( in vivo) by gene therapy
products given directly to the patient
Pharmacy 3
the first human gene therapy used

was to treat adenosine deaminase (ADA)
deficiency, a condition that results in
abnormal functioning of the immune
system.
many companies exploring application of
Gene therapy to treat sickle cell anemia,
malignant melanoma, renal cell cancer, heart
disease, familial hypercholesterolemia, cystic
fibrosis, lung and colorectal cancer, and AIDS
Pharmacy 3
Goal Drug - In theory.

1. Would produce the specifically desired effect
2. Be administered by the most desired route at
minimal dosage and dosing frequency
3. Have optimal onset and duration of activity
4. Exhibit no side effects
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5. Following its desired effect would be

eliminated from the body efficiently and
completely
6. No residual side effect
7. It would be easily produced at low cost
8. Be pharmaceutically elegant
9. Physically and chemically stable under
various conditions of use and storage.
Pharmacy 3
Methods of Drug Discovery

Although some drugs may be the result of
fortuitous discovery, most of drugs are the
result of carefully designed research
programs of screening, molecular
modification, and mechanism-based drug
design
Pharmacy 3
1. Random or untargeted screening

involves the testing of large numbers of
synthetic organic compounds or substances of
natural origin for biologic activity
Purposes:
to detect an unknown activity of the test
compound or substance
to identify the most promising compounds
to be studied by more sophisticated
nonrandom or targeted screens
to determine a specific activity
Pharmacy 3
2. Molecular modification
is chemical alteration of a known
and previously characterized organic
compound (frequently a lead
compound) for the purpose of
enhancing its useful as a drug
Pharmacy 3
PURPOSES:
1. Enhance its specificity for a particular body target
site
2. Increasing its potency
3. Improving its rate and extent of absorption
4. Modifying the advantage its time-course in the body
5. Reducing its toxicity
6. Changing its physical and chemical properties
Pharmacy 3
EXAMPLES:
Dichloroisoproterenol 1st
compd. with beta
adrenoreceptor action; had
partial agonist
(sympathomimetic) activity
Pronetalol - beta
adrenoreceptor blocking
agent relatively free
sympathomimetic; limited
side effect, including lightheadedness, incoordination,
nausea & vomiting
Propranolol - beta
adrenoreceptor, free
sympathomimetic, lacking
side effects
Burimamide - ist
histamine H2 receptor
blocking agent, poor oral
availability
Metiamide - histamine H2
receptor blocking agent;
good oral activity,
produced reversible
agranulocytosis in some
people
Cimetidine - histamine H2
receptor blocking agent;
good oral activity, No
agranulocytosis in man
3. Mechanism-based drug design

is a molecular modification to design a
drug that interferes specifically with the
known or suspected biochemical
pathway or mechanism of a disease
process
Pharmacy 3
PURPOSE:
The intention is the interaction of the drug
with specific cell receptors, enzymes

systems, or metabolic process of pathogens
or tumor cells, resulting in blocking,
disruption, or reversal of the disease
process
Pharmacy 3
Example of Mechanism-based
Drug Design
1. Enalaprilat -Vasotec - inhibits the
angiotensin-coverting enzymes that catalyzes
the conversion of AI to the vasoconstrictor
substance AII. Inhibition of the enzymes results
decreased plasma AII, leading to decrease
vasopressor effects and lower blood pressure
Pharmacy 3
2. Ranitidine - Zantac - an inhibitor of

histamine at the histamine H2-receptors,
including receptors on the gastric cells.
Used to treat gastric ulcers
3. Sertraline - Zoloft - which inhibits the
central nervous systems neuronal uptake
of serotonin, making the drug useful in
the treatment of depression.
Pharmacy 3
LEAD COMPOUND
is a prototype chemical
compound which has a
fundamental desired biologic
or pharmacologic activity.
Pharmacy 3
Example of Lead Compound

