Food and Drug Administration (FDA): FDA overview and Bioresearch Monitoring

1. Food and Drug Administration (FDA): FDA overview andBioresearch Monitoring CDR Tejashri Purohit-Sheth, M.D. Branch Chief, Good Clinical Practice II Division of Scientific Investigations Center for Drug Evaluation and Research Food and Drug Administration

2. Outline • FDA Overview • History • Product Development Process • Bioresearch Monitoring

4. FDA Mission • “The FDA's mission is to promote and protect the public health by helping safe and effective products reach the market in a timely way, and monitoring products for continued safety after they are in use. Our work is a blending of law and science aimed at protecting consumers.”

6. FDA Responsibilities • protecting the public health by assuring the safety, effectiveness, and security of • human and veterinary drugs, vaccines and other biological products, medical devices, our nation’s food supply, cosmetics, dietary supplements, and products that give off radiation • advancing the public health by helping to speed product innovations • helping the public get the accurate, science-based information they need to use medicines and foods to improve their health

7. FDA Regulates • foods, except for most meat and poultry products, which are regulated by the U.S. Department of Agriculture • food additives • infant formulas • dietary supplements • human drugs • vaccines, blood products, and other biologics • medical devices, from simple items like tongue depressors, to complex technologies such as heart pacemakers • electronic products that give off radiation, such as microwave ovens and X-ray equipment • cosmetics • animal feeds and drugs, and devices used in pets, farm animals, and other animals • tobacco products

8. History

9. History • Harvey Wiley – chief chemist in Division of Chemistry in Department of Agriculture Bureau of Chemistry (1901) • Bureau examined chemicals with the aim of standardizing analyses for quality and consistency *FDA: A Century of Consumer Protection – FDLI publication for the FDA Centennial + FDA’s Centennial History sites

10. History • 1902 Biologics Control Act (later called Public Health Service – PHS – Act) • 1901 = death of 10 children after contracting tetanus from horse anti-diphtheria antitoxin • Regulated sale of viruses, serums, toxins, and analogous products • Authorized biologics regulations • Required licensing of manufacturers and establishments • Provided inspection authority

11. History • Pure Food and Drugs Act of 1906 • Passed due to shocking disclosures of insanitary conditions in meat packing plants, use of toxic preservatives in dyes and foods, and cure-all claims for dangerous patent meds • Act prohibits interstate commerce of misbranded and adulterated foods, drinks, and drugs • Manufacturer not required to submit evidence of drug safety or efficacy

12. History • Pure Food and Drugs Act of 1906 (cont.) • Permitted government to take action if a drug proved too dangerous or misbranded • 1911 Supreme Court judgment = Act did not prohibit false therapeutic claims, only false and misleading statements about the ingredients or identity of a drug

13. History • 1912 – Sherley Amendment prohibits labeling medicines with false therapeutic claims intended to defraud the consumer • 1927 – Bureau of Chemistry reorganized • Bureau of Chemistry and Soils • Food, Drug, and Insecticide Administration • 1931 – Agricultural appropriations act changed name to Food and Drug Administration

14. History • 1933-1937- several bills introduced into the Senate to modify the Pure Food and Drugs Act, but to no avail • 1937 – elixir of sulfanilamide tragedy • Sulfanilamide = limited solubility in common solvents • Diethylene glycol (antifreeze) proved an excellent solvent • Pleasing fragrance and sweet flavor – but toxic! • 107 died

15. Food, Drug and Cosmetic Act of 1938 • Required new drugs to be shown safe before marketing (new drug application – NDA) • Authorized factory inspections • Extended controls to cosmetics and therapeutic devices • Authorized standards for foods • Added court injunctions to previous penalties of seizure and prosecution

16. New tragedy reform • 1961 – thalidomide, sedative-hypnotic marketed to pregnant women to combat morning sickness, found to cause birth defects • Safety concerns led FDA’s Dr. Frances Kelsey to keep it off of U.S. market • Distributed in U.S. only as investigational product, though recipients not informed of investigational status

