DRUG DEVELOPMENT from Research Bench to Pharmacy Shelf

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DRUG DEVELOPMENTfromResearch Bench to Pharmacy
Shelf
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Synthesis and Purification

• The drug research process is complicated
• Time-consuming
• Costly
• End result rarely produces a therapeutic
• 1 chance in 5000
• Whole process takes up to 12 years

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Synthesis and Purification

• There is no standard route for drug discovery
• Sometimes a pharmaceutical company will choose a
  particular disease
• Sometimes researchers at a drug company discover
  a therapeutic with several prospects

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Synthesis and Purification

• Quite often the ground breaking work was
  initially completed at a university or government
  laboratory
• The company may decide to pursue this research
• Many drugs arise from an understanding of how the
  cell/body works
• How to interact to correct problems

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Synthesis and Purification

• Sometimes natural products are screened for
  therapeutic benefit
• Example, certain antibiotics from fungi

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Overview

• Basic research results
• Potential uses
• Limited animal trials
• Decisions regarding pre-IND tests
• Extensive animal testing
• Filing Investigative New Drug (IND) application

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Overview

• Accumulating data from all trials and experiments
  including in vitro data and all animal data
• Collect all data about the potential product
• Examine methods of purification of product
• Examine cost of producing product
• Is the market large enough will any profit be
  realized

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Overview

• Writing the IND report
• Filing to the regulatory agencies
• Permission to proceed with phase I trial
• Clinical trial study design
• Selection of phase I candidates
• Submission of results to regulatory agency

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Overview

• Proceed to Phase II
• Patient selection
• Submit results to regulatory agency
• Proceed to phase III
• Extensive data collection monitoring of data
• Release for general use (Phase IV)

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Basic Research

• Run monoclonal antibody against specific type of
  cancers
• Choose cancer type with highest affinity for new
  antibody (or several )
• Choose to do very limited animal studies
• Based upon above data decide is feasible or not
  to proceed to an IND filing

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Pre-Clinical Research

• The data submitted to the FDA will include all
  non-clinical data
• This includes animal data and bench-top data
• During pre-clinical the company evaluates toxic
  effects
• Pharmacological profile of the drug

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Pre-Clinical Research

• Drug absorption and metabolism
• Speed at which the drug is excreted from the body
• A pharmacological profile must be presented
• This would include all toxicity data from at
  least two species (both must be non-human)

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Animal Studies

• Most often conducted by specialized companies
• FDA requires that a minimum number of animals be
  used
• All animal care certificates ensuring proper
  treatment of animals must be submitted to the FDA

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Animal Studies

• Required by Law before any human testing can be
  conducted
• Types of pre-clinical animal studies vary
• From toxicology studies to disease model
  protocols
• Data must be carefully analyzed and submitted as
  apart of the IND

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Animal Studies

• Usually two species are required for toxicity
  studies one rodent one non-rodent
• Drugs effect different animals in different ways
• The animal studies also include absorption into
  the blood
• Tells what the breakdown products are

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Decisions

• What is the market for this potential
  therapeutic?
• Is the product best as a therapeutic or for
  diagnostic
• Is the indication a chronic disease or a
  potentially fatal disease

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Decisions

• What is the market?
• What is the competition?
• Can it be Fast Tracked?
• How many people contracted the disease in the
  U.S.?
• Can we gain a market share?

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Decisions

• Manufacturing considerations
• Will the lab bench top purification procedures
  work in a large scale manufacturing facility?
• Can it be manufactured at a reasonable cost?
• Will the cost be competitive?

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Production

• Choices of manufacture
• e.g. Full size monoclonal antibodies are proteins
  with sugar groups attached (glycoproteins)
• Using biotechnology they must be made in
  eukaryotic cells

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Production

• Smaller derivatives of antibodies can be made
  called fragments (scFv)
• No sugar groups
• Can be made in bacterial cells e.g. E. coli
• Fragments are far more cost effective

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Antibody Design
S
S
scFv
IgG
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Patents

• Must patent new drug
• Must demonstrate its worth
• Patent process takes up to 2 years or more
• Must NOT publish anything on new drug before
  patent
• Even a seminar on product can place it in the
  public domain

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Quality Assurance (QA)

• Important aspect the pharmaceutical/biotech
  industry
• Assures complete records of every procedure
  involved in the drug discovery program
• Also guides behavior of researchers and support
  staff