1. Cephalosporin antibiotics - additional
H2 antagonists from the pioneer drug
Cimetidine
2. Large series of antianxiety drugs
derived from Benzodiazepine structure
and the innovator drug chlordiazepine
-Librium.
Pharmacy 3
3. Most drugs exhibit activities secondary

to their primary pharmacologic action.
Example: Finasteride -Proscar was
originally developed and approved to treat
benign prostatic hyperplasia. Later, the
same drug - Propecia was approved at
lower recommended dosage to treat male
pattern baldness
Pharmacy 3
PRODRUGS
is a term used to described a
compound that requires metabolic
biotransformation following administration
to yield the desired pharmacologically
active compound.
Pharmacy 3
Example of Prodrug
Enapril maleate Vasotec
which, after oral administration,
bioactivated by hydrolysis to enaprilat, an
ACE inhibitor used in the treatment of
hypertension
Prodrug may be design preferentially for
solubility, absorption, biostability and
prolonged release
Pharmacy 3
Solubility
Enabling the use of specifically desired
dosage forms and routes of administration
Absorption
A drug may be made more water or lipid
soluble, as desired, to facilitate absorption
via the intended route of administration
Pharmacy 3
Biostability
An active drug is prematurely destroyed
by biochemical or enzymatic process, the
design of a prodrug may protect the drug
during its transport in the body
Prolonged Release
Depending on a prodrugs rate of
metabolic conversion to active drug, it may
provide prolonged release and extended
therapeutic activity
Pharmacy 3
FDAs Definition of a New Drug

NEW DRUG - is any that is not recognized
as being safe and effective in the conditions
recommended for its use among experts
who are qualified by scientific training and
experience.
A combination of two or more old drugs or a
change in the usual proportions of drugs in an
established combination product is considered
new if the change introduces a question of
safety or efficacy.
Pharmacy 3
A new dosage schedule or regimen, a new

rout of administration, new dosage form all
cause a drug or drug products status to new
and triggers reconsideration for safety and
efficacy
A drug need not be a new chemical entity to
be considered new. A change in a previously
approved drug products formulation or method
of manufacture constitutes newness under
the law, since such changes can alter the
therapeutic efficacy and/or safety of a product.
Pharmacy 3
NOMENCLATURE OR NAMING OF
DRUG
The task of designating appropriate nonproprietary names for newly found
chemical agents rests primarily with the
USAN Council.
The official name for a drug is referred to
as the drug nonproprietary or public
name
Pharmacy 3
in contrast to the proprietary or brand

names or trademark names given by the
specific manufacturers or distributors of
the drug.
The term generic name, has been used
extensively in referring to the
nonproprietary names of the drugs. Brand
name is registered as a trademark with the
United States Patent Office
Pharmacy 3
CATEGORY OR USE
In general, drugs exert their effects by one
of three means:
1. By exerting a physical action such as

the protective effects of ointments
and lotions upon topical application
Pharmacy 3
2. By reacting chemically outside the body

cells.
Examples: antacids counteract
excess acidity in the stomach or
antibiotics to act against invading
pathogenic microorganism.
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3.
By modifying the metabolic activity of

bodys cell. Majority of the drugs
belong to the 3rd manner where brain,
liver, kidney, etc. are affected
Pharmacy 3
Proposals for Nonproprietary

Names
1.
Be short and distinctive in sound and

spelling and not be such that it is
easily confused with existing
names
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2. Indicate the general pharmacologic or

therapeutic class into which the
substance falls or the general chemical
nature of the substance if the latter is
associated with the specific
pharmacologic activity
3. Embody the syllable or syllables
characteristic of a related group of
compounds
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4. The name should be useful primarily to

health care practitioners particularly in
its safety for use in the routine
processes of prescribing, dispensing,
and administering drugs
5. The name should be a single word,
preferably with no more than four
syllables, and should be free from
conflict with other nonproprietary
names and should be neither confusing
nor misleading
Pharmacy 3
6. Distinctive terminology should

be used for specific drugs or drug
groups (e.g. Beta-blockers)
Pharmacy 3
Pharmacology
pharmaco = drugs
logos = study of
is the science concerned with drugs,
their sources, appearance, chemistry,
actions, and uses.
Pharmacy 3
The term can be expanded to

include
1.
2.
3.
4.
biochemical
physiologic effects
mechanism of action
ADME
Pharmacodynamics
the study of the biochemical and physiologic
effects of drugs and their mechanism of action
Pharmacokinetics = ADME
Clinical Pharmacology
applies pharmacologic principles to the study
of the effects and actions of drugs in humans
Pharmacy 3
Pharmacologic profile
= In vitro cultures of cells and enzymes
systems and in vivo animal models are
used to define a chemicals pharmacologic
profile
= Most animal testing is done on small
animals, usually rodents (mouse, rats) for a
number of reasons including cost,
availability, the small amount of drug
required for a study,
Pharmacy 3
the ease of administration by various

