Title: Drug DiscoveryNew Drug Development Process
1DRUG DISCOVERY NEW DRUG DEVELOPMENT PROCESS
BY
Dr. BASAVARAJ K. NANJWADE
Department of Pharmaceutics K L E UNIVERSITY JN
MEDICAL COLLEGE BELGAUM 590010 E-mail
bknanjwade_at_yahoo.co.in
2DRUG
- A substance used in the diagnosis, treatment, or
prevention of a disease or as a component of a
medication recognized or defined by the U.S.
Food, Drug, and Cosmetic Act. - A drug is any chemical or biological substance,
synthetic or non-synthetic
3- A drug is anything that affects the way an
organism works. - Drugs can be taken to enhance function, such as a
student drinking caffeine to enhance alertness. - For now we only consider drugs which are used to
cure a disease.
Continued
4- A disease is often thought of as an infection,
where a bacteria, virus, or other living thing
invades the body. - However, a disease is anything which affects the
proper functioning of the body. - It can be an infection, a genetic disorder, or
the result of environmental conditions such as
malnourishment, poisoning, or stress.
Continued
5- Engineers often find it easy to see the body as a
factory. - Individual organs can be seen as machinery. The
actual nuts, bolts, screwdrivers, and wrenches
that make up all the machinery are the equivalent
of proteins, little chunks of organic material
that move things around in the body and attach
them together. - Most of the work in our body is done by proteins.
Continued
6- The body contains thousands of different kinds of
proteins. - The construction of each is determined by the DNA
in the nucleus of each cell. - DNA may be thought of as long strings of
instructions which code for how each protein is
too be built. - The DNA is just a long string of acids that
serves as a message about how to make proteins.
7How Drugs are Developed
- The processes of new drug discovery and
development are long, complicated and dependent
upon the expertise of a wide variety of
scientific, technical and managerial groups. - If you are new to the industry, it can prove a
significant challenge to understand the
significance of your contribution, even if you
belong to one of the teams directly involved for
those on the periphery, the problem is magnified
to the point where team interactions and
efficiency are adversely threatened.
8Differences and Similarities of Drugs and
Medicinal Plants
- Today there are at least 120 distinct chemical
substances derived from plants that are
considered important drug and are currently in
use in one or more countries in the world - Some of these drugs are simply a chemical or
chemicals extracted from plant materials and put
into a capsule, tablet or liquid. - Eg. In Germany a Cynarin drug is manufactured
and sold to treat hypertension, liver disorders
and highly cholesterol levels.
9Differences and Similarities of Drugs and
Medicinal Plants
- The drug is simply this single chemical or an
Artichoke liquid extract, that has been
concentrated and chemically manipulated to
contain a specific amount of this one chemical
such a preparation is called a standardized
extract. - However in the U.S artichoke extracts are
available as natural products and sold in health
food stores as dietary supplements - Some U.S artichoke products are even
standardized to contain a specific amount of
cynarin, yet they can still be purchased here as
a natural product without a prescription. - There may be little to no difference between the
Cynarin drug produce in Germany and the artichoke
standardized herbal supplements made in the U.S
considering that the same amount of Cynarin is
being delivered, dose for dose
10Need for consumer education about Herbal
supplements Drugs
- Consumers find it very frustrating to sort
through a lot of ambiguous information put out by
natural product manufacturers who cannot legally
label their goods with condition-specific. - Stop them in their tracks in the aisles at the
health food store saying Hey, look at me, if
you have high cholesterol.
11More is Not Always Better
- Be careful about dosage amounts
- Philosophy of excess if some is good, more is
better
12Problem of One Vs Several Chemicals
- While many drugs have originated from
biologically active plant chemicals, and many
plants, medicine uses can be attributed to
various active chemicals found in them, there is
a distinct difference between using a medicinal
plant and a chemical drug. - The difference is one that scares most
conventionally trained doctors with no training
in plants. - Drugs usually consist of a single chemical,
whereas medicinal plants can contain 400 or more
chemicals. - Its relatively easy to figure out the activity
and side effects of a single chemical.
13Plant Based Drugs and Medicines
14Plant Based Drugs and Medicines
15Plant Based Drugs and Medicines
16Plant Based Drugs and Medicines
17Plant Based Drugs and Medicines
18Plant Based Drugs and Medicines
19Plant Based Drugs and Medicines
20Plant Based Drugs and Medicines
21Plant Based Drugs and Medicines
22Plant Based Drugs and Medicines
23Plant Based Drugs and Medicines
24Plant Based Drugs and Medicines
25The New Drug Development Process
(Steps from Test Tube to New Drug Application
Review)
26Non-clinical Drug Development
- Non-clinical drug development is a complex,
regulatory-driven process designed primarily to
assess the safety and viability of new molecular
entities. - Non-clinical, or preclinical, services encompass
toxicology, pharmacology, metabolism,
bioanalysis, pharmaceutical analysis and
biosafety testing in support of non-clinical drug
development.
