The Drug Development Process From Discovery to Market This workforce solution was funded by a grant...

The Drug Development Process

From Discovery to Market

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The Drug Development Process

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PeriapprovalPeriapprovalPeriapprovalPeriapproval

Phase IIIPhase IIIPhase IIIPhase IIIPhase IIPhase IIPhase IIPhase IIResearchResearchResearchResearch

DiscoveryDiscoveryDiscoveryDiscovery DevelopmentDevelopmentDevelopmentDevelopment

Phase IPhase IPhase IPhase I Phase IVPhase IVPhase IVPhase IVPreclinicalPreclinicalPreclinicalPreclinical

INDFiled

Phase IIIbPhase IIIbPhase IIIbPhase IIIb

NDAFiled

NDAApproved

Time to Market 15 Years

Life of Drug Patent20 years

Objectives of Drug Discovery

• Will the drug fulfill an unmet medical need?

• Does the drug work?• Does the drug fit the company

portfolio?• Does the drug have obvious undesirable

properties?• Can the drug be formulated easily?• Can it be economically manufactured?

Sources of a New DrugSynthetic

NovelChemical

NewDrug

Natural ChemicalNot Found in Humans

that has Activityas a Drug

ChemicalsFound in Humans

(Replacement Therapy)

Old Drug Foundto have aNew Use

Modification ofa Known Drug

RandomScreening

Serendipity

Drug Development: CMC

Chemistry, Manufacturing, and Controls

• Drug Substance: New Chemical Entity

(NCE), Test Article, Active Pharmaceutical

Ingredient (API)

• Drug Product: Formulated Drug, including container and packaging


Chemistry• Characterize drug

substance• Assay development• Impurity profile• Formulation

development• Stability of drug

substance and drug product


Manufacturing• Method of synthesis

(Expression system)• Purification• Formulation process• Packaging and

labeling• Storage


Controls• Process control• Quality control• Quality

assurance


• Complete physical and chemical characterization• Well-defined, controlled manufacturing process• Compliance with cGMPs

(current Good Manufacturing Practices)

Drug Development: Preclinical




Phase IPhase IPhase IPhase I Phase IVPhase IVPhase IVPhase IV

PreclinicalPreclinicalPreclinicalPreclinical

INDFiled


NDAFiled

NDAApproved

• Laboratory and animal testing - Toxicology and pharmacokinetics• 1 - 3 years - Studies with various species and durations • 250 compounds


Safety PharmacologyIn vitro and in vivo studies conducted to determine whether this compound has any effects on:

• Brain –central nervous system

• Lungs –respiratory system

• Heart –cardiovascular system


Genetic ToxicologyIn vitro and in vivo studies conducted to determine whether this compound has the potential to induce mutations and chromosomal damage

• bacterial mutation

• cytogenetics

• mammalian gene mutation


Animal Toxicity Studies• Single- and multiple-dose toxicity studies• Developmental and reproductive

toxicology (DART)• Carcinogenicity• Special toxicity studies/evaluations

– Immunotoxicity– Immunogenicity– Photosensitization


Acute Toxicology Studies

•Animals given a single dose by the intended route of exposure and monitored for 14 days

•Clinical signs•Information on overdose effects

•Minimum and median lethal dose

Repeat-Dose Toxicity Studies

•Study cumulative effects

•Extensive clinical

evaluation of test animals

–physical, neurologic,

and ophthalmic exams

–ECG evaluation

–Clinical and anatomic

pathology analyses


Developmental and Reproductive Toxicology (DART)

• Effects on male and female fertility• Teratogenic potential (embryo-fetal toxicity)• Effect on peri- and post-natal development of

offspring, including maternal development• Supports inclusion of women

in clinical trials


Carcinogenicity Studies• Test the potential to produce tumors in

animals• Lifetime exposure in rats and mice (2

years)• Large doses (MTD) are generally used • Effects may be due to exaggerated

pharmacodynamics• Not always needed in advance of safety

and efficacy trials


Exposure Assessment• A few different terms: toxicokinetics,

pharmacokinetics, ADME, bioanalytical• These all describe the science of

determining the levels of the drug that were absorbed into the blood stream or tissues and how long it stayed in the system.

• Key to determining dose levels and frequency the drug can be taken (e.g., two times/day, once/week, every 4 hours, etc.)


Definition “ADME”•Absorption – does the compound get into the body?

