1. U of Arizona Innovation Conference 20 September 2011 Marlene E. Haffner, MD, MPH Haffner Associates, LLC

2. 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.  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.  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.  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.  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.  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.  Often a stumbling block  Acute and long term 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 to FDA to allow human exposure to the experimental drug – Go to FDA website  http://www.FDA.gov/cder/guidance/index.htm 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.  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. 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.  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.  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.  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.  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.  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. Preclinical 3 – 6 years Phase 11 – 2 years Phase 22 – 3 years Phase 3 3 – 4 years ________________________________________ 9 – 15 years FDA review1 year

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