Nutraceutical and Functional Food Regulations in the United States and around the World

Nutraceutical and Functional Food Regulations in the United States and around the World

Third Edition

Edited by

Debasis Bagchi

Table of Contents

Cover image

Title page

Copyright

Dedication

List of contributors

Preface

Part I. Introduction

Chapter 1. Nutraceuticals and functional foods: innovation, insulation, evangelism, and evidence

1.1. Introduction

1.2. The mirage that moves

1.3. Misinformation and missed opportunities

1.4. Value addition or illusion?

1.5. Transforming evangelism into evidence

1.6. Land mines and weapons of brand destruction

1.7. Mirage to mass demand

1.8. Conclusion

Chapter 2. Nutritional supplements and functional foods: functional significance and global regulations

2.1. Introduction

2.2. History

2.3. Health behaviors and food markets

2.4. Research needs: safety and efficacy

2.5. Conclusion

Chapter 3. Global market entry regulations for nutraceuticals, functional foods, and dietary/food/health supplements

3.1. Introduction

3.2. Market entry requirements

Chapter 4. Industry self-regulatory activities complement FDA’s dietary supplement regulations

4.1. Introduction

4.2. Brief overview of legislative and regulatory history

4.3. Definitions

4.4. Dietary supplement safety

4.5. Dietary supplement labeling

4.6. Food and Drug Administration and Federal Trade Commission guidance

4.7. Industry self-regulatory activities

4.8. Transparency initiatives

4.9. Online databases

4.10. Accountability initiatives

4.11. Best practices and voluntary guidelines

4.12. Advertising

4.13. Conclusion

Chapter 5. The Food Safety Modernization Act (FSMA)’s role in the safety of functional foods and their ingredients

5.1. Introduction

5.2. Existing food safety regulatory framework

5.3. Challenges associated with the US regulatory approach

5.4. The Food Safety Modernization Act

5.5. Summary and concluding remarks

Chapter 6. An overview of gluten-free foods and related disorders

6.1. Introduction

6.2. Serological tests for gluten-related disorder—celiac disease

6.3. Treatment of diagnosed individuals with gluten-related disorders/celiac disease

6.4. Gluten-free flours for pasta-making

6.5. Gluten-free flours for making bread

6.6. Gluten-free foods and FDA recommendations

6.7. Gluten-free food market

6.8. Maintaining a balanced diet while eating gluten-free

6.9. Conclusion

Part II. Manufacturing compliance and analytical validation

Chapter 7. Analytical validation and method development for functional food and nutraceutical manufacturing

7.1. Introduction

7.2. Analytical validation

7.3. Method development [6]

7.4. Analytical method development process

7.5. Specificity

7.6. Linearity

7.7. Accuracy

7.8. Precision

7.9. Limit of detection and limit of quantitation

7.10. Stability

7.11. Robustness

7.12. Quality control on assay [5,6]

7.13. Challenges

7.14. Conclusion

Chapter 8. Natural health products and good manufacturing practices

8.1. Overview

8.2. Who do GMP guidelines apply to?

8.3. GMPs: an introduction

8.4. Basic elements of GMP

8.5. Benefits of GMP/HACCP programs

8.6. GMP procedures: considerations for manufacturers

8.7. Quality management system

8.8. Conclusion

Part III. Importance of safety assessment

Chapter 9. Safety assessment of herbal food ingredients and nutraceuticals

9.1. Introduction

9.2. Ingredient characterization

9.3. Generally Regarded as Safe

9.4. New Dietary Ingredient

Chapter 10. Breaking down the barriers to functional foods, supplements, and claims

10.1. Introduction

10.2. Terminology

10.3. The struggle: players and issues

10.4. DSHEA: SFCs and a new safety standard

10.5. The immediate future and the path forward for the FDA

10.6. Discussion

10.7. Conclusion

Chapter 11. NSF International’s role in the dietary supplements and nutraceuticals industries

11.1. A look at the market

11.2. Brief history of NSF International

11.3. What are Good Manufacturing Practices?

11.4. Importance of independent third-party certification

11.5. Future outlook

Part IV. Regulations around the world

Chapter 12. US regulation of food label claims

12.1. Overview

12.2. Food and Drug Administration’s authority for regulating food label claims

12.3. Health claims

12.4. Structure–function claims

12.5. Nutrient content claims

Chapter 13. Regulatory constraints and considerations on new product formulation and advertising in the United States

13.1. Regulatory requirements surrounding product formulation

13.2. Product claim substantiation constraints and considerations

13.3. Conclusion

Chapter 14. Conventional foods and dietary supplements labeling claims in the United States

14.1. Introduction

14.2. Nutrient content claims

14.3. Structure/function claims

14.4. Health claims

14.5. Dietary guidance statements

14.6. Factual statements

14.7. Nutritional claims display on packages

Chapter 15. Understanding medical foods under FDA regulations

15.1. History of medical foods

15.2. FDA guidance

15.3. Good manufacturing practices and import/export

15.4. FDA enforcement of medical foods

15.5. Looking forward

Chapter 16. Canadian regulatory initiatives for natural health products (dietary supplements)

16.1. Introduction

16.2. What is an NHP?

16.3. Current statistics on the NHPD regulatory products: what do the numbers show?

16.4. NHPs transitioning to food products: a regulatory transition process

16.5. A new approach to regulating NHPs

16.6. Recent modifications by the NNHPD facilitating business and regulatory processes

16.7. The larger picture: mutual recognition agreements

16.8. Postmarket activities following product approval

16.9. Natural Health Products Program evaluation and audit

16.10. Conclusion

Chapter 17. Regulation of dietary supplements and functional foods in Canada

17.1. Introduction

17.2. Foods

Chapter 18. Current legislation in the European context: a focus on food labeling, novel foods, nutrition, and health claims

18.1. Introduction

18.2. The framework of European legislation on food

18.3. Conclusions

Chapter 19. Regulation of functional foods in European Union: assessment of health claim by the European Food Safety Authority

19.1. Introduction

19.2. Health claim assessment of water-soluble tomato extract by European Food Safety Authority

19.3. Scientific substantiation of Fruitflow

19.4. Compositional and structural aspects of Fruitflow

19.5. Human trials using Fruitflow

19.6. Commercially available Fruitflow

19.7. Conclusions

Chapter 20. Botanical nutraceuticals (food supplements and fortified and functional foods) and novel foods in the EU, with a main focus on legislative controls on safety aspects

20.1. Introduction

20.2. The concept of a nutraceutical, past and present

20.3. European Union legislation defining botanicals as medicines or foods

20.4. Novel foods and nutraceuticals

20.5. European Union regulatory status of botanicals nutraceuticals (food supplements and fortified and functional foods)

20.6. Quality of botanical nutraceuticals

20.7. Safety of botanical nutraceuticals

20.8. Efficacy of botanical nutraceuticals

20.9. Discussion and future of botanical nutraceuticals in the European Union

20.10. Conclusion

Chapter 21. Salient features of European Union regulations on nutraceuticals and functional foods

21.1. Introduction

21.2. Introduction to food law

21.3. Legal regulations applicable to the ingredients of functional foods and nutraceuticals

21.4. Marketing principles

21.5. Distribution of functional food and nutraceuticals

21.6. Information on functional food and nutraceuticals provided to consumers

21.7. Conclusions

Chapter 22. History and current status of functional food regulations in Japan

22.1. Introduction

22.2. FoSHU

22.3. Food with nutrient function claim

22.4. Revision of FoSHU categories

22.5. Function evaluation of FoSHU

22.6. Safety evaluation of FoSHU

22.7. Food with functional claims, a new health claim labeling system

22.8. Difference between FoSHU and FFC

22.9. Current status of FFC

Chapter 23. Health foods and foods with health claims in Japan

23.1. Introduction

23.2. Historical development of FFs

23.3. HF

23.4. Regulatory systems on HF

23.5. FA

23.6. FHC

23.7. FSDU

23.8. FOSHU

23.9. FNFC

23.10. FFC

23.11. Safety

23.12. Discussion

Chapter 24. Foods with function claims emerging from the framework of so-called health foods

