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Title: Drug DiscoveryNew Drug Development Process


1
DRUG 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
2
DRUG
  • 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.

7
How 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.

8
Differences 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.

9
Differences 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

10
Need 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.

11
More is Not Always Better
  • Be careful about dosage amounts
  • Philosophy of excess if some is good, more is
    better

12
Problem 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.

13
Plant Based Drugs and Medicines
14
Plant Based Drugs and Medicines
15
Plant Based Drugs and Medicines
16
Plant Based Drugs and Medicines
17
Plant Based Drugs and Medicines
18
Plant Based Drugs and Medicines
19
Plant Based Drugs and Medicines
20
Plant Based Drugs and Medicines
21
Plant Based Drugs and Medicines
22
Plant Based Drugs and Medicines
23
Plant Based Drugs and Medicines
24
Plant Based Drugs and Medicines
25
The New Drug Development Process
(Steps from Test Tube to New Drug Application
Review)
26
Non-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.

27
Non-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.

28
Non-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.

29
FDA 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.

30
Subpart 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.

31
Sponsor/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

32
Synthesis 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.

33
Animal 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

34
Short 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.

35
Institutional 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.

36
IND 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

37
IND 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

38
IND 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

39
IND 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)

40
IND 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.

41
IND 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

42
Phase 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.

43
Phase 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

44
Phase 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.

45
Sponsor/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.

46
Phase 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.

47
Phase 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

48
Accelerated 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.

49
Treatment 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.

50
Long 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

51
IND Review Process
52
NDA Review Process
53
Generic Drug (ANDA) Review Process
54
OTC Drug Monograph Review Process
55
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