A safe landing in the US market: how to successfully navigate the US regulatory maze and bring new products to market.

With 200 million consumers who are hungry for functional foods that promise to deliver added value compared with competitors' offerings of just taste, satiety or nutrition, the US is a prime and notably harmonized market for overseas companies that are looking to expand their customer base and product portfolios. Yet, US regulations don't mirror those of the EU, often making it a bit confusing. Understanding the fundamental philosophy of US regulations will help businesses in the EU to successfully launch products overseas.

The Food, Drug and Cosmetic Act: Basic Underlying Concepts

Food safety and the regulation of food and food products are continuously being refined, both in the US and throughout the world. In the landmark reform of the Food Drug and Cosmetic Act of 1958, the Act not only gave a definition to food but set broad ground rules mandating that food products be safe. (1) Importantly, although FDA demands that products must be safe, it is careful not to prescribe a specific pathway regarding exactly how safety must be demonstrated, thus giving the appearance of harmonization. Also, regulations are only promulgated after-the-fact, not prospectively, as this would require that regulations be written in anticipation of a problem and would have to get ahead of the technology; the end result of which would be a stifling affect on innovation. The public has nothing to worry about, however, because if a substance, even after approval by one means or another, proves to be unsafe, FDA has the power to take it off the market immediately.

Public Safety and Pragmatism

Generally Recognized as Safe (GRAS) is an important element of the US regulatory system for which EU food law does not provide a direct equivalent. The concept of GRAS is based on the dual concepts of pragmatism and a faith in the ability of an industry to police itself. In the early 1950s, there was a series of incidents involving the presence of harmful substances in foods. At that time, the laws supporting the US Food and Drug Administration were weak by design and had not been meaningfully updated for many years. Emerging from a series of Congressional hearings, the 1958 Amendment to the Federal Food, Drug and Cosmetic Act (FD&C Act) was implemented and contained the following significant wording regarding GRAS: The term "food additive" means any substance, the intended use of which results or may reasonably be expected to result, directly or indirectly, in its becoming a component or otherwise affecting the characteristics of any food ... if such substance is not generally recognized, among experts qualified by scientific training and experience to evaluate its safety, as having been adequately shown through scientific procedures (or, in the case as a substance used in food prior to 1 January 1958, through either scientific procedures or experience based on common use in food) to be safe under the conditions of its intended use.

In comparison, the EU regulation on food additives reads as follows: "Food additive" shall mean any substance not normally consumed as a food in itself and not normally used as a characteristic ingredient of food, whether or not it has nutritive value, the intentional addition of which to food for a technological purpose in the manufacture, processing, preparation, treatment, packaging, transport or storage of such food results, or may be reasonably expected to result, in it or its by-products becoming directly or indirectly a component of such foods.

Whereas in the EU a food additive is defined by its "technological purpose," under the FD&C Act, anything that becomes a part of food is a "food additive" unless it is shown to be generally recognized as safe. This provision requires all substances to go through one of these two methods of premarket approval and be deemed safe. In contrast to the FDA paradigm, the EU food legislation describes different authorization pathways for several product categories, such as food additives, food enzymes, food flavourings, novel foods and for genetically modified foods and their derivatives. The wording of the 1958 amendment seems a bit turned on its head (that is, a food additive unless GRAS), but Congress was trying to make the point that approval by the GRAS process was an exception to the rule that all substances should be reviewed by the FDA. This GRAS exception was included out of a sense of pragmatism because many substances, such as spices, had been in use for scores, if not hundreds of years, and it would be counter-intuitive to require substances with a history of safe use to be subjected to a prolonged testing regimen and bureaucratic approval process.

Obviously, manufacturers benefited from the GRAS concept because the expense of animal testing and the preparation of petitions for the thousands of ingredients already in use would not be required. FDA was also a beneficiary of GRAS because the Agency would not have been up to the task of responding in a timely manner to the potential flood of food additive petitions. But, the greatest beneficiary was the consumer, who could expect a continued selection of flavourful and nutritious foods.

As noted in the Act, a substance is eligible for GRAS determination if it has been shown to be safe through "scientific procedures" (animal testing data) or, in the case of substances in use (as a food or food ingredient) before 1 January 1958, by "scientific procedures" or experienced based on common use in food. The "experience based" use is not a substitute for a safety review, however, as those making the decision must determine if the history of use was by a substantive amount of people during a substantive period of time, and that the population has a quality of healthcare comparable with the US with a mechanism for reporting adverse effects.