24.1. Introduction

24.2. Foods with function claims system

24.3. So-called health foods to foods with function claims

24.4. Impacts on stakeholders

24.5. Potential challenges

24.6. Conclusion

Chapter 25. Complementary medicine regulation in Australia

25.1. Introduction

25.2. What complementary medicines are

25.3. How complementary medicines are regulated in Australia

25.4. Adverse events reporting for complementary medicines

25.5. Advertising of complementary medicines

25.6. Attitudes of consumers and healthcare professionals to complementary medicines

25.7. Recent reforms

25.8. Commentary

Chapter 26. Russian regulations on nutraceuticals, functional foods, and foods for special dietary uses

26.1. Introduction

26.2. Russian regulations on nutraceuticals

26.3. Russian regulations on functional foods

26.4. Russian regulations on foods for special dietary uses

Chapter 27. Road map to enter Indian nutraceuticals and health supplements business

27.1. Introduction

27.2. Scope of the regulations

27.3. Categories of products

27.4. General requirements of the regulations

27.5. Schedules

27.6. Claims

27.7. Salient features of the regulations

27.8. Approval of nonspecified food and food ingredients

27.9. Conclusion

Chapter 28. Nutraceutical and functional food regulations in India

28.1. Introduction

28.2. Positioning benefits

28.3. Indian market and health

28.4. Regulation

28.5. Emerging opportunities

28.6. Regulation of claims pertaining to nutraceuticals

28.7. Licensing and registration requirements

28.8. Recommendations and conclusion

Chapter 29. Regulations on nutraceuticals, functional foods, and dietary supplements in India

29.1. Introduction

29.2. Food Safety and Standards Act

29.3. Multilevel marketing/direct selling

29.4. Department of Ayurveda, Yoga, and Naturopathy, Unani, Siddha, and Homoeopathy AYUSH

29.5. Probiotic regulatory overview

29.6. Conclusion

Chapter 30. Change in raw materials and claims of health food regulations in China 2013–17

30.1. Introduction

30.2. Definition of health functional foods

30.3. Evolution of permitted claims for health foods

30.4. Update on raw materials used in health functional foods

30.5. Nutrient supplements

30.6. Health functional food approval between 2013 and 2017

Chapter 31. Regulations on health/functional foods in Korea

31.1. Introduction

31.2. The Health/Functional Food Act

31.3. Generic HFFs

31.4. Product-specific HFFs

31.5. Advisory committees

31.6. Future perspectives

Chapter 32. Phytomedicines, nutraceuticals, and functional foods regulatory framework: the African context

32.1. Introduction

32.2. African herbal medicine

32.3. Regulatory status of botanical drugs and functional foods in Africa

32.4. Food nanotech applications

32.5. Conclusion

Chapter 33. Regulation of functional foods in selected Asian countries in the Pacific Rim

33.1. Introduction

33.2. Taiwan

33.3. Hong Kong

33.4. South Korea

33.5. Malaysia

33.6. Indonesia

33.7. Philippines

33.8. Singapore

33.9. Thailand

Chapter 34. Regulations, opportunities, and key trends of functional foods in Malaysia

34.1. Introduction

34.2. Western versus Eastern perspective on functional foods

34.3. Functional foods and the unique Malaysian society

34.4. Functional food research in Malaysia from business and marketing perspectives

34.5. Overview of the regulatory environment in Malaysia

34.6. Functional foods opportunities in Malaysia

34.7. Overview of the Malaysia food retail sector

34.8. Key trends and challenges for functional foods

34.9. Conclusion

Chapter 35. World Trade Organization and food regulation: impact on the food supply chain

35.1. Introduction

35.2. Sanitary and phytosanitary agreements

35.3. Hazard at critical control point

Part V. Kosher & halal certification

Chapter 36. Kosher and halal regulations for nutraceutical and functional foods

36.1. Introduction

36.2. Kosher and halal laws

36.3. The kosher and halal market

36.4. The kosher dietary laws with reference to halal dietary laws

36.5. Additional information about the halal dietary laws

36.6. Both kosher and halal

Chapter 37. Kosher certification of nutraceuticals and dietary supplements

37.1. Introduction

37.2. Vitamin D3 from Peruvian fish oil

37.3. Ashwagandha extract from India

37.4. Kale chips from Mexico

37.5. Kosher status of inactive ingredients: solvents, diluents, and excipients

37.6. Status of uncertified nutraceuticals and functional foods

Part VI. Regulations on pet food

Chapter 38. Functional ingredients in the pet food industry: regulatory considerations

38.1. Introduction

38.2. Regulatory bodies

38.3. Regulatory approval of the manufacturing facility

38.4. Regulatory approval of pet food ingredients

38.5. Globally accepted pet food ingredients

38.6. Regulation trends in pet food ingredients

38.7. Pet food safety

38.8. GMO

38.9. Labeling as natural

38.10. Links

Part VII. Adverse event reporting

Chapter 39. Global adverse event reporting regulations for nutraceuticals, functional foods, and dietary/food/health supplements

39.1. Introduction

39.2. Global adverse event monitoring and reporting regulations

39.3. Postmarket surveillance versus adverse event reporting

39.4. Guidance for industry and regulators

Part VIII. Intellectual property, branding, trademark and regulatory approvals in nutraceuticals and functional foods

Chapter 40. Intellectual property, branding, trademark, and regulatory approvals in nutraceuticals and functional foods

40.1. Introduction

40.2. Nutraceuticals, patent rights, and bioprospecting

40.3. Branding: a hypothetical case scenario

40.4. Conclusion

Chapter 41. Challenges of intellectual property and branding on regulatory approvals

41.1. Introduction

41.2. Patents

41.3. Patents outside the United States

41.4. Trade secrets

41.5. Trademarks

Index

Copyright

Academic Press is an imprint of Elsevier

125 London Wall, London EC2Y 5AS, United Kingdom

525 B Street, Suite 1650, San Diego, CA 92101, United States

50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States

The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom

Copyright © 2019 Elsevier Inc. All rights reserved.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.

This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices

Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.

Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.

To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

Library of Congress Cataloging-in-Publication Data

A catalog record for this book is available from the Library of Congress

British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library

ISBN: 978-0-12-816467-9

For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Charlotte Cockle

Acquisition Editor: Nancy Maragioglio

Editorial Project Manager: Hilary Carr

Production Project Manager: Divya Krishna Kumar

Cover Designer: Mark Rogers

Typeset by TNQ Technologies

Dedication

Dedicated to Dr. Sankar Basak, Ph.D., who is my friend, philosopher, and guide. Sankar is blessed with an unique talent and skill in mathematics, and he taught me mathematics.

List of contributors

Jennifer Adams,     Amin Talati Upadhye LLP, Chicago, IL, United States

Sanjiv Agarwal,     NutriScience LLC, East Norriton, PA, United States

Imtiaz Ahmad,     Cepham Life Sciences, Inc., Baltimore, MD, United States

Sameer K. Akolkar,     Laila Nutraceuticals, Vijayawada, India

Anthony L. Almada,     IMAGINutrition, Inc., Dana Point, CA, United States

Rend Al-Mondhiry,     Amin Talati Upadhye LLP, Chicago, IL, United States

Okezie I. Aruoma

Department of Chemistry and Biochemistry, California State University Los Angeles, Los Angeles, CA, United States

School of Professional Studies, Southern California University of Health Sciences, Whittier, CA, United States

Debasis Bagchi,     Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX, VNI, Inc. Lederach, PA, United States

Theeshan Bahorun,     ANDI Centre of Excellence for Biomedical and Biomaterials Research, University of Mauritius, Réduit, Republic of Mauritius

Jordan R. Bailey,     Venable LLP, Washington, DC, United States

Kiran Bhupathiraju,     Laila Nutraceuticals, Vijayawada, India

Katie Bond,     Amin Talati Upadhye LLP, Chicago, IL, United States

George A. Burdock,     Burdock Group, Orlando, FL, United States

Ioana G. Carabin,     Island ENT, Key West, FL, United States

Alessia Cavaliere,     Department of Environmental Science and Policy, Università degli Studi di Milano, Milan, Italy

