Process for Bringing Functional Foods to Market

Functional foods lie at the low cost, high consumer participation end of the delivery options continuum for health-enhancing bioactive substances and thus may be especially advantageous in lieu of a drug regimen. Many consumers are averse to drugs and may accidentally or purposely avoid taking their prescriptions. Consumption of food does not carry such an aversion and is looked upon much more favorably. Functional foods are an effective way to deliver beneficial agents and should become an integral part of public health programs aimed at reducing disease risk.

The IFT Expert Panel identified a seven step process that would address critical aspects in the design, development and marketing of functional foods. After identifying a potential new bioactive ingredient (step 1), the ingredient’s efficacy and safety must be evaluated (steps 2 and 3).

When selecting an appropriate food vehicle for the bioactive substance (step 4), characteristics of the food, the ingredient and the intended consumer must be considered. An independent peer review and regulatory oversight (step 5) ensures the accuracy of health claims, which must be properly communicated to consumers (step 6). Finally, in-market surveillance confirms the findings of the pre-market assessments (step 7). Although all seven steps would be undertaken for each new bioactive substance and the resulting functional foods, the specific requirements within each step vary depending upon the physical, chemical and biological characteristics of the functional component, the applicable regulatory requirements and the health claims to be made.

Step 1: Identify Relationship Between Food Component and Health Benefit
A sound scientific basis for the relationship between functional foods and health benefits is critical. A wealth of scientific literature describes numerous types of research that can identify potential relationships between functional components and health benefits.

Once potential links have been identified, rigorous investigations are needed to confirm the initial observations through controlled studies with appropriate test materials. A vast range of potentially bioactive substances remains to be cataloged and linked to health outcomes.

Step 2: Demonstrate Efficacy and Determine Intake Level Necessary to Achieve Desired Effect
Demonstrating the efficacy of the bioactive component(s) is critical in building a strong scientific basis for claims related to the intake of a functional food. Unfortunately, demonstration of efficacy is not an easy task.

Identifying Bioactive Components
The ability to identify and quantify the components of interest in functional foods is an important first step in the determination of efficacy. Over the past several decades, the diversity and sensitivity of analytical methods has improved dramatically, and researchers are now able to identify a broader range of substances. Methods with improved sensitivity, specificity, robustness, and reproducibility continue to be developed. The selection of the most appropriate method (or combination of methods) for a particular analysis depends upon a variety of factors:

• What is being analyzed? Is it a single entity or a group of components? • Is the whole component of interest or only the bioactive part of the component? • What are the lowest and highest amounts of an analyte that must be determined? • Does the compound exhibit different potencies depending on the chemical form of the compound (e.g., ascorbic acid vs dehydroascorbic acid; different carotenoids, vitamin E forms, and folic acid (conjugated vs nonconjugated))? • Are there matrix effects (e.g., food or fiber) on method performance? and • Are there food processing effects on the analyte of interest that in turn affect the performance of the analytical procedures?

The method of analysis must be able to accurately measure the compound of interest at the level where the desired or undesired effect is expected. When the compound has the potential for different potencies, accurate and precise measurement is especially important.

Assessing Stability and Bioavailability of Bioactive Substances in Food Matrices
Nutrients and bioactive substances must be stable in the food if they are to be functional at the time of consumption. Advances in food processing technology have provided many techniques for stabilizing nutrients and other valued substances in food. Long-term stability tests must assess the efficacy of bioactive compounds in commercial products. Manufacturers also can use the test results to establish a product shelf life that assures maximum efficacy.

Furthermore, a bioactive substance cannot exert its beneficial effects unless it is bioavailable. Physiological utilization of a food component depends on several factors including the physical and chemical form of the component, the effect of the total diet, the effects of food processing, and environmental factors.

Physical Form
When a food component is coated, microencapsulated, emulsified, or altered in some way from its original state, its absorption and utilization may be affected. Even apparently minor physical changes in the food may affect absorption. And, when the nutrient is administered as a supplement, the form in which the supplement is given can significantly influence the bioavailability of the nutrient.