Experts Qualified by Training and Experience

So, who are the "experts" that make up an independent GRAS panel? The law does not further define the experts, other than they are such through "training and experience." Court decisions have shown us that experts cannot be salesmen, with no training or experience, but have not ruled on conflicts of interest by scientists employed by the manufacturing company, where emotional equity, career goals and performance bonuses may influence decision making. Because of the potential conflict of interest, most companies no longer "self-GRAS," but keep the process at an arms length and hire outside firms to prepare the GRAS dossier and manage the Expert Panel. Importantly, FDA realizes that a decision by these experts does not imply unanimity by all scientists, but a consensus among experts (note the plural) in the field of food ingredient safety.

The FDA has held that animal test data, pivotal to the decision making process of the Experts, must be published, meeting the so-called "common knowledge threshold." The theory is that once this pivotal data is published, the peer-review process, followed by exposure to a population of interested scientists, would uncover any exaggerated claims of safety. How much data is enough to prove safety? Again, this decision is left to the GRAS experts. Although the FDA has stated that there is no difference in the quality and quantity of data to determine the safety of a GRAS substance versus a food additive, there are no regulations requiring a specific data set to demonstrate safety. The FDA has promulgated suggested guidelines, called the "Redbook," but again, the decision on how much data is enough to prove safety is the domain of the GRAS experts.

GRAS Notification versus Affirmation

At one time, there was a process in place wherein a GRAS self-determination could be sent to the FDA for a GRAS Affirmation. For a substance to be GRAS affirmed, the FDA would subject the data to a level of review similar to that for a food additive petition and assumed the responsibility for the ultimate decision on safety (these substances are listed in 21 CFR 184). However, because the GRAS affirmation programme became bogged down as a result of many factors, it was abandoned; and, in 1997, the GRAS Notification process was proposed. The Notification process differs from the Affirmation process in that the FDA does not affirm or approve the Notified substance, but on the basis of the information submitted, either determines that the "Notice does not provide the basis for a GRAS determination" or that the FDA "has no objection at this time." Prior to making a potentially negative decision, the FDA may contact the submitter of the Notification and ask for the clarification or amplification of some points; and, if the submitter cannot respond in a relatively short time period, the Notifier is given an opportunity to withdraw the Notification without prejudice.

Although approximately 12 years have passed since the GRAS Notification process was initiated, it has never been finalized. But, by all accounts, it has been a success by allowing Notifiers some insight as to the FDA's position on the safety determination and providing a level of comfort for potential customers. As of December 2008, a total of 271 substances have been submitted to FDA for review as Notifications, and of this number, 35 were voluntarily withdrawn by the petitioner and approximately half of these (16) were granted another bite at the apple and reconsidered under a new GRN (number)--although not all were successful even the second time around. Another 16 notifications were rejected outright as "Notice does not provide a basis for a GRAS determination," although six of these were resubmitted and all were subsequently successful.

The 271 Notifications probably represent half or less of all non-flavour ingredient GRAS determinations, as the manufacturer, having completed a GRAS, is under no obligation under the law to even inform the FDA that a GRAS determination has been conducted. However, the FDA can query the user of the substance (that is, the food manufacturer who has listed the ingredient on his label), on the basis of determining that the use of the substance in food is safe. At this point, the food manufacturer must respond or accept the risk of having his product declared adulterated as the result of its containing an unapproved food additive. Also, food ingredient GRAS determinations (those Notified and those not notified) represent only a fraction of the total GRAS determinations. For example, the Flavor and Extract Manufacturers Association (FEMA) has GRASed more than 200 ingredients per year for the last few years, on top of the nearly 2000 ingredients already found GRAS by FEMA. None of the FEMA GRAS determinations undergo the Notification process.

Labelling and Claims

In addition to regulating the safety of food ingredients, the FDA also regulates the labelling of food products, including those for claims. The 1990 Nutrition Labeling and Education Act (NLEA) and the 2004 Food Allergen Consumer Protection Act (FALCPA) were two amendments brought about to educate consumers and keep them safe. The 1990 NLEA was approved to assist consumers with healthy dietary practices. (2) FDA required the mandatory and uniform labelling of packaged food products, complete with standard serving size, number of servings the package contained and the nutritional content of each serving. These provisions differ significantly from the EU rules on food labelling and on nutrition labelling. The FALCPA required a warning statement on products that contain or may contain items with the potential for allergic reactions. (3) The list of foods and food ingredients requiring mandatory labelling in this respect is similar to the one of the EU.

To provide consumers with information to make health-related choices for foods and supplements, a reluctant FDA was compelled by Congress to allow the use of health claims for foods and structure/function claims for dietary supplements. A Health Claim made reference to a substance and a disease and the ability of the substance to reduce the incidence of the disease. The substance cannot be said to "diagnose, cure, mitigate, treat or prevent a disease," otherwise it would be defined as a drug--it may only be said to reduce the incidence of a disease. According to FDA, Health Claims are to be based on both weight of evidence and "significant scientific agreement," the latter of which requires endorsement by the National Academy of Sciences or a government entity such as the National Institutes of Health or the Surgeon General's office, followed (significantly), by FDA agreement with the claim.

