Contains Nonbinding Recommendations 
 
 
 
 
 
 
Scientific Evaluation of the Evidence 
on the Beneficial Physiological Effects 
of Isolated or Synthetic Non-Digestible 
Carbohydrates Submitted as a Citizen 
Petition (21 CFR 10.30): Guidance for 
Industry
 
 
 
Additional copies are available from: 
Office of Nutrition and Food Labeling 
Nutrition Programs Staff, HFS-830 
Center for Food Safety and Applied Nutrition 
Food and Drug Administration 
5001 Campus Drive 
College Park, MD  20740 
(Tel) 240-402-1450 
http://www.fda.gov/FoodGuidances 
 
 
You may submit electronic or written comments regarding this guidance at any time.  
Submit electronic comments to http://www.regulations.gov.  Submit written comments to 
the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers 
Lane, rm. 1061, Rockville, MD 20852.  All comments should be identified with the docket 
number FDA-2016-D-3401 listed in the notice of availability that publishes in the Federal 
Register. 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Food Safety and Applied Nutrition 
 
February 2018    Contains Nonbinding Recommendations 
 
 
 
 
 
 
 
 
Table of Contents 
 
 
 
I.   Introduction
 
II.  Background
 
III. Scientific Evaluation of the Beneficial Physiological Effects   
of Isolated or Synthetic Non-Digestible Carbohydrates
 
IV. References
 
V.  Appendix A  Scientific and Technical Review Document
 
 
 
 
  2    Contains Nonbinding Recommendations 
 
 
 
 
 
Scientific Evaluation of the Evidence on the 
Beneficial Physiological Effects of Isolated or 
Synthetic Non-Digestible Carbohydrates Submitted 
as a Citizen Petition (21 CFR 10.30): Guidance for 
Industry1
 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA 
or we) on this topic.  It does not establish any rights for any person and is not binding on 
FDA or the public.  You can use an alternative approach if it satisfies the requirements of 
the applicable statutes and regulations.  To discuss an alternative approach, contact the 
FDA staff responsible for this guidance listed on the title page. 
 
 
 
I. Introduction 
 
This guidance document explains FDAs current thinking on information needed when 
submitting a citizen petition and the scientific review approach we plan to use for 
evaluating scientific evidence to determine whether an isolated or synthetic non-digestible 
carbohydrate that is added to food (hereinafter added non-digestible carbohydrate) has a 
physiological effect that is beneficial to human health.  The purpose of this guidance is to 
provide information to those submitting evidence to us to determine if the added non-
digestible carbohydrate meets the definition of dietary fiber in our regulations for 
nutrition labeling of food for declaring the amount of dietary fiber on the Nutrition and 
Supplement Facts labels. 
 
This guidance document addresses our current thinking for:  (1) identifying publicly 
available scientific articles that evaluate a physiological effect of an added non-digestible 
carbohydrate; (2) evaluating those studies from which scientific conclusions can be drawn; 
and (3) evaluating the strength of scientific evidence to determine whether there is a 
physiological effect that is beneficial to human health of an isolated or synthetic non- 
digestible carbohydrate that is added to foods.  This guidance includes revisions that we  
have made in response, in part, to comments that we received on the draft guidance.2  
                                                           
1 This guidance has been prepared by the Office of Nutrition and Food Labeling in the Center for Food Safety 
and Applied Nutrition at the U.S. Food and Drug Administration. 
2 We intend to address in a subsequent guidance questions about intrinsic and intact fibers, the degree to 
which a non-digestible carbohydrate can be isolated or synthesized from its original plant source, but still be 
considered intrinsic and intact, and whether plant cell wall fibers containing a mix or combination of non-
  3    Contains Nonbinding Recommendations 
 
 
FDA's guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe our current thinking on a topic and should be 
viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited.  The use of the word should in FDA guidances means that something is suggested or 
recommended, but not required.  
 
II. Background 
 
Before 2016, FDA regulations did not define the term dietary fiber.  In the Federal 
Register of May 27, 2016 (81 FR 33742), we published a final rule amending our Nutrition 
and Supplement Facts label regulations (the final rule).  The final rule, among other 
things, defines dietary fiber as non-digestible soluble and insoluble carbohydrates (with 3 
or more monomeric units), and lignin that are intrinsic and intact in plants; isolated or 
synthetic non-digestible carbohydrates (with 3 or more monomeric units) determined by 
FDA to have physiological effects that are beneficial to human health.  The final rule also 
identifies seven non-digestible carbohydrates that we determined have physiological effects 
that are beneficial to human health (hereinafter beneficial physiological effects) (21 CFR 
101.9(c)(6)(i)). 
 
We derived our definition of dietary fiber from a 2001 Institute of Medicine (IOM) report 
that defines dietary fiber as non-digestible carbohydrates and lignin that are intrinsic and 
intact3 (i.e., naturally occurring) in plant-based foods.  The IOM report also defines the 
term added fiber as isolated, non-digestible carbohydrates that have beneficial 
physiological effects in humans.  Added fibers include synthetic non-digestible 
carbohydrates or isolated or extracted non-digestible carbohydrates.  The IOMs provision 
of two definitions recognizes the diversity of non-digestible carbohydrates in the human 
food supply.  Finally, the IOM report defines the term total fiber as the sum of dietary 
fiber and added fiber (IOM, 2001).  We concluded in the final rule that by defining dietary 
fiber based on a physiological effect that is beneficial to human health, we will ensure that 
the dietary fiber declared on the food label will assist consumers in maintaining healthy 
dietary practices (81 FR 33742 at 33853). 
 
Evidence shows that fiber-containing foods such as fruits, vegetables, and whole grains, 
provide health benefits, for example, improve laxation and reduce the risk of 
cardiovascular disease and type 2 diabetes (National Research Council, 1989; IOM, 2002; 
21 CFR 101.77).  These fiber-containing foods are commonly consumed as part of the U.S. 
diet, and are part of the USDA Food Patterns (Dietary Guidelines for Americans, 2015-
2020) and food composition databases (e.g., USDA Food Composition Database), which 
have been used for determining the associations between these foods and health outcomes.  
Fiber-containing foods contain macronutrients, micronutrients, and other biologically 
active compounds that can have distinct physiological effects in humans.  FDA authorized 
                                                           
digestible carbohydrates would be an intrinsic and intact dietary fiber.    
3 The IOM referred to intrinsic fibers as those originating wholly within and intact fibers as those having no 
relevant component removed or destroyed (IOM, 2001).  Intrinsic and intact pertains to non-digestible 
carbohydrates that are naturally occurring in foods.  
 