routes (oral, inhalation, intravenous)
and experience with drug testing in
these species
Animal models: dog or rat - for
hypertension; dog and guinea pig - for
respiratory effects; dog- for diuretic
activity; rabbit - for blood coagulation;
mouse and rats - for CNS studies
Pharmacy 3
Drug Metabolism
1. The extent and rate of drug absorption
from various routes of administration,
including the one intended for human use
2. The rate of distribution of the drug through
the body and the site or sites and duration of
the drugs residence
Pharmacy 3
3. The rate, primary and secondary sites,

and mechanism of the drugs metabolism
in the body and the chemistry and
pharmacology of any metabolites
4. The proportion of administered dose
eliminated from the body and its rate
and route of elimination
Pharmacy 3
Toxicology
Deals with the adverse or undesired
effects of drugs
Not all side effects of new drugs to be
tested in animals will be detected but
the greater the likelihood the effect
also be seen in humans
ill
Example: headache
Pharmacy 3
Purpose of Safety Evaluation

and Toxicity Studies
1. The substances potential for toxicity
with short-term (acute effects) or longterm use (chronic effects)
2. The substances potential for specific
organ toxicity
3. The mode, site, and degree of toxicity
Pharmacy 3
4. Dose-response relationships for low,

high, and intermediate doses over a
specified time
5. Gender, reproductive, or teratogenic
toxicities
6. The substances carcinogenic and
genotoxic potential
Pharmacy 3
Acute or Short-Term Toxicity

Studies
These studies are designed to determine
the toxic effects of a test compound when
administered in a single dose and/or in
multiple dose doses over a short period,
usually a single day.
Pharmacy 3
Animals are observed: eating and

drinking habits; weight changes; toxic
effects; psychomotor changes; feces and
urine are collected.
Animal death: recorded; study on
histology; pathology and statistically
evaluated on the basis of dose response
Pharmacy 3
Subacute or Subchronic
Studies
Animal toxicity studies of a minimum of 2
weeks of daily drug administration at three
or more dosage levels to two animal
species are required to support the initial
administration of a single dose in human
clinical testing.
Pharmacy 3
Chronic toxicity studies

The initial human dose is usually onetenth of the highest nontoxic dose (in
milligrams per kilogram of subjects weight)
shown during the animal studies. For drugs
intended to be given to humans for a week
or more, animal studies of 90 to 180 days
must demonstrate safety.
Pharmacy 3
If the drug is to be used for a chronic

human illness, animal studies 1 year or
longer must be undertaken to support
human use.
Compare the strain, sex, age, dose levels
and ranges, routes of administration,
duration of treatment, observed effects,
mortality, body weight changes, food and
water consumption,
Pharmacy 3
physical examination
(electrocardiography, ophthalmic,
examination), hematology, clinical
chemistry, organ weights, gross
pathology, neoplastic pathology,
histopathology, urinalysis, ADME data
Pharmacy 3
Carcinogenicity Studies
Usually component of chronic testing and is
undertaken when compound has shown
sufficient promise as a drug to enter human
clinical trials.
Carcinogenicity studies are long term (18-24
months), with surviving animals killed and
studied at defined weeks during the test
period
Pharmacy 3
Data on the causes of animal death,

tumor incidence, type and site, and
necropsy findings are collected and
evaluated
Preneoplastic lesions and/or tissuespecific proliferation effects are
important findings
Pharmacy 3
Reproduction Studies
Reproduction studies are undertaken to
reveal any effect of an active ingredient on
mammalian reproduction
Included in these studies are fertility and
mating behavior; early embryonic, prenatal,
and postnatal development,
multigenerational effects, teratology
Pharmacy 3
In these studies, the maternal

parent, fetus, neonates, and weaning
offspring are evaluated for anatomic
abnormalities, growth, and
development. The animal used in other
toxicity studies in reproductive studies,
usually the rats.
Pharmacy 3
In embryotoxicity studies only,

a second mammalian species
traditionally has been required. The
rabbit is the preferred choice for
practically and the extensive
background knowledge accumulated
on this species.
Pharmacy 3
Genotoxicity or Mutagenicity
Studies
Performed to determine whether
the test compound can affect gene
mutation or cause chromosome or DNA
damage. Strains Salmonella
typhimurium are routinely used in
assays to detect mutations.
Pharmacy 3
Early Formulation Studies