•Distribution – where does it go?

•Metabolism – what happens to it when in the body?

•Excretion – how does it get out?

0.1

1

10

100

1000

10000

0 4 8 12 16 20 24 28

Time (hr)

Plas

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Con

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rati

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Female Rats

Filing an IND•Information filed with regulatory agency providing the results from the preclinical phase testing–Chemistry, manufacturing, and control information

–Pharmacology and toxicology information

–Clinical information/ proposed clinical studies to be conducted

• Purpose– Required prior to conducting

clinical studies in humans– Demonstrates the drug is safe

enough to administer to humans– Represents the initiation of the

first phase of clinical development

• i.e., Phase I or First in Human (FIH) studies

• Duration and Success Rates– 30 days for regulatory agency to

review– 88% are approved

Drug Development: Clinical




Phase IPhase IPhase IPhase I

Phase IVPhase IVPhase IVPhase IVPreclinicalPreclinicalPreclinicalPreclinical

INDFiled


NDAFiled

NDAApproved

• Is it safe? • Determine dosage levels• 20 - 100 healthy volunteers• Up to 12 months• 100 compounds


– Initial introduction of drug in humans – Phase I• 20-80 volunteers• May be patients for life-threatening indications

– Single rising dose• monitor clinical signs, laboratory tests, and PK• escalate based on previous dose

– Multiple rising dose trial• duration usually < 2 weeks• monitor clinical signs, laboratory tests, and PK

70% move to Phase IIa



Phase IIIPhase IIIPhase IIIPhase III

Phase IIPhase IIPhase IIPhase II

ResearchResearchResearchResearch



INDFiled


NDAFiled

NDAApproved

• Is it safe and does it work? • Refine dosage levels• 50 - 500 patients• Up to 2 years• 70 compounds


Proof of Concept (POC)•Initial evaluation of safety and efficacy of

drug in patients– 50 - 500 patients

•Dose range based on results of Phase I studies

•Usually done in successive steps– i.e., Phase IIa and Phase IIb– May be done at multiple sites to

enhance recruiting

48% move to Phase III



Phase IIIPhase IIIPhase IIIPhase III

Phase IIPhase IIPhase IIPhase IIResearchResearchResearchResearch



INDFiled


NDAFiled

NDAApproved

• Is it safe? Does it work? Any side effects? • 1,000 - 3,000 patients• Up to 4 years• 30 compounds


Pivotal Studies• Statistical efficacy –

100s to 1,000s of patients

• Reproducible - two studies

• Multiple centers• Placebo or other

controls• Unbiased - blinded,

randomized

Objectives of Phase III• Confirms therapeutic efficacy• Determines product labeling• Definitive efficacy in target

population• Characterize safety

– Patient variations (genetics, life style)

– Extent of adverse effects– Concomitant therapies– Concomitant conditions (liver

impairment, pregnancy, etc.)






INDFiled


NDAFiled

NDAApproved

• New Drug Application (NDA) is prepared and submitted to regulatory authorities • 2 months - 7 years• Phase IIIb studies sometimes conducted

Drug Development: Market

• After NDA approval is obtained, the pharmaceutical company will market the drug.

• There are regulations for product labeling, naming, and marketing (TV and radio commercials and print ads).





Phase IPhase IPhase IPhase I

Phase IVPhase IVPhase IVPhase IV

PreclinicalPreclinicalPreclinicalPreclinical

INDFiled


NDAFiled

NDAApproved

• "Real World" studies• Validate clinical work and/or safety hypothesis• Usually require large numbers of patients• Up to 4 - 5 years


Objectives of Phase IV - Postmarketing Studies• Continue collecting safety/efficacy data after early market

approval• Collect cost-effectiveness data• Collect data for switch from prescription to

over-the-counter

Objectives of Phase IV - Line Extensions• New clinical indications• New dosage forms and formulation development• Extend label (market support)


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Phase IPhase IPhase IPhase I Phase IVPhase IVPhase IVPhase IVPreclinicalPreclinicalPreclinicalPreclinical Phase IIIbPhase IIIbPhase IIIbPhase IIIb

INDFiled

NDAFiled

NDAApproved

The industry spends, on average, approximately

$500 to $800 millionto bring a new medical therapy to market

The industry spends, on average, approximately

$500 to $800 millionto bring a new medical therapy to market

The Drug Development Process From Discovery to Market This workforce solution was funded by a grant...

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