  4    Contains Nonbinding Recommendations 
 
a health claim for fruits, vegetables, and grain products that contain fiber (particularly 
soluble fiber) and risk of coronary heart disease (21 CFR 101.77(a)(3)).  The physiological 
effects of specific isolated or synthetic non-digestible carbohydrates from foods or other 
sources that are added to foods can only be ascertained by evaluating the non-digestible 
carbohydrates individually.  
 
This guidance addresses the scientific evaluation of synthetic non-digestible carbohydrates 
and isolated non-digestible carbohydrate ingredients that are produced as a result of 
processing of foods and other sources, to the extent that the ingredients in and of 
themselves have a specific chemical structure (carbohydrate composition and non-
digestible bond linkages).4  These non-digestible carbohydrates may or may not vary in 
size.  If such isolated or synthetic non-digestible carbohydrates are combined to produce an 
ingredient, for which a firm seeks to declare as a dietary fiber, then each non-digestible 
carbohydrate that is a component of the ingredient would need to demonstrate a beneficial 
physiological effect in order for all of the non-digestible carbohydrates in the ingredient to 
be declared as a dietary fiber.  It would not be necessary, under such circumstances, to 
provide evidence to demonstrate the ingredient has a beneficial physiological effect where 
there is already evidence to support that each non-digestible carbohydrate that is a 
component of the ingredient has such an effect. 
 
An isolated or synthetic non-digestible carbohydrate must be declared in the declaration of 
Total Carbohydrate on the Nutrition and Supplement Facts label.  If FDA determines it 
has a physiological effect beneficial to human health and lists it in our regulations in 21 
CFR 101.9(c)(6)(i), it must also be included in the declaration of Dietary Fiber (21 CFR 
101.9(c)(6)(i)).  If not listed in our regulation, the declaration of an isolated or synthetic 
carbohydrate as dietary fiber would misbrand the product (see section 403(q) of the Federal 
Food, Drug, and Cosmetic Act).  Any interested person may ask us to amend our 
regulations to list a new isolated or synthetic non-digestible carbohydrate as a dietary fiber 
by submitting a citizen petition (as provided in 21 CFR 10.30) or, if the added non-
digestible carbohydrate is the subject of an authorized health claim using the health claim 
petition process in 21 CFR 101.70,5 FDA would consider it to meet the definition of 
dietary fiber and would amend the definition accordingly. 
 
 
III. Scientific Evaluation of the Beneficial Physiological Effects   
of Isolated or Synthetic Non-Digestible Carbohydrates 
 
Our scientific evaluation process involves a series of steps to:  (1) assess publicly available 
scientific studies and other data; (2) eliminate those studies from which scientific 
conclusions about the physiological effects of an added non-digestible carbohydrate cannot 
be drawn; and (3) evaluate the strength of the scientific evidence to determine whether the 
carbohydrate provides a physiological effect that is beneficial to human health. 
                                                           
4 Examples of isolated non-digestible carbohydrate ingredients with a specific chemical structure include 
cellulose, guar gum, and pectin.  Non-digestible carbohydrate ingredients lacking a specific chemical 
structure are outside the scope of this guidance.  
5 Guidance to Industry is already available for the scientific review of health claims (FDA, 2009). The 
significant scientific agreement standard is specific to health claims and does not apply to this guidance. 
  5    Contains Nonbinding Recommendations 
 
 
  Identifying Publicly Available Studies That Evaluate a Beneficial Physiological 
Effect to Human Health 
 
We intend to consider the publicly available data and written information, primarily from 
human intervention studies, regarding the beneficial physiological effect of an added non-
digestible carbohydrate.  We intend to review intervention studies that are submitted to us 
in citizen petitions (21 CFR 10.30) requesting the addition of a specific added non-
digestible carbohydrate to the list of dietary fibers in 21 CFR 101.9(c)(6)(i).  The dietary 
fibers listed in 101.9(c)(6)(i) are those that we already have determined to have a 
beneficial physiological effect to human health, and therefore, must be included in the 
amount of dietary fiber declared on Nutrition and Supplement Facts labels (21 CFR 
101.9(c)(6)(i)).  Interested parties should submit all publicly available human studies on a 
specific isolated or synthetic non-digestible carbohydrate as part of a citizen petition, 
regardless of the studies findings.  Publicly available studies include those studies that are 
in manuscript form and can be available for the public to review.  We may identify 
additional relevant intervention studies through a literature search.  We intend to focus our 
review primarily on articles reporting human intervention studies because these studies can 
provide evidence from which scientific conclusions can be drawn about the beneficial 
physiological effect of a specific isolated or synthetic non-digestible carbohydrate in 
humans.  Observational studies on the beneficial physiological effects of isolated or 
synthetic non-digestible carbohydrates, for example, are not currently available because 
food composition databases currently do not provide the content of these types of 
carbohydrates in food.  Therefore, it is not currently possible to assess intake data for added 
non-digestible carbohydrates in an observational study. 
 
In evaluating the available scientific evidence, we first separate relevant articles on human 
intervention studies from other types of data and information, for example, review articles 
and meta-analyses. 
 
 Intervention Studies 
 
In an intervention study, subjects are provided with a specific amount of added non-
digestible carbohydrate of interest (intervention group), typically either added to a 
conventional food or as a dietary supplement.  Randomized controlled trials typically have 
either a parallel or cross-over design.  Parallel design studies involve two groups of 
subjects, the test group and the control group, which simultaneously receive the added non-
digestible carbohydrate or serve as the control (without the added non-digestible 
carbohydrate).  In a cross-over design study, all subjects cross over from the treatment to 
the control, and vice versa, after a defined time period. 
 
