FDA Review Session December 7, 2010

1. FDA Review SessionDecember 7, 2010 Ralph F. Hall

2. Historical Themes • 1906 • Food adulteration and economic fraud • Adulteration/misbranding concepts • 1938 • Premarket approval concepts • 1958/60 • Food additives and color additives • 1962 • Efficacy requirements • 1976 • Device regulations • 1984 Hatch Waxman • Generic drugs/patent extension

3. Historical Themes • 1980’s • “Fast track” drugs (AIDS and cancer • User fees (PDUFA) • 1990 • NLEA • SMDA • 1994 • Dietary supplements • 1997 • FDAMA • 2002 • Bioterrorism • 2007 • FDAAA

4. FDA Mission • The FDA is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and products that emit radiation. The FDA is also responsible for advancing the public health by helping to speed innovations that make medicines and foods more effective, safer, and more affordable; and helping the public get the accurate, science-based information they need to use medicines and foods to improve their health.

5. Key Policy Concepts • Protect human health • Approval processes • Event reporting systems • Recalls, seizures, etc. • Information • Prevent consumer fraud • Labeling/misbranding • Economic adulteration • Economic factors • Therapy costs • Cost to develop • Drug importation • Regulate to risk level • Dietary supplements • Devices • Role of consumer/patient

6. Core Questions • Interstate commerce • Is it a regulated product/article? • Within some definition in §321 (or PHSA) • Food, drug, device, cosmetic, dietary supplement, etc. • Combination • What’s its current status? • Approved, marketed, under development, recalled, etc • Does it comply with the requirements considering its nature (i.e. food, drug, etc.) and status? • Is the status quo compliant

7. Core Questions • What does the person want to do? • What is the change in status quo that is desired • Market a new product • Conduct research • What are the requirements to implement that change in status • Is the government trying to change the status quo • What are the options • Entity • Other stakeholders • Gov’t

8. Overview Jurisdiction and defining the article Specific requirements (food, drugs, etc.) Adulteration/misbranding Prohibited acts Remedies/enforcement

9. FDCA “Jurisdiction” • Interstate commerce • Broad definition • Constitutional limits • Product regulated • Defined products • Drugs, devices, food, food additives, etc. • Role of other legal structures • Other regulatory systems • FTC, FCA, SEC, etc. • Private litigation • Product liability • Qui tam actions

10. Key Definitions • Articles • Food – 321(f) • Drug – 321 (g) • Device – 321 (h) • Cosmetic – 321 (i) • New drug – 321(p) • Food additive – 321 (s) • Color additive – 321(t) • Dietary supplement -321(ff) • Biologics – 262(i) (PHSA) • Other • Person -321(e) • Label – 321(k) • Labeling – 321 (m)

11. Quasi Definitional Provisions • Prohibited acts - §331 • Adulteration/misbranding • Food - §§342 & 343 • Drugs and devices - §§351-352 • Cosmetics - §§361-362 • Economic and health based concepts in adulteration and misbranding • Food standards - §341

12. Selected Key Cases • 95 Barrels … Apple Cider Vinegar • Nutrilab • National Nutritional Food • Sterling Vinegar & Honey • Kordel • Candy Lollipops • Birelely’s Orange Beverage • Natick Paperboard • Bacto-Unidisk • Park/Dotterweich • Ova II • Anderson Seafood • Pearson • Reigel/Lohr/Levine • Abigail Alliance • Lane Labs & Rx Depot

13. Core Concepts • General adulteration concepts • Covers all products • Harmful • Disgusting (putrid, rancid, etc) • Valuable components extracted • Approval issues • Misbranding concepts • “Misleading in any particular” • 95 Barrels of Apple Cider Vinegar • Information gaps or omissions • Incorrect information • Approval issues • Both health and economic issues • Defined specific categories • Component/accessory regulation

14. Core Concepts • Regulate to risk • Approval requirements • Regulate by article type • Information source • labeling rules • Interface with other statutory systems • FTC, USDA, SEC, etc. • Controlled access to market • Premarket approval (if risk justified) • Premarket notification • None • Ongoing marketing controls • Control at manufacturer/distributor level

15. Types of Definitions Definitional ConceptProduct Functional Food Intended use Drugs Device Cosmetic Characteristics Color Additives Source Dietary Supplement Biologic Status New drug

