Food and Drug Law October 11, 2010

1. Food and Drug LawOctober 11, 2010 Ralph F. Hall

2. Overview • Current events • Food • Dietary supplements • Health claims • Food summary • Drugs • History • Key concepts • Labeling • Restricted drugs

3. Health Claims

4. Health ClaimsBackground and Policies • Increasing knowledge about food, nutrient and health • Old concept – nutrient, taste, aroma • Opportunities for abuse • Health impacts • Actual harm • Diversion from therapy • Consumer protection • Consumer choice • Personal freedom

5. Health ClaimsOverview • NLEA – significant scientific agreement • DSHEA – supplement related claims • FDAMA – authoritative statements • Pearson v. Shalala • 2003 Guidance (response to Pearson v. Shalala) • qualified health claims • Less evidence that other bases for health claims • Recent litigation

6. Key Food Statutes • 343 (q) • Applies to human food • Label must include certain information • Dietary supplements must have certain nutritional information • 343 (r) • Deals with health claims and nutrition claims • Permits claims is there is an “authoritative statement” from US government (sub G) for certain statements • Notice to FDA • Health claims require significant scientific agreement

7. General Labeling Requirements343(q) • Basic NLEA information (q)(1) (2) • Serving size, nutritional levels, etc. • Exceptions (q) (5) • Restaurants and retail sales • Small business • 343 (r)(5) includes other exceptions

8. Nutritional Labeling21 USC § 343 (r) • Characterization of food or nutrient value is misbranding unless exception applies • Special rules for cholesterol, fat, etc. • Multiple ways to make health claims • “authoritative statement” • Substantial Scientific Agreement • Pearson type claim • Dietary supplement

9. Nutritional Labeling21 USC § 343 (r)(2)(G) • Health related claims • authoritative statement by government entity • NAS • NIH • CDC • 120 day prior notification • Challenged by regulation, failure to comply with notification requirements, district court action • Relationship to DSHEA

10. Authoritative StatementNational Research council • Authoritative statements “are limited to those that represent the consensus of a duly appointed committee or views of a duly appointed principal investigator so that they appear explicitly as findings, conclusions, or recommendations in a report that has completed the institutional report review process” • 1997

11. Nutritional Labeling21 USC § 343 (r)(2)(G) • Other elements • Identical to authoritative statement • Agency notification of inadequacy • Accuracy (false or misleading?) • Comprehension • Revocation by regulation (343 (r)(2)(H) • See also 21 USC 343 (r) (3) (C)

12. Nutritional Labeling21 USC § 343 (r)(3) • Health claims based on “significant scientific agreement” • Why agreement and what is it? • Basis of scientific agreement • Qualified experts • Compare to GRASE • Promulgated by regulation • Citizen petitions (21 CFR 10) and (r) (4) • Accurate

13. Pearson v. Shalala164 F.3d 650 (1999) • Challenge to limitations on health claims • limited or inconclusive data to support health claims • Involves 4 specific health claims rejected by FDA • Dietary supplement provides safe harbor from drug requirements • impact of making drug type claims • FDA regulated health claims for supplements under DSHEA • 1st Amendment challenge

14. Pearson v. Shalala1st Amendment • Central Hudson 4 part analysis • Not illegal • ,legitimate government interest or policy • advances legitimate government interest and • least burdensome • Government interest • protect health • prevent fraud • Disclosure preferred over suppression • Alternative disclosure mandated • level of scientific support • FDA doesn’t approve use or statements

15. Pearson v. ShalalaFDA Position • Health claims are inherently misleading • without ‘significant scientific agreement’, statements are inherently misleading • Consumers can’t understand labeling with less than conclusive claims • FDA position viewed as paternalistic • Health claims are potentially misleading • Consumers can’t interpret claims • no access to data • assume FDA agreement with labeling content • Disclaimers inadequate

16. Pearson v. Shalala1st Amendment • Government interests legitimate • Policy advances anti-fraud interest • Answer is more disclosure, not less • Disclosures adequate • Need to define ‘significant scientific evidence” • Led to 2003 guidance