In randomized controlled trials, subjects are assigned to an intervention group or treatment 
sequence by chance.  Randomized controlled trials offer the best assessment of a causal 
relationship between a non-digestible carbohydrate and a physiological effect because they 
control for known confounders of results (i.e., other factors that could affect the 
physiological endpoint) (Kraemer et al., 2005).  Through random assignment of subjects to 
the intervention and control groups, these studies reduce the likelihood of selection bias, 
  6    Contains Nonbinding Recommendations 
 
that is, the possibility that those subjects most likely to have a favorable outcome, 
independent of an intervention, are preferentially selected to receive the intervention.  Even 
after randomization, however, there may be an unequal distribution of characteristics of the 
subjects between the control and treatment groups (e.g., blood [serum or plasma] low-
density lipoprotein (LDL) cholesterol levels are significantly different at baseline).  In 
particular, if the baseline values for biomarkers are not measured or are significantly 
different in a parallel design study, then it can be difficult to determine if differences at the 
end of the study were due to the intervention or to differences present at the beginning of 
the study.   
 
Potential bias also is reduced by blinding the study so that the subjects do not know 
whether they are receiving the intervention, or by double blinding, in which neither the 
subjects nor the researchers who assess the outcomes know who is receiving the treatment 
or control.  By controlling the test environment, including the amount and composition of 
non-digestible carbohydrate consumed and other dietary factors, these studies also can 
minimize the effects of other variables or confounders on the results.6   Therefore, 
randomized, controlled intervention studies provide the strongest evidence of whether there 
is a relationship between an added non-digestible carbohydrate and a physiological effect 
(Greer et al., 2000). 
 
 Observational Studies 
 
Observational studies can be designed to measure associations between dietary patterns, 
foods or food components, and physiological and health-related endpoints.  Observational 
studies lack the controlled setting of intervention studies.  Observational studies are more 
reflective of free-living7 populations and may be able to establish an association between a 
food component, such as an added non-digestible carbohydrate, and a beneficial 
physiological effect.  Unlike intervention studies, observational studies cannot be used to 
determine whether an observed association establishes that the food component caused a 
change in the physiological or health-related endpoint or is a coincidence; that is, 
observational studies do not establish causation (Sempos et al., 1999).  Observational 
studies generally rely on a dietary intake assessment method to estimate food intake.  The 
nutrient content of reported foods is usually determined using some form of food 
composition database.  While there are limitations in evaluating the association between a 
food component and a physiological or health-related endpoint (FDA, 2007), if information 
on the amount of an ingredient added to a food (e.g., an isolated or synthetic non-digestible 
carbohydrate) is available, information from observational studies could be considered as 
part of the totality of evidence.  Food composition databases, however, currently do not 
provide the content of individual types of isolated or synthetic non-digestible carbohydrates 
in foods.  Therefore, observational studies that rely on intake data for evaluating the 
association between an added non-digestible carbohydrate and a beneficial physiological 
                                                           
6 Confounders are factors that are associated with both the physiological benefit in question and the 
intervention, and that, if not controlled for, prevent an investigator from being able to conclude that an 
outcome was caused by an intervention. 
7 Free-living populations represent those who consume diets and have lifestyles (e.g., smoking, drinking, and 
exercise) of their own choice. 
  7    Contains Nonbinding Recommendations 
 
effect are not currently available.  If the findings of such observational studies become 
available, we intend to consider them as part of the totality of evidence. 
 
 Research Synthesis Studies 
 
Reports, such as review articles, which summarize the findings of individual studies, and 
meta-analyses,8 that discuss a number of different studies, do not provide enough 
information on critical elements of the individual studies, such as the study population 
characteristics and the composition of the products used.  Similarly, the lack of detailed 
information on the individual studies prevents us from determining whether the studies are 
flawed in critical elements such as design, conduct of studies, and data analysis.  Reviewing 
the critical elements of each study is necessary to determine whether any scientific 
conclusions can be drawn from it.  Therefore, we intend to use review articles and similar 
publications9 only to identify reports of additional studies that may be useful to our 
scientific review and as background information about the beneficial physiological effect 
of added non-digestible carbohydrates.  If we identify additional studies from their 
description in review articles, we intend to evaluate them individually.  Meta-analyses also 
lack detailed information on the individual studies included in the analysis.  Therefore, we 
intend to use meta-analyses to identify reports of additional studies that may be useful to 
our scientific reviews, and as background information about the beneficial physiological 
effect of added non-digestible carbohydrates. 
 
 Animal and In Vitro Studies 
 
We intend to use animal and in vitro studies as background information regarding 
mechanisms that might be involved in any physiological effect of an isolated or synthetic 
non-digestible carbohydrate.  The physiology of animals is different than that of humans.  
In vitro studies are conducted in an artificial environment and cannot account for a 
multitude of normal physiological processes such as digestion, absorption, distribution, and 
metabolism that affect how humans respond to the consumption of foods and dietary 
substances (IOM, 2005).  Animal and in vitro studies can be used to generate hypotheses, 
investigate biological plausibility of hypotheses, or to explore a mechanism of action of a 
specific food component through controlled animal diets.  However, these studies do not 
provide information from which scientific conclusions can be drawn regarding the 
beneficial physiological effects in humans of a food component, such as added non- 
digestible carbohydrates. 
 
  Evaluating Human Intervention Studies 
 
Once we have identified the relevant human intervention studies, we intend to evaluate 
each study to determine whether any scientific conclusions can be drawn regarding the 
physiological effect of an added non-digestible carbohydrate.  Critical elements of a study, 
such as design, data collection, and data analysis, may be so flawed that it is not possible to 
draw scientific conclusions from the study.  We do not intend to use studies from which we 
                                                           
8 A meta-analysis is the process of systematically combining and evaluating the results of clinical trials that 
have been completed or terminated (Spilker, 1991). 
9 Examples of similar publications include book chapters, abstracts, letters, and committee reports. 
  8    Contains Nonbinding Recommendations 
 
cannot draw any scientific conclusions about the physiological effect, and we intend to 
eliminate such studies from further review. 
 
The following are examples of questions that we intend to consider when evaluating 
whether scientific conclusions can be drawn from an intervention study about the 
physiological effect of an added non-digestible carbohydrate. 
 