Chemical Form
The bioavailability of food components can differ significantly depending on the chemical form in which they are ingested. For instance, iron is more bioavailable from ferrous sulfate or ferrous citrate than from ferric chloride.

Effects of the Total Diet
The other foods consumed in conjunction with a functional food may influence the bioavailability of a food component. In some cases, scientists know that the presence of one substance can affect the absorption of another; in other cases, the exact reason for the change is not as well known.

Effects of Food Processing
Basic food processing methods (e.g., drying, heating, freezing, fermentation and simple chemical methods, such as salting and smoking) have their origins in prehistoric times, and, despite more recent technologies, the basic goal of food processing remains unchanged—to provide a stable, safe and plentiful food supply. Some processes affect the concentrations of nutrients and other bioactive components or their bioavailability.

Fortification is one way in which food processing can alter the bioactive profile of a food. Removal of anti-nutrients—secondary compounds that prevent their corresponding nutrients from being digested— also improves the nutritional value of certain foods. In some cases, knowledge of the different chemical forms of an ingredient is useful to ensure that the desired nutrient value and/or function is achieved in the finished product. Recent studies have identified the ability for food processing to enhance nutrient availability, including lycopenes in cooked tomato sauce.

The need for long shelf life and the desire to meet consumer demands has led researchers to the development of natural compounds for preservation, many of which are also known to provide nutritional benefits.

Formulation techniques can also be used to enhance product efficacy and/or safety.

Environmental Factors
Environmental factors during crop production (e.g., soil, rainfall, temperature, pest infestation, use of fertilizers, geographic location) and subsequent handling (e.g., contamination, transportation, storage, processing) can affect both the bioavailability and the absolute levels of many bioactive compounds.

Demonstrating Efficacy
Demonstrating the efficacy of functional food components is a complex and costly task, but one that is essential to consumer and regulatory acceptance of functional foods. Although filled with scientific challenges, the efficacy of functional foods can be demonstrated in a science-based process that provides the necessary scrutiny in an effective and efficient manner.

Biological Endpoints and Biomarkers
Reliable measures of the effects of bioactive components of functional foods are critical. In some cases, researchers can directly measure the health or disease prevention endpoint (e.g., frequency of urinary tract infections) or the biological effect (e.g., decreased neural tube defects with increased serum folate levels). However, usually researchers must identify a biomarker that functions as a reliable surrogate measure of the underlying biological effects (e.g., improved performance on a physical endurance test). Biomarkers can take a variety of forms, ranging from changes in biological endpoints to changes in overt physical performance, which is imputed to relate to underlying biology. In some cases, the biomarker will be a measure of exposure rather than a measure of effect.

Regardless of form, biological endpoints or biomarkers are critical in demonstrating the exposure to and efficacy of bioactive components of food. Changes in any of the following functions might be associated with a functional food, measured directly or through the use of an appropriate biomarker:

• physical performance; • cognitive, behavioral, and psychological function; • organ or system function (gastrointestinal, genitourinary, bone); and • chronic disease (heart disease, peripheral vascular disease, diabetes, hypertension, obesity, cancer, degenerative and inflammatory arthritis).

Researchers face challenges in identifying appropriate exposure biomarkers. Exposure biomarkers should be stable and should directly reflect over a reasonable period of time the intake of the functional food or, preferably, the bioactive component of interest. Exposure to all food components of interest, however, cannot be identified through the use of exposure biomarkers.

Biomarkers are a specific physical trait used to measure or indicate the effects or progress of a disease or condition. Although scientists have identified many possible biomarkers, few biomarkers have been validated, and many more are needed. For a biomarker to be effective, researchers must confirm the relationships between changes in the biomarker and changes in biological function. For example, exposure biomarkers must accurately reflect intake and bioavailability.

Surrogate biomarkers are often used as a substitute for biomarkers or when a less specific physical trait is being used to measure an effect or condition.