17. 2003 Guidance • Post Pearson • Broader than statute • Adds more allowable claims • Petition and litigation opportunities • Consumer understanding • Variable impacts • Use of specific language

18. Health Claims • Qualifying language used to accurately describe strength of claim • Used to allow less proven statements to be made • Category A – established claim • Category B – “evidence is not conclusive” • Category C – “this evidence is limited and not conclusive • Category D – “little scientific evidence supporting this claim”

19. Key StatutesDietary Supplements • 343 (r) 6 • Applies to dietary supplements • Allows claims with appropriate disclosures • Includes statement that FDA has not evaluated claims • 30 day notice after 1st marketing • 343 (s) • Dietary supplements • Labeling content

20. §343(r)(6) • Applies to dietary supplements • Covered claims • Benefit for a “classical nutrient deficiency disease” • role of dietary supplement in affecting structure/function • Why not a drug? • general well being • Substantiation that statement is truthful and not misleading

21. §343(r)(6) • Disclaimer regarding FDA approval • Required language • No intention to diagnose, mitigate, treat, cure or prevent a specific disease • Compare to (r)(6)(A) • Note structure/function claims v. disease claims • What’s the line? • “Stimulate, maintain promote” are OK • “Restore, correct” are not OK • NLEA and DSHEA are separate • Post marketing notification

22. Dietary Supplements21 USC §343 (s) • Specific misbranding section (343 (s)) • quantity of all ingredients • use of term “dietary supplement” • must conform to specifications in an official compendium • But see Ova II • must meet labeled identity, strength, quality or purity • Not misbranded because of labeled warning or uses • Purpose of this ?

23. MemoProve

24. Dietary Supplement Guidance • Extensive comments • Notice and comment process • Good Guidance Practice • 225,000 (many form letters) • Purpose of guidance documents • How binding • Effect of Pearson and Ephedra litigation • Are these relevant?

25. Dietary Supplement Guidance • Guidelines • Provide useful information to consumers • Scientifically valid support • Do not suggest disease prevention or treatment • “Support” or “maintain” statements allowed if • don’t suggest prevention or treatment • Consumer can evaluate statements • Restorative statements questionable when abnormality implies disease • Avoid NLEA type health claims • Nutritional support claims aren’t drug claims if they avoid reference to specific diseases and don’t make therapeutic promises

26. Dietary Supplements21 USC §343-2 • Labeling exception (343-2) • Not misbranding to use books or peer reviewed articles as sales aids • not false and misleading • Not brand specific • not appended to product • Addresses Sterling Honey & Vinegar and National Nutritional Foods Assoc.

27. Ephedra • Ephedra marketed to enhance athletic performance and weight loss • Ephedra linked to heart attack, stroke and increases in blood pressure • Dietary supplement can be removed from the market if there is a “significant or unreasonable risk of illness or injury • Data required to remove a product from the market

28. Ephedra Chronology • Pre 1994 – marketed in US • 1994 – FDA medical bulletin warns of ephedra risks • 1997 – FDA proposes safety measures • 2000 – various public meetings and proposed rules • 2/2003 – “FDA acts to reduce safety concerns” • public comment • safety risks • adverse events • Record required • new warning label • warning letters

29. Ephedra Chronology • 2003 Rand Study • Risks of Ephedra • 7/2003 • Warning Letters re deceptive claims • 12/2003 • Consumer alert • Intent to publish final rule banning ephedra • 2/2004 • FDA issues regulation banning ephedra • Consumer advice to not use it

30. Ephedra Chronology • 2005-present • Various product seizures and other enforcement actions • “Nature’s Treat Energy #1 seized 12/05 • District court challenge • Issue with >10mg levels • Adequate administrative record? • Burden of proof? • Appellate court agrees with FDA

31. Ephedra Chronology • Court of Appeals -10th Cir. (why 10th Cir.?) • Upheld FDA • Product “adulterated” • Illegal to ship in interstate commerce • Breadth of coverage • Adequate administrative record • FDA permitted (or required) to conduct risk/benefit assessment • Approval type assessment?