 Have the studies specified and measured the isolated or synthetic non-digestible 
carbohydrate? 
 
The added isolated or synthetic non-digestible carbohydrate of interest should be provided 
in its isolated form, rather than in a naturally-occurring form in food.  The added non-
digestible carbohydrate also should not be added in combination with other non-digestible 
carbohydrates or other food components that may affect the physiological endpoint being 
measured.  When a mixture of non-digestible carbohydrates is added to foods, scientific 
conclusions cannot be drawn about the role of the individual added non-digestible 
carbohydrate of interest, unless the other components are controlled by study design.  We 
intend to review studies on added non-digestible carbohydrate ingredients that in and of 
themselves have a specific chemical structure and source from which they are isolated.  
 
 Have the studies appropriately specified and measured an endpoint that has a 
demonstrated beneficial physiological effect? 
 
There are a number of beneficial physiological effects associated with the consumption of 
non-digestible carbohydrates.  Some examples include attenuation of blood glucose,  
insulin, and cholesterol concentrations; reduced energy intake; and improved laxation (i.e., 
the elimination of fecal waste) (81 FR 33742 at 33856, 33858; IOM, 2001; IOM, 2002).  It 
is important that the physiological effect from consuming an isolated or synthetic non-
digestible carbohydrate is associated with a specific endpoint that has been shown to have a 
beneficial physiological effect to human health.  When applicable, we intend to include in 
our review information for subjective measures for a given endpoint (examples are 
provided below). 
 
Attenuation of blood glucose and/or insulin levels is a physiological effect that is beneficial 
to human health.  Fasting blood glucose concentration provides information on the long-
term effects of a dietary intervention and is a surrogate endpoint for type 2 diabetes risk.  
Insulin resistance is also a surrogate endpoint for type 2 diabetes risk.  Attenuation of blood 
glucose or insulin levels may be measured by assessing post-prandial blood glucose and 
insulin levels.  While not a surrogate endpoint, post-prandial blood glucose10 provides 
information on the glycemic response over several hours after consuming a food, beverage, 
or meal.  The rise and fall of blood glucose over several hours after consuming a food, 
beverage, or meal is often reported as the area-under-the-curve (AUC) (sometimes referred 
to as an incremental AUC).  The serial measurements of post-prandial blood glucose should 
be recorded up to at least two hours after consumption of the standardized meal.   
 
                                                           
10 Post-prandial glucose measures the rise and fall of blood glucose after consuming a meal which reflects the 
intestinal absorption and clearance of glucose from the blood. 
  9    Contains Nonbinding Recommendations 
 
When using post-prandial blood glucose and/or insulin measurements to assess whether an 
isolated or synthetic non-digestible carbohydrate has a beneficial physiological effect, it is 
important to include a meal, food, or caloric beverage to determine such an effect.  
Therefore, we do not intend to consider individual non-digestible carbohydrates that are 
only added to water as a measure of post-prandial glucose or insulin levels.  Because 
digestible carbohydrates (glucose and other sugars) provide a glycemic response, glycemic 
index11 and other measures that compare glycemic responses of added non-digestible 
carbohydrates to glucose or other sugars do not provide information on how an isolated or 
synthetic non-digestible carbohydrate affects the glycemic response of a food or beverage 
that contains nutrients (e.g., starch) that affect blood glucose levels.  For this reason, studies 
that add an isolated or synthetic non-digestible carbohydrate to a food, rather than replacing 
carbohydrates that have a glycemic response with the non-digestible carbohydrate, provide 
information about the independent beneficial physiological effect of the non-digestible 
carbohydrate on attenuation of blood glucose levels.  In studies other than addition studies 
(e.g., substitution/replacement studies), the amount of digestible (or available) carbohydrate 
should be controlled by design (e.g., the same between the treatment and control).  
Otherwise, we are unable to determine if there is an independent effect of the non-
digestible carbohydrate or if the effect is due to differences in amounts of digestible 
carbohydrate, which would be expected to impact blood glucose concentrations.  In 
evaluating the strength of the evidence, we intend to consider the AUC and/or the peak 
glucose level (usually at 30 minutes after consumption), rather than other single data points 
fixed in time which provide less information.   
 
Reductions in fasting blood total and LDL cholesterol levels are beneficial physiological 
effects, as well as surrogate endpoints for cardiovascular disease risk.  However, post-
prandial LDL cholesterol levels are not a valid endpoint to evaluate whether an isolated or 
synthetic non-digestible carbohydrate has a beneficial physiological effect because of the 
lack of a rise and fall in LDL cholesterol levels after a meal.  Thus, a measure of LDL 
cholesterol levels taken after a meal would not provide scientific evidence to support the 
existence of a physiological effect from consumption of an added non-digestible 
carbohydrate. 
 
Measures of improved laxation (i.e., the elimination of fecal waste/fecal output) are 
reduced transit time of food through the intestinal tract and increased rates of defecation 
(e.g., number of stools per day, fecal weight per day) (Topping, 2007).  Multiple days of 
stool collection are needed to measure rate of defecation.  We intend to include as part of 
our review subjective measures of laxation, such as self-reported ease of defecation and 
reduced complaint of difficulty in defecation from study subjects to evaluate how changes 
in these subjective measures are associated with changes in the elimination of fecal waste.  
The ingestion of an added non-digestible carbohydrate can increase stool weight (e.g., 
grams per stool), but an increase in stool weight does not necessarily indicate improved 
laxation (IOM, 2002).  We intend to consider stool weight data in our reviews but only to 
                                                           
11 Glycemic index and other measures that compare glycemic responses to glucose or other sugars evaluate the 
increase in blood glucose after ingestion of a set amount of carbohydrate in a test food, compared to the same 
amount of carbohydrate from a reference food (white bread or glucose solution) measured in the same 
individual and under the same conditions, using the initial blood glucose concentrations as a baseline. 
 
  10    Contains Nonbinding Recommendations 
 
evaluate how changes in stool weight, as a result of the consumption of an isolated or 
synthetic non-digestible carbohydrate, are associated with changes in the elimination of 
fecal waste. 
 