Criteria for Evaluating Efficacy
Building a strong scientific basis for functional food claims relies on the ability to demonstrate the efficacy of the food’s bioactive component(s). Demonstrating efficacy in experimental animals, while not trivial, is quite straightforward. Proving efficacy in humans is substantially more difficult. Most of the epidemiological associations of diet and reduced disease risk relate to overall dietary practices, not a single bioactive component. Linking specific benefits to the consumption of individual foods or specific food components is difficult and requires rigorous scientific protocols. Hill (1971) asked, [when “f]aced … with a clear and significant association between some form of sickness and some feature of the environment, what ought we specifically to consider in drawing conclusions about the nature of the relationship, causation or merely association?” The central issue with most observations of diet intake and disease risk is indeed whether the observations can be assigned to cause and effect or to an association of dietary pattern to health outcome.

Hill (1971) proposed specific criteria to use in evaluating research findings, and these criteria have guided the evaluation of diet and health interrelationships for the last two decades. Some structure/function claims for specific foods have been successfully developed and supported by FDA by following these criteria. However, the process has been hampered by limitations in the current regulations and/or government interpretations of those regulations (e.g., the requirement to meet the “nutritive” value stipulation).

Hill’s Criteria (Hill, 1971; Keystone, 1996) Strength of association – how statistically significant and convincing are the data that support the relationship?

Consistency of the observed association – how well do the available data from different sources, areas, and types of studies support the relationship?

Specificity of the association – do the data demonstrate a predictable relationship between the bioactive component and the proposed effect?

Temporal relationship of the observed association – is the proposed effect observed following treatment with the bioactive component?

Dose-response relationship – do the data demonstrate a magnified effect of the bioactive component with increasing dose?

Biological plausibility – is there a plausible mechanism to explain the effects of the bioactive component?

Coherence of the evidence – does the relationship help explain the available data, when viewed as a whole?

In applying the Hill criteria to the research findings, the IFT Expert Panel believes it is also necessary to consider: The amount and type of evidence – The amount and type of evidence sufficient to demonstrate efficacy will vary for each functional food component. Therefore, experts in the relevant area of study must determine the data requirements. All forms of competent and reliable scientific research are considered. As a rule, well controlled human clinical studies are the most directly applicable and understood form of evidence and therefore are given the most weight. Although no specific number of studies can be set, the replication of research results in an independently conducted study adds to the weight of the evidence.

Quality of evidence – The quality of a study is paramount; evidence for reproducibility and internal validation of quality are critical. The design, implementation, and analysis of results must be conducted in a competent and reliable manner following accepted principles for testing hypotheses.

The totality of the evidence – Studies cannot be evaluated in isolation, and all relevant research should be considered. In fact, the context of the scientific evidence is just as important as the internal validity of individual studies. The studies used to substantiate a claim must be largely consistent with the surrounding body of evidence. Inconsistencies in the evidence must be examined to determine whether plausible explanations exist.

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The relevance of the evidence to the specific claim – Research supporting efficacy claims must be relevant to both the food product and the specific benefit being claimed. Necessary questions include: How does the dosage and formulation of the proposed functional food product compare with that used in the study? Does the product contain additional ingredients that might alter the effect of the functional ingredient? Is the product administered in the same manner as the ingredient used in the study? Does the study population reflect the characteristics and lifestyle of the target population? If research conditions differ significantly from the use being promoted, additional research may be needed to support extrapolation from study results to the claimed effect.

The IFT Expert Panel recommends that evaluation of a functional food’s efficacy rely on the Hill criteria. These evaluations must explicitly address the strength and relevance of the data supporting the bioactive component’s specific role in improving the health outcome of interest. Companies developing functional foods will assemble the research necessary to determine the efficacy of the proposed product, but independent peer review will confirm the accuracy of the evaluation. This evaluation process applying the Hill criteria will be most effective when undertaken by an independent expert panel as described in Step 5 below.