Digambar Chahar,     Consulting Quality & Regulatory Affairs Scientist, Mississauga, ON, Canada

Pradip Chakraborty,     Food Safety and Standards Authority of India, New Delhi, India

Jayson Chen,     Product Safety Labs, Dayton, NJ, United States

Gregory J. Chinlund,     Marshall, Gerstein & Borun LLP, Chicago, IL, United States

Leighton K. Chong,     Udell Associates, Castro Valley, CA, United States

Patrick Coppens,     EAS Strategies, Brussels, Belgium

Willette M. Crawford,     Katalyst Consulting, LLC, Tiburon, CA, United States

Amitava Das,     Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, United States

Praneel Datla,     Laila Nutraceuticals, Vijayawada, India

Cristian Del Bo’,     Division of Human Nutrition, Department of Food, Environmental and Nutritional Sciences (DeFENS), Università degli Studi di Milano, Milan, Italy

Bernard W. Downs,     VNI, Inc. Lederach, PA, United States

Meggan F. Duffy,     Marshall, Gerstein & Borun LLP, Chicago, IL, United States

Asim K. Duttaroy,     Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway

Matthew Farrell,     Gowling WLG (Canada) LLP, Ottawa, ON, Canada

Thomas Frey,     NSF International, Ann Arbor, MI, United States

Dilip Ghosh,     Nutriconnect, Sydney, Australia

Nandini Ghosh

Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, United States

Department of Human Nutrition, The Ohio State University, Columbus, OH, United States

Trimurtulu Golakoti,     Laila Nutraceuticals, Vijayawada, India

Raghavendra Gowda,     Product Safety Labs, Dayton, NJ, United States

James C. Griffiths,     Council for Responsible Nutrition, Washington, DC, United States

Neelam Gulati,     Quest Picong Sàrl, Étoy, Switzerland

Om P. Gulati,     Quest Picong Sàrl, Étoy, Switzerland

John R. Harrison,     JRH Toxicology, Ottawa, ON, Canada

Michael Harvey,     NSF International, Ann Arbor, MI, United States

James E. Hoadley,     EAS Consulting Group, Alexandria, VA, United States

Stein Hordvik,     Hordvik’s Consulting, Elkhorn, NE, United States

Chun Hu,     Nutrilite Health Institute, Buena Park, CA, United States

Hideko Ikeda,     Biohealth Research Ltd., Tokyo, Japan

Michelle C. Jackson,     Venable LLP, Washington, DC, United States

Urmila Jarouliya,     School of Studies in Biotechnology, Jiwaji University, Gwalior, India

Sam Jennings,     Berry Ottaway and Associates Limited, Hereford, United Kingdom

Sewon Jeong,     BiofoodCRO Co., Ltd., Seoul, South Korea

Danielle K. Johnson,     Marshall, Gerstein & Borun LLP, Chicago, IL, United States

Raj K. Keservani,     School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Bhopal, India

Ji Yeon Kim,     Department of Food Science and Technology, Seoul National University of Science and Technology, Seoul, South Korea

Seong Ju Kim,     Ministry of Food and Drug Safety, Chungcheongbuk-do, South Korea

Alla A. Kochetkova,     Federal Research Centre of Nutrition, Biotechnology and Food Safety (former Institute of Nutrition of the Russian Academy of Medical Sciences), Moscow, Russia

Alluri V. Krishnaraju,     Laila Nutraceuticals, Vijayawada, India

Lisa Glymph Lattimore,     NSF International, Ann Arbor, MI, United States

Teck-Chai Lau,     Department of International Business, Universiti Tunku Abdul Rahman (UTAR), Cheras, Kajang, Malaysia

Claudia A. Lewis,     Venable LLP, Washington, DC, United States

Daniela Martini,     Human Nutrition Unit, Department of Food and Drugs, University of Parma, Parma, Italy

Nikita McGee,     Coldwell Banker Gundaker, O’Fallon, MO, United States

Colleen McMullin,     Gowling WLG (Canada) LLP, Ottawa, ON, Canada

Odete Mendes,     Product Safety Labs, Dayton, NJ, United States

Sandra Morar,     McGrath North Mullin & Kratz PC LLO, Omaha, NE, United States

Hiroyoshi Moriyama,     The Japanese Institute for Health Food Standards, Bunkyo-ku, Tokyo, Japan

Chelsea M. Murray,     Marshall, Gerstein & Borun LLP, Chicago, IL, United States

Vidushi S. Neergheen-Bhujun

ANDI Centre of Excellence for Biomedical and Biomaterials Research, University of Mauritius, Réduit, Republic of Mauritius

Department of Health Sciences, Faculty of Science University of Mauritius, Réduit, Republic of Mauritius

Haiuyen Nguyen,     Council for Responsible Nutrition, Washington, DC, United States

Hirobumi Ohama,     Biohealth Research Ltd., Tokyo, Japan

Peter Berry Ottaway,     Berry Ottaway and Associates Limited, Hereford, United Kingdom

Tobey-Ann Pinder,     SFI Australasia, Sydney, Australia

Jon-Paul Powers,     Gowling WLG (Canada) LLP, Ottawa, ON, Canada

Rabbi Gavriel Price,     Ingredients Approval Registry, Orthodox Union, New York, NY, United States

Jennifer Radosevich,     Hill’s Pet Nutrition, Topeka, KS, United States

Nancy E. Rawson,     Monell Chemical Senses Center, Philadelphia, PA, United States

Joe M. Regenstein,     Cornell Kosher and Halal Food Initiative, Department of Food Science, Cornell University, Ithaca, NY, United States

Lewis Retik,     Gowling WLG (Canada) LLP, Ottawa, ON, Canada

Chandan K. Sen

Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, United States

Department of Human Nutrition, The Ohio State University, Columbus, OH, United States

Krishanu Sengupta,     Laila Nutraceuticals, Vijayawada, India

Andrew Shao,     Global Nutrition Solutions, LLC, Los Angeles, CA, United States

Anil K. Sharma,     School of Medical and Allied Sciences, GD Goenka University, Gurugram, India

Jeffrey S. Sharp,     Marshall, Gerstein & Borun LLP, Chicago, IL, United States

Julia Shenkar,     Council for Responsible Nutrition, Washington, DC, United States

Svetlana A. Sheveleva,     Federal Research Centre of Nutrition, Biotechnology and Food Safety (former Institute of Nutrition of the Russian Academy of Medical Sciences), Moscow, Russia

Makoto Shimizu

The University of Tokyo, Tokyo, Japan

Tokyo University of Agriculture, Tokyo, Japan

Elena A. Smirnova,     Federal Research Centre of Nutrition, Biotechnology and Food Safety (former Institute of Nutrition of the Russian Academy of Medical Sciences), Moscow, Russia

Boris P. Sukhanov,     Federal Research Centre of Nutrition, Biotechnology and Food Safety (former Institute of Nutrition of the Russian Academy of Medical Sciences), Moscow, Russia

Anand Swaroop,     Cepham Inc., Somerset, NJ, United States

Izabela Tańska,     IGI Food Consulting, Warsaw, Poland

John Travis,     NSF International, Ann Arbor, MI, United States

Victor A. Tutelyan,     Federal Research Centre of Nutrition, Biotechnology and Food Safety (former Institute of Nutrition of the Russian Academy of Medical Sciences), Moscow, Russia

Lawrence J. Udell,     Udell Associates, Castro Valley, CA, United States

Jessica White,     Gowling WLG (Canada) LLP, Ottawa, ON, Canada

Jerzy Zawistowski,     University of British Columbia, Faculty of Land and Food Systems, Food, Nutrition, and Health, Vancouver, BC, Canada

Preface

It is quite exciting and thrilling to restructure and redesign Nutraceuticals and Functional Food Regulations in the United States and around the World for its third edition, highlighting salient features of regulatory updates around the globe and their impact on manufacturers, consumers, traders, and social infrastructure. Innovation and marketing of nutraceuticals and food supplements are one of the fastest growing segments in the world economy [1]. Concurrently, rising costs and the alarming toxicity of drugs and pharmaceuticals are driving the world to move forward with less expensive but safety-affirmed nutraceuticals and functional foods. Backed by scientific research studies and clinical investigations. these well-known and recognized nutraceuticals and functional foods include vitamins, antioxidants, structurally diverse dietary supplements and botanical supplements; functional beverages such as sport and energy drinks; as well as products fortified with probiotics.