Because Health claims are held to such a high standard, they are authorized as a regulation and listed in the Code of Federal Regulations. The ire of Congress was triggered with such a high threshold, as Congress clearly intended that health claims should be modelled on a GRAS Expert Panel concept. A subsequent amendment to the Act was enacted by a chiding Congress in response to what it saw as FDA recalcitrance with this high burden of proof and willful avoidance of a Congressional mandate. In response, the FDA added a lower threshold for proof of efficacy for health claims, called a "qualified health claim," based on so-called "emerging evidence."

Qualified Health Claims, based only on emerging evidence, are not afforded a regulation, but are subject to enforcement discretion (a claim can be made on the label until and unless FDA decides to object). Only FDA-authorized claim wording may be used for either claim type and, as such, the wording for Qualified Health Claims appearing to be so

tentative, have experienced poor acceptance by consumers. Qualified Health Claims have so dissatisfied Congress that the Congressional leadership has announced that it soon expects to force the FDA to abandon the category.

Structure/Function Claims do not make reference to a specific disease but, instead, describe an effect that a substance has on the structure or function of the body (21 CFR 101.14). For example: "fibre maintains bowel regularity," but cannot refer to colon cancer, or; "calcium builds strong bones," but cannot refer to osteoporosis. These types of claims are not required to undergo premarket review by FDA but must be truthful and not misleading to the consumer. A structure/function claim must also be accompanied by a disclaimer that it has not been approved by FDA.

We've Landed!

The importance of regulating food and food safety has been recognized across continents. With today's technologies, the significant economic impact of international trade and the ever-changing availability and quality of food, we all should become familiar with food safety and labelling regulations throughout the world. Navigation through the many different processes and lexicons of the various regulatory systems is a challenge that must be faced to keep up with an evolving market place.

References and Bibliography

(1.) G.A. Burdock and I.G. Carabin, "Generally Recognized as Safe (GRAS): History and Description," Toxicology Letters 150, 3-18 (2004).

(2.) P. Hyman, "US Food and Drug Law and FDA--A Historical Background," in K.R. Pina and W.L. Pines (Eds.), A Practical Guide to Food and Drug Law and Regulation, Second Edition (Food and Drug Law Institute, Washington, DC, USA, 2002) pp 15-45.

(3.) I.G. Carabin and B.A. Mongoose, "New Labeling Requirements for Food Allergens," Nutritional Outlook March 2006 (http://nutritionaloutlook.com) pp 28-32.

(4.) Federal Food, Drug, and Cosmetic Act (FFDCA), as amended through 31 December 2004: www.fda.gov/opacom/laws/fdcact/fdctoc.htm (site accessed 1 December 2008).

(5.) Food Ingredients and Packaging, updated 18 April 2008: www.cfsan.fda.gov/~lrd/ foodadd.html (site accessed 2 December 2008).

(6.) M.L. Foster and D.R. Dwyer, "The Regulation of Dietary Supplements," in K.R. Pina and W.L. Pines (Eds.), A Practical Guide to Food and Drug Law and Regulation, Second Edition (Food and Drug Law Institute, Washington, DC, USA, 2002) pp 226-227.

(7.) E.T. Guarino, "Chapter 23: United States of America," in J. Kellam and E.T. Guarino (Eds.), International Food Law (Prospect Media Pty Ltd, St Leonards, NSW, Australia, for the Food and Drug Law Institute, 2000) pp 539-614.

(8.) D.A. Kracov, "The Regulation of Food and Food Additives," in K.R. Pina and W.L. Pines (Eds.), A Practical Guide to Food and Drug Law and Regulation, Second Edition (Food and Drug Law Institute, Washington, DC, USA, 2002) pp 159-214.

(9.) H. Ross, "Conclusion," in J. Kellam and E.T. Guarino (Eds.), International Food Law (Prospect Media Pty Ltd, St Leonards, NSW, Australia, for the Food and Drug Law Institute, 2000) pp 641-648.

(10.) J.L. Vetter, Food Laws and Regulation (American Institute of Baking, Manhattan, Kansas, USA, 1996) pp 1-231.

(11.) Regulation (EC) No. 1333/2008 of The European Parliament and of the Council of 16 December 2008 on food additives.

For more information

George A. Burdock, PhD (Burdock Group), Simone Koenig (Libra Consulting) and Christine Crincoli, PhD (Burdock Group).

For correspondence, please contact Christine Crincoli

Staff Toxicologist

Burdock Group

801 N. Orange Ave, Suite 710

Orlando, Florida 32801, USA.

Tel. [phone]

[e-mail]

www.burdockgroup.com