Drug Research and Development (R

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Drug Research and Development (RD)

• Karol Godwin DVM

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Cost and time to get drug to market?

• 250 million dollars 5 years
• 500 million dollars 7 years
• 800 million dollars 10 years

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Cost and time to get drug to market?

• Fewer than 1 in 10 drugs tested in man will be
  marketed
• Estimated 200-300 million dollars on compounds
  that will never be sold
• Fewer than 1 in 10-100 drugs tested in animals
  will be tested in man
• Another unknown hundreds of millions in research
  dollars
• For every drug that is marketed, the industry
  must invest 2 billion dollars

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Animals Used in Research in the US

• 10-15 Million/year
• 20-25 Million/year
• 30-35 Million/year

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Animals Used in Research

• US and international requirements for drug
  testing results in extensive animal testing
• One recently approved drug required over 3000
  animals (and that drug had a shorter than normal
  development time)
• Safe and efficacious drugs require extensive and
  judicious use of animals

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Drug Research and Development (RD)

• Overview of process
• Regulations
• Drug Discovery
• Preclinical development
• Clinical Trials
• Drug Approval

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Drug Research Development

• Discovery
• Nonclinical
• IND
• Clinical
• NDA
• Approval

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Regulations

• Food and Drug Administration is an agency
  within the US Department of Health and Human
  Services that regulates new drugs, vaccines,
  biologics, and devices
• The Food and Drug Act of 1908 established the
  agency, and it has been strengthened many times,
  usually in response to a clinical safety problem,
  such as thalidomide-related birth defects
• The Act was amended to require testing in animals
  prior to any studies in man to protect people in
  research studies
• The International Commission on Harmonisation
  (ICH) has established agreement among the
  international community for required testing in
  animals prior to study and marketing of new drugs
  (ICH M3 outlines the basic testing required)
• The result of this act led to some decreased
  testing as many countries required a duplication
  of testing prior to market approval in their
  countrya key refinement for animal welfare

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Regulations

• In the US, the researcher or company submits an
  Investigational New Drug (IND) application with
  required testing prior to starting any clinical
  study
• Prior to marketing a drug, a company must submit
  a New Drug Application (NDA)
• Safety and efficacy of drug
• Manufacturing specs
• Drug stability
• Bioavailability
• Packaging and labeling information
• Approval (can market), approvable (more studies
  needed) or non-approval (start over)
• Post-marketing requires reporting of safety in
  people as well as anything found in other studies
  in people or animals

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Drug Discovery

• The process by which drugs are discovered or
  designed, then improved
• Identify Target
• High throughput screening (HTS) typically done in
  vitro
• Drug design to improve the quality of the drug,
  often employs tests such as pharmacokinetics (PK)
  in animals

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Nonclinical Development

• Stage in development to assess safety and
  pharmacology before and during clinical trials
• Pharmacodynamics (PD)
• Pharmacokinetics (PK)
• Safety Pharmacology
• Toxicology

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Pharmacodynamics

• Studies performed both in vitro and in animals
  models to determine if a potential drug may work
• Typically use disease models (tumor xenograft),
  transgenic models (ob/ob mice), or biomarker
  studies in normal animals (red blood cell counts,
  glucose, etc.)
• Vast majority of this work is in rodents, but can
  run from zebra fish to baboons
• Most animal use in drug development is in this
  area

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Pharmacokinetics (ADME)

• Absorptionin vivo studies to determine how well
  the body absorbs drugs
• Distributionin vivo studies to determine where a
  drug goes in the body and for how long
• Metabolismin vitro and in vivo studies to
  determine how the body breaks down drugs
• Eliminationin vivo studies on how does a drug
  and its by-products get eliminated from the body

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Safety Pharmacology

• These are in vitro and in vivo studies that help
  predict how a drug might affect patients in the
  short time after taking a drug
• Cardiovasculareffects on heart and vascular
  function
• Pulmonaryeffects on lung performance
• Nervous systemeffects on reflexes, perception,
  behavior
• Renal systemeffects on how the body processes
  waste
• Digestive systemeffects on how the body digests
  and absorbs nutrients
• Endocrine systemeffects on how hormones function

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Toxicology

• In vitro and in vivo studies to help predict long
  term effects of drugs
• Requires testing in at least two species to try a
  capture the most effects possible
• Requires rodent (mouse or rat) and nonrodent)
• Dogs common for small molecule and primates often
  needed for antibodies and proteins
• Requires high doses to help predict effects on
  the most sensitive people

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Toxicology Study Types

• General toxicology
• Effects in two species on general health and well
  being
• Genotoxicity and carcinogenicity
• The potential for a compound to cause or promote
  cancer or birth defect when given over a life
  time
• 2-year studies in mice and rats
• Reproductive and Developmental
• The ability to reproduce and have a full safe
  pregnancy with a healthy baby
• Studied in rodents and rabbits from
  pre-conception to the effect on second
  generations
• Special studies are also often needed to
  understand the effects observed in nonclinical
  and clinical studies

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Clinical Trials

• Phase I Small group of healthy volunteers or
  well controlled patients (20-80)
• Assess
• Safety
• Tolerability
• PK
• Sometimes predict efficacy as well
• Dose- ranging
• Determine the limits of how much drug can be
  safety administered

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Clinical Trails cont.

• Phase II - Larger group of volunteers and
  patients (20-300)
• Assess clinical efficacy of the therapy and to
  continue safety assessments
• Provide the proof to companies and regulators
  that a drug should be advanced to full
  development
• Phase III - Large groups of volunteers and
  patients (100s to 1000s)
• Assess clinical efficacy of the therapy and to
  continue safety assessments
• Provide proof that a drug is safe and efficacious
  per the Food and Drug Act

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Adverse Events

• Compound A
• GI emesis, hemorrhage
• Hematology thrombocytopenia, hyperglycemia,
  elevated PT
• CNS convulsions, seizures
• Respiration rate increased

• Compound B
• GI emesis, loss of appetite
• CNS tremors, convulsions, chills, flushing
• Reproduction teratogenic

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Risk Management

• Compound A Aspirin
• Compound B Caffeine

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Submit NDA to FDA

• Approvalpermission to market for agreed uses
• Approvablemore data is neededto approve for
  market (1-2 year delay but can be many years)
• Non-Approvalstart over
• Post Approvalextensive monitoring of how a drug
  performs out in the real world where patients
  dont always do what they are supposed to do

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Questions????