Indeed, we are delighted to partner with Elsevier/Academic Press in publishing the third edition of the book. This edition is particularly expanded to broaden the reader’s scope and understanding of the intricate aspects of nutraceutical and functional food regulatory changes and how these changes will ultimately help consumers, researchers, and scientists working in the field, including regulatory and health professionals and public health advocates.

The term nutraceuticals has no existence in the United States as a regulatory category. However, in 1980, the term functional foods was used by the Japanese government during the regulatory approval process for functional foods, which referred to them as Foods for Specified Health Use (FOSHU). Currently, the International Food Information Council defines functional foods as foods or food components that may provide benefits beyond basic nutrition; possibly, this will serve as a foundational definition.

Despite this lack of a consistent definition, regulatory constraints are enforced in the United States and around the world, and this third edition has made it a point to include those constraints. For example, the European Food Safety Authority (EFSA) has enforced the need to provide scientific requirements for health claims and to find new regulatory issues for health food products. Accordingly, the EFSA asked its Dietetic Products, Nutrition, and Allergies panel to draft additional guidelines on scientific assessment of these claims. A new approach for a strict substantiation of health issues in selected fields, Regulation (EC) No. 1924/2006, established that health claims applications should be authorized only after a high level of scientific validation conducted by the EFSA using appropriate measures in the evaluation. The legislation should not only protect consumers but also define specific research areas with appropriate outcome measures to assess the quality, relevance, safety, and adequacy of studies conducted for the scientific validation of health claims. Similarly, in Japan, which is well-known to be the world’s functional foods birthplace, FOSHU is classified as a food, of which a functional component was identified, of which the biological regulation function has been confirmed in clinical trials, and of which a health claim is permitted by the Ministry of Health, Labor, and Welfare. This new edition explores and addresses the impact of these classification definitions.

The third edition has 11 updated chapters providing health food regulatory aspects from North America, Canada, the United Kingdom, Europe, Australia, Asia, Africa, and selected countries in the Pacific Rim. A chapter is now included from the Council of Responsible Nutrition (CRN), a well-recognized US-based organization whose mission is to enhance a professional and regulatory climate to responsibly develop, manufacture and market dietary supplements [2], functional foods, and nutritional ingredients. A total of 91 well-reputed authors and coauthors contributed to this third edition.

Part I: Introduction. The opening section of this edition discusses the scope and significance of global regulations on nutraceuticals and functional foods, market opportunities, and future directions of nutraceuticals and functional foods. With the inclusion of an exploration of global market entry regulations and the mission of CRN in enhancing the standards and compliance of nutraceuticals and functional foods, the reader will find insight into the role of the Food Safety Modernization Act (FSMA) in the safety of functional food ingredients [3], and the pros and cons of gluten-free foods.

Part II: Manufacturing compliance and analytical validation emphasizes the impact of Good Manufacturing Practice and Current Good Manufacturing Practice compliance on consumer confidence in dietary supplements.

Part III: Importance of safety assessment presents the importance of safety assessments, Generally Recognized As Safe Status, efficacy aspects, and allied claims of the functional foods and nutraceuticals. The international role of NSF in the dietary supplement and nutraceutical industries is included to provide perspective.

Part IV: Regulations around the world includes expert insight into US regulations on food label claims, US regulatory constraints and considerations regarding new product formulations and advertisement aspects, and nutritional claims for functional foods and supplements in the United States. An understanding of medical foods under Food and Drug Administration regulations for US and Canadian regulations and the intricate aspects of the Natural Health Products Directorate are also presented in individual chapters.

European regulations are individually demonstrated, presenting the health claims made for botanically sourced functional and fortified foods and food supplements in the European Union.

Japanese regulations are included, as well as a chapter especially focused on health claims, which also explains the intricate aspects of FOSHU.

Australian and Russian regulations are presented, as are nutraceutical and functional food regulations in India, China, Korea, and Africa. An extensive review is provided of the regulatory system for functional foods in the eight countries of the Pacific Rim (Taiwan, Hong Kong, South Korea, Malaysia, Indonesia, Singapore, the Philippines, and Thailand) as well as their diverse acts, regulations, and guidelines. Moreover, Malaysian regulations are summarized, as is the impact of World Trade Organization and food regulation on the food supply chain.

Part V. Kosher and halal certification is a new part for this edition, highlighting the emerging importance of these foods and their preparation for targeted health as well as societal roles.

Part VI. Regulations on pet foods provides a thorough overview of the stringent pet food regulations.

Part VII. Adverse event reporting. Global adverse event reporting regulations are becoming important for the nutraceutical and functional food industries. Keeping in mind the timely need, a detailed chapter on global adverse event reporting regulations on functional foods as well as dietary, food, and health supplements has been included.

Part VIII. Intellectual property, branding, trademark, and regulatory approvals in nutraceuticals and functional foods. This important aspect is covered with the latest information.

As with the previous editions, this new edition is designed to ensure that health professionals, nutritionists, and regulatory toxicologists can work together strategically to derive appropriate regulations to provide optimal health, nutrition, and therapeutic benefits to mankind.

Finally, I offer my sincere regards and gratitude to all of the eminent scientists, researchers, doctors, and authors who contributed to this book. My very special thanks go to Ms. Nancy Maragioglio, who always extended her utmost and prompt support, cooperation, and criticisms, and Ms. Hilary Carr, for continued support, help, and cooperation.

References

[1] U.S. functional foods market - statistics & facts. https://www.statista.com/topics/1321/functional-foods-market/.

[2] CRN survey reaffirms trust and confidence in dietary supplement industry. https://www.nutraceuticalsworld.com/contents/view_breaking-news/2018-10-19/new-data-from-crn-survey-reaffirm-trust-and-confidence-in-industry/2013.

[3] Understanding FSMA’s impact. https://www.nutraceuticalsworld.com/issues/2014-11/view_columns/understanding-fsmas-impact.

Part I

Introduction

Outline

Chapter 1. Nutraceuticals and functional foods: innovation, insulation, evangelism, and evidence

Chapter 2. Nutritional supplements and functional foods: functional significance and global regulations

Chapter 3. Global market entry regulations for nutraceuticals, functional foods, and dietary/food/health supplements

Chapter 4. Industry self-regulatory activities complement FDA’s dietary supplement regulations

Chapter 5. The Food Safety Modernization Act (FSMA)’s role in the safety of functional foods and their ingredients

Chapter 6. An overview of gluten-­free foods and related disorders

Chapter 1

Nutraceuticals and functional foods

innovation, insulation, evangelism, and evidence

Anthony L. Almada     IMAGINutrition, Inc., Dana Point, CA, United States

Abstract

What factors overcome innovation inertia, compelling a nutrition business entity to develop products that promise and deliver consumer-relevant benefits? In the absence of innovation, and amidst the stream of invention, can an enduring bioactive ingredient or finished good be created that enjoys an extended life cycle? When such innovations are achieved, what recourse does the innovator have to exclude ostensible duplicates and protect the investment? Within a global climate of regulatory underenforcement and ubiquitous messaging of unsubstantiated claims, can a viral spread of science-driven enterprise manifest and infect even 25% of the industry? Will consumer-centric legal actions eclipse the might of governmental agencies and inject a decisive, otherwise lacking swiftness? Will a brand emerge that enjoys an inspiring evidence base on each bioactive or finished good? Where does the ripe, high-hanging fruit rest for the pioneering innovator brand and company willing to climb where others avoid it?