32. Food Summary

33. Food Overview • Food – defined by function (321 (f)) • Food additive – defined by intended use (321 (s)) • Color Additive – defined by capability and use (321 (t)) • Dietary supplement – defined by intended use and type of article (321 (ff) • Dietary Ingredient – intended use and prior use (350b) • Vitamins and minerals – intended use, type of administration and type of article (350) • Infant formula – defined by use

34. Food Overview • Generally no premarket approval or notification • Exceptions for • Food additives • New dietary ingredients • New infant formulas • Manufacturing and processing controls

35. Food Overview • Food standards • Link to misbranding • Adulteration • Breadth • Actual or potential “filth” • Economic adulteration • Misbranding • Term of art • False OR misleading • Safety and economic protection • Labeling requirements • Accuracy • Quality, quantity, nutritional information, etc. • Health claims

36. Drug Regulatory Process

37. Purpose of Drug Provisions • Prevent unsafe or ineffective drugs from being marketed • NDA process • IND process • Protect human rights • IND/IRB provisions • Get new therapies on the market • 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

38. Major issues • Cost of drugs • Cost of drug development • Lack of innovation • R&D spending increasing more than innovation • Safety • Types of drugs being developed • Chronic use • Treat, don’t cure • Blockbuster • “Me-too” • Role of industry with FDA • Speed of process • Generics and biogenerics • Post market surveillance • Recent product issues and recalls

39. Policy Balances New therapies (Faster approvals, less research) Safety (More research, slower approval) Patient Rights (Access) Will cost be the 4th factor

40. Drug Overview • New concepts • Premarket approval required • Defined clinical testing process • Human subjects protection • Good science • Greater control over labeling and speech • Distribution controls • Post market surveillance • Defined adverse event reporting system • User fees • Similar concepts • Misbranding • Adulteration • Prohibited acts

41. “New Drug” • 321 (p) • Types of “newness” • New chemical entity (NCE or NME) • New combination • New indication • New dosage, administration, etc. • MyKocert • What is GRASE • Experts in field • Some statements that it’s not GRASE • High burden for company • Deference to agency

42. Process Overview • Bench testing • Preclinical testing • Human clinical studies • Phase I-III • Investigational new Drug Application (IND) • New Drug Application (NDA) • Risk/benefit approach • Labeling (indications, warnings, etc) • Post market obligations • GMPs • Labeling/promotional controls • Surveillance and reporting

43. Drug Regulatory History • Pre 1906 • Natural materials • Botanicals • Minerals and metals • “Patent” v. “Ethical” drugs • Fraud, safety and efficacy • 1906 • No premarket approval requirements • Adulteration and misbranding concepts • Post hoc enforcement

44. Drug Regulatory History • 1938 • Rise of “chemical” based pharmaceutical products • Post sulfanilamide • premarket approval process • GRAS • Grandfather “old drugs” • 1962 • Thalidomide • Rise of modern pharmaceutical industry • GRASE

45. Drug Regulatory History • 1980s • AIDS • Generics • Speed issues • 1990s • Gene therapy • Genetic research • Health care cost • Role of “Big” pharma • 2000s • Bioterrorism • Individualized therapies • Access issues • Internet/OUS purchases

46. Drug Overview • Types of “drugs” • Pre 1938 • 1938-1962 (old “new drugs”) • “New drugs” • Definition of “Drug” • Intended use • Mode of operation (indirectly) • Definition of new drug (§321(p)) • Post 1938 drug • Pre 1938 drug w/ new indication, use, etc • Not GRASE • Not animal drug

47. Drug Adulteration§351 • Traditional food adulteration concepts • Filthy • insanitary conditions • Containers • Differs from labeling • Content • Quality • Strength

48. Drug Misbranding§352 • Labeling false or misleading “in any particular” • 95 Barrels of Apple Cider Vinegar • Labeling doesn’t contain required information • Manufacturer information • Required information • Import implications

49. Drug Misbranding§352 • Dangerous when used as labeled • Dosage • Frequency • Manner • Registration • Listing • Uniform labeling symbols

50. Misbranding Debates • Nue-Ovo • Difference of opinion as a defense • Expertise of FDA • Role of disclaimers under §321 (n)? • Control of labeling via approval process • Claims of GRASE? • What is “generally” • Does §352 (j) make sense for post 1962 drugs