Estimating Dietary Intake
To achieve a health benefit, a bioactive substance must be consumed in adequate quantities to achieve the desired effect. In theory, the calculation of dietary intake for a nutrient or bioactive substance is simple and straightforward. The amount of each food, beverage, dietary supplement, and drug consumed is multiplied by the concentration of the substance of interest in each product. The resulting intake from each product is then summed to estimate total intake. In practice, however, dietary intake assessments are often associated with a significant amount of variability and uncertainty.

Variability arises as a result of natural variation in the levels of the bioactive compound in different lots of the food, variations in the methods of preparation, and in the amounts consumed. Uncertainty stems from the complex and variable nature of the data sources used to estimate intake and the inherent variability in consumers’ behavior and biological response to dietary components.

Increasing or decreasing the consumption of a nutrient or bioactive substance has both efficacy and safety implications. Evaluating the impact on safety and effectiveness requires quantitative knowledge about intake by the target population, potential high consumers, or population subgroups with special risks or benefits. As technology improves, foods designed for specific population groups are likely to enter the market. Therefore, evaluation of intake by the target population may need to determine if significant numbers in that group are either low or high consumers of the designated food(s) or food components.

Step 3: Demonstrate Safety of the Functional Component at Efficacious Levels
In general, the safety of functional foods should be based on the long-standing principle that foods are safe. Further, the safety assessment should accept the safety of components already considered through preestablished programs such as generally recognized as safe (GRAS) substances and approved food additives.

That said, an objective, science-based evaluation process must establish that functional components are safe at their projected use levels. The scope of potential new functional foods is extremely broad, and the safety assessment framework should be effective for many types of functional ingredients over a broad range of consumer intake levels. The safety assessment must be sufficiently flexible to consider the many factors associated with consumer responses to food and food ingredients, including genetic predisposition, age, sex, nutrition status, and lifestyle. The nature of the ingredient and the sensitivity of subgroups of the population should be considered.

Guidelines for Safety Assessments
The most appropriate safety assessment for a functional food ingredient will be determined on a case-by-case basis. Typically, the safety assessment will include the following:

• documented history of food use (if not a new chemical entity);
• estimates of current and proposed intakes of the functional component(s) (Intake/consumption should be estimated for the general population and by age and gender, including consumers who are likely to consume higher than typical levels. Intake estimates should be realistic and not overly conservative.); and
• toxicological/safety assessment of new intake levels. Substances without a prior history of safe use will require a comprehensive and critical review of the scientific literature on the biological effects of the ingredient and on chemically related substances. Based on an initial review, specific studies will generally be required to define:
• bioavailability - likely modes of action in vivo (in the living organism);
• estimated half-life in vivo;
• estimated dose-response for a range of potential effects;
• known pharmacologic/toxic effects; • evidence of allergenicity; and
• toxicity and safety (human, experimental animals, and in vitro [an artificial environment outside the living organism] systems including microorganisms, cells in culture, and micro arrays [microscopic analysis of fluorescent DNA fragments]).

The safety assessment will vary depending on whether the component will be present at micronutrient or macronutrient levels. The requirements also will depend on the mode of action of the active component and its toxic effects.

When the bioactive component(s) of a functional food are not known (e.g., cranberries), epidemiological studies demonstrating the safety of the whole food would be an important part of the safety assessment.

Use of Epidemiological Data
Epidemiological studies can confirm relationships between dietary patterns and biomarkers or disease occurrence. People eat foods, not isolated ingredients, so food intake studies cannot directly assess the intake of a specific bioactive component. Therefore epidemiological studies combine the food intake data with other data to estimate the intake of the substances of interest.

Food composition databases are used, but many bioactive components have not been well characterized and quantitative data for such components may be very limited or nonexistent. In addition, isolating the effect(s) of a specific food or nutrient can be difficult because the substances are consumed in combination and may have synergistic effects. The validity of any dietary assessment tool depends on the individual’s ability to recall their diet and to accurately report portion size and frequency of intake.