As a promising compound is
characterized for biological activity, it is
also evaluated with regard to chemical
and physical properties that have bearing
on its ultimate and successful formulation
into stable and effective pharmaceutical
product
Pharmacy 3
This is the area of responsibility of

pharmaceutical scientists and
formulation pharmacists trained in
pharmaceutics
Pharmacy 3
Preformulation Studies
Each drug substance has intrinsic
chemical and physical characteristic that
must be considered before the
development of a pharmaceutical
formulation
Among these are the drugs solubility,
partition coefficient, dissolution rate,
physical form, and stability
Pharmacy 3
Drug Solubility
A drug substance administered by any
route must posses some aqueous
solubility for systemic absorption and
therapeutic response
Poorly soluble compounds (example less
than 10mg per ml aqueous solubility) may
exhibit incomplete, erratic, and or slow
absorption and thus produce a minimal
response at desired dosage
Pharmacy 3
Partition Coefficient
A drug partition coefficient is a measure of its
distribution in a lipophilic-hydrophilic phase
system and indicates its ability to penetrate
biologic multiphase system
Dissolution Rate
Is the speed at which a drug substance
dissolves in a medium
Pharmacy 3
Physical Form
The crystal or amorphous forms and or the
particle size of a powdered drug can affect
the dissolution rate, thus the rate and extent
of absorption, for a number of drugs
Stability
The chemical and physical stability of a drug
substance alone, and when combined with
formulation components, is a critical to
preparing a successful pharmaceutical
product
Pharmacy 3
Initial Product Formulation and

Clinical Trial Materials
Prepared for Phase 1 and Phase 2 for
clinical trials
Phase 1 studies, for orally administered
drugs, capsules are employed containing
the active ingredient alone, without
pharmaceutical excipients
Pharmacy 3
Phase 2, the final dosage form is

selected and developed for Phase 3
trials, this is the formulation that is
submitted to the FDA for marketing
approval
Pharmacy 3
Clinical Supplies or Clinical

Trial Materials
Comprise all dosage formulations used in the
clinical evaluation of a new drug
This includes the proposed new drug,
placebos (inert substances for controlled
studies) and drug products against which the
new drug is to be compared (compactor
drugs or drug products)
Blinded Studies
Are controlled studies in which at least
one of the parties (example, patient,
physician) does not know which
product is being administered
Some studies are open label, in which
case all parties may know what
products are administered
Pharmacy 3
In all clinical study programs, the package label of

the investigational drug must bear the statement
Caution: new drug limited by federal ( or United
States) law to investigational use
Blister packaging is commonly used in

clinical studies, with intermediate labels
containing the clinical study or protocol number,
patient identification number, sponsor number,
directions for use, code number to distinguish
between investigational drug, placebo, and or
compactor product, and other relevant
information
Pharmacy 3
INVESTIGATIONAL NEW DRUG

1. Full description of new drug
2. Where and how it is manufactured
2. All quality control information and
standards
4. Stability
Pharmacy 3
5. Analytical method
6. Pharmacology
7. Toxicology
8. Efficacy in animals
9. Persons who will do the clinical studies
Pharmacy 3
Content of the IND

The content of an IND is prescribed in
the Code of Federal Regulations and is
submitted under a cover sheet
Name, address, and telephone number of
the sponsor of the drug
Name and title of the person responsible for
monitoring the conduct and progress of the
investigation
Pharmacy 3
Names and titles of the persons

responsible for the review and
evaluation of information relevant to t
he
safety of the drug
Name and address of any contract
research organization involved in the
study
Identification of the phase or phases of
the clinical investigation to be
conducted
Pharmacy 3
Introductory statement and general

investigational plan
Description of the investigational plan
Brief summary of previous human
experience with the drug (domestic or
foreign)
Chemistry, manufacturing, control
information
Pharmacology and toxicology information
Pharmacy 3
If the new drug is a combination of

previously investigated components, a
complete preclinical summary of these
components when administered singly and
any data or expectations relating to
the
effect when combined
Clinical protocol for each planned study
Commitment that an Institutional Review
Board has approved the clinical study
and will continue to review and monitor
the investigation
Pharmacy 3
Investigator brochure
Commitment not to begin clinical
investigations until the IND is in
effect, the signature of the
sponsor
or authorized representative, and the
date of the signed application
Pharmacy 3
Clinical Protocol
As a part of IND application, clinical
protocol must be submitted to ensure the
appropriate design and conduct of the
investigation, include:
Statement of the purpose and objectives of
the study
Outline of the investigational plan and study
design
Pharmacy 3
Estimate of the number of patients to be

involved
Basis for subject selection, with inclusion
and exclusion criteria
Description of the dosing plan, including
dose levels, route of administration,
and duration of patient exposure
Description of the patient observations,
measurements, and tests to be used
Pharmacy 3
Clinical procedures, laboratory tests,

and monitoring to be used in
minimizing patient risk
Names, addresses, and credentials
of the principal investigators and co
investigators
Locations and descriptions of the
clinical research facilities to be
used
Pharmacy 3
FDA Review of an IND

