Chapter 2 New Drug and Development

Chapter 2
New Drug Development

and
Approval Process
NEW CHEMICAL ENTITY
SOURCES:
Organic Synthesis
Molecular Modification
Isolation from plants
Genetic Engineering
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2016 UST: NTT Chapter 2
PRECLINICAL STUDIES
Including:
Chemistry
Physical Properties
Biological
Pharmacology
ADME
Toxicology
Preformulation
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INVESTIGATIONAL NEW
DRUG APPLICATION (IND)
Submission
FDA Review
CLINICAL TRIALS PRECLINICAL STUDIES (Continued)

Phase I long term animal toxicity
Phase II product formulation
Phase III Manufacturing and controls
Package and label design
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NEW DRUG
APPLICATION (NDA)
Submission
FDA Review
Pre-approval Plant inspection
FDA action
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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 Development
P
H
Lead IND A I
Phase Phase Phase
Registration
Finding Track S II III
E
I
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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)
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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
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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
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DRUG PRODUCT FLOW
P
H
Lead IND Phase A
Phase Phase
Registration
Finding Track I II S III
E
2
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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 drug
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Controlled clinical trials (randomized,
blinded, 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
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evaluate dosage needed
detail how and why drug works in
the body and side effect it
causes
the drug must be effective and
safe
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DRUG PRODUCT FLOW
P
H
Lead IND Phase Phase A
Phase
Registration
Finding Track I II III S
E
3
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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
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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
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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
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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
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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
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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 10-15%
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Drug Discovery Process
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The Long Road to a New Medicine
Clinical Data
Registration
Analysis
Full
Development
Studies in 100-300
Patients (Phase II)
Candidate Medicine Tested in
3-10,000 Patients (Phase III)
Large Amounts of
Candidate Medicine
Synthesized
Studies in Healthy
Volunteers Phase Extensive
I Safety
Studies
Candidate
Exploratory Development Formulations

Developed
Early
Safety
Project Team Studies
and Plans Synthesis Screening
of Compounds
Discovery
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~100 Discovery Approaches
High Risk Process:

11-15 Years, $800MM+
Millions of
Compounds Screened
Preclinical
Pharmacology
Preclinical Safety
1-2
Clinical Pharmacology Products
& Safety
Discovery Exploratory Development Full Development

Phase I Phase II Phase III
0 5 10 15
Idea 11 - 15 Years
Drug
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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)
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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)
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Preclinical Clinical NDA Review Post Marketing
Research and Research and Development Surveillance
Development
Initial synthesis Adverse
and reaction
characterization Phase 1
Phase 2 Surveys/sampling
testing
Phase 3
Animal testing
Short term
Long term Inspection
Average 61/2 Average 7 years Average 1 1/2

years years
FDA 30-day safety review NDA submitted NDA approval
Average of approx. 15 years from initial synthesis to approval of NDA

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

Monitoring
PHARMACOLOGY
Mechanistic Follow-
Investigate up Studies and Other
Side-Effect Therapeutic
Issues Indications
Investigate Side- Clinical

NDA Effect Issues and Trials
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)
Supercompression of Drug Discovery
Cell & Molecular Biotechnology

Sciences
R
Genetics Robotics
Informatics &
Combinatorial Computer & Databases
Chemistry Inform. Technology
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
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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
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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
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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
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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.
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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
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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
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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
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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
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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)
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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.
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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
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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
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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
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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.
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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
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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
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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.
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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
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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
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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
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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
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EXAMPLES:
Dichloroisoproterenol 1st Burimamide - ist histamine
compd. with beta
H2 receptor blocking agent,
adrenoreceptor action; had
partial agonist poor oral availability
(sympathomimetic) activity Metiamide - histamine H2
Pronetalol - beta receptor blocking agent;
adrenoreceptor blocking agent good oral activity, produced
relatively free reversible agranulocytosis in
sympathomimetic; limited side some people
effect, including light-
Cimetidine - histamine H2
headedness, incoordination,
nausea & vomiting receptor blocking agent;
good oral activity, No
Propranolol - beta
adrenoreceptor, free agranulocytosis in man
sympathomimetic, lacking side
effects
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
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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
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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
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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.
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LEAD COMPOUND
is a prototype chemical
compound which has a
fundamental desired
biologic or pharmacologic
activity.
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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.
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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
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PRODRUGS
is a term used to described a
compound that requires metabolic
biotransformation following administration
to yield the desired pharmacologically
active compound.
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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
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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
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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
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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.
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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.
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NOMENCLATURE OR NAMING OF
DRUG
The task of designating appropriate non-
proprietary 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
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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
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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
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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
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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
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6. Distinctive terminology should
be used for specific drugs or drug
groups (e.g. Beta-blockers)
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Pharmacology
pharmaco = drugs
logos = study of
is the science concerned with drugs,