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Quality Assurance

• Every experiment ever conducted in the research
  laboratory must be recorded in a note book and
  signed by two researchers
• Researchers must change lab coats daily
• Researchers with infectious illness (cold) must
  report to supervisor

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Quality Assurance

• During phase III trials (or even at Phase II)
  inspectors from the regulatory agency have a site
  visit
• All records and procedures are scrutinized
• All equipment used to research and prepare drug
  are inspected
• The company may also be scrutinized with respect
  to its financial position

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Quality Assurance

• Ensures record keeping and history of every piece
  of equipment used on the drug discovery program
• Logs must be kept as to usage and maintenance
• From pH meters to expensive chromatographic
  machines

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Investigational New DrugApplication (IND)

• Produced after all in vitro and animal studies
  are complete
• And after company decides the therapeutic is
  worth marketing
• The IND is filed with the regulatory agency
• Basically it is the request for permission to
  proceed to human clinical trials

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Investigational New DrugApplication (IND)

• The IND becomes effective if the regulatory body
  (FDA) does not disapprove within 30 days
• The IND shows the results of all early
  experimental data
• All in vitro data

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Investigational New DrugApplication (IND)

• The IND contains all of the chemistry of the drug
• How it will be purified (in the lab and in the
  plant)
• Mechanism of action (how it works in the body)
• ANY toxic effects in the animal studies

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Investigational New DrugApplication (IND)

• Where will the human trials be conducted?
• Who is the independent clinical trials physician?
• The report from the Review Board of the
  institution where the trials will be completed
• An agreement to submit annual reports

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Pre-clinical
Phase I
Phase II
Phase III
FDA
YEARS
3.5
1-2
2.0
3.5
2.5
Patients
20-80
100-300
1000-3000
Biological Activity and safety
Long term use Effectiveness Adverse reactions
Safety and dosage
Effectiveness And safety
Purpose
Total time 12 years minimum
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Pre-clinical
Clinical Studies
NDA Review
Synthesis and Purification
Phase I
Phase II
Phase III
Animal Testing
Accelerated Development
IND Submitted
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Phase I

• This is the initial introduction of the drug into
  humans
• Most often conducted in healthy volunteers
• Sometimes patients
• Phase I studies are to determine the metabolic
  and pharmacological actions in humans

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Phase I

• Studies include side-effects with increased drug
  administered
• If patients are used, early evidence of
  effectiveness
• This phase gives data as to, pharmacokinetics and
  pharmacological effects

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Phase I

• These studies also are used to determine or
  confirm mechanism of action
• Determine if drug would perform better as a
  diagnostic tool
• During Phase I the regulatory agency can shut
  down the trial at any time
• The regulatory agency may advise as to the
  continuation of the trial

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Phase II

• Controlled studies of 100-300 patient volunteers
  with the disease
• Assess the drugs effectiveness
• Takes about 2 years
• Phase two also helps determine short-term side
  effects
• Risks associated with the drug are also evaluated

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Phase III

• Phase three last for around three years
• Involves 1000-3000 patients
• These patients are monitored very closely to
  assess efficacy and adverse reactions
• They are an expanded version of Phase II
• Only performed after complete regulatory agency
  approval

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Phase III

• Benefit risk evaluations can be assessed at
  this level
• Larger patient population base allows for a more
  accurate extrapolation to the larger general
  population
• Patient population in phase III is up to 3000

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Phase III

• Most of the information for the insert label is
  gathered from Phase III data
• The regulatory agency can interrupt the study if
  the protocol is deemed incorrect or not
  sufficient
• Also, the trial can be stopped if the current
  state of scientific knowledge changes

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Approval

• Regulatory body approval of the NDA
• Drug becomes available to physicians
• The company must continue to submit periodic
  reports
• Particular monitoring of adverse reactions
• For some drugs a Phase IV is required (this is
  for long term effects)

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Approval

• Research pharmaceutical companies invested 12.6
  billion in RD in 2001
• Average cost per successful drug is between
  100-300 million
• 1 chance in 5000 from bench top
• 1 chance in five through clinical trials

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Approval

• Rituximab an anti-cancer antibody against
  non-Hodgkins lymphoma grossed 1.3 billion in
  the first 18 months