Increased intestinal absorption of minerals of public health significance, such as calcium, is 
a physiological effect that is beneficial to human health.  Calcium is considered to be a 
nutrient of public health significance, and the relationship between calcium absorption and 
the risk of osteoporosis is strong (21 CFR 101.72).  Bone mineral density is a surrogate 
endpoint for the risk of osteoporosis, and we intend to consider it along with calcium 
absorption and other related endpoints to understand the effects of an added non-digestible 
carbohydrate on bone health. 
 
Reduced energy intake from food consumption also is considered a beneficial physiological 
effect.  In evaluating the strength of the evidence, we intend to consider studies that 
measure energy intake either by direct measurement of the food that is left over after an ad 
libitum meal, which is the gold standard, or by 24-hour recalls and food diaries kept by 
study subjects, which are less reliable, subjective methods.  Furthermore, a reduction in 
energy intake observed at a subsequent meal should not be compensated for at other meals 
throughout the day.  We also intend to consider subjective measures of satiety (a state of 
fullness) to understand the mechanism by which a potential reduction in energy intake 
from food might occur with the consumption of an isolated or synthetic non-digestible 
carbohydrate.  Satiety is often measured using a Visual Analogue Scale that subjectively 
measures various endpoints such as hunger, appetite, and feelings of fullness. 
 
Fermentation and changes in the microbiota in the large intestine are considered to be 
processes, rather than physiological effects.  Viscosity and fermentability of non-digestible 
carbohydrates are considered to be physicochemical properties, rather than physiological 
effects (IOM, 2001).  While physiological effects that are beneficial to human health may 
be an outcome of viscosity, fermentation, or changes in the colonic microbiota, we do not 
consider these processes or properties in and of themselves to be physiological effects 
because they are not measures of functions of the human body.  
 
 
 Were the study subjects healthy or did they have a disease, condition, undergo a surgical 
procedure, or receive a treatment that could influence the physiological effect being 
studied? 
 
Declarations made on Nutrition and Supplement Facts labels are intended for the general 
healthy population.  We intend to consider evidence from studies with subjects who have a 
disease that is associated with the beneficial physiological effect of interest when 
extrapolating to individuals who do not have the disease is scientifically appropriate.  If 
evidence that would allow for such extrapolation is not available, we cannot draw any 
scientific conclusions from studies with subjects who have a disease or condition, or that 
had a procedure that is associated with the physiological endpoint (e.g., improved laxation 
in individuals with an ileostomy, who are tube-fed or non-ambulatory, or have diarrhea or 
fecal incontinence).  However, we intend to consider studies that include individuals at risk 
of developing a disease (e.g., elevated LDL cholesterol levels, metabolic syndrome, or 
abnormal glucose tolerance test) or who have an unrelated disease to the physiological 
  11    Contains Nonbinding Recommendations 
 
effect being measured because the unrelated disease would not affect the particular endpoint 
being measured (e.g., individuals with osteoporosis being evaluated for attenuation of blood 
glucose levels).  In some cases, we can consider a study that includes individuals who may 
have a related disease to the physiological endpoint being measured, and extrapolate the 
findings to the healthy population because the mechanism of action would not be different 
in the healthy or diseased populations (e.g., constipation and improved laxation).   
 
 Did the study include an appropriate control? 
 
An appropriate control group represents study subjects who did not receive, or consumed a 
low amount, of the added non-digestible carbohydrate of interest.  All other aspects of the 
study design (e.g., duration, other dietary factors) for the control and treatment groups 
should be similar.  If an appropriate control group was not used, it is impossible to ascertain 
whether changes in the endpoint of interest were due to the added non-digestible 
carbohydrate or to unrelated and uncontrolled extraneous factors (Spilker, 1991; National 
Research Council, 2011).  Without an appropriate control, scientific conclusions cannot be 
drawn about a beneficial physiological effect of an added non-digestible carbohydrate.  
Therefore, we do not intend to use these types of studies to evaluate whether there is a 
beneficial physiological effect of an added non-digestible carbohydrate. 
 
When the intervention study involves providing subjects with a whole food, along with an 
added non-digestible carbohydrate, or a combination of non-digestible carbohydrates or 
other components, the experimental and control diets should be similar enough that the 
relationship between the added non-digestible carbohydrate and beneficial physiological 
effect can be evaluated.  The composition of the experimental and control diets should be 
similar for all food components, except for the added non-digestible carbohydrate of 
interest.  For example, various factors besides non-digestible carbohydrates can influence 
the glycemic response of a food, including the presence of fat and protein (IOM, 2002). 
 
When evaluating glycemic response, the amount of digestible (or available) carbohydrate 
should be the same between the treatment and control.  Furthermore, the control and test 
diets should be relevant to diets consumed by the general U.S. population. 
 
When the added non-digestible carbohydrate of interest is provided as a dietary 
supplement, a placebo should be provided as a control.  When the substance is a food, it  
may not be possible to provide a placebo and therefore subjects in such a study may not be 
blinded.  Although the study may not be blinded in this case, a control group is still needed 
to draw conclusions from the study. 
 
 How long was the study conducted? 
 
Studies that measure a physiological endpoint should be of a duration that is long enough to 
ensure that any change in the endpoint results from the dietary intervention.  If the study is 
conducted for a time period that is too short to evaluate the effects of the added non-
digestible carbohydrate, then scientific conclusions cannot be drawn about the beneficial 
physiological effect of the non-digestible carbohydrate.  Therefore, we would not consider 
such a study to evaluate whether there is a beneficial physiological effect of an added non-
  12    Contains Nonbinding Recommendations 
 
digestible carbohydrate.  For example, we consider three weeks to be the minimum 
duration for evaluating the effect of a dietary intervention on serum LDL cholesterol (Kris-
Etherton and Dietschy, 1997).  On bowel function, we consider studies conducted for at 
least one week to account for adaptation to the diet, passage of fecal material, and a 
sufficient amount of time for collecting stool samples.  More than 80% of markers used for 
measuring transit time are passed within 120 hours for most healthy subjects (Evans et al., 
1992).  Measurement of post-prandial blood glucose involves an overnight fast followed by 
multiple measurements of blood glucose concentrations up to at least two hours after 
consumption of the test products. 
 
