Drug Development 101 – I discovered a drug which will cure the world of disease – now what

1. Drug Development 101 – I discovered a drug which will cure the world of disease – now what U of Arizona Innovation Conference 20 September 2011 Marlene E. Haffner, MD, MPH Haffner Associates, LLC

2. Historical Perspective: Why Regulate Drug and Biological products 1800’s – US Customs Laboratories were established to administer the Import Drugs Act of 1848 --Mission – US should not be a dumping ground – purity and potency standards of the USP

3. Late 1800s • Opium, morphine, heroin, and cocaine – no restrictions • Cows weren’t tested for TB • Victories over infectious diseases just beginning – Robert Koch; Louis Pasteur • Agricultural to industrial economy

4. Pure Food and Drug Act of 1906 • Prohibited Interstate Commerce of misbranded and adulterated foods and drugs and poisonous patent medicines • Specific labeling – morphine, cannabis, chloral hydrate, … • Did not address • Food or drug standards • Enforced by Division of Chemistry of the Department of Agriculture

5. Additional Laws • 1938 – Food, Drug, and Cosmetic Act • Elixir of sulfanilamide • Safety • Safe tolerances • 1962 Kefauver-Harris • Thalidomide • Efficacy and safety before marketing • Adverse events • Further improvements to safety in subsequent years • Each added to the better and more costly products

6. Who and What is FDA • 8000 + dedicated and talented employees across the US • ~ 50% in the Washington, DC area • MDs, pharmacists, statisticians, nurses, dentists, policy analysts, PhDs, engineers, and more • No one in the agency bites! They really wish to be helpful • They are short staffed for the responsibilities they have • Listen carefully to what you are told in meetings

7. Overview of Drug Development - 2011 • Discovery • Screening – including product characterization, formulation, PK, and drug disposition • Pre-Clinical Toxicology testing • IND Application • Phases 1, 2, 3 – clinical trials • New Drug Application (NDA)/ Biologics Licensing Agreement (BLA) • Post marketing commitments (REMS – risk evaluation and mitigation strategy)

8. Pre clinical Toxicology Testing • Often a stumbling block • Acute and longterm toxicity in animals – one rodent and one non- rodent • Genetic • Reproductive • Carcinogenicity • How is the drug absorbed, distributed, metabolized and excreted in animals

9. Apply for your IND (Investigational New Drug) • Apply to FDA to allow human exposure to the experimental drug – Go to FDA website • http://www.FDA.gov/cder/guidance/index.htm • Qualification Process for Drug Development tools (DDT) • IND describes for what the product is being developed, safety issues as known, studies to be undertaken – assures safety for first in humans

10. Determine Clinical Endpoints • Chances are you are not going to “cure” the disease • How will you show efficacy? • Is your endpoint a clinical endpoint, or a surrogate endpoint? • Discuss with FDA. If you and FDA do not agree, why? • Further discussion with FDA

11. Clinical Trials MEET WITH FDA REVIEW DIVISION – EARLY AND OFTEN • Phases 1, 2, 3 • Phase 1 – • usually healthy volunteers • 10 – 80 – determine safety of dosage (12 – 18 mos) • Phase 2 – • 100 – 300 patients volunteers (24 mos) • Dosage, adverse events (AEs), early efficacy • Phase 3 – • 1000 – 3000 patient volunteers • confirm efficacy, • monitor AEs (30 – 40 mos)

12. Phase 1 • Begin 30 days following submission of IND providing no “clinical hold” • 20 – 80 volunteers • Duration: 1 year • Determine bioavailability and safety • Determine adverse events associated with increasing doses • Gain early evidence of efficacy

13. Phase 2 • Consult with FDA – often • Assess efficacy in the disease or condition • Monitor safety and AEs • 100 – 300 patient volunteers • Duration: 2 years • Less than 33% of INDs survive Phase 2

14. Phase 3 • Consult with FDA • 1,000 – 3,000 patient volunteers • Multiple testing sites • Duration 3 – 4 years • Confirm safety and efficacy – no drug is ever confirmed as completely safe

15. New Drug Application (NDA) • Formal proposal to FDA for approval of a new drug to be marketed in the US • Must provide sufficient evidence for the FDA to determine: • Benefits outweigh the risk of the product • Drug is safe and effective for its intended use • Proposed labeling is appropriate • Manufacturing methods and controls maintain drug identity, strength, quality, purity and stability

16. My product has been Approved! • Must assure continued safe and stable production • Must continue to monitor AEs • FDA may determine need for REMS – especially if study done on small number of patients • Must report significant Adverse Events to FDA • Adverse events may not be known for many years – e.g. VIOXX

17. WHAT TAKES SO LONG Preclinical 3 – 6 years Phase 1 1 – 2 years Phase 2 2 – 3 years Phase 3 3 – 4 years ________________________________________ 9 – 15 years FDA review 1 year

18. ? Marlene E. Haffner, MD, MPH 301 984 5729 www.mhaffner.com mhaffner3@verizon.net