Natural Health Products in a Global Marketplace: Scientific and Regulatory Perspectives

1. Natural Health Products in a Global Marketplace: Scientific and Regulatory Perspectives Joseph M. Betz, Ph.D. Office of Dietary Supplements U.S. National Institutes of Health http://dietary-supplements.info.nih.gov

2. Overview • Dietary Supplement Overview • Introduction to Regulations • Introduction to National Institutes of Health • Overview of ODS Programs

3. Dietary Supplements in 2001: $17.7 Billion Minerals Vitamins Herbs / Botanicals Other Supplements Sports Nutrition Source: NBJ, derived from a variety of sources

4. Top 10 Dietary Supplementsfor 2005 Multivitamins/minerals Calcium B vitamins Vitamin C Glucosamine/Chondroitin Vitamin E Fish oils Coenzyme Q10 Noni juice Probiotics Nutrition Business Journal

5. Ten Most Common Reasons for Taking Supplements(The Slone Survey) • General health/good for you (16%) • Arthritis (7%) • Memory improvement (6%) • Energy (5%) • Immune booster (5%) • Joints (4%) • Supplement diet (4%) • Sleep aid (3%) • Prostate (3%) • No reason (2%) • All other reasons (45%) JAMA, 2002

6. Traditional (Herbal) Medicine in the U.S. • Practice of medicine and the licensing of physicians are regulated by the 50 individual states • National laws deal mostly with products • U.S. Food and Drug Administration (FDA)

7. FD&C Act • Products • Foods, dietary supplements, or drugs based on “intended use” • e.g Psillyium husk can be a food, dietary supplement or drug • Applicable regulations for the category apply • Intended use is ascertained by accompanying labeling claims, advertising materials, or oral or written statements

8. Botanical Drugs • Intended use to cure, treat, mitigate, etc. • Subject to current drug regulations • Pre-market approval for GRASE • Unique qualities recognized by the FDA • inherently more complex than synthetics • more likely to be components in mixtures • active constituents and activity not always well defined

9. DSHEA(Dietary Supplement Health and Education Act - 1994) • Amended the FD & C Act • Defined dietary supplements • Established regulatory framework • Food and Drug Administration (FDA) • As foods, not as drugs • Established rules for what a label should contain • Gave FDA authority to write GMP • Called for creation of the Office of Dietary Supplements • Placed it in the Office of the Director at the National Institutes of Health

10. Dietary Supplement • “...any product (other than tobacco) that contains a vitamin, mineral, herb, or other botanical or amino acid and is intended as a supplement to the diet.” • A concentrate, metabolite, constituent, or combination of the above • Prior to DSHEA, most botanicals treated as food additives or as drugs • Approved, unapproved

11. Dietary Supplement • Foods, therefore safe by definition • No premarket safety approval except “new dietary ingredients” (75 day notification) • Statements of Nutritional Support (“Structure/Function”) claims permitted • No premarket approval for efficacy required (30 day notification) • Disease claims prohibited • Intended for ingestion • NOT REPRESENTED AS CONVENTIONAL FOOD Guide to Dietary Supplements http://vm.cfsan.fda.gov/~dms/dietsupp.html

12. New Dietary Ingredients • Not marketed in U.S. prior to 10/15/94 • Not a new ingredient: • If ingredient was “in the food supply… in a form... not chemically altered” • No list of “FDA approved” ingredients • Mfr. Determines whether “new” • notifies FDA 75 d pre-market • Exempt from food additive provisions

13. Dietary Supplements • 21 CFR Part 111 • Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements; Final Rule • Published June 25, 2007 • http://www.cfsan.fda.gov/~lrd/fr07625a.html

14. Dietary Supplements • 21 CFR Part 111 • Requires manufacturers to set specifications • Requires manufacturers to test to see if specifications are met using “scientifically valid” methods

15. General Provisions • CGMP applies to activities associated with • manufacturing • packaging • holding • distributing • Manufacturer needs to comply with requirements applicable to operations performed • contractor needs to comply with applicable requirements and • contracting firm responsible for contractor’s performance