 How were the results analyzed statistically? 
 
Appropriate statistical analysis of the study data is critical because it provides the 
comparison between consuming and not consuming the added non-digestible carbohydrate 
in order to determine whether there is a beneficial physiological effect.  The appropriate 
statistical analysis will vary depending on factors such as the study design and the research 
question.  For example, when conducting statistical analyses among more than two study 
groups or when more than two comparisons are being made within and between groups, the 
data should not be analyzed by a t-test and should include adjustments for multiple 
comparisons (e.g., Bonferroni, Duncan).  When statistical analyses are not performed 
between the control and treatment, or are conducted inappropriately, scientific conclusions 
cannot be drawn.  Therefore, we do not intend to use such studies to evaluate whether there 
is a beneficial physiological effect of an added non-digestible carbohydrate. 
 
 Were the relevant baseline data on the physiological endpoint (e.g., LDL cholesterol) 
statistically significantly different between the control and intervention groups? 
 
Interpreting the findings of a dietary intervention study can be difficult if the baseline 
values for the endpoint being measured are statistically significantly different between the 
control and intervention groups (P < 0.05).  For example, in a parallel-design study on the 
effect of an added non-digestible carbohydrate on LDL cholesterol, having different 
baseline LDL cholesterol levels between the intervention group and the control group 
would lead to uncertainty as to whether any observed effect resulted from the difference in 
the intake of the added non-digestible carbohydrate, or the difference in the baseline LDL 
cholesterol levels between the two groups. 
 
Randomization, adequate sample size, and adequate lead-in12 diets or wash-out 
periods13 for studies with a cross-over design, can help reduce the likelihood of statistically 
different baseline values.  If baseline values are statistically different between groups in a 
parallel design study, a statistical analysis that includes adjustment for baseline, or 
calculations of change from baseline, should be used.  
 
 Where were the studies conducted? 
 
                                                           
12 A lead-in diet is one that is provided to all study groups prior to randomization. 
13 A wash-out period is the time period within a cross-over design study during which subjects do not 
receive an intervention. 
  13    Contains Nonbinding Recommendations 
 
It is important that the study population is relevant to the general U.S. population.  
Therefore, we intend to evaluate each study to determine, for example, if the study 
population lives in an area where malnutrition is common, and/or where the prevalence or 
etiology of the outcome that is being considered is not similar to that in the United States.  
Differences in prevalence or etiology of the outcome, as well as nutrition and diet, between 
the United States and the country where a study was conducted may mean that the study 
results cannot be extrapolated to the U.S. population.  It may be difficult, for example, to 
draw scientific conclusions about the physiological effects of an added non-digestible 
carbohydrate in a population that consumes much higher or much lower amounts of dietary 
fiber, or other nutrients, that have an effect on the physiological endpoint. 
 
  Evaluating the Strength of the Scientific Evidence 
 
We intend to evaluate the strength of the evidence to determine whether there is a beneficial 
physiological effect of an added non-digestible carbohydrate using the publicly available 
studies from which scientific conclusions can be drawn.  We intend to conduct this 
evaluation by considering the number of studies and sample sizes of each study, the dose 
response data, the types of foods tested, the relevance of the body of scientific evidence to 
the U.S. population or target subgroup, and the overall consistency14,15 of the total body of 
evidence.  These factors are considered when determining whether the evidence is 
sufficient to support a conclusion that there is a beneficial physiological effect. 
 
Our evaluation of the strength of the evidence considers: 
 
 Number of studies and number of subjects per group/study. 
 
 Doses provided across studies and dose-response analyses conducted within a study.16 
 
 The type of foods, for example, solid foods, beverages, or dietary supplements, to which 
the non-digestible carbohydrate was added. 
 
 Outcome (i.e., a beneficial effect, no effect, or an adverse effect) and method used to 
measure the physiological endpoint.  For the outcome of an intervention study to 
demonstrate a beneficial physiological effect, the results of the treatment group would need 
to be statistically significantly different from the control group (P < 0.05). 
                                                           
14 In this guidance, consistency is used to mean the level of agreement among the studies from which 
scientific conclusions could be drawn about the non-digestible carbohydrate/beneficial physiological effect 
relationship. 
15 Consistency of findings among similar and different study designs is important for evaluating causation and 
the strength of scientific evidence (Hill, 1965). See also: Agency for Healthcare Research and Quality, 
Systems to Rate the Scientific Evidence, which defines consistency as the extent to which similar findings 
are reported using similar and different study designs. 
[http://www.ahrq.gov/clinic/epcsums/strengthsum.htm#Contents]. 
16 We consider the beneficial physiological effects that are observed or not observed for different study doses 
to understand the relevance of the effective doses to consumer consumption levels.  Observed dose-response 
data within a study can increase the strength of the scientific evidence.  Demonstration of a dose-response 
relationship would depend on the levels provided. For example, a dose-response relationship would not be 
expected if the dose(s) provided exceed a range of intake for which a linear relationship occurs. 
  14    Contains Nonbinding Recommendations 
 
 
 Consistency of findings.  In general, the greater the consistency among the studies in 
showing a beneficial physiological effect, the higher the level of confidence that a 
relationship between an added non-digestible carbohydrate and a beneficial physiological 
effect exists.  Conflicting results do not disprove an association because the elements of the 
study design may account for the lack of a beneficial effect in negative studies, but 
conflicting results tend to weaken confidence in the strength of the association. 
 
 Relevance to the general U.S. population.  For example, 
 
To what extent did the studies that showed a benefit include populations and diets 
that are relevant to the general healthy U.S. population? 
 
Do the studies suggest that the intake level of the added non-digestible 
carbohydrate that provides a beneficial physiological effect significantly exceeds 
levels that are typically consumed in the United States or that may cause adverse 
effects? 
 
We intend to evaluate whether the scientific evidence supports a beneficial physiological 
effect to the general U.S. population.  If the evidence only supports finding a beneficial 
physiological effect for a subgroup, for example, only in children one through three years 
of age, we intend to consider that information to determine whether the beneficial 
physiological effect is appropriate for the declaration of the added non-digestible 
carbohydrate as a dietary fiber on the Nutrition and Supplement Facts label on foods 
represented or purported to be specifically for that subgroup. 
 