Keywords

Bioactive; Class action lawsuit; Clinical trial; Functional beverage; Functional food; Gluten; Glycemic index; Innovation; Nutraceutical; Patent and freedom to operate

You’ve got to start with the customer experience and work backwards to the technology. You can’t start with the technology and try to figure out where you’re going to try to sell it.

Steve Jobs

1.1. Introduction

The nutrition industry thrives within a global footprint, enjoying substantial economic momentum and growth. Attending this trajectory are incremental regulatory enforcement actions and civil litigation. In this chapter I define nutraceuticals, an industrial term languishing without a regulatory definition, as supplements or complements to the diet composed of bioactives occurring in food or produced de novo in human metabolism, biologicals (e.g., a probiotic strain), and botanicals (or their constituents), each intended to impart a physiological or medicinal effect after ingestion; and vitamins and minerals, delivered in forms that differ from conventional foods or beverages (e.g., solid dosage forms such as capsules, tablets, powders, or liquid extracts). Functional foods and beverages, another nutrition industry/scientific community descriptor lacking a regulatory parent, I define as before, yet delivered in conventional food and beverage formats (e.g., a single-serving beverage, a fermented dairy product, or a food bar). This may also include fortified foods and beverages such as vitamin D–enriched milk, calcium-enriched almond milk, or a probiotic-enriched bread. Collectively, I will refer to these two classes as NFx. Biologically, NFx are intended to impart a physiological, pharmacological, or medicinal effect, without or in addition to a nutritional effect.

1.2. The mirage that moves

The consumer promise of an NFx holds the allure of improved or preserved physiologic and/or metabolic function, or it may be in the context of physical or anatomical features. The spectrum of consumer expectation ranges from disease or condition prophylaxis to disease or condition treatment, and even to cure. The quest for natural and –free, the drive to engage in self-care, and the nearly boundless access to the virtual, ostensibly omniscient reference libraries called the Internet, social media, and customer reviews have forged a new breed of companies and consumers. Armed and dangerous, with a modicum of evidence or a scroll of testimonials, bioactives are birthed, brands are born, products are launched, tribes are formed, and evangelists disseminate the faith-based message. Indeed, the global NFx industrial complex may vie with organized religion for the title of largest faith-based industry. Few consumers activate critical thinking skills and employ scrutinizing due diligence in their path to buy a new NFx, to the degree seen when buying a durable good (e.g., a new computer, car, or home appliance). Given the absence of a central depository, an authoritative and ultracurrent clearinghouse for brand-specific evidence, the mirage of improved health and function moves through new ingredient and theme deserts, unaccompanied by thoroughly informed navigators and caravans of confidence.

1.3. Misinformation and missed opportunities

In the world of NFx, from a seedling of science often emerges a fad or a trend. In 1981, a Canadian research team developed the glycemic index (GI), a tool conceived to provide a physiological metric related to a carbohydrate-containing food, supplement, or beverage and its influence on blood glucose dynamics [1]. An NFx exhibiting a high GI value is widely believed to deliver its glucose to the circulation at a faster rate, whereas an NFx displaying a low GI value is believed to deliver its glucose at a slower rate. However, the GI does not reflect the rate of digestion and absorption of glucose entering the blood [2–7]. Rather, it is simply the net result of glucose influx into the blood (from the gut and hepatic gluconeogenesis) less glucose efflux (primarily disposal into tissues, especially skeletal muscle and liver among insulin-sensitive individuals) over a certain time interval (usually 2   h). Despite this, numerous influencers and NFx marketers assert that GI is correlated to the rate of glucose influx and the insulinemic response, that fiber has a slowing effect, or that a low GI NFx is equivalent to a slow-burning carbohydrate [8–11], despite zero or contravening, direct evidence in place [2–7].

A more recent entrant into the faith-fueled NFx category is the gluten-free moniker. Despite the identifier, a gluten-free NFx is not free or devoid of gluten but exhibits <5–20 parts per million (ppm) of gluten in the final consumable form, varying by country or region (Note: The most stringent regulatory standard is in Australia and New Zealand, where an ingestible good bearing the gluten-free moniker must have undetectable gluten, currently <5   ppm. In Canada [Health Canada], the European Union [Codex Alimentarius], and the United States [Food and Drug Administration], <20   ppm earns a gluten-free badge). An NFx that is gluten-free yet contains gluten below the regulatory definition ceiling may differ from what many consumers would expect. It may be unsettling to a person newly diagnosed with celiac disease, after years of a fruitless diagnostic sojourn, that an NFx bearing a certified gluten-free imprint does not require quantitative postmanufacturing testing for gluten on each batch of any certified product. This imparts a questionable degree of confidence to the gluten-sensitive or celiac individual (who typically pays a premium for gluten-free). What if a manufacturing or labeling error or omission was committed, or an intentional act of domestic bioterrorism was perpetrated within a manufacturing facility, rendering an NFx labeled as gluten-free to be effectively gluten-rich?

The introduction of gluten-free Cheerios (oats are devoid of gluten but at risk for cross-contamination in postharvest processing) in July, 2015 was swiftly met by a US-wide recall equivalent to the population of the state of West Virginia: 1.8   million boxes [12]. Because the brand owner (General Mills) did not conduct postproduction/finished good quantitative gluten assays on each batch, the misbranded cereal entered commerce and the guts of celiacs and gluten-sensitive individuals. Had quantitative gluten testing been implemented, the incendiary error (addition of wheat flour to the dry blend) would have been detected and the defective lots would have been destroyed. Recent analyses of gluten-free manufactured and restaurant foods in Australia, where the most rigorous standard for gluten-free status resides (<5   ppm), revealed that numerous offerings do not meet this criterion; some display a gluten content of up to 51   ppm [13,14].

The prevalence of finished good-quality assurance practices that are below consumer expectations invites consumer diffidence and offers a distinctive brand or positioning opportunity: the tenacious pursuit and communication of consumer confidence through chemical quality assurance.

In the first edition of this book, I wrote:

From this author’s perspective the NFx products that enjoy (or have enjoyed) robust, sustainable revenues are those defined by one of two phenomena: 1) consumer experience, and 2) high circulation, incremental media editorial messaging.

Reflecting on this passage, I see the lack of emphasis on the operative phrase one of two and the word sustainable as problematic. Numerous NFx action words and phrases (low glycemic; gluten-free; probiotic, personalized; and ketogenic) enjoy moderate to broad consumer awareness, linked to salutary or desirable effects. However, few enjoy robust and sustainable (or incremental) revenues, with less being buttressed by an even semicompelling evidence base.

1.4. Value addition or illusion?

Our own market and scientific research continues to indicate that less than one out of 1000 finished NFx products—not individual bioactive ingredients, but the final form purchased and ingested by a consumer—enjoys at least a single randomized controlled trial (RCT) performed against a placebo or a positive control (e.g., an appropriate drug), demonstrating a statistically significant outcome superior to that of the placebo, or equivalent or even superior to a positive drug comparator. Add the additional criterion of such an RCT published in a reviewed journal, and the percentage of qualifying NFx falls precipitously. What is more unsettling is our finding that of the approximately 300–400 RCTs conducted on NFx products in North America annually, only a fraction are made public (via presentation or publication). This underscores the prevalence of publication bias and reveals the far more haunting truth that data suppression is common. Sadly, the gagging of investigators related to dissemination of clinical trial data on NFx products reaches the ranks of publicly traded and multinational NFx marketing entities. Burial of these data is achieved by increasing numbers of studies performed with contract research and clinical service organizations, where data ownership and intellectual property rights are exclusive to the study sponsor.