17. Kefauver-Harris amendments of 1962 • Required • Demonstration of efficacy • Informed consent • Control of investigational drugs • 1963 – implemented via Investigational New Drug (IND) regulations requiring • Submission of protocols • Identification of clinical investigators involved and submission of their qualifications • Identification of facilities involved with the studies

18. Judicial concurrence • 1970 – Court of Appeals upholds enforcement of 1962 amendments – rules commercial success alone ≠ substantial evidence of safety and efficacy • 1973 – Supreme Court upholds effectiveness law and endorses FDA regulatory actions to control entire classes of products rather than relying on time-consuming litigation

19. Other additions • 1971 – Bureau of Radiological Health • 1972 • Regulation of biologics, including serums, vaccines, and blood products transferred from NIH • Over-the-Counter (OTC) drug review initiated • 1976 (and 1990) – Medical Device regulations

20. FDA-Legal Authority • 1902 – Biologics Control Act • 1906 – Pure Food and Drug Act • 1938 – Federal Food, Drug, and Cosmetic Act • 1944 – Public Health Service Act • 1951 – Food, Drug, and Cosmetics Act Amendments • 1962 – Food, Drug, and Cosmetics Act Amendments • 1966 – Fair Packaging and Labeling Act • 1976 – Medical Device Regulation Act • 1987 – Prescription Drug Marketing Act

21. FDA-Legal Authority • 1988 – Anti–drug Abuse Act • 1990 – Nutrition Labeling and Education Act • 1992 – Prescription Drug User Fee Act • 1994 – Dietary Supplement Health and Education Act • 1997 – Food and Drug Modernization Act • 2002 – Bioterrorism Act • 2002 – Medical Device User Fee and Modernization Act (MDUFMA) • 2003 – Animal Drug User Fee Act • 2007 – Food and Drug Administration Amendments Act of 2007

22. Product Development Process

23. Phases of Product DevelopmentCBER and CDER • Preclinical Studies • Phase I • Phase II • Phase III • Approval or Licensing • Phase IV or Post Approval Studies

24. Drug Development and Review Process Preclinical Testing Phase I Phase II Phase III FDA Approval 1 2 8 9 10 YEARS 3 4 5 6 7 20to80 Healthy Volunteers Test Population 100 to 300 Subject Volunteers 1,000 to 3,000 Subject Volunteers Laboratory and Animal Studies Post-marketing safety monitoring Verify effectiveness, monitor adverse reactions from Cumulative dosing and delayed Toxicity Evaluate effectiveness. Look for Side effects. • Review • usually • takes • about • - 1 year Assess toxicity and biological activity Determine Acute Toxicity and Dosage Distribution FILE IND PURPOSE FILE NDA Expedited Review: Phases II and III combined to shorten approval process on new medicines for serious & life-threatening diseases. Education % of all new drugs that pass • 70% of • INDs • 33% of • INDs • 27% of • INDs • 20% of • INDs

25. Goals of Product Development • Safety • Efficacy

26. Preclinical Studies • Animal studies • GLPs = Good Laboratory Practices

28. Pre-Approval: Phase I, II, III • Phase I, II and III studies are conducted prior to the approval or licensure of a product • Exception: post-approval for new indication • These studies are conducted under IND or IDE • IND = Investigational New Drug Application • IDE= Investigational Device Exemption

29. Phase I • First time evaluation in humans • Generally small numbers of subjects (20 to 80) • Determine early safety concerns • Determine safe dose range • Identify side effects • Route of administration

30. Phase II • Larger group of subjects (hundreds) • Further evaluate safety • Evaluation of appropriate dose • Evaluate early effectiveness • Determine common side effects • Usually with comparator product

31. Phase III • Large group of subjects (thousands) • Confirm effectiveness • Continue to evaluate safety • Evaluate risk/benefit relationship • Provide adequate basis for labeling • Randomization