16. Key Articles • Food • food additives • dietary supplements • New dietary ingredients • medicinal foods/special dietary uses (350(c)3) • infant formula (350a) • Drugs • “old drugs” (date or GRASE) • new drugs • generic drugs • Orphan drugs • Pediatric drugs • IND • Rx v. OTC

17. Key Articles • Devices • “old devices” • Class I, II and III (510(k) and PMA) • HDE • IDE • Pediatric devices • Custom devices • Biologics • Cosmetics • Color additives • Veterinary products

18. Food Overview • Functional definition • Components • Packaging • Common definition or statutory • No general premarket approval process • Establishment registration • Inspections • Three regulatory control systems • §§341, 342, 343 • Food standards (§341) • specific to products • created via regulation • mandated compliance

19. Food Overview • Adulteration issues • Filth, putrid, contaminated food • Risk of filth, etc • Storage • Handling • Actual contamination not required • Other defined types of adulteration (§342) • Manufacturing controls/HACCP • “Natural” contaminants • Anderson Seafood

20. Food Overview • Misbranding • False or misleading information • 95 Barrels • Quantity, quality, contents, etc. • Definition of misbranding - §343 • Labeling requirements – 2 prongs • Misbranding requirements - general • Other specific requirements • Food Allergen labeling • NLEA requirements • Contents, nutritional information, etc.

21. Food Labeling • Key statutes - content • NLEA • DSHEA • Food allergens • Ingredients, quality, quantity • Uses • Effects/impacts • Warnings?

22. Food OverviewCurrent issues • Relationship to dietary supplements • Definitional issues • Health risk • Health claims (§343 for example) • Treating “disease”/structure/function • Food and color additives • Safety and use • Bioterrorism • Obesity, salt and other health issues • Genetically modified foods • Risk based regulatory systems

23. Food Additives (§348) • Definitional issues • When is a component a “food” versus a “food additive” • 321 (s) • Intended use • Becomes a component or affects food • Food contact substance • Approval requirements • GRAS • Old additives • Testing • Notification • Reporting obligations

24. Dietary Supplements • Definitions (321 (ff)) • Source • Relationship to food, food additives • Intended use and drug definition • Approval status • “old” supplements • New dietary ingredients • Approval requirements • Reporting obligations • Adulteration/misbranding

25. Dietary supplements • Labeling rules • Quantity, contents, etc. • Use of ancillary books, peer reviewed articles, etc. (§343-2) • Adulteration and misbranding • GMP type requirements • Clinical trial requirements for labeling • Recall and health risks • Ephedra

26. Health Claims • Health claims • NLEA – significant scientific agreement • DSHEA – supplement claims • FDAMA – authoritative statements • 2003 guidance for qualified health claims • A-D scale • Role of level of evidence • Disclaimers • Type and effect • Role of 1st Amendment

27. Color Additives • Definitional issues (321(t)) • Impart color • Includes black, white and gray • Approval requirements • GRAS concepts • Review of old additives • Batch certification • Reporting obligations

28. Drugs • Definition • Intended use • Mode of action • Disease/function or structure • Approval requirements • Indication based • Old drugs • NDAs • Rx drugs • Clinical trials (INDs) • Phase I, II and III • Patient protection • Data integrity • IRB/clinical investigator roles

29. Purpose of Drug Provisions • Prevent unsafe or ineffective drugs from being marketed • IND and NDA process • Protect human rights • IND/IRB provisions • Require robust manufacturing • GMPs • Require adequate and truthful information to decision makers • Content requirements • Promotion restrictions • Monitor drug effects • Recall or warn HCPs of issues as appropriate

30. New Drug Development Process(21 USC §355) • NCE (or NME) identification • Use and risk identification • Bench testing • in vitro, test tube, simulation, etc. • Animal testing • Manufacturing development • Human testing via IND process • Phase I, II and III • FDA approval • Indications • Warnings • Post market surveillance

31. Drug Approval Process *http://www.fda.gov/

32. NDA Process§355 • Used to approve new drugs or new indications • “Full report of investigations” re safety and efficacy (i.e. IND information) • Animal • Human • Third party sources • Composition, manufacturing and packaging • Proposed labeling • Possible role of advisory committees • FACA

33. Substantial Evidence • Well controlled clinical studies • Generally multiple studies • Differing indications and populations • Placebo controls • Conducted by qualified experts • Covers multiple scientific areas • Pharmacology • Toxicology • Mutagenicity • Drug interactions • Searching for the rare event