Application
To protect the safety and
rights of the human subjects and
to help ensure that the study
allows the evaluation of the drugs
safety and effectiveness.
Pharmacy 3
FDA Drug Classification System

By Chemical Type
Type 1 New Molecular entity, not

marketed in US
Type 2 New ester, new salt, or other
derivative of an approved
active moiety
Type 3 New formulation of a drug
marketed in US
Pharmacy 3
Type 4 New combination of two or

more compounds
Type 5 New manufacturer of a drug
marketed in US
Type 6 New therapeutic indication
for an approved drug
By Therapeutic Classification
Type P Priority review, a therapeutic gain
Type S Standard review, similar to other
approved drugs
Pharmacy 3
Additional Classification
Type AA For treatment of AIDS or HIVrelated disease
Type E For life-threatening or
severely debilitating disease
Type F Review deferred pending
data validation
Additional Classification
Type G Data validated, removal of F rating
Type N Nonprescription drug
Type V Drug having orphan drug status
Pharmacy 3
Drug Dosage and Terminology

The safe and effective dose of a drug
depends on different FACTOR:
1. Characteristics of the drug substance
2. The dosage form and its route of
administration
3. Variety patient factors - age, body weight,
general health status, pathologic conditions
4. Concomitant drug therapy
Pharmacy 3
Usual Adult Dose

the amount of drug that will produce the
desired effect in most adult patients.
Usual Dosage Range
indicates the quantitative range or
amounts of the drug that may be
prescribed safely within the framework
of usual medical practice.
Pharmacy 3
Underdosage / Overdosage
doses falling outside of the usual range
Usual Pediatric Dose

dose usually given to children
Schedule of dosage or Dosage

Regimen
determined during the clinical investigation
and is based largely on a drugs inherent
duration of action, its pharmacokinetics, and
characteristics of the dosage form
Pharmacy 3
Pharmacy 3
Minimum Effective Concentration (MEC)

An average blood serum concentration
represents the minimum concentration that can
be expected to produce the drugs desired effects
in a patient
Minimum toxic Concentration (MTC)

The second level of serum concentration of
drugs expected to produce dose-related toxic
effects in the average individual
Pharmacy 3
MED Median Effective Dose of a

drug is the amount that will produce
the desired intensity of effect in 50%
of the individuals tested.
Pharmacy 3
MTD Median Toxic Dose - is the

amount that will produce a defined
toxic effect in 50% of the individuals
tested
The relationship between the desired
and undesired effects of a drug is commonly
expressed as the Therapeutic index and is
defined as the ratio between a drugs median
toxic dose and its median effective dose,
TD50/ED50.
Pharmacy 3
Some factors of patients considered in

determining a drugs dose in clinical
investigations and in medical practice include
the following:
Age
Body Weight
Body Surface Area
Sex
Pathologic State
Tolerance
Pharmacy 3
Therapeutic and Toxic Blood Level Concentrations of Some Drugs

Substance
Drug Substances concentration, mg/L Drug

Therapeutic
Toxic
Lethal
Acetaminophen
10-20
400
1500
Amitriptyline
0.5-.20
0.4
10-20
1
1-5
~10
7
10-30
40-60
10
30
80-100
0.05-0.2
5-10
57
Barbiturate
Short Acting
Intermediate
Long Acting
Dextropropoxyphene
Diazepam
0.5-2.5
Digoxin
0.0006-0.0013
Imipramine
0.05-0.16
Lidocaine
5-20
0.002-0.009
1.2-5.0
:50
--
0.7
--
Lithium
4.2-8.3
13.9
13.9-34.7
Meperidine
0.6-0.65
30
Morphine
0.05-4
0.1
--
Phenytoin
100
5-22
50
3-6
10
Quinidine
201650
UST: NTT
Chapter 2
Pharmacy 3
30-
Therapeutic Indices For Various Drug Substances

