Drug DiscoveryNew Drug Development Process

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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
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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

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• 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
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• 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
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• 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
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• 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.

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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.

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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.

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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

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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.

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More is Not Always Better

• Be careful about dosage amounts
• Philosophy of excess if some is good, more is
  better

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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.

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Plant Based Drugs and Medicines
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Plant Based Drugs and Medicines
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Plant Based Drugs and Medicines
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Plant Based Drugs and Medicines
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Plant Based Drugs and Medicines
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Plant Based Drugs and Medicines
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Plant Based Drugs and Medicines
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Plant Based Drugs and Medicines
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Plant Based Drugs and Medicines
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Plant Based Drugs and Medicines
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Plant Based Drugs and Medicines
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Plant Based Drugs and Medicines
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The New Drug Development Process
(Steps from Test Tube to New Drug Application
Review)
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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.

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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.

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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.

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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.

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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.

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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

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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.

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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

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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.

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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.

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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

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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

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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

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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)

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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.

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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

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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.

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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

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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.

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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.

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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.

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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

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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.

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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.

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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

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IND Review Process
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NDA Review Process
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Generic Drug (ANDA) Review Process
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OTC Drug Monograph Review Process
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Thank you for.....