Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
The Drug Development Process From Discovery to Market This workforce solution was funded by a grant awarded under the President’s Community-Based Job Training Grants as implemented by the U.S. Department of Labor’s Employment and Training Administration. The solution was created by the grantee and does not necessarily reflect the official position of the U.S. Department of Labor. The Department of Labor makes no guarantees, warranties, or assurances of any kind, express or implied, with respect to such information, including any information on linked sites and including, but not limited to, accuracy of the information or its completeness, timeliness, usefulness, adequacy, continued availability, or ownership. This solution is copyrighted by the institution that created it. Internal use by an organization and/or personal use by an individual for non-commercial purposes is permissible. All other uses require the prior authorization of the copyright owner. The Drug Development Process Discovery Periapproval Development Research Preclinical Phase I Phase II Phase III 10,000 250 100 70 30 IND Filed Phase IIIb Phase IV 20 NDA Filed Time to Market 15 Years Life of Drug Patent 20 years NDA Approved 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 Drug Random Screening Chemicals Found in Humans (Replacement Therapy) Synthetic Novel Chemical New Drug Serendipity Old Drug Found to have a New Use Modification of a Known Drug Natural Chemical Not Found in Humans that has Activity as a Drug 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 Drug Development: CMC • • • • • Chemistry Characterize drug substance Assay development Impurity profile Formulation development Stability of drug substance and drug product Drug Development: CMC • • • • • Manufacturing Method of synthesis (Expression system) Purification Formulation process Packaging and labeling Storage Drug Development: CMC Controls • Process control • Quality control • Quality assurance Drug Development: CMC • Complete physical and chemical characterization • Well-defined, controlled manufacturing process • Compliance with cGMPs (current Good Manufacturing Practices) Drug Development: Preclinical Discovery Periapproval Development Research Phase I Phase II Phase III Phase IIIb Phase IV Preclinical IND Filed NDA Filed NDA Approved • Laboratory and animal testing - Toxicology and pharmacokinetics • 1 - 3 years - Studies with various species and durations • 250 compounds Drug Development: Preclinical Safety Pharmacology In 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 Drug Development: Preclinical Genetic Toxicology In 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 Drug Development: Preclinical • • • • Animal Toxicity Studies Single- and multiple-dose toxicity studies Developmental and reproductive toxicology (DART) Carcinogenicity Special toxicity studies/evaluations – Immunotoxicity – Immunogenicity – Photosensitization Drug Development: Preclinical 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 Drug Development: Preclinical • • • • 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 Drug Development: Preclinical • • • • • 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 Drug Development: Preclinical 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.) Drug Development: Preclinical Definition “ADME” •Absorption – does the compound get into the body? Plasma Concentration (ng/mL) 10000 1000 Male Rats Female Rats 100 10 1 0.1 0 4 8 12 16 Time (hr) 20 24 •Distribution – where does it go? •Metabolism – what happens to it when in the body? •Excretion – how does it get out? 28 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 Discovery Research Periapproval Development Preclinical Phase II Phase III Phase IIIb Phase IV Phase I IND Filed • Is it safe? • Determine dosage levels • 20 - 100 healthy volunteers • Up to 12 months • 100 compounds NDA Filed NDA Approved Drug Development: Clinical – 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 Drug Development: Clinical Discovery Research Periapproval Development Preclinical Phase III Phase I Phase IIIb Phase IV Phase II IND Filed • Is it safe and does it work? • Refine dosage levels • 50 - 500 patients • Up to 2 years • 70 compounds NDA Filed NDA Approved Drug Development: Clinical 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 Drug Development: Clinical Discovery Research Periapproval Development Preclinical Phase I Phase IIIb Phase IV Phase II Phase III IND Filed NDA Filed NDA Approved • Is it safe? Does it work? Any side effects? • 1,000 - 3,000 patients • Up to 4 years • 30 compounds Drug Development: Clinical • • • • • 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.) Drug Development: Clinical Discovery Research Periapproval Development Preclinical Phase I Phase II Phase III Phase IV Phase IIIb IND Filed NDA Filed NDA Approved • 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). Drug Development: Market Discovery Research Periapproval Development Preclinical Phase I Phase II Phase III Phase IIIb Phase IV IND Filed NDA Filed NDA Approved • "Real World" studies • Validate clinical work and/or safety hypothesis • Usually require large numbers of patients • Up to 4 - 5 years Drug Development: Market 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) Drug Development: Market Discovery Periapproval Development Research Preclinical Phase I Phase II Phase III 10,000 250 100 70 30 IND Filed Phase IIIb Phase IV 20 NDA Filed NDA Approved The industry spends, on average, approximately $500 to $800 million to bring a new medical therapy to market