The emergence and adoption of clinical trials registries (http://clinicaltrials.gov/; http://www.controlled-trials.com; https://www.clinicaltrialsregister.eu/ctr-search/search) has augmented the integrity of reporting while reducing publication bias, albeit in biomedical journals that require timely clinical trial registration (before enrolling the first participant within a specified grace period). A large proportion of the journals that entertain a large number of NFx publications do not require registration of a clinical trial as an inclusion criterion for publication (and editors of the elite journals may assert that the rigor and sample size of many NFx manuscripts do not warrant inclusion in their journals). That a notable number of registered clinical trials on NFx do not publish their results after completion suggests that clinical trial registration alone is insufficient to convey transparency of research outcomes. Nevertheless, the adoption of clinical trial registration requirements [15] by the editors of journals that de facto cater to NFx manuscripts would raise the bar.

The importance and utility of NFx are defined not by revenues, share price, the annualized number of product introductions, or calculated annual growth rate of the sector. NFx should serve the consumer by making a favorable, measurable impact on her or his biology, congruent with the claimed benefit of the product and perhaps beyond. A branded kombucha beverage that improves laxation and decreases the incidence of upper respiratory tract infections over a winter period could become a product that creates a tectonic plate shift in this wholly non-validated claims category. The provision of NFx products, in its purest form, can be viewed as a public health initiative centered on offering consumer goods that meet four criteria: (1) excellent tolerability and hedonics, at least equal to the conventional food or beverage category leader (for solid dose forms, excellent tolerability, acceptable dose amount/frequency, and ease of use or swallowing); (2) demonstration of consumer-relevant and scientific community-relevant efficacy through an incremental series of systematic studies in humans; (3) aligning with existing, demographically dense unmet or under-met needs; and (4) remaining within a consumer price comfort zone for a large consumer base (which could mean as few as 200,000 persons, like a rare or orphan disease in the United States).

Aversion to good-for-you foods and beverages can be a significant deterrent for many consumers. The emergence of plant protein-derived NFx, arguably pioneered by Vega in British Columbia, has likely expanded the base of protein-centric consumers. However, the trajectory of broad consumer adoption has been variably blunted by sensory aversion to the mouthfeel aspects of relatively insoluble proteins (relative to milk-derived proteins) within a large retail club chain in the United States [16]. Creating an equal or superior sensory experience with a functional food or beverage can have a dramatic impact on consumer trial and repeat purchasing. The post-ingestive experience also has significant import, especially in relation to gastrointestinal symptoms. NFx products that are intended to have a gastrointestinal effect (e.g., prebiotics, probiotics, or synbiotics) have a high likelihood of causing transient gut distress (bloating and flatulence). Solid dose forms need to be delivered in a manner that does not require multiple dosing throughout the day or large dose formats (e.g., large tablets or capsules). Liquids need to be easily measured and palatable, with masking/debitterizing agents considered for use. Powders need to be easily mixable and nonhygroscopic under normal storage conditions. Unrelenting growth and interest in natural and sugar-free also demands NFx compositions to seek natural, non- or low-caloric bulk and/or high-intensity sweetener systems that exhibit high gut tolerability and palatability.

1.5. Transforming evangelism into evidence

One cannot emphasize the critical need for a series of clinical trials on an NFx. The most prevalent micronutrient deficiency in North America is not a vitamin, fatty acid, or trace mineral. It is vitamin C²: CONSUMER CONFIDENCE. One element lacking among consumers and critics of NFx products is confidence: in the claims, in the taste, in the composition, and in the brand. A specific consumer product buttressed by even one well-designed, independent RCT, in which the number of servings or dose used in the study matches the labeled use directions and is not cost-prohibitive, can exalt a brand into a new level of equity with consumers. It is a widely held misperception that sponsoring an RCT requires a budget in excess of $100,000. Harkening back to our finding of less than 0.1% prevalence of an NFx with at least one RCT demonstrating efficacy, even an RCT pilot study with a sample size of 12–20 (or half this, if employing a crossover design) would confer distinction. A follow-up study, fueled by incremental revenues from the sales of the NFx, with a larger sample size and longer duration, would allow for the creation of a foundation of evidence.

Considering the allocation of resources by NFx companies to marketing, advertising, promotions, and sales, it is typically feasible for even early-stage companies to capitalize a clinical research program. It is not a matter of economics: it requires an executive commitment to invest in evidence-based NFx goods. Unlike pharma and life sciences industries, the vast majority of individuals leading NFx business entities are science-illiterate and -averse and have escalated the ranks through sales, marketing, or business development capacities. This is coupled with an ignorance of how to monetize product-specific human science, which further magnifies the resistance to invest. The design of resource allocations and financial forecasts that integrate a gross proceeds or revenue-dependent allocation (percentage, e.g., 0.5%–2.5%) of cash to human/research investigations allows for the generation of research and development tax credits and an evidence-plus demand creation-anchored business.

A pivotal element in the monetization of product-specific clinical science is the public communication of positive results (oral or poster presentation at a national or international scientific or medical conference) and/or publication of the RCT (in a reviewed journal, ideally at or above the median impact factor for journals in the relevant category). This can become the axis of a strategic communications campaign that yields editorial mention in print (newspapers and magazines), online (health and medical news-focused websites), and on air (television and radio). Editorial mention of science linked to a branded NFx can generate dialogue among consumers, elevate awareness, and potentially increase demand and trial purchase velocity. Global surveys suggest that the best communicator of such evidence (outside editorial journalism) may be a technical or academic expert, or the chief executive officer (CEO), on behalf of a brand or company [17]. This survey (n   >   33,000) by Edelman Intelligence speaks to the impact of fake news and profiles the precipitous fall of trust across all institutions (nongovernmental organizations, business, media, and government) among the United States’ informed public, those with higher levels of income and education. Leveraging these data as part of an integrated media or brand messaging strategy may complement the creation of evidence-based NFx compositions and augment demand and brand allegiance.

The path to strategic innovation mandates both a keen awareness of consumer needs and linked demographics, those that are unmet and under-met. Latent needs (not readily apparent or acknowledged by the consumer), albeit a potentially viable pursuit, often require more intensive education and awareness generation. An unmet need would be an NFx that reproducibly reduces lesion size and count, symptom score, and patient-reported outcome measures [18] among persons living with psoriasis (there does not appear to be an NFx that enjoys solid evidence of such). An under-met need would be an NFx that reduces the score of atopic eczema [19] and increases sleep quality. Demographics and market size are important elements to consider for innovation direction. NFx products targeted to orphan applications (e.g., scleroderma or McArdle disease) are altruistic and admirable but may produce unsatisfactory yields if they are positioned as a primary revenue generator. These pursuits may also require higher retail pricing to obtain a satisfactory return on investment.

Cost to the consumer (the price they must pay to begin enjoying the benefits of an NFx) must be determined before allocating resources. This will vary from country to country. The price will have a segmenting effect upon which socioeconomic demographic the product needs to be positioned. One interesting phenomenon that could happen with higher or premium-priced NFx products is the bandwagon effect [13]. This is described as consumer demand increasing as the number of consumers buying the good increases. This is often achieved by the conspicuous consumption or overt recommendation of a good by a celebrity or media luminary. Part of the monetization strategy of NFx innovation and commercialization warrants the prudent selection of influential users or endorsers of a specific product, especially an endorser who aligns with the brand by personal or medical need (a celebrity living with diabetes or with a history of acne) or by vocation (a current or former professional footballer or cricket player, or an Olympian gold medalist, plagued with injuries, advocating an NFx that has increased mobility, pain-free performance, etc.)

1.6. Land mines and weapons of brand destruction

An NFx based on an extract of hemp (containing less than 0.25% Δ9-tetrahydrocannabinol in the finished composition) is birthed after a 14-month gestational period in which a small, single RCT was conducted (capturing intestinal brush cytologic samples, using rescue medications, calculating the bowel function score and intestinal permeability index). Results are written up and presented at a national biomedical conference, aligned with strategic media events and a follow-along national advertising and promotions campaign in print, on air, on demand, online, and in person. The manuscript for the RCT is nearing the completion of its editorial review before imminent publication. The only positive outcome is a reduction in defecation urge (among patients with inflammatory bowel disease). Eight months later, cumulative sales have eclipsed the $5   million mark, with annualized projections exceeding $12   million. After the winter holiday, an early morning priority envelope is delivered directly to the CEO’s desk from a prestigious law firm. It remains unopened for 3   h in her absence. Just before noon, as the CEO walks into the office for the first time in the new year, she courses by the office of the general counsel (GC). The CEO asks the GC, who is visibly ashen and distressed, if he is okay. Silently, he hands her paperwork indicating a lawsuit that the company had been served moments before her entry. It is a class action lawsuit alleging fraudulent claims (improved gut function, reduced gut permeability, improved quality of life, and reduced inflammation). She takes the suit to her desk and notices the urgent parcel. Hoping for better news, she opens the envelope and the enclosed two-page letter. Atop its first page are the transfixing words Cease and Desist. Further down she notes a phrase common to her company’s patent law firm, the same one that represents the primary (presumed) bioactive in their NFx that is enjoying meteoric success: patent infringement.