27Non-clinical Drug Development
- A sponsor must first submit data showing that
the drug is reasonably safe for use in initial,
small-scale clinical studies. - Depending on whether the compound has been
studied or marketed previously, the sponsor may
have several options for fulfilling this
requirement. - 1. Compiling existing non-clinical data from
past in vitro - laboratory or animal studies on the
compound - 2. Compiling data from previous clinical
testing or marketing of the - drug in the U.S or another country whose
population is relevant to - the U.S population
- 3. Undertaking new preclinical studies
designed to provide the - evidence necessary to support the safety
of administering the - compound to humans.
28Non-clinical Drug Development
- During preclinical drug development, a sponsor
evaluates the drugs toxic and pharmacologic
effects through in vitro and in vivo laboratory
animal testing. - Genotoxicity screening is performed, as well as
investigations on drug absorption and metabolism,
the toxicity of the drugs metabolites and the
speed with which the drug and its metabolites are
excreted from the body.
29FDA will generally ask
- Develop a pharmacological profile of the drug
- Determine the acute toxicity of the drug in at
least two species of animals - Conduct short-term toxicity studies ranging from
2 weeks to 3 months, depending on the proposed
duration of use of the substance in the proposed
clinical studies.
30Subpart E
- CFR (Code of Federal Regulations) establishes
procedure to expedite the development, evaluation
and marketing of new therapies intended to treat
people with life-threatening and
severely-debilitating illnesses, especially where
no satisfactory alternatives exist.
31Sponsor/FDA Meetings ( Pre-IND)
- Prior to clinical studies, the sponsor needs
evidence that the compound is biologically
active, and both sponsor and the FDA need data
showing that the drug is reasonably safe for
initial administration to humans. - Meeting at such an early stage in the process are
useful opportunities for open discussion about
testing phases, data, requirements, and any
scientific issues that may need to be resolved
prior to IND submission - At these meeting, the sponsor and FDA discuss and
agree upon the design of the animal studies
needed to initiate human testing
32Synthesis and Purification
- The research process is complicated,
time-consuming, and costly and the end result is
never guaranteed. - Literally hundreds and sometimes thousands of
chemical compounds must be made and tested in an
effort to find one that can achieve a desirable
result. - FDA estimates that it takes approximately eight
and half years to study and test a new drug
before it can be approved for the general public. - Computers can be used to simulate a chemical
compound and design chemical structures that
might work against it. - Enzymes attach to the correct site on a cells
membrane, which causes the disease. - A computer can show scientists what the receptor
site looks like and how one might tailor a
compound to block an enzyme from attaching there.
33Animal Testing
- Drug companies make every effort to use as few
animals as possible and to ensure their humane
and proper care. - Generally two or more species ( one rodent, one
non-rodent). - Animal testing is used to measure how much of a
drug is absorbed into the blood, how it is broken
down chemically in the body, the toxicity of the
drug and its breakdown products metabolites, and
how quickly the drug and its metabolites are
excreted from the body
34Short and Long Term Animal Testing
- Short-term testing in animals ranges in duration
from 2 weeks to 3 months, depending on the
proposed use of the substance. - Long-term testing in animals ranges in duration
from a few weeks to several years. - - Some animal testing continues after human
tests begin to learn whether long-term use of a
drug may cause cancer or birth defects.
35Institutional Review Board
- Institutional review boards (IRB) are used to
ensure the rights and welfare of people
participating in clinical trials both before and
during their trial participation. - An IRBs at hospitals and research institutions
throughout the country make sure that
participants are fully informed and have given
their written consent before studies ever begin. - An IRBs are monitored by the FDA to protect and
ensure the safety of participants in medical
research. - An IRBs must be composed of no less than five
experts and lay people with varying background to
ensure a complete and adequate review of
activities commonly conducted by research
institutions. - An IRBs must be composed of people whose concerns
are in relevant areas.