IV. References 
 
We have placed the following references on display in the Dockets Management Staff, 
Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.  You 
may see them at that location between 9 a.m. and 4 p.m., Monday through Friday.  As of 
February 12, 2018, FDA had verified the Web site address for the references it makes 
available as hyperlinks from the Internet copy of this guidance, but FDA is not responsible 
for any subsequent changes to Non-FDA Web site references after February 12, 2018. 
 
1.  U.S. Department of Health and Human Services and U.S. Department of Agriculture. 
Dietary Guidelines for Americans 20152020, 8th ed. Washington, DC: U.S. 
Government Printing Office, 20152020.  Retrieved from:  
https://health.gov/dietaryguidelines/2015/guidelines/ 
 
2.  U.S. Food and Drug Administration.  2009.  Guidance for Industry: Evidence-Based 
Review System for the Scientific Evaluation of Health Claims. 
http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInfor 
mation/ucm073332.htm 
 
  15    Contains Nonbinding Recommendations 
 
3.  Evans  RC, Kamm MA, Hinton JM, Lennard-Jones JE.  The normal range and simple 
diagram for recording whole gut transit time. International Journal of Colorectal Disease 
1992;7:15-17.  
 
4.  Federal Judicial Center, Reference Manual on Scientific Evidence, Third Edition.   
2011. 
 
5.  Greer N, Mosser G, Logan G, Halaas GW.  A practical approach to evidence grading. 
Joint Commission Journal on Quality Improvements 2000; 26:700-712. 
 
6.  Hill AB.  The environment and disease: association or causation?  Proceedings of the  
Royal Society of Medicine 1965; 58:295-300. 
 
7.  Institute of Medicine.  Dietary Supplements:  A Framework for Evaluating Safety.  The 
National Academies Press, Washington, DC.  2005. 
 
8.  Institute of Medicine.  Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, 
Fatty Acids, Cholesterol, Protein and Amino Acids.  The National Academies Press, 
Washington, DC.  2002. 
 
9.  Institute of Medicine.  Dietary Reference Intakes.  Proposed Definition of Dietary 
Fiber.  The National Academies Press, Washington, DC.  2001. 
 
10. Kraemer HC, Lowe KK, Kupfer DJ.  To Your Health:  How to Understand What 
Research Tell Us About Risk.  Oxford University Press.  2005. 
 
11. Kris-Etherton PM, Dietschy J.  Design criteria for studies examining individual fatty 
acid effects on cardiovascular disease risk factors: human and animal studies.  American 
Journal of Clinical Nutrition 1997; 65:1590S-1596S. 
 
12. National Research Council.  Diet and Health: Implications for Reducing Chronic 
Disease Risk.  Washington, DC; National Academy Press.  1989. 
 
13. Sempos CT, Liu K, Earnst ND.  Food and nutrient exposures:  what to consider when 
evaluating epidemiologic data.  American Journal of Clinical Nutrition 1999; 
69:1330S-1338S. 
 
14. Spilker B.  Guide to Clinical Studies.  Raven Press, New York.  1991. 
 
15. Topping D.  Cereal complex carbohydrates and their contribution to human health. 
Journal of Cereal Science 2007; 46:220-229. 
 
16. USDA Food Composition Database.  https://ndb.nal.usda.gov/ndb/. 
 
17. Wilson E.B.  An Introduction to Scientific Research.  Dover Publications, New York.   
1990. 
 
  16    Contains Nonbinding Recommendations 
 
V. Appendix A  Scientific and Technical Review Document 
 
  Background 
 
In the Federal Register of May 27, 2016 (81 FR 33742), we published a final rule which, 
among other things, defined the term dietary fiber as non-digestible soluble and 
insoluble carbohydrates (with 3 or more monomeric units), and lignin that are intrinsic and 
intact in plants; isolated or synthetic non-digestible carbohydrates (with 3 or more 
monomeric units) determined by FDA to have physiological effects that are beneficial to 
human health (81 FR 33742 at 33979).  We also announced that we had determined that 
seven isolated or synthetic non-digestible carbohydrates (NDCs) (beta-glucan soluble fiber 
(as described in  101.81(c)(2)(ii)(A)), psyllium husk (as described in 101.81(c)(2)(ii)(B), 
cellulose, guar gum, pectin, locust bean gum, and hydroxypropylmethylcellulose) must be 
declared as dietary fibers on a Nutrition and Supplement Facts label because they have 
physiological effects that are beneficial to human health (81 FR 33742 at 33979).      
 
Any interested person may seek to amend the list of NDCs that meet the definition of 
dietary fiber through our citizen petition process in 21 CFR 10.30 (81 FR 33742 at 33853).  
In the Federal Register of November 23, 2016 (81 FR 84516), we announced the 
availability of two documents for public comment:  (1) a draft guidance titled, Scientific 
Evaluation of the Evidence on the Beneficial Physiological Effects of Isolated or Synthetic 
Non-digestible Carbohydrates Submitted as a Citizen Petition (21 CFR 10.30): Guidance 
for Industry (2016 draft guidance); and (2) a document titled Science Review of Isolated 
and Synthetic Non-Digestible Carbohydrates (2016 science review).  In addition to 
requesting comments on these two documents, we published a separate notice in the 
Federal Register requesting any other additional scientific data and information that would 
help us determine whether any other NDCs should be added to the list of fibers that meet 
our definition of dietary fiber (81 FR 84595).   
 
  Summary of the Issues 
  
Based on a science review of the publicly available studies, we identified five isolated or 
synthetic NDCs (cellulose, pectin, guar gum, locust bean gum, and hydroxypropylmethyl-
cellulose) in the final rule that provide a physiological effect that is beneficial to human 
health and therefore are considered dietary fibers.17  We also included two other NDCs 
(beta-glucan soluble fiber and psyllium husk) in our list of dietary fibers because we had 
previously determined that they have beneficial physiological effects related to the risk of 
coronary heart disease in one of our authorized health claims regulations (21 CFR 101.81).   
 
