Drug Research and
Development (R&D)
Karol Godwin DVM
Cost and time to get drug
to market?
 250 million dollars – 5 years
 500 million dollars – 7 years
 800 million dollars – 10 years
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
Animals Used in Research
in the US
 10-15 Million/year
 20-25 Million/year
 30-35 Million/year
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
Drug Research and
Development (R&D)






Overview of process
Regulations
Drug Discovery
Preclinical development
Clinical Trials
Drug Approval
Drug Research &
Development






Discovery
Nonclinical
IND
Clinical
NDA
Approval
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 country—a key refinement for animal welfare
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 nonapproval (start over)
 Post-marketing requires reporting of safety in people as well as
anything found in other studies in people or animals
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
Nonclinical Development
 Stage in development to assess safety
and pharmacology before and during
clinical trials
 Pharmacodynamics (PD)
 Pharmacokinetics (PK)
 Safety Pharmacology
 Toxicology
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
Pharmacokinetics (ADME)
 Absorption—in vivo studies to
determine how well the body
absorbs drugs
 Distribution—in vivo studies to determine
where a drug goes in the body and for how
long
 Metabolism—in vitro and in vivo studies to
determine how the body breaks down drugs
 Elimination—in vivo studies on how does a
drug and its by-products get eliminated from
the body
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





Cardiovascular—effects on heart and vascular function
Pulmonary—effects on lung performance
Nervous system—effects on reflexes, perception, behavior
Renal system—effects on how the body processes waste
Digestive system—effects on how the body digests and
absorbs nutrients
 Endocrine system—effects on how
hormones function
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
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
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
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 (100’s to 1000’s)
 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
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
Risk Management
 Compound A = Aspirin
 Compound B = Caffeine
Submit NDA to FDA
 Approval—permission to market
for agreed uses
 Approvable—more data is needed
to approve for market
(1-2 year delay but can be many years)
 Non-Approval—start over
 Post Approval—extensive monitoring of how a
drug performs out in the real world where
patients don’t always do what they are
supposed to do
Questions????