Drug Research and Drug Research and Development Development (R&D)(R&D)Karol Godwin DVMKarol Godwin DVM

Cost and time to get drug Cost and time to get drug to market?to market?

250 million dollars – 5 years250 million dollars – 5 years

500 million dollars – 7 years500 million dollars – 7 years

800 million dollars – 10 years800 million dollars – 10 years

Cost and time to get drug Cost and time to get drug to market?to market?

Fewer than 1 in 10 drugs tested in man will be Fewer than 1 in 10 drugs tested in man will be marketed marketed Estimated $200-300 million dollars on compounds Estimated $200-300 million dollars on compounds

that will never be soldthat will never be sold Fewer than 1 in 10-100 drugs tested in animals Fewer than 1 in 10-100 drugs tested in animals

will be tested in manwill be tested in man Another unknown hundreds of millions in research Another unknown hundreds of millions in research

dollars dollars For every drug that is marketed, the industry For every drug that is marketed, the industry

must invest $2 must invest $2 billionbillion dollars dollars

Animals Used in Research Animals Used in Research in the USin the US

10-15 Million/year10-15 Million/year

20-25 Million/year20-25 Million/year

30-35 Million/year30-35 Million/year

Animals Used in ResearchAnimals Used in Research US and international requirements for US and international requirements for

drug testing results in extensive animal drug testing results in extensive animal testingtesting

One recently approved drug required over One recently approved drug required over 3000 animals (and that drug had a 3000 animals (and that drug had a shorter than normal development time)shorter than normal development time)

Safe and efficacious drugs require Safe and efficacious drugs require extensive and judicious use of animalsextensive and judicious use of animals

Drug Research and Drug Research and Development (R&D)Development (R&D)

Overview of processOverview of process RegulationsRegulations Drug DiscoveryDrug Discovery Preclinical developmentPreclinical development Clinical TrialsClinical Trials Drug ApprovalDrug Approval

Drug Research & Drug Research & DevelopmentDevelopment

DiscoveryDiscovery NonclinicalNonclinical INDIND ClinicalClinical NDANDA ApprovalApproval

RegulationsRegulations Food and Drug Administration – is an agency within the US Food and Drug Administration – is an agency within the US

Department of Health and Human Services that regulates new Department of Health and Human Services that regulates new drugs, vaccines, biologics, and devicesdrugs, vaccines, biologics, and devices The Food and Drug Act of 1908 established the agency, and it has The Food and Drug Act of 1908 established the agency, and it has

been strengthened many times, usually in response to a clinical safety been strengthened many times, usually in response to a clinical safety problem, such as thalidomide-related birth defectsproblem, such as thalidomide-related birth defects

The Act was amended to require testing in animals prior to any The Act was amended to require testing in animals prior to any studies in man to protect people in research studiesstudies in man to protect people in research studies

The International Commission on Harmonisation (ICH) has The International Commission on Harmonisation (ICH) has established agreement among the international community for established agreement among the international community for required testing in animals prior to study and marketing of new required testing in animals prior to study and marketing of new drugs (ICH M3 outlines the basic testing required)drugs (ICH M3 outlines the basic testing required) The result of this act led to some decreased testing as many countries The result of this act led to some decreased testing as many countries

required a duplication of testing prior to market approval in their required a duplication of testing prior to market approval in their country—a key refinement for animal welfarecountry—a key refinement for animal welfare

RegulationsRegulations In the US, the researcher or company submits an “Investigational In the US, the researcher or company submits an “Investigational

New Drug” (IND) application with required testing prior to starting New Drug” (IND) application with required testing prior to starting any clinical studyany clinical study

Prior to marketing a drug, a companyPrior to marketing a drug, a company must submit a New Drug Application (NDA) must submit a New Drug Application (NDA) Safety and efficacy of drugSafety and efficacy of drug Manufacturing specsManufacturing specs Drug stabilityDrug stability BioavailabilityBioavailability Packaging and labeling informationPackaging and labeling information

Approval (can market), approvable (more studies needed) or non-Approval (can market), approvable (more studies needed) or non-approval (start over)approval (start over)

Post-marketing requires reporting of safety in people as well as Post-marketing requires reporting of safety in people as well as anything found in other studies in people or animalsanything found in other studies in people or animals

Drug DiscoveryDrug Discovery The process by which drugs are The process by which drugs are

discovered or designed, then improved discovered or designed, then improved IdentifyIdentify Target Target High throughput High throughput screeningscreening (HTS) (HTS)

typically done in vitro typically done in vitro Drug Drug design design to improve the quality of the to improve the quality of the

drug, often employs tests such as drug, often employs tests such as pharmacokinetics (PK) in animalspharmacokinetics (PK) in animals

Nonclinical DevelopmentNonclinical Development Stage in development to assess safety Stage in development to assess safety

and pharmacology before and during and pharmacology before and during clinical trialsclinical trials

Pharmacodynamics (PD)Pharmacodynamics (PD) Pharmacokinetics (PK)Pharmacokinetics (PK) Safety PharmacologySafety Pharmacology ToxicologyToxicology

PharmacodynamicsPharmacodynamics Studies performed both in vitroStudies performed both in vitro

and in animals models to determine and in animals models to determine if a potential drug may work if a potential drug may work

Typically use disease models (tumor Typically use disease models (tumor xenograft), transgenic models (ob/ob mice), or xenograft), transgenic models (ob/ob mice), or biomarker studies in normal animals (red blood biomarker studies in normal animals (red blood cell counts, glucose, etc.)cell counts, glucose, etc.)