1.  Consideration of Clinical Studies Conducted in Diseased Populations 
 
The 2016 science review excluded consideration of any clinical studies that were 
conducted on diseased populations because the Nutrition Facts label is not targeted to 
                                                           
17 U.S. Food and Drug Administration, Memorandum to the File:  Scientific Review of the Beneficial 
Physiological Effects of Non-digestible Carbohydrates for Meeting the FDA Definition of Dietary Fiber, May 
9, 2016. 
  17    Contains Nonbinding Recommendations 
 
individuals with a particular acute or chronic disease, but rather is intended to provide the 
general U.S. population with information to help consumers make more informed and 
healthy dietary choices (81 FR 33742 at 33750).  We have reconsidered this approach and 
determined that, for certain endpoints, studies conducted on individuals diagnosed with a 
specific disease can be considered as part of our evaluation of the totality of the evidence 
when deciding whether an NDC meets our definition of dietary fiber.  For example, certain 
NDCs can attenuate post-prandial blood glucose levels or improve laxation because of their 
presence in the gastrointestinal tract, rather than systemically (e.g., the failure of cells to 
respond to insulin (insulin resistance)).  Therefore, we can include studies evaluating 
whether an NDC affects post-prandial blood glucose levels in diabetic individuals or 
laxation in constipated individuals as part of our evaluation of the totality of the evidence.  
When evaluating the strength of the evidence, scientific evidence showing a beneficial 
effect in healthy populations would increase the strength of the evidence for purposes of 
deciding whether an NDC is a dietary fiber on the Nutrition and Supplement Facts label.   
 
However, exclusion of studies involving individuals diagnosed with a specific disease can 
be appropriate in other situations.  For example, we decline to extrapolate findings on 
individuals with diarrhea to the healthy population for evaluating improved laxation 
because there are multiple causes of diarrhea, and most causes of diarrhea are not related to 
how an NDC might improve laxation.  Therefore, as discussed in the 2018 final guidance, 
we will consider evidence from studies with subjects who have a disease that is associated 
with the physiological effect of interest when extrapolating to individuals who do not have 
the disease is scientifically appropriate.  
 
2.  Studies Involving a Combination of NDCs 
 
Studies involving a combination of NDCs also may be relied upon to demonstrate a 
relationship between an isolated or synthetic NDC that is added to food and a 
physiological effect that is beneficial to human health.  A principal consideration is 
whether the data from such studies can evaluate the independent physiological effect of 
the individual NDC.  We will not consider data from studies in which a combination of 
NDCs or food components are provided to study subjects if the individual NDC of 
interest may contribute to a beneficial physiological effect, but cannot be shown to have 
an independent effect (e.g., the other NDCs or food components are not controlled for). 
 
Thus, the 2018 final guidance clarifies that, if a combination of isolated NDCs is used as 
an ingredient, each isolated NDC would need to demonstrate a beneficial physiological 
effect for the NDC combination to be declared as a dietary fiber.  Otherwise, a citizen 
petition can be submitted that provides data on that specific combination, and we will 
evaluate the data on that specific combination to determine if the combination provides a 
physiological effect that is beneficial to human health.    
 
3.   Physiological Endpoints and Baseline Values 
 
With respect to physiological endpoints, the 2018 final guidance provides additional 
examples of physiological endpoints that we consider, but this is not an exhaustive list.  
  18    Contains Nonbinding Recommendations 
 
For example, we consider fecal output/fecal weight as measured on the basis of 
grams/day as a measure of laxation.  
 
The 2018 final guidance also clarifies that, if baseline values are statistically different 
between groups in a parallel design study, a statistical analysis that includes adjustments 
for baseline, or calculations of change from baseline, should be used.  The appropriate 
statistical analysis will vary depending on factors, such as the study design and the research 
question posed by the study.   
 
4.  Factors FDA Considers in Evaluating the Strength of the Evidence 
 
The 2018 final guidance provides more detail on the factors that we consider when 
evaluating the strength of the evidence (e.g., types of foods tested).  The preamble to the 
final rule titled, Food Labeling: Revision of the Nutrition and Supplement Facts Labels 
discussed the scientific evidence needed to demonstrate a beneficial physiological effect 
(see 81 FR 33742 at 33855 to 33856).  The 2018 final guidance provides additional 
information on the scientific evidence we recommend be included in a citizen petition 
and the approach we intend to use when reviewing the scientific evidence.  For example, 
the 2018 final guidance provides more information on what we intend to consider when 
evaluating the strength of the evidence, such as, the number of studies, doses provided in 
a study and dose-response analysis conducted within a study, and type of foods.  The 
factors we identify in the 2018 final guidance for the review of the strength of the 
scientific evidence to demonstrate a beneficial physiological effect to human health 
include general, broadly accepted scientific principles and approaches to the review of 
scientific evidence.  In addition, our review of the sufficiency of the scientific evidence 
for any request to support an NDC as a dietary fiber is a public process and provides an 
opportunity for interested persons to comment on scientific evidence and our scientific 
review of the evidence on a case-by-case basis.  
 
5.  Consideration of Unpublished Data  
 
We stated, in the preamble to the final rule titled, Food Labeling: Revision of the 
Nutrition and Supplement Facts Labels, that a petition to request an amendment to the 
definition to include an additional dietary fiber should include all publicly available 
evidence relevant to the review (81 FR 33742 at 33856).  A citizen petition is filed by the 
Dockets Management Staff to which an interested person may submit comments (21 CFR 
10.30(c) and (d)).  Information submitted to FDA will be handled in accordance with all 
applicable laws, including the Freedom of Information Act (5 U.S.C.  552), the Trade 
Secrets Act (18 U.S.C.  1905), and applicable FDA regulations (e.g., 21 CFR part 20).  
Under 21 CFR 20.61(c), data and information submitted or divulged to FDA which fall 
within the definitions of a trade secret or confidential commercial or financial 
information are not available for public disclosure.  However, we encourage the 
submission of publicly available information because, if we propose to amend the list of 
NDCs that meet the definition of dietary fiber, the proposed rule would be a public 
rulemaking process, and we would want to provide an opportunity for interested persons to 
comment on the scientific information we received in a petition or in comments to a 
petition. 
  19