Drug Research and Development (R&D)

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

2. Cost and time to get drug to market? • 250 million dollars – 5 years • 500 million dollars – 7 years • 800 million dollars – 10 years

3. 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

4. Animals Used in Research in the US • 10-15 Million/year • 20-25 Million/year • 30-35 Million/year

5. 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

6. Drug Research and Development (R&D) • Overview of process • Regulations • Drug Discovery • Preclinical development • Clinical Trials • Drug Approval

7. Drug Research & Development • Discovery • Nonclinical • IND • Clinical • NDA • Approval

8. 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

9. 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 non-approval (start over) • Post-marketing requires reporting of safety in people as well as anything found in other studies in people or animals

10. 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

11. Nonclinical Development • Stage in development to assess safety and pharmacology before and during clinical trials • Pharmacodynamics (PD) • Pharmacokinetics (PK) • Safety Pharmacology • Toxicology

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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 Adverse Events

20. Risk Management • Compound A = Aspirin • Compound B = Caffeine

21. Submit NDA to FDA • Approval—permission to market for agreed uses • Approvable—more data is neededto 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

22. Questions????