Vast majority of this work is in rodents, but can Vast majority of this work is in rodents, but can run from zebra fish to baboonsrun from zebra fish to baboons

Most animal use in drug development is in this Most animal use in drug development is in this areaarea

Pharmacokinetics (ADME)Pharmacokinetics (ADME) Absorption—in vivo studies to Absorption—in vivo studies to

determine how well the body determine how well the body absorbs drugsabsorbs drugs

Distribution—in vivo studies to determine Distribution—in vivo studies to determine where a drug goes in the body and for how where a drug goes in the body and for how longlong

Metabolism—in vitro and in vivo studies to Metabolism—in vitro and in vivo studies to determine how the body breaks down drugsdetermine how the body breaks down drugs

Elimination—in vivo studies on how does a Elimination—in vivo studies on how does a drug and its by-products get eliminated from drug and its by-products get eliminated from the bodythe body

Safety PharmacologySafety Pharmacology These are in vitro and in vivo studies that help predict These are in vitro and in vivo studies that help predict

how a drug might affect patients in the short time after how a drug might affect patients in the short time after taking a drugtaking a drug Cardiovascular—effects on heart and vascular functionCardiovascular—effects on heart and vascular function Pulmonary—effects on lung performancePulmonary—effects on lung performance Nervous system—effects on reflexes, perception, behaviorNervous system—effects on reflexes, perception, behavior Renal system—effects on how the body processes wasteRenal system—effects on how the body processes waste Digestive system—effects on how the body digests and Digestive system—effects on how the body digests and

absorbs nutrientsabsorbs nutrients Endocrine system—effects on howEndocrine system—effects on how

hormones function hormones function

ToxicologyToxicology In vitro and in vivo studies to help predict long In vitro and in vivo studies to help predict long

term effects of drugsterm effects of drugs Requires testing in at least two species to try a Requires testing in at least two species to try a

capture the most effects possiblecapture the most effects possible Requires rodent (mouse or rat) and nonrodent) Requires rodent (mouse or rat) and nonrodent)

Dogs common for small molecule and primates often Dogs common for small molecule and primates often needed for antibodies and proteinsneeded for antibodies and proteins

Requires high doses to help predict effects on the Requires high doses to help predict effects on the most sensitive peoplemost sensitive people

Toxicology Study TypesToxicology Study Types General toxicologyGeneral toxicology

Effects in two species on general health and well beingEffects in two species on general health and well being Genotoxicity and carcinogenicityGenotoxicity and carcinogenicity

The potential for a compound to cause or promote cancer or The potential for a compound to cause or promote cancer or birth defect when given over a life timebirth defect when given over a life time

2-year studies in mice and rats2-year studies in mice and rats Reproductive and DevelopmentalReproductive and Developmental

The ability to reproduce and have a full safe pregnancy with a The ability to reproduce and have a full safe pregnancy with a healthy babyhealthy baby

Studied in rodents and rabbits from pre-conception to the Studied in rodents and rabbits from pre-conception to the effect on second generationseffect on second generations

Special studies are also often needed to understand Special studies are also often needed to understand the effects observed in nonclinical and clinical studiesthe effects observed in nonclinical and clinical studies

Clinical TrialsClinical Trials Phase IPhase I – Small group of healthy volunteers or – Small group of healthy volunteers or

well controlled patients (20-80)well controlled patients (20-80) AssessAssess

SafetySafety TolerabilityTolerability PKPK Sometimes predict efficacy as wellSometimes predict efficacy as well

Dose- rangingDose- ranging Determine the limits of how much drug can be Determine the limits of how much drug can be

safety administeredsafety administered

Clinical Trails cont.Clinical Trails cont. Phase IIPhase II - Larger group of volunteers and - Larger group of volunteers and

patients (20-300)patients (20-300) Assess clinical efficacy of the therapy and to Assess clinical efficacy of the therapy and to

continue safety assessmentscontinue safety assessments Provide the proof to companies and regulators that Provide the proof to companies and regulators that

a drug should be advanced to full developmenta drug should be advanced to full development Phase IIIPhase III - Large groups of volunteers and - Large groups of volunteers and

patients (100’s to 1000’s)patients (100’s to 1000’s) Assess clinical efficacy of the therapy and to Assess clinical efficacy of the therapy and to

continue safety assessmentscontinue safety assessments Provide proof that a drug is safe and efficacious per Provide proof that a drug is safe and efficacious per

the Food and Drug Actthe Food and Drug Act

Adverse EventsAdverse Events Compound A:Compound A:

GI – emesis, GI – emesis, hemorrhagehemorrhage

Hematology – Hematology – thrombocytopenia, thrombocytopenia, hyperglycemia, hyperglycemia, elevated PTelevated PT

CNS – convulsions, CNS – convulsions, seizuresseizures

Respiration – rate Respiration – rate increasedincreased

Compound B:Compound B: GI – emesis, loss of GI – emesis, loss of

appetiteappetite CNS – tremors, CNS – tremors,

convulsions, chills, convulsions, chills, flushingflushing

Reproduction – Reproduction – teratogenicteratogenic

Risk ManagementRisk Management Compound A = AspirinCompound A = Aspirin

Compound B = CaffeineCompound B = Caffeine

Submit NDA to FDASubmit NDA to FDA Approval—permission to marketApproval—permission to market

for agreed uses for agreed uses Approvable—more data is neededApprovable—more data is needed

to approve for market to approve for market (1-2 year delay but can be many years)(1-2 year delay but can be many years)

Non-Approval—start overNon-Approval—start over

Post Approval—extensive monitoring of how a Post Approval—extensive monitoring of how a drug performs out in the real world where drug performs out in the real world where patients don’t always do what they are patients don’t always do what they are supposed to dosupposed to do

Questions????Questions????