their sources, appearance, chemistry,
actions, and uses.
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The term can be expanded to
include
1. biochemical
2. physiologic effects
3. mechanism of action
4. 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
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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,
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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
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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
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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
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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
ill also be seen in humans
Example: headache
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Purpose of Safety Evaluation
and Toxicity Studies
1. The substances potential for toxicity
with short-term (acute effects) or long-
term use (chronic effects)
2. The substances potential for specific

organ toxicity
3. The mode, site, and degree of toxicity
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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
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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.
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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
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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.
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Chronic toxicity studies
The initial human dose is usually one-
tenth 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.
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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,
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physical examination
(electrocardiography, ophthalmic,
examination), hematology, clinical
chemistry, organ weights, gross
pathology, neoplastic pathology,
histopathology, urinalysis, ADME data
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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
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Data on the causes of animal death,
tumor incidence, type and site, and
necropsy findings are collected and
evaluated
Preneoplastic lesions and/or tissue-

specific proliferation effects are
important findings
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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
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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.
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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.
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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.
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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
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This is the area of responsibility of
pharmaceutical scientists and
formulation pharmacists trained in
pharmaceutics
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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
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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
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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
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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 HIV-

related 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
Drug Substances concentration, mg/L Drug
Substance Therapeutic Toxic Lethal
Acetaminophen 10-20 400 1500
Amitriptyline 0.5-.20 0.4 10-20
Barbiturate
Short Acting 1 7 10
Intermediate 1-5 10-30 30
Long Acting ~10 40-60 80-100
Dextropropoxyphene 0.05-0.2 5-10 57
Diazepam 0.5-2.5 5-20 :50
Digoxin 0.0006-0.0013 0.002-0.009 --
Imipramine 0.05-0.16 0.7 2
Lidocaine 1.2-5.0 6 --
Lithium 4.2-8.3 13.9 13.9-34.7
Meperidine 0.6-0.65 5 30
Morphine 0.1 -- 0.05-4
Phenytoin 5-22 50 100
Quinidine 3-6 10 30-50
Theophylline 20-100 -- -- Pharmacy 3
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 under the tongue
parenteral 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 SITE
intraocular eye
intranasal nose
aural ear
intrarespiratory lung
rectal rectum
vaginal vagina
urethral 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

Chapter 2 New Drug and Development

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Chapter 2 New Drug and Development

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Chapter 2

New Drug Development

CLINICAL TRIALS PRECLINICAL STUDIES (Continued)

Adverse Reaction Reporting

design to determine that the drug is

Exploratory Development Formulations

High Risk Process:

Discovery Exploratory Development Full Development

Long term Inspection

Average 61/2 Average 7 years Average 1 1/2

FDA 30-day safety review NDA submitted NDA approval

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

Phase IV GENERAL IND

Investigate Side- Clinical

Cell & Molecular Biotechnology

R and D activities on new Rx drugs for human

OTC drugs, generic drugs, biotechnology

development of new agents, such as

antineoplastic or anticancer drugs,

immunosuppressive agents to assist the bodys

contraceptives to prevent pregnancy

tranquilizers and antidepressant drugs to treat

1. Efavirenz - Sustiva - to treat AIDS

1. Naturally occurring materials in both

Examples: Ergot, opium, curare,

2. Synthesis of organic compounds

Example: morphine, atropine,

2. Periwinkle or Vinca rosea - use as treatment of

3. Vinblastine and Vincristine - Vinca rosea -

5. Dioscorea - Mexican yams - chemical steroid

6. Endocrine glands of cattle, sheep, and swine -

8. Animals - serum, vaccines, toxins

9. Renal monkey tissue - poliomyelitis

10. Fluid of chick embryo - mumps and

12. Skin of Bovine calves inoculated

13. Cell and Tissue cultures - new vaccines

- human insulin, human growth hormone,

Example: Pregnancy testing products

Human body contains up to 100,000

adenine and thymine (A and T,

modification of the genetic material of living

many companies exploring application of

2. Be administered by the most desired route at

3. Have optimal onset and duration of activity

4. Exhibit no side effects

6. No residual side effect

7. It would be easily produced at low cost

9. Physically and chemically stable under

is chemical alteration of a known

is a molecular modification to design a

1. Enalaprilat -Vasotec - inhibits the

3. Sertraline - Zoloft - which inhibits the

1. Cephalosporin antibiotics - additional

2. Large series of antianxiety drugs

Example: Finasteride -Proscar was

Prodrug may be design preferentially for

A combination of two or more old drugs or a

A drug need not be a new chemical entity to

The official name for a drug is referred to