Allergen Management
Food allergies are abnormal (heightened) responses of the immune system to components of certain foods. The components of foods that elicit these abnormal immune responses are typically naturally occurring proteins in the foods. Foods contain millions of individual proteins, but only a comparative few of the proteins have been identified as allergens. Whether naturally occurring or added in product formulations, all proteins that elicit an allergic response warrant special attention. Functional foods are no exception, unless the allergenic component of the food has been reduced or eliminated.

Any new protein in a functional food should be evaluated for potential allergic reactions. While no single test can perfectly predict the potential allergenicity of a novel protein from a source with no history of allergenicity, the application of a series of tests provides reasonable assurance that the novel protein is not likely to become an allergen.

Step 4: Develop a Suitable Food Vehicle for Bioactive Ingredients
The goal of this phase of development is to select a suitable food vehicle that is appropriate for the intended consumer and delivers the bioactive ingredient at the desired levels. Selection of a food vehicle depends on its acceptability, the stability and bioavailability of the bioactive ingredient within the food, and the consumption and lifestyle practices of the intended audience.

Selection and development of the appropriate food vehicle is an important step to the total success of a functional food. Consumer compliance is key to a functional food’s success. If an ingredient is consumed at a level well below that recommended, it will be ineffective. Alternatively, if consumed in amounts much greater than intended, the ingredient may become toxic.

Bioactive ingredients challenge product developers because they often possess disagreeable sensory and/or physicochemical characteristics. Fortunately, new food technologies can address many of these issues. The food vehicle should provide a stable environment that will preserve the bioactive ingredient in its desired bioavailable form.

Selection of the food vehicle also must address the characteristics of the target audience. For example, adults with elevated cholesterol levels are the target for sterols and stanols that reduce blood low density lipoprotein levels, so these substances should be added to foods regularly consumed by this target population. If a functional food were being developed for children, the appropriate food vehicles might be very different.

Step 5: Demonstrate Scientific Sufficiency of Evidence for Efficacy
Regulatory standards require that all functional food labeling be truthful and not misleading. Claims for the benefit of a functional food must be based on scientific evidence of safety and efficacy and should be confirmed by appropriate independent experts.

Independent Peer Review
The IFT Expert Panel believes the evaluation of efficacy and safety will be most effective and costefficient if it is undertaken by panels of independent experts with appropriate scientific expertise. This approach has been successfully applied to GRAS determinations for many substances. A parallel process should be used to confirm the efficacy findings for a functional food.

Establishing an independent expert panel to make a generally recognized as efficacious (GRAE) determination would encourage public confidence while conserving government resources. As envisioned by the IFT Expert Panel, GRAE panel reports (accompanied by relevant scientific literature and data) would be submitted to FDA under a GRAE notification process described below. The material submitted would be available for public review, and the composition of the panel would be fully disclosed.

The GRAE panel would be comprised of respected scientists qualified to determine efficacy of the component under consideration. The multi-disciplinary nature of the panel would provide a broad context for data and assure that the resulting conclusions are scientifically defensible and relevant to consumer practices. The GRAE panel would use the Hill criteria to determine if the proposed claims are supported by the available evidence.

GRAE panels could be assembled and managed in a variety of ways as long as the composition of the group is fully disclosed and the panel’s independence is assured. GRAE panels could be organized by a professional organization, by a private consulting organization, or by the company developing the functional food (provided the panel is given complete autonomy).

Regulatory Approval When Necessary
The process for obtaining approval to market a new functional food will vary based on the nature of the functional component and the proposed claims.