36IND Submitted
- Introduction
- Current requirements and practices
- Clarifications of present IND regulation
- Cover Sheet (FDA Form 1571)
- Table of contents
- Introductory statement and general
investigational plan - Investigator's brochure
- Protocols
37IND Submitted
- F. Chemistry, Manufacturing, and Control
information - Chemistry and manufacturing introduction
- Drug substance
- A description of the drug substance, including
its physical, chemical, or biological
characteristics - The name and address of its manufacturer
- The general method of preparation of the drug
substance - The acceptable limits and analytical methods used
to assure the identity, strength, quality, and
purity of the drug substance. - Information to support the stability of the drug
substance during the toxicology studies and the
proposed clinical study
38IND Submitted
- 3. Drug product
- A list of all components, which may include
reasonable alternatives for inactive compounds,
used in the manufacture of the investigational
drug product, including both those components
intended to appear in the drug product and those
which may not appear, but which are used in the
manufacturing process. - Where applicable, the quantitative composition of
the investigational new drug product, including
any reasonable variations that may be expected
during the investigational stage. - The name and address of the drug product
manufacturer
39IND Submitted
- d. A brief, general description of the method of
manufacturing and packaging procedures as
appropriate for the product. - e. The acceptable limits and analytical methods
used to assure the identity, strength, quality,
and purity of the drug product. - f. Information to support the stability of the
drug substance during the toxicologic studies and
the proposed clinical study(ies)
40IND Submitted
- 4. A brief general description of the
composition, manufacture, and control of any
placebo to be used in the proposed clinical
trial. - 5. A copy of all labels and labeling to be
provided to each investigator. - 6. A claim for categorical exclusion from or
submission of an environmental assessment.
41IND Submitted
- G. Pharmacology and Toxicology information
- Pharmacology and drug distribution.
- 2. Toxicology Integrated summary.
- 3. Toxicology- Full data tabulation.
- H. Previous human experience with the
investigational drug
42Phase 1 Clinical Studies
- Phase 1 includes the initial introduction of an
investigational new drug into human. - Phase 1 studies usually conducted in healthy
volunteer. - Phase 1 studies are designed to determine the
metabolic and pharmacologic actions of the drug
in humans, the side effects associated with
increasing doses, and if possible to gain early
evidence on effectiveness.
43Phase 1 Clinical Studies
- Phase 1 studies also evaluate drug metabolism,
structure-activity relationships, and the
mechanism of action in humans. - The total number of subjects included in Phase I
studies varies with the drug, but is generally in
the range of 20 to 80
44Phase 2 Clinical Studies
- Phase 2 includes the early controlled clinical
studies conducted to obtain some preliminary data
on the effectiveness of the drug for a particular
indication or indications in patients with the
disease or condition. - This phase of testing also helps determine the
common short-term side effects and risks
associated with the drug. - Phase 2 studies are typically well-controlled,
closely monitored, and conducted in a relatively
small number of patients usually involving
several hundred people.
45Sponsor/FDA Meeting (End of Phase 2)
- One month prior to the end of the Phase 2, the
sponsor should submit the background information
and protocols for phase 3 studies. - This information should include data supporting
the claim of the new drug product, chemistry
data, animal data and proposed additional animal
data, results of Phase 1 and 2 studies,
statistical methods being used, specific
protocols for phase 3 studies, as well as a copy
of the proposed labeling for a drug, if
available. - This summary provides the review team with
information needed to prepare for a productive
meeting.
46Phase 3 Clinical Studies
- Phase 3 studies are expanded controlled and
uncontrolled trials. - They are performed after preliminary evidence
suggesting effectiveness of the drug has been
obtained in Phase 2 and are intended to gather
the additional information about effectiveness
and safety that is needed to evaluate the overall
benefit-risk relationship of the drug.
47Phase 3 Clinical Studies
- Phase 3 studies also provide an adequate basis
for extrapolating the results to the general
population and transmitting that information in
the physician labeling. - Phase 3 studies usually include several hundred
to several thousand people. - Great care is taken to ensure that this
determination is not made in isolation, but
reflects current scientific knowledge, agency
experience with the design of clinical trials,
and experience with the class of drugs under
investigation
48Accelerated Development/ Review
- Accelerated development/review is a highly
specialized mechanism for speeding the
development of drugs that promise significant
benefit over existing therapy for serious or
life-threatening illnesses for which no therapy
exists. - The fundamental element of this process is that
manufacturers must continue testing after
approval to demonstrate that the drug indeed
provides therapeutic benefit to the patient. - If not, the FDA can withdraw the product from the
market more easily than usual.
49Treatment IND
- Treatment investigational new drug are used to
make promising new drugs available to desperately
ill patients as early in the drug development
process as possible. - An immediately life-threatening disease means a
stage of a disease in which there is a reasonable
likelihood that death will occur within a matter
of months or in which premature death is likely
without early treatment. - Treatment INDs are made available to patients
before general marketing begins, typically during
Phase 3 studies. - Treatment INDs also allow FDA to obtain
additional data on the drugs safety and
effectiveness.
50Long Term Testing
- Long-term testing in animals ranges in duration
from a few weeks to several years. - Some animal testing continues after human tests
begin to learn whether long-term use of a drug
may cause cancer or birth defects. - Much of this information is submitted to FDA when
a sponsor requests to process with human clinical
trials. - The FDA reviews the preclinical research data and
then makes a decision as to whether to allow the
clinical trials to proceed
51IND Review Process
52NDA Review Process
53Generic Drug (ANDA) Review Process
54OTC Drug Monograph Review Process
55Thank you for.....