Either of the two vignettes in this scenario, although compressed into 1   day, has stricken a staggering number of middle-market to large NFx companies. The dissemination of claims that lack directly supportive evidence, especially if contravened by other evidence [20], is a perfect storm for class action litigation in the United States. Through my work with a wide variety of business founders and leaders I remain astonished by the complete lack of familiarity with the phrase freedom to operate (FTO). An FTO analysis is performed by examining issued and pending patents for overlap with the claims, method of manufacture, and/or composition of an NFx that one is considering for commercialization. It is equivalent to confirming that a parcel of property in the middle of the desert is unencumbered and whose deed or title is not held by any individual(s) or entity/entities. The up-front investment to obtain an FTO opinion from a competent professional or legal firm can yield a multiplicative return on investment and provide investors and board members with a rare, increased element of confidence and corporate Kevlar, keeping the patent trolls in their dark caves [21].

The other, more rare legal threat to brands emanates from the nearly ubiquitous practice of data piracy, otherwise known as borrowing science. The attribution of evidence from a chemo-similar yet nonidentical composition, at least in the United States, is tantamount to labeling a garment made in some country outside Europe (or Italy) with Made in Italy. The litigation brought by Amarin Pharma, Inc., marketers of the eicosapentaenoic acid–centric drug Amarin, against Coromega Health, Inc., a California-based marketer of a fish oil–based dietary supplement, alleges the use of Amarin’s data from the REDUCE-IT trial [22] by Coromega, marketing a product with a very different composition.

Assembling an NFx message or claim profile that closely or perfectly aligns with an evidence base, performing thorough FTO searches (and maintaining vigilance on patent applications that are queuing up to be granted), and avoiding the herd mentality–inspired practice of data piracy are essential prophylactic measures for any NFx and can protract its product life cycle.

1.7. Mirage to mass demand

The nutrition industry and academic communities continue to have a fascination with various –omics platforms, from epigenomics to lipidomics, proteomics, metabolomics, and microbiomics. This focus appears to maintain a myopic vista of consumer relevance. For the consumer, a personalized –omics profile offers a fascination (arguably) to the innovator or informed consumer only, which is a small to very small fraction of the population at large. The illusion of personalized nutrition via personalized biometric profiling bears minimal relevance to what is a valued return on investment by the consumer: a novel, validated path to superior health and biofunctioning. What merits integration into –omics-centric business models in the NFx industry are comparator trials that pose–omics-guided NFx intervention against conventional NFx intervention, with consumer/patient/clinician-relevant outcome measures. For example, facial skin and fecal microbiomics profiling from a cohort of adults with chronic facial acne would lead to a select suite of NFx products that would be expected to be effective (e.g., a multinutrient supplement that lacked vitamin B12) [23]. Via a crossover design (with an appropriate washout period), subjects would receive the –omics-guided NFx and maintain their normal diet or pursue a nascent, evidence-based dietary intervention at different times. If the NFx intervention proved superior in the outcome measures, which are easily quantifiable in this example, the economic and biological ramifications of this finding could have a disruptive and incendiary effective on the category and industry. As of the writing of this second edition, no such achievement has been made public. Hopefully, its revelation is not too distant.

Far less cost- and time-intensive, perhaps less risky, but requiring executive fortitude and change-meister prowess is the path of disruptive pioneering. One example is illustrated by probiotics, widely believed to require live and viable organisms to exert enteric or systemic effects. The probiotics cartel, across the value chain, has invested an enormous amount of intellectual and financial capital to reinforce this. In contradistinction, one finds that one of the first biotic agents used was derived from heat-killed Lactobacillus acidophilus organisms extracted from human stool (Lacteol), which enjoys a variety of published RCTs [24,25], as do other tyndallized organisms [26,27]. Studies suggest that an effect on visceral fat mass (via magnetic resonance imaging) may be superior with a tyndallized version of the same strain [28]. The mounting body of evidence on tyndallized probiotics, or parabiotics, arms a start-up/contrarian brand marketer with a compelling and controversial storytelling message platform.

1.8. Conclusion

The promise of nutraceuticals and functional foods is prodigious. The challenge of creating finished goods that create sustainable and robust revenues, and provide sufficient investment returns coupled with large legions of brand zealots, is equally substantial. The paucity of NFx products that enjoy a reputable and robust evidence base affords a compelling opportunity for industrial and academic alliances that integrate consumer relevance, from concept to container. Of equal importance is the need to insert an intellectual property strategy from the inception point, both offensive (adequate working capital and vigilance) and defensive (preemptive). Delivering on the promise of NFx that exert preventive, therapeutic, or quality of life enhancement can inject consumer confidence into a sector viewed with diffidence by both consumers and the medical community, augment investor enchantment, and buoy industrial growth with science-driven revenues and intellectual assets.

References

[1] Jenkins D.J, Wolever T.M, Taylor R.H, Barker H, Fielden H, Baldwin J.M, et al. Glycemic index of foods: a physiological basis for carbohydrate exchange.  Am J Clin Nutr . 1981;34:362–366.

[2] Schenk S, Davidson C.J, Zderic T.W, Byerley L.O, Coyle E.F. Different glycemic indexes of breakfast cereals are not due to glucose entry into blood but to glucose removal by tissue.  Am J Clin Nutr . 2003;78:742–748.

[3] Eelderink C, Moerdijk-Poortvliet T.C.W, Wang H, Schepers M, Preston T, Boer T.The glycemic response does not reflect the in vivo starch digestibility of fiber-rich wheat products in healthy men.  J Nutr . 2012;142:258–263.

[4] Eelderink C, Schepers M, Preston T, Vonk R.J, Oudhuis L, Priebe M.G. Slowly and rapidly digestible starchy foods can elicit a similar glycemic response because of differential tissue glucose uptake in healthy men.  Am J Clin Nutr . 2012;96:1017–1024.

[5] Eelderink C, Noort M.W.J, Sozer N, Koehorst M, Holst J.J, Deacon C.F, Rehfeld J.F, et al. Difference in postprandial GLP-1 response despite similar glucose kinetics after consumption of wheat breads with different particle size in healthy men.  Eur J Nutr . 2017;56:1063–1076.

[6] Boers H.M, van Dijk T.H, Hiemstra H, Hoogenraad A.R, Mela D.J, Peters H.P.F, et al. Effect of fibre additions to flatbread flour mixes on glucose kinetics: a randomised controlled trial.  Br J Nutr . 2017;118:777–787.

[7] Almada A.L. Carbohydrate and muscle glycogen metabolism: exercise demands and nutritional influences. In: Bagchi D, Nair S, Sen C.K, eds.  Nutrition and enhanced sports performance. Muscle building, endurance, and strength . 2nd ed. London: Elsevier; 2019:395–406.

[8] https://www.youtube.com/watch?v=BX79fJs92yA.

[9] https://drhyman.com/blog/2015/08/20/slow-carbs-not-low-carbs-the-truth-about-low-carb-diets/.

[10] https://www.bulkpowders.co.uk/sports-nutrition/carbohydrates/slow-release-carbohydrates.html.

[11] www.soloenergybar.ca/en/diet-and-weight-management.

[12] Gordon C, Maloy T, Nahas A, Taylor K. Cheerios Gluten-Free recall 2015. 2018. https://www.kelseyrtaylor.com/s/Cheerios-Case-Study.pdf.