Less Than 5
Between 5 and 10
Greater Than 10
Amitriptyline
Barbiturates
Acetaminophen
Chlordiazepoxide
Diazepam
Bromide
Diphenhydramine
Digoxin
Chloral hydrate
Ethchlorvynol
Imipramine
Glutethimide
Lidocaine
Meperidine
Meprobamate
Methadone
Paraldehyde
Nortriptyline
Procainamide
Primidone
Pentazocine
Quinidine
Thioridazine
Propoxyphene
Routes Of Drug Administration

TERM
SITE
oral
mouth
peroral (per os, p.o.)

gastrointestinal tract via mouth
sublingual
parenteral
under the tongue

other than GIT (by injection)
intravenous
vein
intraarterial
artery
Pharmacy 3
TERM
SITE
intracardiac
heart
intraspinal/intrathecal
spine
intraosseous
bone
intraarticular
joint
intrasynovial
joint-fluid area
intracutaneous/intradermal skin
subcutaneous
beneath the skin
intramuscular
muscle
Pharmacy 3
Routes Of Drug Administration

TERM
SITE
epicutaneous (topical)
skin surface
transdermal
skin surface
conjunctival
conjunctiva
Pharmacy 3
TERM
intraocular
intranasal
aural
intrarespiratory
rectal
vaginal
urethral
SITE
eye
nose
ear
lung
rectum
vagina
urethra
Pharmacy 3
Drug Product Labeling (Package

Inserts)
1. Description of the product
2. Clinical Pharmacology
3. Indications and usage
4. Contraindications
5. Warnings
Pharmacy 3
6.Precautions
7.Adverse reactions
8.Drug abuse and Dependence
9.Over dosage
10.Dosage and Administration
11. How supplied
Pharmacy 3
Supplemental, Abbreviated, and

Other Applications
Supplemental New Drug Application
Abbreviated New Drug Application
Biologics License Application
Animal Drug Applications
Medical Devices
Pharmacy 3

New Drug Development and Approval Process

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New Drug Development and Approval Process

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Chapter 2

New Drug Development

NEW CHEMICAL ENTITY

2016 UST: NTT Chapter 2

PRECLINICAL STUDIES (Continued)

2016 UST: NTT Chapter 2

2016 UST: NTT Chapter 2

POST MARKETING TRIALS

Adverse Reaction Reporting

DRUG PRODUCT FLOW

2016 UST: NTT Chapter 2

4 Phases Of Clinical Studies In Man

2016 UST: NTT Chapter 2

Tolerability and toxicity

How well does Phase I prepare

2016 UST: NTT Chapter 2

DRUG PRODUCT FLOW

2016 UST: NTT Chapter 2

Sample size: 100 300 patients

optimal dosage of the Pharmacy

Typically 100-500 patients with disorder

2016 UST: NTT Chapter 2

PHASE II (Clinical Investigation)

DRUG PRODUCT FLOW

2016 UST: NTT Chapter 2

PHASE III (Clinical Trials)

Duration: 3-4 years

2016 UST: NTT Chapter 2

PHASE III (Clinical Trials)

2016 UST: NTT Chapter 2

Parallel to Phase III

Ongoing toxicity tests

2016 UST: NTT Chapter 2

PHASE IV (Post Marketing

2016 UST: NTT Chapter 2

New Drug Application (FDA)

2016 UST: NTT Chapter 2

Upon desirable results from Phase III, New Drug

2016 UST: NTT Chapter 2

FDA scientists review all the data

2016 UST: NTT Chapter 2

Drug Discovery Process

2016 UST: NTT Chapter 2

The Long Road to a New Medicine

Candidate Medicine Tested in

2016 UST: NTT Chapter 2

High Risk Process:

11-15 Years, $800MM+

2016 UST: NTT Chapter 2

Some products, however, have been

Some products, however, have been

Dexfenfluramine HCL (Redux)

2016 UST: NTT Chapter 2

FDA 30-day safety review

Average of approx. 15 years from initial synthesis to approval of NDA

ManyISTs Involved in Pharma

2016 UST: NTT Chapter 2

ManyISTs Involved in Pharma

2016 UST: NTT Chapter 2

ManyISTs Involved in Pharma

2016 UST: NTT Chapter 2

ManyISTs Involved in Pharma

ManyISTs Involved in Pharma