34. Measuring effectiveness • Use of “end points” • Objective • Clinically relevant • Mortality reduction • Time to conclusion • Morbidity reduction • Which measures • Clinical endpoints • Biomarkers/surrogate endpoints • Faster and cheaper • Accuracy? • What is “safe” • Risk/benefit issues

35. Drugs • Approval process (NDA) (§355) • Supplemental applications (sNDA) • Standard for approval • withdrawal provisions (355(d) and (e)) • Labeling • Uses/indications • Risks, warnings & contraindications • Other information • Promotional activities • Off label promotion • DTC advertising

36. NDA Approval355(c), (d) & (e) • Approved if no reason to deny exists • Reasons for denial • Drug is unsafe • Drug isn’t shown to be safe • GMP issues • Lack of substantial evidence of efficacy • False of misleading labeling • Risk/benefit assessment • Potential for misuse? • Burden is on applicant • Ubiotica case • Chevron/Skidmore deference • Withdrawal

37. Drugs • Sample controls • Manufacturing controls • GMPs • handling & storage • Change control • Adverse events • Investigation • Reporting • Corrective actions • Adulteration/misbranding concepts • Recall process • Pediatric and similar special groups

38. Drugs • Fast track provisions • medical need • Limited efficacy data • Post market obligations • Orphan drugs • Small populations • market exclusivity • Pediatric drugs • Efforts to increase research • Required consideration • Market exclusivity

39. Drugs • Post market requirements • Complaint handling • Investigations • Reporting • Recalls • REMS • Specific products • Mitigate risk • Identify new risks • Types of controls

40. Generic Drugs • ANDA process • Master file of safety and efficacy data • Application requirements • Generic drug scandals • Linkage to patent issues • exclusivity rights • Patent litigation • Challenges to existing patents

41. DrugsCurrent Issues • Combination products • Personalized medicine • Time & cost of new drugs • Drug interactions • chronic uses • Access for special groups • Pediatrics • Orphan drugs • Drug Importation • DTC

42. Biologics • Regulated under PHSA §262 • Definition • Vaccines • Antitoxins • Blood & blood products • Genetic products • Approval requirements • Biologics License Application • INDs • Labeling and promotion controls • Incorporation of FDCA requirements

43. Biologics • Post market obligations • Similar to drugs • Savings clause • Tissue regulation • Organs • Tissue types • Gene therapy

44. Cosmetics • Definition • Intended use • Includes implanted articles • Affect, alter appearance, beautify, etc. • Excludes soaps • Risk of advertising creating a drug • No premarket approval requirement • Only approved color additives • Basic adulteration/misbranding concepts • Basic GMP requirements

45. Device Concepts • Devices present range of risk • Not the view about drugs • Effort to match risk and regulation • Builds on core 1906 concepts • Technology differences • Faster changes • Shorter life cycles • Different clinical trial needs • Total Product Life Cycle (TPLC) approach

46. Devices • Definition • Intended use • Mode of action • element of combination products • Approval requirements • Class I • Class II • 510(k) substantial equivalence • Class III • PMAs • clinical trials • Modified devices

47. Device Classification Purpose • The goal of the classification system is to tailor the level of regulation to the characteristics of the device • Risk • Complexity • History or knowledge • FDA divides all devices into three classes • Classes I, II and III • Consistency requirement

48. Device Classification • Class I - general controls are sufficient to provide reasonable assurance of safety and effectiveness • General controls include: • FDA’s misbranding and adulteration powers • Registration requirements and reporting obligations • Basic manufacturing controls • Most Class I devices are exempt premarket notification or approval • Class I includes tongue depressors, elastic bandages, ice bags, and bedpans

49. Device Classification • Class II - general controls are not sufficient and for which special controls will provide the necessary assurance • Special controls can include • Post market surveillance or patient registries • Guidelines (including guidelines for the submission of clinical data and premarket notification submissions) • Other administrative controls (including 510(k)s) • Class II includes such products as syringes, bone plates, hearing aids, and resuscitation devices

50. Device Classification • Class III - devices that cannot be adequately regulated under either Class I or II • General controls are not sufficient, and not enough is known about the device to regulate it adequately with special controls • Class III devices are subject to the requirement of a premarket approval application containing valid scientific evidence of the safety and effectiveness of the device • Class III contains such products as pacemakers, IUDs, and artificialhearts