[13] Halmos E.P, Clarke D, Pizzey C, Tye-Din J.A. Gluten in gluten-free manufactured foods in Australia: a cross-sectional study.  Med J Aust . 2018 doi: 10.5694/mja18.00457.

[14] Halmos E.P, Di Bella C.A, Webster R, Deng M, Tye-Din J.A. Gluten in gluten-free food from food outlets in Melbourne: a cross-sectional study.  Med J Aust . 2018;209:42–43.

[15] Huser V, Cimino J.J. Evaluating adherence to the international committee of medical journal editors’ policy of mandatory, timely clinical trial registration.  J Am Med Inform Assoc . 2013;20:e169–e174.

[16] Avila T.  Personal communication . July 2018. .

[17] https://www.edelman.com/sites/g/files/aatuss191/files/2018-10/2018_Edelman_Trust_Barometer_Global_Report_FEB.pdf.

[18] Ogbechie-Godec O, Azarchi S, Lee J, Cohen D.E, Neimann A, Nagler A.R. Validated patient-reported outcome measurements for psoriasis may not reflect patients’ current preferences.  J Am Acad Dermatol . 2018 doi: 10.1016/j.jaad.2018.09.019.

[19] Navarro-López V, Ramírez-Boscá A, Ramón-Vidal D, Ruzafa-Costas B, Genovés-Martínez B, Chenoll-Cuadros E, et al. Effect of oral administration of a mixture of probiotic strains on SCORAD index and use of topical steroids in young patients with moderate atopic dermatitis.  JAMA Dermatol . 2018;154:37–1643.

[20] Naftali T, Mechulam R, Marii A, Gabay G, Stein A, Bronshtain M, et al. Low-dose cannabidiol is safe but not effective in the treatment for Crohn’s disease, a randomized controlled trial.  Dig Dis Sci . 2017;62:1615–1620.

[21] Stump E, Almada A. Patent trolls strike supplements.  Nutr Bus J . 2013;18:36–37.

[22] Bhatt D.L, Steg P.G, Miller M, Brinton E.A, Jacobson T.A, Ketchum S.B, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia.  N Engl J Med . 2019;380:11–322.

[23] Kang D, Baochen S, Erfe M.C, Craft N, Li H. Vitamin B12 modulates the transcriptome of the skin microbiota in acne pathogenesis.  Sci Transl Med . 2017;7:293ra103.

[24] Halpern G.M, Prindiville T, Blankenburg M, Hsia T, Gershwin M.E. Treatment of irritable bowel syndrome with Lacteol fort: a randomized, double-blind, cross-over trial.  Am J Gastroenterol . 1996;98:1579–1585.

[25] Salazar-Lindo E, Figueroa-Quintanilla D, Caciano M.I, Reto-Valiente V, Chauviere G, Colin P, Lacteol Study Group. Effectiveness and safety of Lactobacillus LB in the treatment of mild acute diarrhea in children.  J Pediatr Gastroenterol Nutr . 2007;44:571–576.

[26] Shinkai S, Toba M, Saito T, Sato I, Tsubouchi M, Taira K. Immunoprotective effects of oral intake of heat-killed Lactobacillus pentosus strain b240 in elderly adults: a randomised, double-blind, placebo-controlled trial.  Br J Nutr . 2013;109:1856–1865.

[27] Hirose Y, Murosaki S, Yamamoto Y, Yoshikai Y, Tsuru T. Daily intake of heat-killed Lactobacillus plantarum L-137 augments acquired immunity in healthy adults.  J Nutr . 2006;136:3069–3073.

[28] Pedret A, Valls R.M, Calderón-Pérez R, Llauradó E, Companys J, Pla-Pagà L, et al. Effects of daily consumption of the probiotic Bifidobacterium animalis subsp. lactis CECT 8145 on anthropometric adiposity biomarkers in abdominally obese subjects: a randomized controlled trial.  Int J Obes . 2018 doi: 10.1038/s41366-018-0220-0.

Further reading

[1] Leibenstein H. Bandwagon, snob, and Veblen effects in the theory of consumers’ demand.  Q J Econ . 1950;64:183–207.

Chapter 2

Nutritional supplements and functional foods

functional significance and global regulations

Nandini Ghosh ¹ , ² , Amitava Das ¹ , and Chandan K. Sen ¹ , ²       ¹ Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, United States      ² Department of Human Nutrition, The Ohio State University, Columbus, OH, United States

Abstract

Originally, foods that have the property to modulate body functions that contribute to preventing a disease were called functional foods. However, the term is now widely understood to mean foods that claim such biological effects beyond ordinary nutritional effects, based on scientific validation. Today, we eat food materials of compromised nutritive value because of milling and processing. Furthermore, there is not enough time for a healthy balanced meal. Dietary supplements and functional foods are a prudent choice to offset these limitations in our daily lives. The term physiologically functional foods or simply functional foods was conceived in the context of nutrition during space travel. The modern concept of functional food for the general population was proposed by the Japanese academic society in the early 1980s and legislation on functional foods was first implemented as Foods for Specified Health Use (FOSHU). Decisions and policies from global regulatory bodies have become increasingly influential for dietary supplement companies. Such bodies include Codex Alimentarius, the World Health Organization, and the Food and Agriculture Organization. The International Alliance of Dietary Food Supplement Associations works together with these international organizations to ensure that the views of the dietary supplement industry are considered in developing policy. The Dietary Supplement Health and Education Act of 1994 was directed at ensuring that a dietary supplement is safe before it is marketed in the United States. In 1991, the Japanese Ministry of Health and Welfare established the FOSHU labeling regulation. It was implemented by adding a new category of FOSHU to Foods for Special Dietary Uses in the Nutrition Improvement Law. Momentum in Japan seems to be in the right direction, providing the rest of the world with an opportune platform for further development.

Keywords

Functional foods; Health behavior and global regulations; Nutritional supplements

2.1. Introduction

Natural health products and functional food have become an important part of the global food industry. Increasing consumer awareness and interest in acceptance of these products has gradually expanding the size of the global market for functional food. Dietary supplements, isolated nutrients, herbal products, special diets, processed foods, and beverages [1] are all examples of functional foods or nutraceuticals. High margins and minimal regulatory requirements have made these nutraceuticals attractive to food and beverage companies. Increasing consumer desire to lead a healthy life, rising health concerns, and the attempt to avoid dependence on synthetic drugs are major drivers contributing to the growth of this market. Other nutraceuticals aimed at improving cardiac health have also increased market growth. All of these factors have led to growing demand for nutraceuticals. According to an annual survey conducted by Ipsos Public Affairs on behalf of the Council for Responsible Nutrition, 71% of US adults—more than 170   million—take dietary supplements either daily or occasionally [2–5].

The dietary supplement industry is rapidly growing and is a multibillion-dollar industry with steady growth. This is a global phenomenon, and similar trends are observed in several countries. In the United States, the supplement industry boasts annual sales of nearly $30   billion; Americans spent around $36.7   billion on dietary supplements in 2014 [6]. Adults and children of all ages widely use dietary supplements including vitamins, minerals, herbs, and amino acids.

2.2. History

Two hundred years ago, processed sugar was available only in drugstores [7]. Today, it is one of the most successfully marketed nutritional chemicals, posing an addiction for consumers from when they are very young. On the one hand, we are eating food materials of compromised nutritive value because of milling and processing [8]. On the other hand, there is not enough time for a healthy balanced meal. To compensate for these losses, dietary supplements and functional foods are a must in today’s lifestyle [9–12].

Dietary supplements refer to preparations intended to compensate for the nutrients that otherwise might not be sufficiently present in the diet. Dietary supplements are categorized as food in some countries, whereas in other countries they are considered drugs or natural health products. The term functional foods refers to supplements that have new or added ingredients, resulting in enhanced function and improvement in health [13]. These types of foods are composed of processed foods as well as those enriched with health-promoting additives. The search for functional foods, or functional food