16. Proposed Requirement Highlights • Personnel • Physical plant internal environment • Equipment and utensils • Production and process controls • quality control unit • master manufacturing & batch production records

17. Public Law 109–462 • Dietary Supplement and Nonprescription Drug Consumer Protection Act • http://www.fda.gov/opacom/laws/pl109462.html • 22 Dec 2006, took effect Dec 2007 • Mandatory Serious Adverse Event Reporting for OTC drugs and Dietary Supplements • Manufacturer must provide a mechanism for reporting (reports to manufacturer) • Manufacturer must report serious events to FDA

18. Public Health Security and Bioterrorism Preparedness and Response Act of 2002 • Signed into law June 12, 2002 • Relevant Provision is Title 3: Protecting Safety and Security of Food and Drug Supply. • Title 3 contains 15 sections with relevant provisions to the DS industry.

19. Homeland Security • SECTION 303: Administrative Detention • FDA may order the detention of foods when credible evidence exists that they present a threat of serious adverse health consequences or death to humans or animals • SECTION 305: Registration of Facilities • Requires that any facility engaged in manufacturing, processing, packaging or holding food for consumption in the U.S. register with the Secretary

20. Homeland Security • SECTION 414: Maintenance/Inspection of Records • Companies and individuals involved in any aspect of food production must make and keep records • If FDA suspects dangerous adulteration, records must be made available • SECTION 307: Prior Notice of Imported Food Shipments • Require submission of prior notice of arrival providing each of the following: • Identity of: article, manufacturer and shipper, grower, country of origin, country from which article is shipped, port of entry • Articles failing to meet these requirements shall be refused admission to the U.S

21. The National Institutes of Health

22. DSHEA and the NIH • DSHEA called for creation of the Office of Dietary Supplements • Placed at the National Institutes of Health in the Office of the Director • Formally established in 1995 • Strategic planning process guided the first few years of its activities

23. NIH is the Nation’s Medical Research Agency • 27 Institutes and Centers • Total NIH Budget for 2006: $28 billion • Grants, Contracts, Cooperative Agreements • Department of Health & Human Services www.nih.gov

24. Research • Intramural- “in-house” at Institutes • Extramural • Grants, Cooperative Agreements, Contracts • http://grants.nih.gov/grants/funding/funding.htm • More than 80% of the NIH budget • Subject to competitive review • Investigator-initiated • Request for Application (RFA)

25. The Primary Function of NIH is to Conduct and Support Medical Research • 65% Basic Research • 25% Translational • 15% Clinical

26. NIH Funding for Dietary Supplement Research Has Increased Significantly $ Million

28. THE OFFICE OF DIETARY SUPPLEMENTS

29. ODS Mission is to Strengthen Knowledge and Understanding of Dietary Supplements • Evaluate Scientific Information • Stimulate and Support Research • Disseminate Research Results • Educate the Public to Foster an Enhanced Quality of Life and Health for U.S. Population Echinacea Echinacea purpurea

30. Office of Dietary SupplementsFY 2003 $23.0 M

31. ODS Has a Broad Array of Programs • Co-funding with NIH Institutes • Evidence-Based Reviews • Botanical Research Centers • Training • Analytical Methods and Reference Materials • Communications and Information St. John’s Wort Hypericum perforatum

32. ODS Activities are Comprehensive and Global • Dietary Supplement Databases • Surveys of Supplement Use • International Collaborations • Workshops, Conferences, Seminars Ginkgo Ginkgo biloba

33. RESEARCH AGENDA: Grants Co-funded with NIH ICs

34. ODS Grant “Portfolio” • Growth of ODS co-funded grant portfolio: • 1996: 6 grants initiated, $300,000 • 2002: 39 grants initiated, total of 59 (new and continuing), $9.3 million • 2003: total of 72 grants, $13.5 million • Broad portfolio: basic, clinical, training • Details available on the ODS website