32. Randomization • Subjects are assigned by chance to receive the study product or placebo/standard treatment • Intervention group – those subjects receiving the investigational product • Control group – those subjects receiving placebo or standard care

33. Blinding • Prevents bias • Single blind – subject does not know if they receive investigational product or placebo • Double blind – neither subject or investigator know if the subject receives investigational product or placebo

34. Approval or Licensing • NDA = New Drug Application (drugs) • BLA = Biologics Licensing Application (biologics) • ANDA=Abbreviated New Drug Application (generics) • PMA = Pre-market approval (devices) • NADA = New Animal Drug Application

35. Terminology • Drugs and devices are approved • Biologics are licensed

36. Phase IV • Post approval or post licensure • Safety Monitoring • AERS = Adverse Event Reporting System (Med Watch); CDER & CBER • VAERS = Vaccine Adverse Event Reporting System; CDC & CBER • Lot Release

38. Drug Approval • FDA’s determinations on drug approval depend on the submission of reliable data from clinical trials • Regulatory review of the data is a multidisciplinary approach • Clinical, pharmacology/toxicology, clinical pharmacology, drug quality (chemistry), and statistics • FDA’s assessment on the validity/reliability of the data is often based on inspections at the time of marketing application submission • Clinical investigators • Sponsors • Contract Research Organizations (CROs)

39. Bioresearch Monitoring

40. How Does FDA Ensure Data Integrity and Human Subject Protection? BIORESEARCH MONITORING PROGRAM (BIMO)

41. BIMO Program Comprehensive program of on-site inspections and data audits designed to monitor all aspects of the conduct and reporting of FDA-regulated research

42. BIMO Program Objectives • Protect the rights, safety, and welfare of subjects in FDA-regulated trials • Determine the accuracy and reliability of clinical trial data submitted to FDA in support of research or marketing applications; and • Assess compliance with FDA’s regulations governing the conduct of clinical trials, including those for informed consent and ethical review

43. BIMO Inspections • Each FDA Center has oversight of inspections of research related to the product(s) it regulates • Inspections are usually conducted by ORA field investigators • Field inspectors are NOT specifically assigned to CDER • All Field inspectors are responsible for conducting inspections for all centers (CBER, CDER, CDRH, CFSAN, etc.)

44. BIMO Inspections Completed FY09 CenterCIIRBSpon/MonGLPTotal CBER 83 15 11 6 115 CDER*458 102 73 36 674 CDRH163 79 59 4 305 CFSAN0 0 0 1 1 CVM26 na 4 15 45 All Centers730 196 147 53 1135

45. FDA/CDER GCP Regulations These are legally enforceable requirements

46. Clinical Investigators • Compliance Program • Inspections of CIs (physicians, researchers) conducting clinical trials on drug and biologic products • Inspection • Usually preannounced • Inspection includes • an interview with the clinical investigator and pertinent study staff • an in-depth study/data audit – to validate study findings and verify compliance with regulations

47. FDA Expectations of Clinical Investigators • Adherence to Code of Federal Regulations • Knowledge of Clinical Investigator regulations • Understanding Clinical Investigator responsibilities

48. General Clinical Investigator Responsibilities • Ensuring that an investigation is conducted according to the • Signed investigator statement (Form 1572) • Investigational plan • Applicable regulations • Control of drugs under investigation • Adequate Recordkeeping • Ensuring that informed consent is adequately obtained according to 21 CFR 50 • Ensuring IRB review, approval and reporting requirements are met IAW 21 CFR 56

49. Most Common CI Deficiencies • Failure to follow the investigational plan • Protocol deviations • Inadequate recordkeeping • Inadequate accountability for the investigational product • Inadequate subject protection – including informed consent issues

50. Administrative/regulatory options • Untitled or Warning letter • Initiation of disqualification procedures • Sharing information with Office of Criminal Investigations (OCI) for pursuit of prosecution • Recommendation for rejection of site/study data