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 From the time a compound is discovered to the time it hits the market, the entire process takes approximately 15 years.

The Drug Development Process 30 70 10,000 100 250 20 Periapproval Phase III Phase II Research Discovery Development Phase I Phase IV Preclinical IND Filed Phase IIIb NDA Approved Time to Market 15 Years Life of Drug Patent 20 years The Discovery phase occurs at a pharmaceutical company or university. 10,000 compounds are researched. Of the 10,000 compounds, 250 will make it to the Development phase. The first part of the Development phase, is Preclinical testing. In the preclinical phase, animal studies are conducted. New compounds cannot be tested in humans until certain studies are conducted in animals to demonstrate safe dose levels. When the studies are completed, the pharmaceutical company will file an “IND,” Investigational New Drug exemption application, with the FDA. When the IND is approved, the compound can be tested in humans. The Phase I, II, and III trials are human trials. After specific studies are completed, the pharmaceutical company will file an “NDA,” New Drug Application, with the FDA. If an NDA is approved, the pharmaceutical company will begin market research to prepare for commercialization of the drug.

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 New Drug Synthetic Novel Chemical Serendipity Random Screening New Drug Old Drug Found to have a New Use Chemicals Found in Humans (Replacement Therapy) Modification of a Known Drug Natural Chemical Not Found in Humans that has Activity as a Drug

Chemistry, Manufacturing, and Controls 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 How long does it take for a drug to go from discovery to market? What is CMC? Name two objectives of drug discovery.

Drug Development: Preclinical Periapproval Phase III Phase II Research Discovery Development Phase I Phase IV Preclinical IND Filed Phase IIIb NDA Approved Laboratory and animal testing - Toxicology and pharmacokinetics 1 - 3 years - Studies with various species and durations 250 compounds

Drug Development: Preclinical International Conference on Harmonization (ICH) Guidelines Joint approval between Europe, Japan, and USA Requirements: safety pharmacology genetic toxicology animal toxicology exposure assessment (i.e., ADME)

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 Goals of Acute and Repeat-Dose Toxicity Studies Target organ toxicity Dose response Biomarkers Safety Requirements for Phases I and II EU and I to III Japan and USA

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? Distribution – where does it go? Metabolism – what happens to it when in the body? Excretion – how does it get out?

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 What organ systems do safety pharmacology studies test? What are DART studies? What are carcinogenicity studies? What does “ADME” stand for? If your IND is approved, what happens next?

Drug Development: Clinical Periapproval Phase III Phase II Research Discovery Development Phase I Phase IV Preclinical IND Filed Phase IIIb NDA Approved Is it safe? Determine dosage levels 20 - 100 healthy volunteers Up to 12 months 100 compounds

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 70% move to Phase IIa

Drug Development: Clinical Periapproval Phase III Phase II Research Discovery Development Phase I Phase IV Preclinical IND Filed Phase IIIb NDA Approved Is it safe and does it work? Refine dosage levels 50 - 500 patients Up to 2 years 70 compounds

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 Periapproval Phase III Phase II Research Discovery Development Phase I Phase IV Preclinical IND Filed Phase IIIb 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 What key question should Phase I trials answer? How many patients might be involved on a Phase II trial? Name two objectives of Phase III.

Drug Development: Clinical Periapproval Phase III Phase II Research Discovery Development Phase I Phase IV Preclinical IND Filed Phase IIIb 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 Periapproval Phase III Phase II Research Discovery Development Phase I Phase IV Preclinical IND Filed Phase IIIb 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 30 70 10,000 100 250 20 Periapproval Phase III Phase II Research Discovery Development Phase I Phase IV Preclinical Phase IIIb IND Filed NDA Approved The industry spends, on average, approximately $500 to $800 million to bring a new medical therapy to market

Drug Development Activity Let’s review a product label.