35. RESEARCH AGENDA: Evidence-Based Review

36. Evidence-Based Review Program • Systematic review of the literature, with meta-analysis as appropriate, on DS efficacy and safety • In collaboration with the Agency for Healthcare Research and Quality (AHRQ) Evidence-Based Practice Center Network • Major reason for conducting these reviews is to assist NIH in the development of research agendas

37. ODS Evidence-Based Review Program • Chromium and insulin sensitivity* • Ephedra for weight management and athletic performance enhancement* (with NCCAM) • Omega-3 fatty acids for cardiovascular disease prevention* (with NHLBI) and other health indications • Health effects of soy (with NCCAM) • Antioxidant phytochemicals/B vitamins and neurodegenerative diseases*(with NCCAM) • Multivitamins/multiminerals and chronic disease prevention (with OMAR) • Coagulation, diet, and dietary supplements • Health effects of vitamin D (with multiple partners) *Congressional mandate

38. Evidence • Pre-Clinical • Ecologic • Observational • Cohort • Intervention • RCT

39. Ephedra Efficacy and Safety • Systematic review: weight management and athletic performance enhancement • All languages, both published and unpublished • Conclusions: • Modest effect on weight in short term and no evidence of effect on athletic performance • Some side effects seen in trials, some serious adverse events filed with FDA and to a major ephedra manufacturer • Released by Secretary of DHHS, Feb 2003 • Shekelle P et al, JAMA 289:1537-1545, 2003 • ODS and NCCAM convened expert panel to recommend research agenda based on review

40. Evidence-Based Review of Vitamin D in Relation to Bone Health Conducted by University of Ottawa Evidence-Based Practice Centre Funded by NIH Office of Dietary Supplements & Agency for Health Care Research and Quality Available at http://www.ahrq.gov/clinic/tp/vitadtp.htm & the ODS website

42. Conference Objectives • Evaluate available evidence on the efficacy and safety of vitamin D, using the AHRQ evidence-based review titled, Effectiveness and Safety of Vitamin D in Relation to Bone Healthas the framework. • Identify gaps in knowledge on the efficacy and safety of vitamin D in general and across the life cycle. .

43. Findings from the Evidence Based Review • Strong evidence that Vitamin D supplementation reduces falls, fractures and bone loss in men and women 60+ y • Not possible to separate the impact of vitamin D from Ca supplementation— typical amounts used were 700-800 IU Vitamin D/d and 500-1,200 mg Ca/d • Sparse data on other subgroups • Difficult to identify a specific blood level of 25(OH) D indicative of optimal bone health in all population subgroups

45. Health Effects of Omega-3 Fatty Acids • Asthma • Cancer • Cardiovascular Disease • Cardiovascular Disease Risk Factors • Arrhythmogenic Mechanisms • Child and Maternal Health • Cognitive Function • Eye Health • Type II Diabetes, Rheumatoid Arthritis, and Other Diseases • Mental Health • Organ Transplantation

46. Omega-3 Fatty Acids • 11 reports; 3 EPCs • 9 focused on human studies • 2 focused on animal and in vitro models • Collaborated on methodological elements • Multiple NIH Institutes and Centers • Multiple diseases and risk factors

47. Omega-3 Fatty Acids Or Photo of Menhaden - Courtesy of National Oceanic and Atmospheric Administration (NOAA)

48. Omega-3 and Cancer • RAND EPC (MacLean CH, JAMA 295:403, 2006) • Tumor incidence: prospective cohort studies • Clinical outcomes: RCTs • Tumor behavior: animal, cell culture studies

49. Omega-3 and Tumor Incidence • 19 prospective cohorts, 11 cancers • Breast: 2 significant (1 positive, 1 negative), 5 not significant • Lung: 2 significant (1 positive, 1 negative), 4 not significant • Supported by another systematic review (Hooper L, BMJ 332:752, 2006)

50. Health Effects of Omega-3 Fatty Acids • Secondary CVD Prevention • Reduces all cause mortality and other CVD outcomes (sudden death, cardiac death, MI) • Primary CVD Prevention • Large, consistent beneficial effect found for serum triglyceride levels • Little or no effect found for other CV risk factors and markers of CVD