As envisioned by the IFT Expert Panel, FDA would consider the comprehensive GRAE report as part of an orderly process similar to that used for GRAS notifications. FDA should establish a notification procedure whereby any person may notify FDA of a determination that a particular use of a substance is GRAE. FDA would evaluate whether each submitted notice provides a sufficient basis for a GRAE determination and whether information in the notice or otherwise available to FDA raises issues that lead the Agency to question whether use of the substance is GRAE. Following this evaluation, FDA would respond by letter to the notifier within a specified time frame (typically 90 days). FDA could respond in one of three ways:

• The Agency does not question the basis for the notifier’s GRAE determination; • The Agency concludes that the notice does not provide a sufficient basis for a GRAE determination (e.g., because the notice does not include appropriate data and information or because the available data and information raise questions about the efficacy of the notified substance); or • The Agency has, at the notifier’s request, ceased to evaluate the GRAE notice. If FDA does not reply within the specified time frame, it would be presumed that the Agency does not question the basis for the GRAE determination and the product could proceed to use the proposed claims.

Step 6: Communicate Product Benefits to Consumers
Once a science-based claim is validated, that information must be communicated to consumers. If consumers are uninformed about the potential benefits of functional foods, few will purchase and benefit from the foods, and the food industry will have little incentive to develop new functional foods.

This communication must establish meaningful connections between the attributes of functional foods and the health-related consequences of consuming those foods. Regulatory policies must allow food manufacturers to accurately characterize a functional food’s health benefits and the science supporting those claims. All parties must ensure that the messages describing these relationships are properly understood by consumers. Consumer research regarding understanding and perceived benefit is crucial. As knowledge develops, it must be communicated fully, clearly, and in a timely manner. The food industry, health professionals, educators, government officials, and the media can provide this information to consumers through a variety of health messages.

Step 7: Conduct In-market Surveillance to Confirm Efficacy and Safety
The term “in-market surveillance” (IMS) refers to the process of obtaining information on the effects of the functional ingredient after it has been introduced into the marketplace. IMS can confirm the conclusions reached during pre-market evaluations regarding safety and efficacy by monitoring actual consumption patterns and the impact on consumers’ dietary patterns and determining if there are any adverse health effects (complaints) that were not identified in pre-market testing.

In limited situations, IMS may be required by regulatory agencies. An IMS program should be a part of an ongoing monitoring program for new highly fortified functional foods. However, an IMS program may be inappropriate in other situations, such as when claims are made for foods already widely consumed (e.g., cruciferous vegetables and their impact on cancer). The most appropriate type of IMS program must be determined on a case-by-case basis.

An IMS program may be active or passive. In active IMS, a sponsor, typically the food manufacturer, engages an appropriate professional group to systematically poll consumers regarding intake patterns. The sponsor may elect to share the information with the appropriate regulatory agency. An active IMS program also may include additional research to further evaluate tolerability or efficacy or to address scientific questions that arose after marketing. In the case of an acute effect (e.g., folic acid), such studies may be feasible. However, in many cases, especially when the desired effects are only seen over the long term, such an active IMS program may be unrealistic.

Passive IMS involves the collection, documentation, and evaluation of complaints about the product (e.g., organoleptic, possible contamination), and may include reports of adverse health events. Frequently, a passive IMS program consists of placing a toll-free telephone number or Internet-access information on the label of the product containing the ingredient in question. The importance of such systems in confirming safety has been proven by almost 50 years of experience in the pharmaceutical industry. Although the information obtained from passive IMS cannot establish a causal relationship between the ingredient and the alleged adverse health effect, these programs remain very useful by documenting trends over time and identifying unanticipated effects that may require further evaluation.

Hill, A.B. 1971. Statistical evidence and inference. In “Principles of Medical Statistics,” 9th ed., pp. 309-323. Oxford University Press, NY.

Keystone. 1996. Keystone national policy dialogue on food, nutrition, and health. Final report. Keystone Center, Keystone, CO, and Washington, DC

Recognizing the tremendous health benefits offered by functional foods, the Institute of Food Technologists commissioned an expert panel to review the available scientific literature related to functional food development. The panel’s report is divided into nine sections: Definitions, Introduction, Food and Genes, Current Legal Standards, Scientific Standards, Policy Limitations, Bringing Functional Foods to Market, Role of Research, and Conclusions. Copies of the report are available at Founded in 1939, the Institute of Food Technologists is an international not-for-profit scientific society for food science and technology.